Phenalkylamines, and methods for preparing and using them.

Abstract

The present disclosure provides phenalkylamine compounds and their uses in treating medical disorders, such as psychiatric diseases and disorders. Pharmaceutical compositions and methods of making the various phenalkylamine compounds are provided.

Description

[Technical Field]

[0001] Mental illnesses, including depression and anxiety, represent serious damage to health and effective human function worldwide. [Background technology]

[0002] Although several psychiatric medications are available and widely prescribed, these drugs fail to provide relief for many individuals. Even when patients do respond, changes in mood and behavior are often slow to manifest. In recent years, the continued need for improvements in pharmacotherapy for treating mental disorders has led to consideration of previously harmful options. For example, classic serotonergic hallucinogens, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), are considered experimental treatments for various psychiatric symptoms. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009 [Non-Patent Document 2] Patel Steroselective Biocatalysts, Marcel Decker; New York 2000 [Non-Patent Document 3] aléandrov et al., 2015 [Non-Patent Document 4] Leahy, 2019 [Overview of the project] [Problems that the invention aims to solve]

[0004] However, such compounds induce severe hallucinogenic effects and disrupt the normal functioning of individuals treated with them. Therefore, these compounds are currently classified as Schedule I drugs under the Controlled Substances Act due to their high potential for abuse, lack of medical approval, and lack of established safety. These effects are primarily mediated through the association of serotonin receptors. Of particular importance is the agonism of the serotonin 2A receptor (5-HT2A), which is thought to be crucial not only for the problematic hallucinogenic activity of these compounds but also for their so-called therapeutic effects. Therefore, compounds that offer therapeutic benefits while limiting hallucinogenic activity and thus the potential for abuse and adverse events would have high therapeutic value. [Means for solving the problem]

[0005] This disclosure provides, for example, compounds that are modulators of the 5-HT2A receptor (5-HT2A), their use as pharmaceuticals, methods for their preparation, and pharmaceutical compositions containing them alone or in combination with other pharmaceuticals as active ingredients, as well as their use as pharmaceuticals and / or in the manufacture of pharmaceuticals for the activation of 5-HT2A in warm-blooded animals, such as humans. In particular, this disclosure relates to compounds useful for the treatment of mental illness or disorder. Furthermore, this disclosure provides compounds that induce useful therapeutic effects while exhibiting attenuated hallucinogenic effects or without exhibiting any hallucinogenic effects. Pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier are also provided. [Brief explanation of the drawing]

[0006] [Figure 1] This graph shows dose-response curves for six selected compounds and DOIs in a mouse head unicontraction assay. The curves were fitted using a Gaussian distribution in GraphPad Prism 9. [Figure 2]This graph shows the total number of head unicontractions counted over 20 minutes in mice for compound 23, in the presence or absence of the 5-HT2A receptor antagonist MDL100907. ****p<0.0001 [Figure 3] This graph shows the ex vivo receptor occupancy rates of compounds 22 and 23 15 minutes after drug administration. Both compounds showed significant occupancy rates of the 5-HT2A receptor, but there were no significant differences between them and the drug-treated group. *p<0.05, **p<0.01 [Figure 4] This graph shows the time spent immobile in a forced swimming test in rats 24 hours after drug administration. Both compounds 22 and 23 showed a significant reduction in the time spent immobile. **p<0.01, ****p<0.0001 [Figure 5] In a glass bead cover test 30 minutes after drug administration, the total number of glass beads covered during the 30-minute observation period is shown. Both compounds 22 and 23 showed a significant dose-dependent decrease in the total number of covered glass beads. Comparison with vehicle: ***p<0.001, ****p<0.0001 [Figure 6] This chart shows the class and subclass probabilities of compounds 23 and 22 in SmartCube® (Psychogenics). The upper panel shows the percentage probability that each compound belongs to the class indicated on the left. The lower panel shows the percentage probability that each compound belongs to the subclass indicated on the left. Compound 23 has the highest probability of belonging to the anxiolytic class (yellow), while compound 22 has the highest probability of belonging to the hallucinogen class (magenta). The numbers along the x-axis represent dose (in mg / kg). [Modes for carrying out the invention]

[0007] Features and other details of this disclosure are described more specifically here. Before further description of this disclosure, certain terms used in this specification, examples and appended claims are collected here. These definitions should be read in the context of the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0008] definition "To treat" includes any action that results in improvement of a condition, disease, disorder, etc., such as mitigating, reducing, modulating, or eliminating.

[0009] As used herein, the term "alkoxy" refers to a linear or branched alkyl group (alkyl-O-) bonded at oxygen. Examples of alkoxy groups, but not limited to those listed herein, include alkoxy groups with 1 to 6 or 2 to 6 carbon atoms, which are referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Examples of alkoxy groups, but not limited to those listed herein, include methoxy, ethoxy, and isopropoxy.

[0010] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbons. Examples of alkyl groups include, but are not limited to, linear or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms, which are referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0011] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon having one or more double bonds. Exemplary alkenyl groups include, but are not limited to, linear or branched hydrocarbons having one double bond and containing 2-6, 2-4, or 2-3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, and homoallyl.

[0012] The term “aryl,” used alone or as part of a larger term such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term “aryl” can be used interchangeably with the term “aryl ring.” In certain embodiments of this disclosure, “aryl” refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthrasyl, etc., and may have one or more substituents. Also included in the scope of the term “aryl” are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, as used herein.

[0013] As used herein, the term "cyano" refers to the -CN group.

[0014] The terms "cycloalkyl" or "carbocyclic group," as used herein, refer to saturated or partially unsaturated cyclic hydrocarbon groups of, for example, 3-6 or 4-6 carbon atoms, which are C3-C6 cycloalkyl or C3-C6 cycloalkyl groups. 4~ These are referred to herein as C6 cycloalkyl groups. Examples of cycloalkyl groups, but not limited to these, include cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

[0015] As used herein, the term "cycloalkylalkyl" refers to saturated, linear, or branched hydrocarbons that are saturated or partially unsaturated and substituted with, for example, 3-6 or 4-6 carbon cyclic hydrocarbon groups. Exemplary cycloalkylalkyl groups, but not limited to, include cyclopropylmethyl, cyclopentylmethyl, and 2-cyclopropylethyl.

[0016] The terms "halo" or "halogen" as used herein refer to F, Cl, Br, or I.

[0017] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger term such as "heteroaralkyl" or "heteroaralkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, with 6, 10, or 14 π electrons shared in the cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups, without limitation, include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-” also, as used herein, include groups in which an aromatic heterocycle is fused to one or more aryl, cyclic aliphatic, or heterocyclyl rings, the group or bond being located on the aromatic heterocycle. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazine-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a ring that is optionally substituted. The term "heteroaralkyl" refers to an alkyl group that is substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are optionally substituted independently.

[0018] The terms “heterocyclyl” or “heterocyclic group” are accepted in the art and refer to a saturated or partially unsaturated, 4- to 10-membered ring structure comprising a bridged or fused ring, wherein the ring structure contains 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclyl ring may be bonded to adjacent groups via carbon or nitrogen. Examples of heterocyclyl groups, but not limited to, include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, and dihydrofuran.

[0019] As used herein, the terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0020] "Pharmacologically or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans as needed, do not produce harmful, allergic, or other adverse reactions. For administration to humans, preparations should meet the sterility, pyrogenicity, overall safety, and purity standards required by the FDA Office of Biologics standards.

[0021] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersions, coatings, isotonic agents, and absorption retarders, etc., that are suitable for the administration of a pharmacopoeia. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide auxiliary, additional, or enhanced therapeutic functions.

[0022] When used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein, which is formulated together with one or more pharmaceutically acceptable carriers.

[0023] "Individual," "patient," or "subject" is used interchangeably and includes any animal, preferably a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, or primate, and most preferably a human. The compounds of this disclosure can be administered to mammals, e.g., humans, but can also be administered to other mammals, e.g., animals requiring veterinary treatment, e.g., domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Mammals treated by the methods of this disclosure are preferably mammals for which treatment of mental illness or disorder is desired. "Modulation" includes antagonistism (e.g., inhibition), agonism, partial antagonistism, and / or partial agonism.

[0024] In this specification, the term “therapeutic dose” means the amount of a compound of interest that elicits a biological or medical response in a tissue, system or animal (e.g., mammal or human) being explored by researchers, veterinarians, medical doctors or other clinicians. The compounds of this disclosure are administered in therapeutic doses to treat a disease. Instead, the therapeutic dose of a compound is the amount required to achieve the desired therapeutic and / or prophylactic effect, e.g., the amount that results in a reduction of symptoms of a mental disorder.

[0025] The term "pharmaceutically acceptable salt," as used herein, refers to a salt of an acidic or basic group that may be present in a compound used in a composition. Compounds included in the compositions of the present invention that are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, which include, but are not limited to, salts of malic acid, oxalic acid, chloride, bromide, iodide, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, superphosphate, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid (i.e., salts of 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Compounds contained in the acidic compositions of the present invention can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly salts of calcium, magnesium, sodium, lithium, zinc, potassium, and iron. Compounds contained in the compositions of the present invention, which include basic or acidic portions, can also form pharmaceutically acceptable salts with various amino acids. Compounds of the present disclosure may also contain both acidic and basic groups, for example, one amino acid and one carboxylic acid group. In such cases, the compound may exist as an acid addition salt, an amphoteric ion, or a base salt.

[0026] The compounds of this disclosure contain one or more chiral centers and therefore may exist as stereoisomers. The term “stereoisomer,” as used herein, comprises all enantiomers or diastereomers. These compounds may also be designated with the symbols “(+)”, “(-)”, “R” or “S” depending on the stereoconfiguration of substituents around the stereogenic carbon atom, and those skilled in the art will recognize that the structure may implicitly represent a chiral center. This disclosure encompasses a variety of stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, and those skilled in the art will recognize that the structure may implicitly represent a chiral center.

[0027] The compounds of this disclosure contain one or more double bonds and therefore may also exist as geometric isomers resulting from the arrangement of substituents around carbon-carbon double bonds. [ka] 'C' represents a bond that may be a single, double, or triple bond as described herein. Substituents around a carbon-carbon double bond are designated to be in a 'Z' or 'E' configuration, and the terms 'Z' and 'E' are used in accordance with IUPAC standards. Unless otherwise specified, structures representing a double bond encompass both 'E' and 'Z' isomers. Substituents around a carbon-carbon double bond may also be called 'cis' or 'trans', where 'cis' refers to a substituent on the same side as the double bond and 'trans' refers to a substituent on the opposite side of the double bond.

[0028] The compounds of this disclosure contain a carbocyclic or heterocyclic ring and can therefore exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as being in a "Z" or "E" stereoconfiguration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures representing a carbocyclic or heterocyclic ring encompass both "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring can also be called "cis" or "trans," where "cis" refers to substituents on the same side as the ring face and "trans" refers to substituents on the opposite side of the ring face. A mixture of compounds in which substituents are located on both the same side as and the opposite side of the ring face is designated "cis / trans."

[0029] The individual enantiomers and diastereomers of the compounds of this disclosure can be prepared by synthesis from commercially available starting materials containing asymmetric or stereocenters, or by preparation of racemic mixtures followed by separation methods well known to those skilled in the art. These separation methods are exemplified by: (1) separation of the mixture of diastereomers by attachment of the enantiomer mixture to chiral auxiliary groups, recrystallization, or chromatography, and liberation of the optically pure product from the auxiliary; (2) formation of salts using optically active decomposers; (3) direct separation of the mixture of optical enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture can also be separated into its component enantiomers by well known methods, e.g., chiral phase liquid chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis, chemical, or enzymatic reactions in which a single reactant forms an heterogeneous mixture of stereoisomers during the formation of a new stereocenter or the transformation of a pre-existing one are well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0030] The compounds disclosed herein can exist in solvated and non-solvated forms with pharmaceutically acceptable solvents, such as water and ethanol, and this disclosure is intended to encompass both solvated and non-solvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is in crystalline form.

[0031] The present disclosure also encompasses isotopically labeled compounds of the present disclosure that are identical to those recited herein, except that one or more atoms are replaced by atoms having an atomic weight or mass number different from that typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, respectively 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. For example, the compounds of the present disclosure may have one or more H atoms replaced by deuterium.

[0032] Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C labeled ones) are useful in compound and / or substrate tissue distribution assays. Tritium-labeled (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to the ease of their preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2 H) can result in certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dosage) arising from greater metabolic stability and may thus be preferred in some situations. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures similar to those disclosed in the examples herein, by using isotopically labeled reagents instead of non-isotopically labeled reagents.

[0033] I. Phenalkylamine Compounds In some embodiments, the present disclosure has the structure:

Chemical formula

[0034] In some embodiments, the present disclosure relates to a structure: [Chemical formula] [Chemical formula] To provide a compound having the following or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure relates to a structure: [Chemical formula] To provide a compound having the following or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present disclosure relates to a structure: [Chemical formula] To provide a compound having the following or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present disclosure relates to a structure: [Chemical formula] To provide a compound having the following or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present disclosure relates to a compound of formula (I) [Chemical formula] [wherein, R [[ID=六十八]] 1 [[ID=六十九]]is C4-C8 alkyl, -S(C4-C8 alkyl), C4-C8 cycloalkylalkyl, -S(C4-C8 cycloalkylalkyl), or C4-C8 alkoxy, R1 It is substituted with one or more substituents, each substituent being fluoro. R 2 is hydrogen, hydroxyl, C1-C3 alkyl, halo, -CF3, -OCF3, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 3 is hydrogen, hydroxyl, C1-C3 alkyl, halo, -CF3, -OCF3, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 2 and R 3 Neither of them is hydrogen, R 4 is hydrogen, hydroxyl, C1-C3 alkyl, halo, -CF3, -OCF3, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 5 is hydrogen or C1-C3 alkyl, R 6 is hydrogen or benzyl, and the phenyl ring of benzyl is R 6a It is replaced by one to five instances of at will, Each R 6a Each instance of a character is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and halogen, or Any two adjacent R 6a These may, together with the atoms to which they are bonded, form an optionally substituted C5-C7 cycloalkyl or optionally substituted 3-7 membered heterocyclyl ring. R 1 is -SCH2CH2CH2CH2F, and R 2 , R 5 , and R 6 If each of them is hydrogen, then R 3 or R 4 At least one of them is not -OMe. Or provide a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, this disclosure is, R1 However, it is a C4-C8 alkyl, -S(C4-C8 alkyl), or C4-C8 alkoxy. R 1 It is substituted with one or more substituents, each substituent being fluoro, R 2 is hydrogen, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 3 is hydrogen, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 2 and R 3 Both are not hydrogen, R 4 is hydrogen, C1-C3 alkoxy, or -S(C1-C3 alkyl), R 5 is hydrogen or C1-C2 alkyl, R 6 is hydrogen or benzyl, and the phenyl ring of benzyl is R 6a It is replaced by one to five instances of at will, Each R 6a However, each time it appears, it is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, and halogen, or Any two adjacent R 6a However, these may, together with the atoms to which they are bonded, form a 3- to 7-membered heterocyclyl ring that is optionally substituted. R 1 is -SCH2CH2CH2CH2F, and R 2 , R 5 , and R 6 If each of them is hydrogen, then R 3 or R 4 At least one of them is not -OMe, The compound of formula (I) is provided.

[0040] In some embodiments, this disclosure is, R 1 is C4-C8 alkyl or -S(C4-C8 alkyl), R 1It is substituted with one or more substituents, each substituent being fluoro, R 2 is hydrogen or C1-C3 alkoxy, R 3 is hydrogen or C1-C3 alkoxy, R 2 and R 3 Both are not hydrogen, R 4 is hydrogen or C1-C3 alkoxy, R 5 is hydrogen or C1-C2 alkyl, R 6 That is hydrogen, R 1 is -SCH2CH2CH2CH2F, and R 2 , R 5 , and R 6 If each of them is hydrogen, then R 3 or R 4 At least one of them is not -OMe, The compound of formula (I) is provided.

[0041] In some embodiments, this disclosure is, R 1 is C4-C8 alkyl or -S(C4-C8 alkyl), R 1 It is substituted with one or more substituents, each substituent being fluoro, R 2 is hydrogen, -OMe, or -OEt, R 3 is hydrogen, -OMe, or -OEt, R 2 and R 3 Both are not hydrogen, R 4 is -OMe or -OEt, R 5 is hydrogen, Me, or Et, R 6 That is hydrogen, R 1 is -SCH2CH2CH2CH2F, and R 2 , R5 and R 6 When each of them is hydrogen, R 3 or R 4 At least one of them is other than -OMe, provides a compound of formula (I).

[0042] In some embodiments, the present disclosure provides a compound of formula (I-a): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present disclosure provides a compound of formula (I-b): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the present disclosure provides a compound of formula (I-c): [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, R 1 is -S(C4-C8 alkyl) substituted with one or more substituents, and each substituent is fluoro.

[0046] In some embodiments, R 1 is C4-C8 alkyl substituted with one or more substituents, and each substituent is fluoro.

[0047] In some embodiments, R 1 is substituted with 1, 2, or 3 substituents, and each substituent is fluoro.

[0048] In some embodiments, R 1is -S(C4-C8 alkyl), and is substituted with 1, 2, or 3 substituents each selected from the group consisting of halogen. In some embodiments, R 1 is -S(C4 alkyl), and is substituted with 1, 2, or 3 substituents each selected from the group consisting of halogen. In some embodiments, R 1 is -S(C5 alkyl), and is substituted with 1, 2, or 3 substituents each selected from the group consisting of halogen. In some embodiments, R 1 is -S(C6 alkyl), and is substituted with 1, 2, or 3 substituents each selected from the group consisting of halogen. In some embodiments, R 1 is -S(C7 alkyl), and is substituted with 1, 2, or 3 substituents each selected from the group consisting of halogen.

[0049] In some embodiments, R 1 is -S(C4-C8 alkyl) and is substituted with one halogen. In some embodiments, R 1 is -S(C4-C8 alkyl) and is substituted with fluoro. In some embodiments, R 1 is -S(C4-C8 alkyl) and is substituted with three halogens. In some embodiments, R 1 is -S(C4-C8 alkyl) and is substituted with three fluoro groups.

[0050] In some embodiments, R 1 is selected from the group consisting of -SCH2CH2CH2CH2F, -SCH2CH2CH2CH2CH2F, -SCH2CH2CH2CH2CH2CH2F, and -SCH2CH2CH2CH2CH2CH2CH2F.

[0051] In some embodiments, R 1 is selected from the group consisting of -SCH2CH2CH2CF3, -SCH2CH2CH2CH2CF3, -SCH2CH2CH2CH2CH2CF3, and -SCH2CH2CH2CH2CH2CH2CF3.

[0052] In some embodiments, R 1 is -SCH2CH2CH2CH2F. In some embodiments, R 1 is -SCH2CH2CH2CF3. In some embodiments, R 1 is -SCH2CH2CH2CH2CH2F. In some embodiments, R 1 is -SCH2CH2CH2CH2CF3. In some embodiments, R 1 is -SCH2CH2CH2CH2CH2CH2F. In some embodiments, R 1 is -SCH2CH2CH2CH2CH2CF3. In some embodiments, R 1 is -SCH2CH2CH2CH2CH2CH2CH2F. In some embodiments, R 1 It is -SCH2CH2CH2CH2CH2CH2CF3.

[0053] In some embodiments, R 1 R is a C4-C8 alkyl group, each substituted with one, two, or three substituents selected from the group consisting of halogens. In some embodiments, R 1 R is a C4 alkyl group, each substituted with one, two, or three substituents selected from the group consisting of halogens. In some embodiments, R 1 R is a C5 alkyl group, each substituted with one, two, or three substituents selected from the group consisting of halogens. In some embodiments, R 1 R is a C6 alkyl group, each substituted with one, two, or three substituents selected from the group consisting of halogens. In some embodiments, R 1 It is a C7 alkyl group, each substituted with one, two, or three substituents selected from the group consisting of halogens.

[0054] In some embodiments, R 1 is a C4-C8 alkyl group and is substituted with one halogen. In some embodiments, R 1 R is a C4-C8 alkyl group and is substituted with fluoropolymer. In some embodiments, 1It is a C4-C8 alkyl group and is substituted with three halogens. In some embodiments, R 1 It is a C4-C8 alkyl group and is substituted with three fluoro groups.

[0055] In some embodiments, R 1 The group is selected from the group consisting of -CH2CH2CH2CH2F, -CH2CH2CH2CH2CH2F, -CH2CH2CH2CH2CH2CH2F, and JP-CH2CH2CH2CH2CH2CH2CH2F.

[0056] In some embodiments, R 1 The group is selected from the group consisting of -CH2CH2CH2CF3, -CH2CH2CH2CH2CF3, -CH2CH2CH2CH2CH2CF3, and JP-CH2CH2CH2CH2CH2CH2CF3.

[0057] In some embodiments, R 1 is -CH2CH2CH2CH2F. In some embodiments, R 1 is -CH2CH2CH2CF3. In some embodiments, R 1 is -CH2CH2CH2CH2CH2F. In some embodiments, R 1 is -CH2CH2CH2CH2CF3. In some embodiments, R 1 is -CH2CH2CH2CH2CH2CH2F. In some embodiments, R 1 is -CH2CH2CH2CH2CH2CF3. In some embodiments, R 1 is -CH2CH2CH2CH2CH2CH2CH2F. In some eigenlocations, R 1 It is -CH2CH2CH2CH2CH2CH2CF3.

[0058] In some embodiments, this disclosure is, [ka] The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts thereof.

[0059] In some embodiments, the present disclosure relates to a compound of formula (II): [ka] [In the formula, R 1 It is C4-C8 alkyl or -S(C4-C8 alkyl), C4-C8 alkyl groups are independently classified as hydroxyl, oxo, -CN, and -NR. 7 R 8 The molecules may be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxys, C1-C3 alkyls, phenyls, 5-6 member heteroaryls, C3-C6 cycloalkyls, and 3-6 member heterocyclines. R 3 It is selected from the group consisting of hydrogen, halogens, and C1-C3 alkyl groups. R 5 is hydrogen or C1-C3 alkyl, R 7 and R 8 Each instance of a C1-C3 alkyl group is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl groups. or R 7 and R 8 These may, together with the nitrogen to which they are bonded, form a 4- to 6-membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N, and this 4- to 6-membered heterocyclic ring may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl. R 1 If R is -SCH2CH2CH2CH3, 3 and R 5 [Neither of them is hydrogen] Or provide a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, this disclosure is, R 1is C4-C8 alkyl or -S(C4-C8 alkyl), Each C4-C8 alkyl group may be independently substituted with one or more substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, and C3-C6 cycloalkyl groups, as can be optionally substituted. R 3 However, it is selected from the group consisting of hydrogen, halogens, and C1-C3 alkyl groups. R 5 is hydrogen, Me, or Et, R 1 If R is -SCH2CH2CH2CH3, 3 and R 5 This provides a compound of formula (II) in which neither of the elements is hydrogen.

[0061] In some embodiments, this disclosure is, R 1 is C4-C8 alkyl or -S(C4-C8 alkyl), The C4-C8 alkyl group is unsubstituted. R 3 The group is selected from hydrogen, halogens, and Me. R 5 is hydrogen, Me, or Et, R 1 If R is -SCH2CH2CH2CH3, 3 and R 5 This provides a compound of formula (II) in which neither of the elements is hydrogen.

[0062] In some embodiments, R 5 It is hydrogen.

[0063] In some embodiments, R 5 These are C1-C2 alkyl groups.

[0064] In some embodiments, R 5 This is Me.

[0065] In some embodiments, R 5 It is Et.

[0066] In some embodiments, the present disclosure relates to a compound of formula (III): [ka] [In the ceremony R 1 These are C4-C8 alkyl, -S(C4-C8 alkyl), and -(CH2) 1~2 Selected from the group consisting of O(C1~C3 alkyl), C4-C8 alkyl groups are independently classified as hydroxyl, oxo, -CN, and -NR. 7 R 8 The molecules may be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxys, C1-C3 alkyls, phenyls, 5-6 membered heteroaryls, C3-C6 cycloalkyls, and C3-C6 heterocyclines. R 2 is hydrogen or C1-C3 alkyl, R 4 is hydrogen or C1-C3 alkoxy, R 5 is hydrogen or a C1-C3 alkyl group, and the C1-C3 alkyl group is optional and may be substituted with hydroxyl. R 7 and R 8 Each instance of a C1-C3 alkyl group is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl groups. or R 7 and R 8 These may, together with the nitrogen to which they are bonded, form a 4- to 6-membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N, and this 4- to 6-membered heterocyclic ring may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl. R 1 is -S(n-butyl) or -SCH2CH2CH2CH2F, and R 4 If R is -OMe,2 and R 5 Neither of them is hydrogen, R 1 is -S(n-butyl), -S(sec-butyl), -S(n-pentyl), n-pentyl, n-hexyl, n-heptyl, or -CH2CH2CH2OMe, and R 4 is -OMe, R 2 If R is hydrogen, 5 [It is not methyl] Or provide a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the present disclosure relates to a compound of formula (IV): [ka] [In the ceremony R 1 It is selected from the group consisting of -CN, C4-C8 alkyl, and -S(C4-C8 alkyl), C4-C8 alkyl groups are independently classified as hydroxyl, oxo, -CN, and -NR. 7 R 8 The molecules may be optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkoxys, C1-C3 alkyls, phenyls, 5-6 membered heteroaryls, C3-C6 cycloalkyls, and C3-C6 heterocyclines. R 2 is hydrogen or C1-C3 alkoxy, R 3 is hydrogen or C1-C3 alkoxy, R 2 and R 3 Neither of them is hydrogen, R 5 is hydrogen or C1-C3 alkyl, Each R 6a Each instance of a character is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and halogen, or Any two adjacent R 6aThese may, together with the atoms to which they are bonded, form an optionally substituted C5-C7 cycloalkyl or optionally substituted 3-7 membered heterocyclyl ring. R 7 and R 8 Each instance of a C1-C3 alkyl group is independently selected from the group consisting of hydrogen and C1-C3 alkyl groups, and the C1-C3 alkyl group may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl groups. or R 7 and R 8 These may, together with the nitrogen to which they are bonded, form a 4- to 6-membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N, and this 4- to 6-membered heterocyclic ring may be optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, oxo, and hydroxyl. R 1 is -CN, R 2 H is R 3 is -OMe, R 6a If R is orthohydroxyl or ortho-OMe, 5 [It is not hydrogen] Or provide a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, R 1 The group is selected from the group consisting of -CN, C1-C8 alkyl, and -S(C4-C8 alkyl), and C1-C8 alkyl and C4-C8 alkyl are independently hydroxyl, fluoro, -CN, and -NR, respectively. 7 R 8 , C1~C6 alkoxy, C 1~3 It may be optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of alkyl, phenyl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl. In some embodiments, R 1The group is selected from -CN, C4-C8 alkyl, and -S(C4-C8 alkyl), and each of the C4-C8 alkyl groups is independently hydroxyl, fluoro, -CN, and -NR. 7 R 8 , C1~C6 alkoxy, C 1~3 It may be optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of alkyl, phenyl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl. In some embodiments, R 1 The group is selected from the group consisting of -CN, C1-C8 alkyl, and -S(C4-C8 alkyl), and C1-C8 alkyl and C4-C8 alkyl are independently hydroxyl, fluoro, -CN, and -NR, respectively. 7 R 8 , C1~C3 alkoxy, C 1~3 It may be optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of alkyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl. In some embodiments, R 1 The group is selected from -CN, C4-C8 alkyl, and -S(C4-C8 alkyl), and each of the C4-C8 alkyl groups is independently hydroxyl, fluoro, -CN, and -NR. 7 R 8 , C1~C3 alkoxy, C 1~3 It may be optionally substituted with 1, 2, 3, or more substituents selected from the group consisting of alkyl, C3-C6 cycloalkyl, and C3-C6 heterocyclyl. In some embodiments, R 1 R is selected from the group consisting of -CN, C1-C8 alkyl, and -S(C4-C8 alkyl), and the C1-C8 alkyl and C4-C8 alkyl may be optionally substituted with hydroxyl or fluoro. In some embodiments, 1 R is selected from the group consisting of -CN, C4-C8 alkyl, and -S(C4-C8 alkyl), and the C4-C8 alkyl may be optionally substituted with hydroxyl or fluoro. In some embodiments, 1is C1-C8 alkyl or -S(C4-C8 alkyl), and the C1-C8 alkyl and C4-C8 alkyl may be optionally substituted with fluoro. In some embodiments, R 1 is C4-C8 alkyl or -S(C4-C8 alkyl), where the C4-C8 alkyl is fluoro and may be optionally substituted. In some embodiments, R 1 R is selected from the group consisting of -CN, C1-C8 alkyl, and -S(C4-C8 alkyl). In some embodiments, R 1 R is selected from the group consisting of -CN, C4-C8 alkyl, and -S(C4-C8 alkyl). In some embodiments, R 1 is -CN. In some embodiments, R 1 is C1-C8 alkyl or -S(C4-C8 alkyl). In some embodiments, R 1 is C4-C8 alkyl or -S(C4-C8 alkyl). In some embodiments, R 1 is a C1-C8 alkyl group. In some embodiments, R 1 is a C4-C8 alkyl group. In some embodiments, R 1 R is selected from the group consisting of methyl, n-pentyl, neopentyl, n-hexyl, and isohexyl. In some embodiments, R 1 R is selected from the group consisting of n-pentyl, n-hexyl, and isohexyl. In some embodiments, R 1 is -S (C4~C8 alkyl). In some embodiments, R 1 R is selected from the group consisting of -S(n-propyl), -S(n-butyl), -S(n-pentyl), -S(neopentyl), -S(n-hexyl), and -S(isohexyl). In some embodiments, R 1 The group is selected from -S(n-butyl), -S(n-pentyl), -S(n-hexyl), and -S(isohexyl).

[0069] In some embodiments, R 2 R is hydrogen or a C1-C3 alkoxy. In some embodiments, R 2R is hydrogen or a C1-C3 alkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C3 alkoxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 It is methyl.

[0070] In some embodiments, R 3 R is selected from the group consisting of hydrogen, halogens, and C1-C3 alkyl groups. In some embodiments, R 3 R is hydrogen or a C1-C3 alkoxy. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a C1-C3 alkoxy. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is methyl. In some embodiments, R 3 It is Bromo.

[0071] In some embodiments, R 2 is hydrogen, R 3 is methoxy. In some embodiments, R 2 is methoxy, and R 3 is hydrogen. In some embodiments, R 2 and R 3 Neither of them is hydrogen.

[0072] In some embodiments, R 4 R is hydrogen or a C1-C3 alkoxy. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C3 alkoxy. In some embodiments, R 4 It is methoxy.

[0073] In some embodiments, R 5 R is hydrogen or a C1-C3 alkyl group. In some embodiments, R 5 is hydrogen. In some embodiments, R 5is a C1-C3 alkyl group. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 It is hydroxymethyl.

[0074] Some implementation methods, each R 6a Each R is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, and halogen. In some embodiments, each R 6a Each R is independently selected from the group consisting of hydroxyl, C1-C3 alkoxy, and halogen. In some embodiments, each R 6a Each R is independently selected from the group consisting of hydroxyl, -OMe, and fluoro (flouro) each time it appears. In some embodiments, each R 6a R is hydroxyl or C1-C6 alkoxy. In some embodiments, each R 6a R is hydroxyl or C1-C3 alkoxy. In some embodiments, each R 6a is hydroxyl. In some embodiments, each R 6a R is a C1-C6 alkoxy. In some embodiments, each R 6a R is a C1-C3 alkoxy. In some embodiments, each R 6a is methoxy. In some embodiments, each R 6a is fluoro. In some embodiments, any two adjacent R 6a These may, together with the atoms to which they are bonded, form optionally substituted C5-C7 cycloalkyl or optionally substituted 3-7 membered heterocyclyl rings. In some embodiments, any two adjacent R 6a These may, together with the atoms to which they are bonded, form a methylenedioxy ring.

[0075] In some embodiments, R 6 teeth, [ka] It is selected from the group consisting of the following.

[0076] In some embodiments, this disclosure is, [ka] [ka] [ka] [ka] The present invention provides compounds selected from the group consisting of the above, or pharmaceutically acceptable salts thereof.

[0077] Salts of the compounds of this disclosure can be prepared by reacting the compounds of this disclosure with a suitable acid or base in a suitable solvent or mixture of solvents (e.g., ether, e.g., diethyl ether, or alcohol, e.g., ethanol, or aqueous solvent) using conventional procedures. Salts of the compounds of this disclosure can be exchanged for other salts by processing using conventional ion exchange chromatography procedures.

[0078] If it is desired to obtain a specific enantiomer of a compound of the present disclosure, it can be produced from a corresponding mixture of enantiomers by utilizing any suitable conventional procedure for separating the enantiomers. For example, a diastereomer derivative (e.g., a salt) can be produced by reacting a mixture of enantiomers of a compound of the present disclosure (e.g., a racemate) with a suitable chiral compound (e.g., a chiral acid). The diastereomer can then be separated by any conventional means, for example, crystallization, to recover the desired enantiomer (e.g., by treatment with a base if the diastereomer is an acidic salt). Alternatively, a racemic mixture of esters can be separated by kinetic hydrolysis using various biocatalysts (see, for example, Patel Steroselective Biocatalysts, Marcel Decker; New York 2000).

[0079] In an alternative separation process, the racemic mixture of the compounds disclosed herein can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained using a suitable chiral intermediate in one of the methods described above. If it is desired to obtain specific geometric isomers of the compounds disclosed herein, chromatography, recrystallization, and other conventional separation procedures can also be used for intermediates or final products.

[0080] II. Method Another aspect of this disclosure provides a method for modulating the activity of 5-HT2A. Such a method involves exposing the receptor to a compound described herein. In some embodiments, the compound used in one or more of the aforementioned methods is one of the general, subordinate, or specific compounds described herein, e.g., a compound of formula I, Ia, Ib, Ic, II, III, or IV. The ability of the compounds described herein to modulate, activate, or inhibit 5-HT2A can be evaluated by procedures known in the art and / or described herein. Another aspect of this disclosure provides a method for treating diseases related to the expression or activity of 5-HT2A in patients. For example, a hypothetical method involves administering a disclosed compound in a patient in an amount sufficient to establish 5-HT2A activation effective in reducing the symptoms of a mental disorder or disability. Furthermore, treatment with the disclosed compound may also increase neuroplasticity or neurogenesis in a 5-HT2A-dependent manner.

[0081] In certain embodiments, the compound used in one or more of the aforementioned methods is one of the general, subordinate, or specific compounds described herein, for example, a compound of formula I, Ia, Ib, Ic, II, III, or IV.

[0082] In some embodiments, the Disclosure provides a method for treating a mental illness or disorder, comprising the step of administering a therapeutically effective dose of one of the compounds of the Disclosure to a patient in need thereof.

[0083] In some embodiments, this disclosure relates to a method for treating a mental illness or disorder, which is provided to a patient in need of such treatment. [ka] [ka] [ka] [ka] [ka] [ka] [ka] The present invention provides a method comprising the step of administering a therapeutically effective amount of a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the mental disorder or condition is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal anxiety disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

[0085] In some embodiments, the mental disorder or disorder is selected from the group consisting of bipolar disorder I, bipolar disorder II, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition.

[0086] In some embodiments, the mental disorder or disorder is a substance-related disorder or a substance use disorder.

[0087] In some embodiments, the mental disorder or condition is selected from the group consisting of separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder, panic disorder, panic attach, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0088] In some embodiments, the mental disorder or condition is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, feeding behaviors and eating disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

[0089] In some embodiments, the mental disorder is a cognitive disorder.

[0090] In some embodiments, the mental illness or disorder is a treatment-resistant illness or disorder.

[0091] This disclosure further provides a method for enhancing creativity or cognition in a subject, the method comprising administering to the subject a composition comprising an effective amount of a compound of this disclosure.

[0092] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders, including depressive disorders such as major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal anxiety disorder, psychotic depression, severe mood dysregulation, substance / medication-induced depressive disorder, and depressive disorders due to other medical conditions.

[0093] Compounds, methods, and compositions for treating patients suffering from treatment-resistant depression, for example, depressive disorders that do not respond to and / or have never responded to at least one or at least two other antidepressant compounds or therapeutic agents. As used herein, “depressive disorder” encompasses treatment-resistant depression.

[0094] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders including bipolar disorder and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medicine-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to other medical conditions.

[0095] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders, including substance-related disorders, for example, to prevent substance use cravings, reduce substance use cravings, and / or to promote the cessation or discontinuation of substance use. Substance use disorders include the abuse of psychoactive compounds, such as alcohol, caffeine, hemp, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” refers to psychoactive compounds that may be addictive, such as alcohol, caffeine, hemp, hallucinogen, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods and compositions can be used to promote smoking cessation or the cessation of opioid use.

[0096] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders including anxiety disorders, such as separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorders due to other medical conditions.

[0097] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, abrasion disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to other medical conditions.

[0098] In some embodiments, compounds, methods, and compositions can be used to treat a group of trauma- and stressor-related disorders, including, for example, reactive love disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0099] In some embodiments, compounds, methods, and compositions can be used to treat eating behaviors and eating disorders, including mental disorders such as anorexia nervosa, bulimia nervosa, distractive eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder.

[0100] In some embodiments, compounds, methods, and compositions can be used to treat mental disorders, including, for example, delirium, dementia, mild cognitive impairment, dementia or mild cognitive impairment due to Alzheimer's disease, frontotemporal dementia or mild frontotemporal cognitive impairment, dementia or mild cognitive impairment with Lewy body dementia, vascular dementia or mild vascular cognitive impairment, dementia or mild cognitive impairment due to traumatic brain injury, substance / medicine-induced dementia or mild cognitive impairment, dementia or mild cognitive impairment due to HIV infection, dementia or mild cognitive impairment due to prion disease, dementia or mild cognitive impairment due to Parkinson's disease, dementia or mild cognitive impairment due to Huntington's disease, dementia or mild cognitive impairment due to another medical condition, and dementia or mild cognitive impairment due to multiple etiologies.

[0101] In some embodiments, compounds, methods, and compositions can be used to treat neurodevelopmental disorders, including mental disorders such as autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorder, Tourette syndrome, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder.

[0102] In some embodiments, the compounds, methods, and compositions can be used to treat personality disorders, including mental disorders such as borderline personality disorder.

[0103] In some embodiments, compounds, methods, and compositions may be used to treat sexual dysfunction, including mental disorders such as delayed ejaculation, erectile dysfunction, female orgasm disorder, female sexual interest / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / pharmaceutical-induced sexual dysfunction.

[0104] In some embodiments, compounds, methods, and compositions can be used to treat gender dysphoria, for example, mental disorders including gender dysphoria.

[0105] In some embodiments, compounds, methods, and compositions can be used to treat headache disorders. In some embodiments, the headache disorder is a migraine or a cluster headache.

[0106] In some embodiments, the compounds, methods, and compositions can be used to treat inflammatory disorders. In some embodiments, the inflammatory disorder is inflammatory bowel disease, including ulcerative colitis and Crohn's disease. In some embodiments, the inflammatory disorder is inflammatory bowel syndrome. In some embodiments, the inflammatory disorder is inflammation-related cardiovascular disorders, such as atherosclerosis and coronary artery disease. In some embodiments, the inflammatory disorder is TNF-α activity-dependent inflammatory disorders.

[0107] In some embodiments, compounds, methods, and compositions can be used to treat high intraocular pressure.

[0108] The compounds of this disclosure may be administered to patients (animals and humans) requiring such treatment in doses that provide optimal pharmacokinetic efficacy. It is understood that the dose required for any particular use will vary from patient to patient, depending not only on the specific compound or composition selected, but also on the route of administration, the nature of the condition being treated, the patient's age and condition, any concurrent drug therapies or special dietary therapies the patient is undergoing at that time, and other factors recognized by those skilled in the art, and that ultimately the appropriate dose will be at the discretion of the attending physician. To treat the conditions and diseases mentioned above, the compounds of this disclosure may be administered orally, subcutaneously, topically, parenterally, by inhalation spray, by evaporation, intranasally, or rectally, in dosage units containing conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous injection, intravenous or intramuscular injection, or intravenous infusion techniques.

[0109] Treatment can be continued for any desired duration, longer or shorter. The composition may be administered, for example, in regimens of 1 to 4 times per day or more. An appropriate treatment period may be, for example, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, at least about 1 year, or indefinite. The treatment period can be terminated when the desired outcome, for example, reduction of symptoms of the mental disorder, is achieved. The treatment regimen may include an adjustment phase, during which a dose sufficient to provide symptomatic relief is administered, followed by a maintenance phase, during which a lower dose sufficient to prevent symptom relapse is administered. An appropriate maintenance dose is likely to be found in the lower part of the dose range provided herein, but adjustment and maintenance doses can be readily established for individual subjects by those skilled in the art based on the disclosure herein, without excessive experimentation. The maintenance dose can be used to maintain remission in subjects whose symptoms have been previously controlled by other means, including treatment with other pharmacologically active substances.

[0110] In some embodiments, the method includes the step of treating a mental disorder, such as a depressive disorder, by administering to a patient in need a pharmaceutical composition containing about 0.01 mg to about 400 mg of the compound of the present disclosure. In some embodiments, the doses are, for example, about 0.01 to 400 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.1 mg, 0.1 to 400 mg, 0.1 to 30 mg 0mg, 0.1~250mg, 0.1~200mg, 0.1~150mg, 0.1~100mg, 0.1~75mg, 0.1~50mg, 0.1~25mg, 0.1~20mg, 0.1~15mg, 0.1~10mg, 0. 1~5mg, 0.1~1mg, 10~400mg, 10~300mg, 10~250mg, 10~200mg, 10~150mg, 10~100mg, 10~50mg, 10~25mg, 10~15mg, 20~400mg, The range may be 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-100mg, 20-50mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-100mg, 100-400mg, 100-300mg, 100-250mg, or 100-200mg, for example, approximately 0.01mg, 0.025mg, 0.05mg, 0.1mg, 0.15mg, 0.25mg. Examples of dosages include g, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0111] In some embodiments, the dose may include, for example, amounts of the compound of the Disclosure or a pharmaceutically acceptable salt thereof in the range of about 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 0.1 mg to 10 mg, 0.1 to 5 mg, or 0.1 to 1 mg, including 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.5 mg, 1.0 mg. Specific examples of dosages include mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 10 mg, 11 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg.

[0112] Typically, doses of the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered to patients who require them once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, once a month, every two months, every three months, twice a year, or once a year. In some embodiments, the dose is, for example, about 0.1 to 400 mg / dose, 0.1 to 300 mg / dose, 0.1 to 250 mg / dose, 0.1 to 200 mg / dose, 0.1 to 100 mg / dose, 0.1 to 50 mg / dose, or 0.1 to 25 mg / dose, for example 300 mg / dose, 250 mg / dose, 200 mg / dose, 150 mg / dose, 100 mg / dose, 75 mg / dose, 50 mg / dose, 25 mg / dose, 20 mg / dose, 10 mg / dose, 5 mg / dose, 2.5 mg / dose, 1 mg / dose, 0.5 mg / dose, 0.25 mg / dose, or 0.1 mg / dose.

[0113] In some embodiments, pharmaceutical compositions for parenteral or inhalation administration, e.g., by spray or mist, of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, have concentrations ranging from about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition contains the compound of the Disclosure or a pharmaceutically acceptable salt thereof at concentrations of, for example, about 5 mg / mL to about 500 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 50 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.05 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, or about 0.005 mg / mL to about 0.1 mg / mL.

[0114] In some embodiments, the composition contains the compound of the Disclosure or a pharmaceutically acceptable salt thereof at concentrations of, for example, about 0.05 mg / mL to about 500 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.005 mg / mL to about 1 mg / mL, about 0.005 mg / mL to about 0.25 mg / mL, about 0.005 mg / mL to about 0.05 mg / mL, or about 0.005 mg / mL to about 0.025 mg / mL. In some embodiments, the pharmaceutical composition is formulated in a total volume, for example, about 0.1 mL, 0.25 mL, 0.5 mL, 1 mL, 2 mL, 5 mL, 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0115] Typically, the dosage may be administered to the subject once, twice, three or four times daily, every other day, every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year. In some embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning or once in the evening. In some embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning and once in the evening. In some embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is administered to the subject three times a day (e.g., at breakfast, lunch, and dinner) in a dose of, for example, 0.5 mg / dose (e.g., 1.5 mg / day).

[0116] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 0.5 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 1 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 2.5 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 5 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 10 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 15 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 20 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 25 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 30 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 40 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 50 mg / day in one or more doses. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are administered to a subject at a dose of 75 mg / day in one or more doses. In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a subject in one or more doses at a dose of 100 mg / day.

[0117] In some embodiments, the dose of the compound of the Disclosure or a pharmaceutically acceptable salt thereof is 0.0005 to 5 mg / kg, 0.001 to 1 mg / kg, 0.01 to 1 mg / kg, or 0.1 to 5 mg / kg once, twice, three or four times a day. For example, in some embodiments, the dose is 0.0005 mg / kg, 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, or 5 mg / kg once, twice, three or four times a day. In some embodiments, subjects are administered a total daily dose of 0.01 mg to 500 mg of the compound or a pharmaceutically acceptable salt thereof once, twice, three or four times daily. In some embodiments, the total amount administered to the subject within 24 hours is, for example, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, and 500 mg. In some embodiments, the subject may start with a low dose, and the dose is increased in stages. In some embodiments, the subject may be started with a high dose and then reduced.

[0118] In some embodiments, the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered to patients under the supervision of a healthcare provider.

[0119] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to patients under the supervision of a healthcare provider in a hospital specializing in the provision of psychotropic treatments.

[0120] In some embodiments, the compounds of the Disclosure are administered to a patient under the supervision of a healthcare provider in high doses intended to induce a hallucinatory experience in the subject, for example, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.

[0121] In some embodiments, high-dose administration to patients under the supervision of a healthcare provider is performed regularly, for example, every three days, twice a week, once a week, twice a month, once a month, four times a year, three times a year, twice a year, or once a year, in order to maintain therapeutic effects in the patient.

[0122] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient themselves at home or otherwise away from the supervision of a healthcare provider.

[0123] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered by the patient themselves at home or away from the supervision of a healthcare provider in low doses intended to induce psychotropic effects below or above the threshold of perception, for example, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, or 4 mg.

[0124] In some embodiments, low doses administered by the patient themselves are given regularly, for example, daily, every other day, every three days, twice a week, once a week, twice a month, or once a month, to maintain the therapeutic effect in the patient.

[0125] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof may be administered at specified intervals, for example, by inhalation or orally. For example, during treatment, the patient may be administered the compounds of the Disclosure at intervals of, for example, 1 year, 6 months, 4 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.

[0126] III. Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, oral buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, intranasal, aerosol, or evaporation administration, but in any case the most suitable mode of administration will depend on the degree and severity of the condition being treated and the properties of the specific compounds used. For example, the disclosed compositions may be formulated as unit doses and / or for oral or subcutaneous administration.

[0127] The exemplary pharmaceutical compositions of this disclosure may be used in the form of pharmaceutical preparations, for example, solid, semi-solid, or liquid, which contain one or more compounds of this disclosure as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral application. The active ingredients may be formulated with ordinary non-toxic, pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use. The active compound of interest is included in the pharmaceutical composition in an amount sufficient to produce the desired effect in the course or state of the disease.

[0128] For the preparation of solid compositions, such as tablets, the main active ingredient may be mixed with a pharmaceutical carrier, such as a conventional tableting agent, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other pharmaceutical diluents, such as water, to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of this disclosure or a non-toxic, pharmaceutically acceptable salt thereof. When these preliminary formulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0129] For solid dosage forms for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the target composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants. , for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, for example, paraffin; (6) absorption enhancers, for example, quaternary ammonium compounds; (7) wetting agents, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, for example, kaolin and bentonite clay; (9) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0130] Tablets may be prepared by compression or molding with one or more optional adjuncts. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or crosslinked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of the composition to be prepared, moistened with an inert liquid diluent, in appropriate equipment. Tablets and other solid dosage forms, such as sugar-coated tablets, capsules, pills, and granules, may optionally be slitted or prepared with coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation technology.

[0131] Compositions for inhalation or inhalation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the composition in question, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0132] The suspension may contain, in addition to the target composition, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0133] Formulations for rectal or vaginal administration may be presented as suppositories, which can be prepared by mixing the composition with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the body cavity and release the activator.

[0134] Dosage forms for transdermal administration of the target composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or sprays.

[0135] Ointments, pastes, creams, and gels may contain, in addition to the target composition, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0136] The powder and spray formulations may contain, in addition to the target composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. The spray formulations may further contain conventional spraying agents such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0137] The compositions and compounds of this disclosure may be administered as aerosols instead. This is achieved by preparing aqueous aerosols, liposome preparations, or solid particles containing the compounds. Non-aqueous (e.g., fluorocarbon sprays) suspensions may also be used. Ultrasonic nebulizers may be used because they minimize drug shear, which can lead to the decomposition of compounds contained in the composition of interest. Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the composition of interest together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the particular composition of interest but usually include nonionic surfactants (Tweens, Pluronic, or polyethylene glycol), harmless proteins, e.g., serum albumin, sorbitan esters, oleic acid, lecithin, amino acids, e.g., glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0138] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be restored to an injectable sterile solution or dispersion immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that impart an isotonic formulation with the blood of the recipient of the interest, or suspending agents or thickeners.

[0139] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate and cyclodextrin). Appropriate fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0140] In another embodiment, the present disclosure provides enteral pharmaceutical formulations comprising disclosed compounds and enteric-coated materials; and pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials refer to polymers that are substantially insoluble in the acidic environment of the stomach but are primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5. Therefore, enteric-coated materials remain insoluble until the pH reaches, for example, approximately 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.2, 8.4, 8.6, 8.8, 9.0, 9.2, 9.4, 9.6, 9.8, or 10.0. Exemplary enteric-coated materials include cellulose phthalate acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitic acetate, hydroxypropyl methylcellulose succinate, cellulose succinate acetate, cellulose hexahydrophthalate acetate, cellulose propionic acid phthalate, cellulose maleate acetate, cellulose butyrate acetate, cellulose propionic acid acetate, copolymer of methyl methacrylate and methyl methacrylate, copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal colophorum, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit Examples include FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is either known or readily determinable in vitro.The aforementioned materials are a list of possible materials, but those skilled in the art who would benefit from this disclosure will recognize that this is not exhaustive and that other enteric-coated materials exist that would satisfy the purposes of this disclosure.

[0141] Advantageously, this disclosure also provides kits for use by consumers requiring treatment with the disclosed compounds. Such kits include a suitable dosage form, e.g., one described above, and instructions describing how to use such dosage forms to treat a medical disorder, e.g., a mental illness or disorder. The instructions guide consumers or healthcare professionals to administer the dosage forms according to a mode of administration known to those skilled in the art. Such kits may be packaged and sold in single or multi-pack units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of a material, preferably a transparent plastic material, covered with foil. During the packaging process, grooves are formed in the plastic foil. The grooves have the size and shape of the tablet or capsule to be packaged. The tablet or capsule is then placed in the groove, and the relatively rigid sheet is sealed against the plastic foil with the foil side opposite to the direction in which the grooves were formed. As a result, the tablets or capsules are sealed within the groove between the plastic foil and the sheet. Preferably, the sheet is strong enough so that pressure can be applied to the groove by hand, thereby forming an opening in the sheet at the location of the groove, allowing the tablets or capsules to be removed from the blister pack. The tablets or capsules can then be removed through the opening.

[0142] It may be desirable that the kit provide memory aids, for example, in the form of a number next to each tablet or capsule, where this number corresponds to the day of the regimen on which the identified tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday...etc., Week 2, Monday, Tuesday...etc." Other variations of memory aids are also readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this.

[0143] Methods and compositions comprising a second activator, or administration of a second activator, are also envisioned herein.

[0144] Example The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the descriptions of the synthetic methods below, it should be understood that all proposed reaction conditions, including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures, can be selected to be standard conditions for the reaction unless otherwise noted. It is understood by those skilled in the art of organic synthesis that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions are obvious to those skilled in the art, and therefore alternative methods are shown. Starting materials for the examples are commercially available or readily prepared from known materials by standard methods.

[0145] It is assumed that at least some of the compounds identified as “intermediates” in this specification are compounds of this disclosure.

[0146] General procedure The compounds disclosed herein can be prepared by techniques well known in organic synthesis and familiar to those skilled in the art. For example, the compounds can be prepared by the chemical transformations described in the following examples. However, these may not be the only means of synthesizing or obtaining the desired compounds.

[0147] Abbreviation DOI = 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine 25D-NBOMe=2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethane-1-amine 2C-TFM=1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)propan-2-amine 25CN-NBOH=4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile LSD = (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindro[4,3-fg]quinoline-9-carboxamide = lysergic acid diethylamide Mescaline = 2-(3,4,5-trimethoxyphenyl)ethane-1-amine DMT = 2-(1H-indole-3-yl)-N,N-dimethylethane-1-amine = N,N-dimethyltryptamine 2C-B=2-(4-bromo-2,5-dimethoxyphenyl)ethane-1-amine 2C-E=2-(4-ethyl-2,5-dimethoxyphenyl)ethane-1-amine Psyrosine = 3-(2-(dimethylamino)ethyl)-1H-indole-4-ol = 4-hydroxy-N,N-dimethyltryptamine 5-MeO-DMT=2-(5-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine=5-methoxy-N,N-dimethyltryptamine

[0148] intermediate Preparation 1: Preparation of tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (intermediate 1) [ka]

[0149] Step 1: Preparation of tert-butyl(2,5-dimethoxyphenethyl)carbamate To a solution of 3-(2,5-dimethoxyphenyl)propanoic acid (10 g, 47.57 mmol, 1 equivalent) in toluene (150 mL), DPPA (15.71 g, 57.08 mmol, 12.37 mL, 1.2 equivalents) and TEA (9.63 g, 95.14 mmol, 13.24 mL, 2 equivalents) were added. The mixture was stirred at 80°C for 5 hours, then t-BuOH (17.63 g, 237.84 mmol, 22.75 mL, 5 equivalents) was added to the solution, and the reaction mixture was stirred at 80°C for 7 hours. At completion, the solvent was removed under vacuum. The residue was purified by silica gel chromatography (PE:EA100:1~10:1) to obtain tert-butyl(2,5-dimethoxyphenethyl)carbamate (7 g, 24.9 mmol, yield 52%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 6.81 - 6.77 (m, 1H), 6.76 - 6.71 (m, 2H), 4.73 - 4.60 (m, 1H), 3.80 - 3.73 (m, 6H), 3.40 - 3.29 (m, 2H), 2.84 - 2.74 (m, 2H), 1.44 (s, 9H).

[0150] Step 2: Preparation of tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (intermediate 1) To a solution of tert-butyl(2,5-dimethoxyphenethyl)carbamate (4 g, 14.22 mmol, 1 equivalent) in MeCN (50 mL), NBS (3.29 g, 18.48 mmol, 1.3 equivalents) was added at 20°C. The mixture was stirred at 20°C for 1 hour. At completion, the mixture was poured into a saturated aqueous solution of Na2S2O3 (5 mL) and extracted with EA (5 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1~8:1) to obtain tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (4.9 g, 13.60 mmol, yield 96%) as a brownish oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 7.05 - 7.02 (m, 1H), 6.76 - 6.71 (m, 1H), 4.62 (br s, 1H), 3.87 - 3.83 (m, 3H), 3.81 - 3.77 (m, 3H), 3.37 - 3.28 (m, 2H), 2.81 - 2.74 (m, 2H), 1.45 - 1.41 (m, 9H).

[0151] Preparation 2: Preparation of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (intermediate 2) [ka]

[0152] Step 1: Preparation of ethyl(E)-3-(4-bromo-2,5-dimethoxyphenyl)-2-methyl acrylate To a suspension of NaH (5.39 g, 134.66 mmol, 60% purity, 1.1 equivalents) in THF (300 mL), ethyl 2-diethoxyphosphorylpropanoate (32.08 g, 134.66 mmol, 29.43 mL, 1.1 equivalents) was added dropwise at 0°C. The resulting solution was stirred at 0°C for 30 minutes. Then, a solution of 4-bromo-2,5-dimethoxybenzaldehyde (30 g, 122.41 mmol, 1 equivalent) in THF (50 mL) was added by syringe. The reaction mixture was stirred at 25°C for 2 hours. At completion, the mixture was quenched with saturated NH4Cl aqueous solution (100 mL). The organic layer was separated, and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain ethyl(E)-3-(4-bromo-2,5-dimethoxyphenyl)-2-methyl acrylate (29 g, 88.10 mmol, yield 72%) as a white solid. 1 H NMR (400 MHz, DMSO -d6) δ ppm 10.29 (s, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 7.04 (s, 1H), 4.23 - 4.17 (m, 2H), 3.90 - 3.84 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 1.98 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H).

[0153] Step 2: Preparation of ethyl 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoate To a solution of ethyl(E)-3-(4-bromo-2,5-dimethoxyphenyl)-2-methyl acrylate (14 g, 42.53 mmol, 1 equivalent) in EtOH (140 mL) and THF (140 mL), PtO2 (2.80 g, 12.33 mmol, 0.29 equivalents) was added under N2. The suspension was degassed several times under vacuum and purged with H2. The mixture was stirred at 15°C under H2 (15 psi) for 1 hour. At completion, the reaction mixture was filtered, and the filtrate was concentrated to obtain ethyl 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoate (13 g, crude) as a yellow oil.

[0154] Step 3: Preparation of 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoic acid A mixture of ethyl 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoate (7 g, 21.14 mmol, 1 equivalent) and LiOH·H2O (1.24 g, 29.59 mmol, 1.4 equivalents) in THF (25 mL), H2O (25 mL), and EtOH (25 mL) was stirred at 25°C for 12 hours. At completion, the reaction mixture was quenched by adding aqueous HCl (1 M) until the pH was 6-7, then the mixture was diluted with H2O (100 mL) and extracted with siRNA (200 mL x 2). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoic acid (6 g, 19.79 mmol, yield 94%) as a white solid.

[0155] Step 4: Preparation of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (intermediate 2) To a solution of 3-(4-bromo-2,5-dimethoxyphenyl)-2-methylpropanoic acid (15 g, 49.48 mmol, 1 equivalent) in toluene (150 mL), DPPA (14.98 g, 54.43 mmol, 11.79 mL, 1.1 equivalents) and TEA (15.02 g, 148.44 mmol, 20.66 mL, 3 equivalents) were added. The mixture was stirred at 15°C for 1 hour, and then phenylmethanol (10.70 g, 98.96 mmol, 10.29 mL, 2 equivalents) was added dropwise. The resulting mixture was stirred at 80°C for 12 hours. At completion, the mixture was quenched with H2O (100 mL). The layers were separated, and the aqueous phase was extracted with SiO2 (200 mL x 3). The combined organic layers were washed with brine (200 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (18.7 g, crude product) as a white solid. 1 H NMR (400 MHz, DMSO - d6) δ ppm 7.35 - 7.24 (m, 5H), 7.14 (s, 1H), 6.93 (s, 1H), 4.51 - 4.49 (d, J = 5.6 Hz, 2H), 3.83 - 3.77 (m, 1H), 3.72 (s, 6H), 2.72 - 2.57 (m, 2H), 1.06 (t, J = 6.8 Hz, 3H).

[0156] Preparation 3: Preparation of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)butan-2-yl)carbamate (intermediate 3) [ka]

[0157] Step 1: Preparation of ethyl(E)-2-(4-bromo-2,5-dimethoxybenzylidene)butanoate To a suspension of NaH (1.80 g, 44.9 mmol, 60% purity, 1.1 equivalents) in THF (20 mL), ethyl 2-diethoxyphosphoryl butanoate (11.3 g, 44.9 mmol, 10.7 mL, 1.1 equivalents) was added dropwise. The resulting solution was stirred at 0°C for 30 minutes. Then, 4-bromo-2,5-dimethoxybenzaldehyde (10 g, 40.8 mmol, 1 equivalent) in THF (10 mL) was added. The reaction mixture was stirred at 15°C for 12 hours. At completion, the mixture was quenched with saturated NH4Cl aqueous solution (40 mL). The layers were separated, and the aqueous phase was extracted with DCM (40 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution (20 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain ethyl(E)-2-(4-bromo-2,5-dimethoxybenzylidene)butanoate (10 g, 29.14 mmol, yield 71%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.70 - 7.64 (m, 1H), 7.10 (s, 1H), 6.86 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.87 - 3.84 (m, 3H), 3.83 - 3.80 (m, 3H), 2.48 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H).

[0158] Step 2: Preparation of ethyl 2-(2,5-dimethoxybenzyl)butanoate To a solution of ethyl(E)-2-(4-bromo-2,5-dimethoxybenzylidene)butanoate (7.00 g, 20.40 mmol, 1 equivalent) in MeOH (70 mL), Pd / C (1.40 g, 140 mmol, 10% Pd, 6.9 equivalents) was added under N2. The suspension was degassed several times under vacuum and purged with H2. The mixture was stirred at 30°C under H2 (15 psi) for 120 hours. At completion, the reaction mixture was filtered, and the filtrate was concentrated to obtain ethyl 2-(2,5-dimethoxybenzyl)butanoate (5.98 g, crude) as a yellow oily substance.1 H NMR (400 MHz, chloroform-d) δ 6.81 - 6.68 (m, 3H), 4.08 (q, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.82 (d, J = 7.2 Hz, 2H), 2.72 - 2.62 (m, 1H), 1.72 - 1.50 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.97 - 0.88 (m, 3H).

[0159] Step 3: Preparation of 2-(2,5-dimethoxybenzyl)butanoic acid To a solution of ethyl 2-(2,5-dimethoxybenzyl)butanoate (5.98 g, 22.45 mmol, 1 equivalent) in H2O (20 mL), THF (20 mL), and EtOH (20 mL), LiOH·H2O (2.83 g, 67.4 mmol, 3 equivalents) was added at 0°C. The mixture was then stirred at 50°C for 10 hours. At completion, the pH of the mixture was adjusted to 3 with 1 M aqueous HCl (10 mL). The residue was washed with water (50 mL x 2). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (60 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 2-(2,5-dimethoxybenzyl)butanoic acid (4.5 g, 18.9 mmol, yield 84%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 6.80 - 6.69 (m, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 2.94 - 2.86 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.65 (m, 1H), 1.73 - 1.52 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).

[0160] Step 4: Preparation of benzyl(1-(2,5-dimethoxyphenyl)butan-2-yl)carbamate To a solution of 2-(2,5-dimethoxybenzyl)butanoic acid (2.5 g, 10.49 mmol, 1 equivalent) in toluene (10 mL), DPPA (2.89 g, 10.49 mmol, 2.27 mL, 1 equivalent) and TEA (3.19 g, 31.48 mmol, 4.38 mL, 3 equivalents) were added. The mixture was stirred at 15°C for 1 hour. Then phenylmethanol (3.40 g, 31.48 mmol, 3.27 mL, 3 equivalents) was added. The mixture was then stirred at 80°C for 10 hours. At completion, the mixture was poured into H₂O (50 mL). The layers were separated, and the aqueous phase was extracted with SiO₂ (50 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution (50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain benzyl(1-(2,5-dimethoxyphenyl)butan-2-yl)carbamate (1.8 g, crude product) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.40 - 7.28 (m, 5H), 6.82 - 6.64 (m, 3H), 5.04 (s, 2H), 3.87 - 3.79 (m, 1H), 3.78 - 3.72 (m, 7H), 2.76 (br d, J = 6.8 Hz, 2H), 1.68 - 1.52 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).

[0161] Step 5: Preparation of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)butan-2-yl)carbamate (intermediate 3) To a solution of benzyl(1-(2,5-dimethoxyphenyl)butan-2-yl)carbamate (1.7 g, 4.95 mmol, 1 equivalent) in MeCN (20 mL), NBS (1.76 g, 9.90 mmol, 2 equivalents) was added. The mixture was stirred at 25°C for 10 hours. At completion, the residue was added to water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain benzyl(1-(4-bromo-2,5-dimethoxyphenyl)butan-2-yl)carbamate (3 g, crude product) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.41 - 7.28 (m, 5H), 7.03 (s, 1H), 6.74 (s, 1H), 5.11 - 4.97 (m, 2H), 4.79 (br d, J = 8.4 Hz, 1H), 3.78 (br d, J = 12.8 Hz, 7H), 2.98 (s, 3H), 2.78 (s, 2H), 1.66 - 1.41 (m, 3H), 0.97 (t, J = 7.2 Hz, 3H). [Examples]

[0162] (Example 1) Preparation of 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-amine (2) [ka]

[0163] Step 1: Preparation of 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-one A mixture of 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-one (4 g, 14.65 mmol, 1 equivalent), penta-4-enylboronic acid (2.00 g, 17.57 mmol, 1.2 equivalents), Pd(dppf)Cl2 (536 mg, 732.3 μmol, 0.05 equivalents), and K3PO4 (9.33 g, 43.94 mmol, 3 equivalents) in toluene (60 mL) was stirred and heated at 110 °C for 12 hours. Upon completion, the mixture was cooled, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 40:1 to 20:1) to obtain 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-one (1.9 g, 7.24 mmol, yield 50%) as a yellow oily substance.

[0164] Step 2: Preparation of 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-amine A mixture of 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-one (1.5 g, 5.72 mmol, 1 equivalent), NH4OAc (2.20 g, 28.59 mmol, 5 equivalents), and NaBH3CN (719 mg, 11.44 mmol, 2 equivalents) in MeOH (20 mL) was stirred at 15°C for 12 hours. Upon completion, the solvent was removed. The residue was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (20 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-amine (1.9 g, crude) as a yellow oil. LCMS R T =2.257 minutes, MS calculated value: 263.19, [M+H] + =264.2).

[0165] Step 3: Preparation of tert-butyl(1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-yl)carbamate A solution of 1-(2,5-dimethoxy-4-(penta-4-en-1-yl)propan-2-amine (1.3 g, 4.94 mmol, 1 equivalent), Boc2O (1.29 g, 5.92 mmol, 1.36 mL, 1.2 equivalents), and TEA (999 mg, 9.87 mmol, 1.37 mL, 2 equivalents) in DCM (15 mL) was stirred at 20°C for 2 hours. At completion, the solvent was removed. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1) to obtain tert-butyl(1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-yl)carbamate (1 g, 2.75 mmol, yield 56%) as a yellow solid.

[0166] Step 4: Preparation of tert-butyl(1-(2,5-dimethoxy-4-(4-oxobutyl)phenyl)propan-2-yl)carbamate A mixture of tert-butyl(1-(2,5-dimethoxy-4-(penta-4-en-1-yl)phenyl)propan-2-yl)carbamate (1.5 g, 4.13 mmol, 1 equivalent) and NaIO4 (4.41 g, 20.63 mmol, 1.14 mL, 5 equivalents) in THF (30 mL) and H2O (10 mL) was cooled to 0°C. Then OsO4 (419.65 mg, 1.65 mmol, 85.64 µl, 0.4 equivalents) was added. The mixture was stirred at 20°C for 1 hour. Upon completion, the mixture was poured into EA (30 mL), washed with saturated Na2SO3 aqueous solution (50 mL) and brine, dehydrated with Na2SO4, filtered, and concentrated to obtain tert-butyl(1-(2,5-dimethoxy-4-(4-oxobutyl)phenyl)propan-2-yl)carbamate (1.4 g, crude product) as a yellow oily substance. LCMS R T =1.136 min, MS calculated value: 365.22, [M+H-100] + =266.3).

[0167] Step 5: Preparation of tert-butyl(1-(4-(4-hydroxybutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate A solution of tert-butyl(1-(2,5-dimethoxy-4-(4-oxobutyl)phenyl)propan-2-yl) carbamate (2.7 g, 7.39 mmol, 1 equivalent) in THF (20 mL) was cooled to -10°C. Then LiAlH4 (561 mg, 14.78 mmol, 2 equivalents) was added. The mixture was stirred at -10°C for 0.5 hours. At completion, the mixture was quenched with H2O (0.3 mL) and 30% NaOH aqueous solution (0.3 mL). The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1~3:1) to obtain tert-butyl(1-(4-(4-hydroxybutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (1.2 g, 2.35 mmol, yield 32%, purity 72%) as a yellow solid. LCMS R T =1.071 min, MS calculated value: 367.24, [M+H-100] + =268.3).

[0168] Step 6: Preparation of tert-butyl(1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate A solution of tert-butyl(1-(4-(4-hydroxybutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (1.2 g, 3.27 mmol, 1 equivalent) in DCM (15 mL) was cooled to 0°C. Then DAST (1.05 g, 6.53 mmol, 2 equivalents) was added. The mixture was stirred at 0°C for 0.5 hours. At completion, the mixture was poured into a saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 60%~80%, 10 min) to obtain tert-butyl(1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (100 mg, 270.66 μmol, yield 8%) as a white solid. 1H NMR (400 MHz, Chloroform-d6) δ ppm 6.68 - 6.63 (m, 2H), 4.81 - 4.69 (m, 1H), 4.56 - 4.51 (m, 1H), 4.42 (t, J = 5.6 Hz, 1H), 3.89 (br s, 1H), 3.81 - 3.76 (m, 6H), 2.79 - 2.67 (m, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.82 - 1.65 (m, 4H), 1.43 - 1.35 (m, 9H), 1.17 - 1.11 (m, 3H).

[0169] Step 7: Preparation of 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-amine(2) A solution of tert-butyl(1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (160 mg, 433 μmol, 1 equivalent) in DCM (1 mL) and TFA (1 mL) was stirred at 20°C for 1 hour. Upon completion, the solvent was removed. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 17%~43%, 7 min) to obtain 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)propan-2-amine (100 mg, 371.26 μmol, yield 86%, purity 100%, HCl salt) as a white solid. LCMS R T = 1.913 min, MS calculated: 269.18, [M+H] += 270.1; 1H NMR (400 MHz, chloroform-d6, HCl salt) δ ppm 8.17 (br s, 3H), 6.68 (d, J = 4.0 Hz, 2H), 4.53 (t, J = 6.0 Hz, 1H), 4.46 - 4.35 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.67 (s, 1H), 3.06 (dd, J = 6.4, 13.2 Hz, 1H), 2.87 (dd, J = 7.6, 13.2 Hz, 1H), 2.62 (t, J = 7.2 Hz, 2H), 1.82 - 1.63 (m, 4H), 1.36 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.01, 150.74, 129.25, 122.50, 114.00, 113.09, 84.51, 82.91, 55.85, 46.94, 34.81, 29.76, 29.57, 29.18, 25.26, 25.21, 17.87.

[0170] (Example 2) Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine (3) [ka]

[0171] Step 1: Preparation of 4-(butylthio)-2,5-dimethoxybenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent) and butane-1-thiol (1.44 g, 15.91 mmol, 1.70 mL, 1.3 equivalents) in toluene (30 mL), N2-based DIEA (4.75 g, 36.72 mmol, 6.40 mL, 3 equivalents), DPPF (679 mg, 1.22 mmol, 0.1 equivalent), and Pd2(dba)3 (1.12 g, 1.22 mmol, 0.1 equivalent) were added. The mixture was stirred and heated at 110°C for 3 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 30:1) to obtain 4-(butylthio)-2,5-dimethoxybenzaldehyde (3 g, 11.80 mmol, yield 96%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.38 - 10.34 (m, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 1.78 - 1.71 (m, 2H), 1.56 - 1.50 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0172] Step 2: Preparation of (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 11.80 mmol, 1 equivalent) was dissolved in nitroethane (17.71 g, 235.9 mmol, 16.86 mL, 20 equivalents), to which NH4OAc (2.73 g, 35.39 mmol, 3 equivalents) was added. The mixture was stirred and heated at 110°C for 3 hours. At completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 30:1) to obtain (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (2.6 g, 8.35 mmol, yield 71%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.28 (s, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 3.87 (d, J = 1.2 Hz, 6H), 2.98 - 2.94 (m, 2H), 2.43 (d, J = 1.2 Hz, 3H), 1.74 - 1.69 (m, 2H), 1.55 - 1.49 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[0173] Step 3: Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine (3) (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (2.6 g, 8.35 mmol, 1 equivalent) was dissolved in THF (40 mL) and LiAlH4 (1.27 g, 33.40 mmol, 4 equivalents) was added all at once at 0°C under N2. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 4.5 hours. At completion, the reaction mixture was quenched at 0°C by dropwise addition of H2O (1.5 mL) and 30% NaOH aqueous solution (1.5 mL), then the solid was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%~45%, 20 min) to obtain 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine (380 mg, 1.19 mmol, yield 14%, purity 100%, HCl salt) as a white solid. LCMS R T = 2.069 minutes, MS calculated: 283.16, [M+H] += 284.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.26 (br s, 3H), 6.86 (s, 1H), 6.80 (s, 1H), 3.75 (d, J = 4.4 Hz, 6H), 3.41 - 3.34 (m, 1H), 2.96 - 2.87 (m, 3H), 2.71 (dd, J = 8.4, 13.3 Hz, 1H), 1.54 (m, 2H), 1.40 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.52, 150.28, 123.82, 122.28, 114.29, 111.12, 56.21, 56.02, 46.82, 34.55, 30.46, 30.27, 21.37, 17.80, 13.49.

[0174] (Example 3) Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine (4) and its enantiomers (4ent1 and 4ent2) Preparation of racemic mixture (4) [ka]

[0175] Step 1: Preparation of 4-hexyl-2,5-dimethoxybenzaldehyde A mixture of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent), hexylboronic acid (1.59 g, 12.24 mmol, 1 equivalent), Pd(dppf)Cl2 (447 mg, 612 μmol, 0.05 equivalent), and K3PO4 (5.20 g, 24.48 mmol, 3 equivalents) in toluene (30 mL) was stirred at 110 °C for 12 hours. Upon completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 4-hexyl-2,5-dimethoxybenzaldehyde (2.6 g, 10.39 mmol, yield 85%) as a yellow oil.

[0176] Step 2: Preparation of (E)-1-hexyl-2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)benzene A mixture of 4-hexyl-2,5-dimethoxybenzaldehyde (2.6 g, 10.39 mmol, 1 equivalent) and NH4OAc (1.60 g, 20.78 mmol, 2 equivalents) in nitroethane (20 mL) was stirred and heated at 115 °C for 1 hour. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1~5:1) to obtain (E)-1-hexyl-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (2.4 g, 7.81 mmol, yield 75%) as a yellow oil.

[0177] Step 3: Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine (4) A solution of (E)-1-hexyl-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (2.4 g, 7.81 mmol, 1 equivalent) in THF (40 mL) was cooled to 0°C. Then LiAlH4 (1.19 g, 31.23 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (2 mL) was added. Then 2 mL of 30% NaOH aqueous solution was added. The mixture was stirred to obtain a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×70mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%~55%, 20 min) to obtain 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine (450 mg, 1.42 mmol, yield 18%, HCl salt) as a white solid. LCMS R T = 2.310 min, MS calculated: 279.42, [M+H] + = 280.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.12 (br s, 3H), 6.79 (s, 2H), 3.73 (s, 6H), 3.50 - 3.35 (m, 1H), 2.91 (dd, J = 5.6, 13.2 Hz, 1H), 2.69 (dd, J = 8.4, 13.2 Hz, 1H), 2.54 (s, 2H), 1.62 - 1.43 (m, 2H), 1.28 (s, 6H), 1.12 (d, J = 6.4 Hz, 3H), 0.93 - 0.80 (m, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.96, 150.71, 129.76, 122.29, 113.97, 113.01, 55.85, 55.84, 46.90, 34.75, 31.08, 29.62, 29.53, 28.60, 22.04, 17.80, 13.92. Preparation of enantiomers (4ent1 and 4ent2) [ka]

[0178] Step 1: Preparation of benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl)carbamate To a solution of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (0.3 g, 735 μmol, 1 equivalent) in toluene (3 mL), hexylboronic acid (143 mg, 1.10 mmol, 1.5 equivalents), K3PO4 (468 mg, 2.20 mmol, 3 equivalents), and Pd(dppf)Cl2 (53.8 mg, 73.5 μmol, 0.1 equivalent) were added. The mixture was stirred and heated at 120 °C for 12 hours. Upon completion, the reaction was cooled, brine (30 mL) and DCM (30 mL) were added, the mixture was filtered, and the filtrate was extracted with DCM (30 mL). The organic phase was dehydrated with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA=5 / 1) to obtain benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl)carbamate (0.2 g, 459 μmol, yield 63%, purity 95%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.42 - 7.22 (m, 5H), 7.15 (d, J =8.4 Hz, 1H), 6.73 (s, 2H), 4.96 (d, J =5.2 Hz, 2H), 3.85 - 3.75 (m, 1H), 3.74 - 3.59 (m, 6H), 2.74 - 2.58 (m, 2H), 1.49 (d, J =7.6 Hz, 2H), 1.27 (s, 6H), 1.04 (d, J =6.4 Hz, 2H), 1.01 - 0.97 (m, 1H), 0.90 - 0.82 (m, 3H).

[0179] Step 2: Separation of benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl) carbamate enantiomer Dispense racemic benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl) carbamate (0.2g, 483.62μmol, 1 equivalent) into SFC (column: DAIEL CHIRALPAK) The isomer was separated using an IG (250 mm × 30 mm, 10 μm); mobile phase: A: CO2, B: 0.1% NH3H2O ​​in MeOH; B% = 20%, 10 min). The first isomer to elute (Cbz-ent1, RT = 0.997 min) was obtained as benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl) carbamate (90 mg, 217.6 μmol, yield 45%) as a white solid, and the second isomer to elute (Cbz-ent2, RT = 1.061 min) was obtained as benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl) carbamate (80 mg, 193.5 μmol, yield 40%) as a white solid. Retention times were determined using the following chiral analysis method: Column: Chiralpak IG-3, 50 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: MeOH (0.05% IPAm, volume / volt); Gradient: (time (min) / A% / B%), (0.0 / 95 / 5, 0.2 / 95 / 5, 1.2 / 50 / 50, 2.2 / 50 / 50, 2.6 / 95 / 5, 3.0 / 95 / 5); Flow rate: 3.4 mL / min; Column temperature: 35°C; ABPR: 1800 psi. Cbz-ent1, RT = 0.997 min (assigned as the R isomer). 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.38 - 7.29 (m, 5H), 6.67 - 6.61 (m, 1H), 5.05 (s, 2H), 3.95 (s, 1H), 3.84 - 3.68 (m, 6H), 2.83 - 2.65 (m, 2H), 2.61 - 2.49 (m, 2H), 1.62 - 1.56 (m, 2H), 1.39 - 1.29 (m, 6H), 1.18 (d, J = 6.4 Hz, 3H), 0.95 - 0.86 (m, 3H); Cbz-ent2, RT=1.061 min (assigned as the S isomer), 1H NMR (400 MHz, Chloroform-d) δ ppm 7.40 - 7.28 (m, 5H), 6.67 - 6.62 (m, 1H), 5.10 - 5.03 (m, 2H), 4.01 - 3.89 (m, 1H), 4.01 - 3.89 (m, 1H), 3.80 - 3.72 (m, 6H), 2.85 - 2.65 (m, 2H), 2.61 - 2.53 (m, 2H), 1.62 - 1.55 (m, 2H), 1.38 - 1.28 (m, 6H), 1.18 (d, J =6.4 Hz, 3H), 0.93 - 0.87 (m, 3H).

[0180] Step 3: Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine, enantiomer 1 (4ent1) To a solution of the rapidly eluting isomer of benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl)carbamate (Cbz-ent1, 50 mg, 120.9 μmol, 1 equivalent) in MeOH (10 mL) and NH3·H2O (1 mL), Pd(OH)2 (34 mg, 241.8 μmol, 2 equivalents) was added under H2 (15 psi). The mixture was stirred at 20°C for 2 hours. At completion, the reaction was filtered, the filter cake was washed with MeOH (50 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%~70%, 8 min) to obtain 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine enantiomer 1 (4ent1, assigned as the R isomer, 25 mg, 89.47 μmol, yield 74%, purity 100%) as a white solid. The chiral HPLC retention time was determined using the following chiral analysis method: column: Chiralpak IG-3, 100×4.6mm ID, 3μm; mobile phase: A: hexane, B: iPrOH (0.05% IPAm, volume / volume); B%=5%; flow rate: 0.5 mL / min; column temperature: 30°C. Chiral HPLC RT=6.055min; LCMS (ESI+): m / z 280.2, [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.74 - 6.66 (m, 2H), 3.69 (d, J =3.2 Hz, 6H), 3.05 - 2.92 (m, 1H), 2.49 - 2.41 (m, 4H), 1.48 (d, J =7.6 Hz, 2H), 1.27 (d, J =3.2 Hz, 6H), 0.92 (d, J =6.4 Hz, 3H), 0.88 - 0.81 (m, 3H).

[0181] Step 4: Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine, enantiomer 2 (4ent2) To a solution of the slow-eluting isomer of benzyl(1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-yl)carbamate (Cbz-ent2, 50 mg, 120.9 μmol, 1 equivalent) in MeOH (10 mL) and NH3·H2O (1 mL), Pd(OH)2 (34 mg, 241.8 μmol, 2 equivalents) was added under H2 (15 psi), and the mixture was stirred at 20°C for 2 hours. Upon completion, the reaction was filtered, the filter cake was washed with MeOH (50 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%~80%, 8 min) to obtain 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine enantiomer 2 (4ent2, which was assigned as the S isomer, 10 mg, 35.8 μmol, yield 30%, purity 100%) as a white solid. The chiral HPLC retention time was determined using the following chiral analysis method: Column: Chiralpak IG-3, 100 × 4.6 mm ID, 3 μm; Mobile phase: A: Hexane, B: iPrOH (0.05% IPAm, volume / volt); B% = 5%; Flow rate: 0.5 mL / min; Column temperature: 30°C. Chiral HPLC RT = 6.498 min; LC-MS (ESI+): m / z 280.2, [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.71 (d, J = 9.2 Hz, 2H), 3.70 (d, J =3.2 Hz, 6H), 2.99 (m, 1H), 2.47 (s, 4H), 1.49 (d, J = 6.8 Hz, 2H), 1.28 (d, J =3.2 Hz, 6H), 0.93 (d, J = 6.4 Hz, 3H), 0.89 - 0.82 (m, 3H).

[0182] (Example 4) Preparation of 1-(4-heptyl-2,5-dimethoxyphenyl)propan-2-amine (5) [ka]

[0183] Step 1: Preparation of 4-heptyl-2,5-dimethoxybenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (1.2 g, 4.90 mmol, 1.0 equivalent) in toluene (20 mL), heptylboronic acid (846.2 mg, 5.88 mmol, 1.2 equivalents), K3PO4 (3.12 g, 14.69 mmol, 3 equivalents), and Pd(dppf)Cl2 (179.14 mg, 244.83 μmol, 0.05 equivalents) were added. The mixture was stirred at 110°C for 14 hours. At completion, the reaction mixture was filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain 4-heptyl-2,5-dimethoxybenzaldehyde (1.2 g, 4.54 mmol, yield 93%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.41 (s, 1 H), 7.27 - 7.29 (m, 1 H), 6.80 (s, 1 H), 3.90 (s, 3 H), 3.83 (s, 3 H), 2.60 - 2.68 (m, 2 H), 1.54 - 1.63 (m, 2 H), 1.25 - 1.38 (m, 8 H), 0.89 (t, J = 6.8 Hz, 3 H).

[0184] Step 2: Preparation of (E)-1-heptyl-2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)benzene To a mixture of 4-heptyl-2,5-dimethoxybenzaldehyde (1.2 g, 4.54 mmol, 1.0 equivalent) and NH4OAc (700 mg, 9.08 mmol, 2.0 equivalents), nitroethane (6.81 g, 90.79 mmol, 6.49 mL, 20.0 equivalents) was added in one step under N2 conditions at 20°C. The mixture was stirred at 115°C for 2 hours. At completion, the solvent was removed. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1) to obtain (E)-1-heptyl-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (1.05 g, 3.27 mmol, yield 72%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.30 (s, 1 H), 6.77 (d, J = 7.6 Hz, 2 H), 3.85 (s, 3 H), 3.80 (s, 3 H), 2.60 - 2.67 (m, 2 H), 2.43 (s, 3 H), 1.57 - 1.63 (m, 2 H), 1.27 - 1.38 (m, 9 H), 0.90 (t, J = 6.8 Hz, 3 H).

[0185] Step 3: Preparation of 1-(4-heptyl-2,5-dimethoxyphenyl)propan-2-amine (5) (E)-1-heptyl-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (1.05 g, 3.27 mmol, 1 equivalent) was added in a mixture of THF (20 mL) to LiAlH4 (495.91 mg, 13.07 mmol, 4 equivalents) in a single addition at 0°C under N2. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 3.5 hours. At completion, the mixture was cooled to 0°C. The reaction mixture was quenched at 0°C by sequentially adding H2O (0.5 mL) and 30% NaOH aqueous solution (0.5 mL) dropwise, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%, 10 min) to obtain 1-(4-heptyl-2,5-dimethoxyphenyl)propan-2-amine (380 mg, 1.15 mmol, yield 35%, purity 100%, HCl salt) as a white solid. LCMS R T = 2.420 min, MS calculated: 293.24, [M+H] + = 294.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.15 (br s, 3H), 6.78 (s, 2H), 3.72 (d, J = 1.2 Hz, 6H), 3.41 - 3.36 (m, 1H), 2.91 (dd, J = 5.6, 13.2 Hz, 1H), 2.68 (dd, J = 8.8, 13.2 Hz, 1H), 2.53 - 2.50 (m, 2H), 1.54 - 1.46 (m, 2H), 1.31 - 1.22 (m, 8H), 1.11 (d, J = 6.4 Hz, 3H), 0.88 - 0.83 (m, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.96, 150.70, 129.75, 122.31, 113.97, 112.99, 55.84, 55.82, 46.91, 34.75, 31.24, 29.62, 29.58, 28.91, 28.51, 22.05, 17.79, 13.92.

[0186] (Example 5) Preparation of 2-(2,5-dimethoxy-4-pentylphenyl)ethaneamine (6) [ka]

[0187] Step 1: Preparation of 1,4-dimethoxy-2-[(E)-2-nitrovinyl]-5-pentylbenzene A solution of 2,5-dimethoxy-4-pentyl-benzaldehyde (3 g, 12.70 mmol, 1 equivalent) and NH4OAc (1.96 g, 25.40 mmol, 2 equivalents) in nitromethane (13.95 g, 228.60 mmol, 12.35 mL, 18 equivalents) was heated and stirred at 115°C for 0.5 hours. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain 1,4-dimethoxy-2-[(E)-2-nitrovinyl]-5-pentylbenzene (2.89 g, 10.35 mmol, yield 82%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.145 (d, J = 13.6 Hz, 1 H), 7.866 (d, J = 13.6 Hz, 1 H), 6.856 (s, 1 H), 6.778 (s, 1 H), 3.917 (s, 3 H), 3.824 (s, 3 H), 2.601 - 2.672 (m, 2 H), 1.534 - 1.638 (m, 2 H), 1.298 - 1.405 (m, 4 H), 0.860 - 0.966 (m, 3 H).

[0188] Step 2: Preparation of 2-(2,5-dimethoxy-4-pentylphenyl)ethaneamine (6) A solution of 1,4-dimethoxy-2-[(E)-2-nitrovinyl]-5-pentylbenzene (2.89 g, 10.35 mmol, 1 equivalent) in THF (40 mL) was cooled to 0°C. Then LiAlH4 (1.57 g, 41.3 mmol, 4 equivalents) was added. The mixture was stirred at 60°C for 5 hours. At the end of this time, the mixture was cooled to 0°C. Then H2O (1.6 mL) was added dropwise while stirring, followed by 30% NaOH aqueous solution (1.6 mL). The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%, 10 min) to obtain 2-(2,5-dimethoxy-4-pentylphenyl)ethaneamine (1.5g, 5.21 mmol, yield 50%, purity 100%, HCl) as a white solid. LCMS R T = 2.154 min, MS calculated: 251.19, [M+H] + = 252.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.11 (br s, 3H), 6.78 (d, J = 4.4 Hz, 2H), 3.73 (d, J = 2.8 Hz, 6H), 2.94 (dd, J = 5.2, 8.4 Hz, 2H), 2.87 - 2.79 (m, 2H), 2.53 - 2.50 (m, 2H), 1.56 - 1.45 (m, 2H), 1.34 - 1.23 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.81, 150.77, 129.66, 122.84, 113.33, 112.99, 55.85, 38.65, 31.16, 29.58, 29.29, 27.92, 21.94, 13.90.

[0189] (Example 6) Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (7) [ka]

[0190] Step 1: Preparation of 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-enyl]-5-pentylbenzene A mixture of 2,5-dimethoxy-4-pentyl-benzaldehyde (1 g, 4.23 mmol, 1 equivalent) and NH4OAc (652.37 mg, 8.46 mmol, 2 equivalents) in 1-nitropropane (6.79 g, 76.17 mmol, 6.80 mL, 18 equivalents) was stirred and heated at 115°C for 5 hours. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-enyl]-5-pentylbenzene (830 mg, 2.70 mmol, yield 64%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.26 (s, 1 H), 6.79 (s, 1 H), 6.757 (s, 1 H), 3.83 - 3.85 (m, 3 H), 3.79 - 3.81 (m, 3 H), 2.869 (d, J = 7.2 Hz, 2 H), 2.60 - 2.66 (m, 2 H), 1.58 - 1.62 (m, 2 H), 1.34 - 1.38 (m, 4 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.92 (t, J = 6.8 Hz, 4 H).

[0191] Step 2: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (7) A solution of 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-enyl]-5-pentylbenzene (830 mg, 2.70 mmol, 1 equivalent) in THF (20 mL) was cooled to 0°C. Then LiAlH4 (409.89 mg, 10.80 mmol, 4 equivalents) was added. The mixture was stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.6 mL) was added. Then 30% NaOH (0.6 mL) was added. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80×40mm×3μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 22%~50%, 7 min) to obtain 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (350 mg, 1.07 mmol, yield 40%, purity 96.8%, HCl) as a white solid. LCMS R T = 2.320 min, MS calculated: 279.42, [M+H] + =280.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.06 - 7.90 (m, 3H), 6.82 (s, 1H), 6.78 (s, 1H), 3.77 - 3.69 (m, 6H), 3.28 - 3.20 (m, 1H), 2.80 (d, J = 6.4 Hz, 2H), 2.54 - 2.51 (m, 2H), 1.55 - 1.46 (m, 4H), 1.35 - 1.25 (m, 4H), 0.89 (td, J = 7.2, 18.4 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.00, 150.71, 129.77, 122.17, 114.06, 112.99, 55.84, 55.81, 52.19, 32.58, 31.16, 29.57, 29.22, 24.73, 21.91, 13.87, 9.40.

[0192] (Example 7) Preparation of 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine (8) [ka]

[0193] Step 1: Preparation of 3,5-dimethoxy-4-pentylbenzaldehyde A mixture of 4-bromo-3,5-dimethoxybenzaldehyde (6 g, 24.48 mmol, 1 equivalent), K3PO4.H2O (5.64 g, 24.48 mmol, 1 equivalent), pentylboronic acid (4.26 g, 36.72 mmol, 1.5 equivalents), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (2.01 g, 4.90 mmol, 0.2 equivalents), and Pd(OAc)2 (550 mg, 2.45 mmol, 0.1 equivalents) in toluene (70 mL) was stirred and heated at 105°C under N2 for 2 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 3,5-dimethoxy-4-pentylbenzaldehyde (5.6 g, 23.70 mmol, 97% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 9.91 (s, 1 H), 6.96 - 7.12 (m, 2 H), 3.89 (s, 6 H), 2.62 - 2.74 (m, 2 H), 1.48 (m, 2 H), 1.29 - 1.38 (m, 4 H), 0.90 (t, J = 6.8 Hz, 3 H).

[0194] Step 2: Preparation of (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene A mixture of 3,5-dimethoxy-4-pentylbenzaldehyde (3 g, 12.70 mmol, 1 equivalent) and NH4OAc (1.96 g, 25.39 mmol, 2 equivalents) in CH3NO2 (20 mL) was then stirred at 115°C for 2 hours. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 50:1 to 0:1) to obtain (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene (1.2 g, 4.30 mmol, yield 34%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 7.98 (d, J = 13.6 Hz, 1 H), 7.59 (d, J = 13.6 Hz, 1 H), 6.69 (s, 2 H), 3.86 (s, 6 H), 2.63 - 2.68 (m, 2 H), 1.44 - 1.49 (m, 2 H), 1.30 - 1.36 (m, 4 H), 0.88 - 0.92 (m, 3 H).

[0195] Step 3: Preparation of 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine (8) To a solution of (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene (1.2 g, 4.30 mmol, 1 equivalent) in THF (15 mL), LiAlH4 (652 mg, 17.18 mmol, 4 equivalents) was added over 10 minutes at 0°C. The resulting mixture was stirred at 60°C for 4 hours. At completion, the mixture was cooled to 0°C. Then, H2O (0.6 mL) was added dropwise while stirring, followed by 0.6 mL of 30% NaOH aqueous solution. The mixture was stirred to form a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~55%, 10 min) to obtain 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine (350 mg, 1.17 mmol, yield 27%, purity 96.04%, HCl) as a white solid. LCMS R T = 2.214 min, MS calculated: 251.19, [M+H]+ = 252.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.08 (br s, 3H), 6.51 (s, 2H), 3.76 (s, 5H), 3.11 - 2.98 (m, 2H), 2.91 - 2.79 (m, 2H), 2.49 - 2.46 (m, 2H), 1.41 - 1.20 (m, 6H), 0.85 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.70, 136.10, 116.26, 104.34, 55.59, 33.41, 31.30, 28.44, 22.19, 21.92, 13.87.

[0196] (Example 8) Preparation of 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (9) [ka]

[0197] Step 1: Preparation of 4-(butylthio)-3,5-dimethoxybenzaldehyde To a mixture of 4-bromo-3,5-dimethoxybenzaldehyde (5 g, 20.40 mmol, 1 equivalent) and butane-1-thiol (2.39 g, 26.52 mmol, 2.84 mL, 1.3 equivalents) in toluene (50 mL), DIEA (7.91 g, 61.21 mmol, 10.66 mL, 3 equivalents), DPPF (1.13 g, 2.04 mmol, 0.1 equivalent), and Pd2(dba)3 (1.87 g, 2.04 mmol, 0.1 equivalent) were added all at once under N2 conditions at 20°C. The mixture was stirred at 110°C for 2 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 4-(butylthio)-3,5-dimethoxybenzaldehyde (4 g, 15.73 mmol, yield 77%) as a brownish oily substance. 1¹H NMR (400 MHz, chloroform-d) δ ppm: 9.93 (s, 1H), 7.07 (s, 2H), 3.96 (s, 6H), 2.95 (t, J = 7.2 Hz, 2H), 1.54 - 1.46 (m, 2H), 1.45 - 1.35 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0198] Step 2: Preparation of (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan A mixture of 4-(butylthio)-3,5-dimethoxybenzaldehyde (3 g, 11.80 mmol, 1 equivalent) and NH4OAc (1.82 g, 23.6 mmol, 2 equivalents) in 1-nitroethane (14.40 g, 235.9 mmol, 12.74 mL, 20 equivalents) was stirred and heated at 115°C for 1 hour. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (2.6 g, 8.74 mmol, yield 74%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.97 (d, J = 13.6 Hz, 1H), 7.60 (d, J = 13.6 Hz, 1H), 6.71 (s, 2H), 3.94 (s, 6H), 2.92 (t, J = 7.2 Hz, 2H), 1.54 - 1.46 (m, 2H), 1.45 - 1.37 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0199] Step 3: Preparation of 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (9) A solution of (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (2.6 g, 8.74 mmol, 1 equivalent) in THF (50 mL) was cooled to 0°C. Then LiAlH4 (1.33 g, 34.97 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (1.33 mL) was added. Then 30% NaOH (1.33 mL) was added. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 80×40mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 20%~40%, 8 min) to obtain 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (1.4g, 5.20 mmol, yield 59%) as a white solid. LCMS R T = 1.834 min, MS calculated: 269.14, [M+H] + = 270.1; ¹H NMR (400 MHz, chloroform-d) δ ppm 6.4 (s, 2H), 3.85 (s, 6H), 2.97 (br s, 2H), 2.80 - 2.68 (m, 4H), 1.51 - 1.32 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 160.88, 141.62, 107.99, 104.55, 56.03, 43.11, 40.41, 33.73, 31.59, 21.76, 13.58.

[0200] (Example 9) Preparation of 2-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethaneamine (10) [ka]

[0201] Step 1: Preparation of 2-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (10) 2-(4-butylsulfanyl-3,5-dimethoxyphenyl)ethaneamine (900 mg, 3.34 mmol, 1 equivalent) and 2-methoxybenzaldehyde (363.87 mg, 2.67 mmol, 0.8 equivalents) were dissolved in 10 mL of DCE, to which 0.1 mL of AcOH was added. The mixture was stirred at 20°C for 1 hour. Then, 1.42 g, 6.68 mmol, 2 equivalents of NaBH(OAc)3 were added. The mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution, stirred, and then extracted with 2 x 10 mL of DCM. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%, 20 min) to obtain 2-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethaneamine (310 mg, 796 μmol, yield 24%, HCl) as a white solid. LCMS R T = 2.203 minutes, MS calculated: 389.20, [M+H] + = 390.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 9.21 (br s, 2H), 7.52 - 7.48 (m, 1H), 7.44 - 7.39 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.57 (s, 2H), 4.13 (s, 2H), 3.83 (s, 3H), 3.79 (s, 6H), 3.17 (d, J = 4.0 Hz, 2H), 3.04 - 2.97 (m, 2H), 2.69 (t, J = 6.8 Hz, 2H), 1.36 - 1.30 (m, 4H), 0.83 - 0.78 (m, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 160.51, 157.47, 139.06, 131.45, 130.77, 120.37, 119.74, 111.10, 107.92, 104.84, 55.99, 55.59, 47.27, 44.89, 32.68, 31.75, 31.18, 21.04, 13.50.

[0202] (Example 10) Preparation of 1-(3,5-dimethoxy-4-pentylphenyl)propan-2-amine (11) [ka]

[0203] Step 1: Preparation of 3,5-dimethoxy-4-pentylbenzaldehyde A mixture of 4-bromo-3,5-dimethoxybenzaldehyde (6 g, 24.48 mmol, 1 equivalent), K3PO4.H2O (5.64 g, 24.48 mmol, 1 equivalent), pentylboronic acid (4.26 g, 36.72 mmol, 1.5 equivalents), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (2.01 g, 4.90 mmol, 0.2 equivalents), and Pd(OAc)2 (549.66 mg, 2.45 mmol, 0.1 equivalents) in toluene (70 mL) was stirred and heated at 105°C under N2 for 2 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 3,5-dimethoxy-4-pentylbenzaldehyde (5.6 g, 23.7 mmol, 97% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 9.91 (s, 1 H), 6.96 - 7.12 (m, 2 H), 3.89 (s, 6 H), 2.62 - 2.74 (m, 2 H), 1.48 (m, 2 H), 1.29 - 1.38 (m, 4 H), 0.90 (t, J = 6.8 Hz, 3 H).

[0204] Step 2: Preparation of (E)-1,3-dimethoxy-5-(2-nitropropa-1-en-1-yl)-2-pentylbenzene 3,5-dimethoxy-4-pentylbenzaldehyde (3 g, 12.70 mmol, 1 equivalent) was dissolved in nitroethane (20 mL), to which NH4OAc (1.96 g, 25.39 mmol, 2 equivalents) was added. The mixture was stirred at 115°C for 2 hours. At completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 50:1 to 0:1) to obtain (E)-1,3-dimethoxy-5-(2-nitropropa-1-en-1-yl)-2-pentylbenzene (2 g, 6.82 mmol, yield 54%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.08 (s, 1 H), 6.60 (s, 2 H), 3.84 (s, 6 H), 2.62 - 2.67 (m, 2 H), 2.51 (s, 3 H), 1.44 - 1.51 (m, 2 H), 1.34 (d, J = 3.6 Hz, 4 H), 0.90 (t, J = 6.8 Hz, 3 H).

[0205] Step 3: Preparation of 1-(3,5-dimethoxy-4-pentylphenyl)propan-2-amine (11) (E)-1,3-dimethoxy-5-(2-nitropropane-1-en-1-yl)-2-pentylbenzene (2 g, 6.82 mmol, 1 equivalent) was mixed in THF (20 mL) and LiAlH4 (1.04 g, 27.27 mmol, 4 equivalents) was added all at once at 0°C under N2. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 4 hours. At completion, the mixture was cooled to 0°C and stirred. H2O (1 mL) was added dropwise. Then 30% NaOH aqueous solution (1 mL) was added dropwise. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%~45%, 20 min) to obtain 1-(3,5-dimethoxy-4-pentylphenyl)propan-2-amine (0.4 g, 1.25 mmol, yield 18%, purity 94.4%, HCl) as a white solid. 368 mg was subjected to LCMS R T =2.238 minutes, MS calculation: 265.20, [M+H] + =266.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.17 (br s, 3H), 6.49 (s, 2H), 3.75 (s, 6H), 3.49 - 3.36 (m, 1H), 2.96 (dd, J = 5.6, 13.2 Hz, 1H), 2.65 (dd, J = 8.4, 13.2 Hz, 1H), 2.50 - 2.45 (m, 2H), 1.41 - 1.22 (m, 6H), 1.16 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.65, 135.52, 116.29, 104.89, 55.58, 47.91, 40.56, 31.31, 28.42, 22.23, 21.92, 17.82, 13.86.

[0206] (Example 11) Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)propan-2-amine (12) [ka]

[0207] Step 1: Preparation of (E)-butyl(2,6-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan A mixture of 4-(butylthio)-3,5-dimethoxybenzaldehyde (1.5 g, 5.90 mmol, 1 equivalent) and NH4OAc (909.19 mg, 11.80 mmol, 2 equivalents) in nitroethane (8.85 g, 117.95 mmol, 8.43 mL, 20 equivalents) was stirred and heated at 115°C for 1 hour. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain (E)-butyl(2,6-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (1.5 g, 4.82 mmol, yield 82%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.05 (s, 1H), 6.61 (s, 2H), 3.92 (s, 6H), 2.89 (t, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.54 - 1.47 (m, 2H), 1.45 - 1.36 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H).

[0208] Step 2: Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)propan-2-amine(12) A solution of (E)-butyl(2,6-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (1.1 g, 3.53 mmol, 1 equivalent) in THF (30 mL) was cooled to 0°C. Then LiAlH4 (536 mg, 14.13 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.54 mL) was added. Then 30% NaOH (0.54 mL) was added. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%~55%, 10 min) to obtain 1-(4-(butylthio)-3,5-dimethoxyphenyl)propan-2-amine (340 mg, 1.20 mmol, yield 34%) as a white solid. LCMS R T = 1.929 min, MS calculated: 283.43, [M+H] + = 284.1; 1H NMR (400 MHz, chloroform-d) δ ppm 6.40 (s, 2H), 3.86 (s, 6H), 3.25 - 3.16 (m, 1H), 2.77 (t, J = 7.2 Hz, 2H), 2.70 (dd, J = 4.8, 13.2 Hz, 1H), 2.47 (dd, J = 8.4, 13.2 Hz, 1H), 1.50 - 1.43 (m, 2H), 1.43 - 1.34 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform -d6) δ ppm: 160.89, 141.55, 108.28, 105.03, 56.09, 48.28, 47.09, 33.79, 31.66, 23.55, 21.79, 13.60.

[0209] (Example 12) Preparation of 2-(2,5-dimethoxy-4-pentylphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (13) [ka]

[0210] Step 1: Preparation of 2-(2,5-dimethoxy-4-pentylphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (13) A solution of 2-(2,5-dimethoxy-4-pentylphenyl)ethaneamine (1.1 g, 4.38 mmol, 1 equivalent), 2-methoxybenzaldehyde (476.64 mg, 3.50 mmol, 0.8 equivalents), and AcOH (52.56 mg, 875.23 μmol, 50.06 μL, 0.2 equivalents) in DCE (10 mL) was stirred at 15°C for 1 hour. Then NaBH(OAc)3 (1.85 g, 8.75 mmol, 2 equivalents) was added. The mixture was stirred at 15°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NAHCO3 aqueous solution, then stirred, and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 35%~65%, 20 min) to obtain 2-(2,5-dimethoxy-4-pentylphenyl)-N-[(2-methoxyphenyl)methyl]ethaneamine (360 mg, 867.41 μmol, yield 20%, purity 98.3%, HCl) as a white solid. LCMS R T = 2.527 minutes, MS calculated: 371.25, [M+H] += 372.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 9.10 - 8.99 (m, 2H), 7.49 - 7.39 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.78 (s, 2H), 4.13 (s, 2H), 3.83 (s, 3H), 3.72 (d, J = 4.0 Hz, 6H), 3.08 - 3.01 (m, 2H), 2.96 - 2.89 (m, 2H), 2.52 (s, 2H), 1.55 - 1.45 (m, 2H), 1.32 - 1.26 (m, 4H), 0.86 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.48, 150.81, 150.77, 131.44, 130.77, 129.81, 122.63, 120.36, 119.69, 113.23, 113.09, 111.09, 55.86, 55.58, 46.23, 44.89, 31.15, 29.57, 29.29, 26.32, 21.93, 13.90.

[0211] (Example 13) Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)propan-2-amine (14) [ka]

[0212] Step 1: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)propan-2-amine (14) A solution of 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (700 mg, 2.64 mmol, 1 equivalent), 2-methoxybenzaldehyde (251.38 mg, 1.85 mmol, 0.7 equivalents), and AcOH (15.84 mg, 263.76 μmol, 15.09 μL, 0.1 equivalent) in DCE (10 mL) was stirred at 20°C for 1 hour. Then NaBH(OAc)3 (1.12 g, 5.28 mmol, 2 equivalents) was added. The mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 35%~65%, 20 min) to obtain 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)propan-2-amine (400 mg, 948 μmol, yield 36%, purity 100%, HCl) as a white solid. LCMS R T = 2.546 minutes, MS calculated: 385.54, [M+H] + = 386.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.97 - 8.90 (m, 1H), 8.71 - 8.63 (m, 1H), 7.50 - 7.41 (m, 2H), 7.12 - 7.09 (m, 1H), 7.04 - 6.99 (m, 1H), 6.82 - 6.75 (m, 2H), 4.22 - 4.14 (m, 2H), 3.87 - 3.65 (m, 9H), 3.42 - 3.35 (m, 1H), 3.12 (dd, J = 4.4, 13.2 Hz, 1H), 2.74 - 2.68 (m, 1H), 2.55 - 2.51 (m, 2H), 1.55 - 1.47 (m, 2H), 1.35 - 1.24 (m, 4H), 1.22 - 1.11 (m, 3H), 0.93 - 0.80 (m, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.50, 150.85, 150.77, 131.36, 130.77, 129.96, 122.18, 120.37, 119.85, 113.89, 113.09, 111.05, 55.90, 55.83, 55.54, 53.56, 42.89, 33.10, 31.14, 29.56, 29.22, 21.90, 15.63, 13.87.

[0213] (Example 14) Preparation of N-benzyl-2-(2,5-dimethoxy-4-methylphenyl)ethaneamine (15) [ka]

[0214] Step 1: Preparation of 1-allyl-2,5-dimethoxy-4-methylbenzene A mixture of 1-bromo-2,5-dimethoxy-4-methylbenzene (4 g, 17.31 mmol, 1 equivalent), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.36 g, 25.96 mmol, 1.5 equivalents), Pd(dppf)Cl2.CH2Cl2 (1.41 g, 1.73 mmol, 0.1 equivalent), and K2CO3 (7.18 g, 51.93 mmol, 3 equivalents) was stirred in dioxane (50 mL) and H2O (5 mL) and heated at 110°C for 12 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 20:1 to 5:1) to obtain 1-allyl-2,5-dimethoxy-4-methylbenzene (2.7 g, 14.04 mmol, yield 81%) as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ ppm 6.70 (s, 1H), 6.65 (s, 1H), 6.04 - 5.94 (m, 1H), 5.10 - 5.01 (m, 2H), 3.78 (s, 6H), 3.36 (d, J = 6.4 Hz, 2H), 2.22 (s, 3H).

[0215] Step 2: Preparation of 2-(2,5-dimethoxy-4-methylphenyl)acetaldehyde A mixture of 1-allyl-2,5-dimethoxy-4-methylbenzene (2.7 g, 14.04 mmol, 1 equivalent) and NaIO4 (9.01 g, 42.13 mmol, 3 equivalents) in THF (30 mL) and H2O (10 mL) was cooled to 0°C. Potassium osmium(VI) dihydrate (1.03 g, 2.81 mmol, 0.2 equivalents) was then added. The mixture was stirred at 0°C for 10 minutes. At completion, the mixture was poured into a saturated Na2SO3 aqueous solution and extracted with EA (20 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 1:1) to obtain 2-(2,5-dimethoxy-4-methylphenyl)acetaldehyde (0.6 g, 3.09 mmol, yield 22%) as a yellow solid. 1H NMR (400 MHz, CDCl3-d) δ ppm 9.69 - 9.66 (m, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.62 (d, J = 2.0 Hz, 2H), 2.24 (s, 3H).

[0216] Step 3: Preparation of N-benzyl-2-(2,5-dimethoxy-4-methylphenyl)ethanamine (15) A solution of 2-(2,5-dimethoxy-4-methylphenyl)acetaldehyde (500 mg, 2.57 mmol, 1 equivalent) and phenylmethaneamine (413.77 mg, 3.86 mmol, 1.5 equivalents) in MeOH (10 mL) was stirred at 20°C for 1 hour. Then NaBH3CN (323.54 mg, 5.15 mmol, 2 equivalents) was added. The mixture was stirred at 20°C for 12 hours. At completion, the solvent was removed. The residue was dissolved in DCM (20 mL), washed with water and brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: HUAPU C18 250×50mm×10μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 10%~40%, 20 min) to obtain N-benzyl-2-(2,5-dimethoxy-4-methylphenyl)ethanamine (113 mg, 395.96 μmol, yield 15%, HCl) as a white solid. LCMS R T = 1.988 min, MS calculated: 285.17, [M+H] + = 286.1; 1H; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 9.29 (br s, 2H), 7.55 (dd, J = 1.6, 7.6 Hz, 2H), 7.48 - 7.39 (m, 3H), 6.82 (s, 1H), 6.76 (s, 1H), 4.16 (s, 2H), 3.74 - 3.69 (m, 6H), 3.10 - 2.99 (m, 2H), 2.99 - 2.88 (m, 2H), 2.13 (s, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.27, 150.87, 132.22, 130.26, 129.13, 128.86, 125.18, 122.70, 114.20, 113.05, 56.06, 55.89, 50.02, 46.34, 26.67, 16.21.

[0217] (Example 15) Preparation of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-fluorobenzyl)ethanamine (16) [ka]

[0218] Step 1: Preparation of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-fluorobenzyl)ethanamine (16) A solution of 2-(2,5-dimethoxy-4-methylphenyl)acetaldehyde (800 mg, 4.12 mmol, 1 equivalent) and (2-fluorophenyl)methaneamine (618.54 mg, 4.94 mmol, 562.31 uL, 1.2 equivalents) in MeOH (10 mL) was stirred at 20°C for 1 hour. Then NaBH3CN (517.66 mg, 8.24 mmol, 2 equivalents) was added. The mixture was stirred at 20°C for 12 hours. At completion, the solvent was removed. The residue was dissolved in DCM (20 mL), washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%~35%, 10 min) to obtain 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-fluorobenzyl)ethanamine (130 mg, 399.01 umol, yield 10%, purity 100%, HCl) as a white solid. LCMS R T = 2.014 min, MS calculated: 303.16, [M+H] + = 304.1; 1H; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 9.22 (br s, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.34 - 7.27 (m, 2H), 6.83 (s, 1H), 6.78 (s, 1H), 4.22 (s, 2H), 3.72 (d, J = 4.0 Hz, 6H), 3.14 - 3.07 (m, 2H), 2.96 - 2.89 (m, 2H), 2.13 (s, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.85, 150.45, 132.09, 132.05, 131.26, 131.18, 124.79, 124.46, 124.42, 122.20, 115.43, 115.22, 113.80, 112.69, 55.64, 55.47, 46.33, 42.90, 42.86, 26.19, 15.67.

[0219] (Example 16) Preparation of 1-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)propan-2-amine (17) [ka]

[0220] Step 1: Preparation of (E)-1,4-dimethoxy-2-methyl-5-(2-nitropropa-1-en-1-yl)benzene To a mixture of 2,5-dimethoxy-4-methylbenzaldehyde (3 g, 16.65 mmol, 1 equivalent) in 1-nitroethane (21.25 g, 283.02 mmol, 20.23 mL, 17 equivalents), NH4OAc (2.57 g, 33.30 mmol, 2 equivalents) was added all at once under N2 conditions at 20°C. The mixture was stirred at 115°C for 2 hours. Upon completion, the reaction mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain 1,4-dimethoxy-2-methyl-5-[(E)-2-nitropropa-1-enyl]benzene (2.2 g, 9.27 mmol, yield 56%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 4 H) 2.38 (s, 4 H) 3.77 (s, 4 H) 3.81 (s, 4 H) 6.95 (s, 1 H) 7.01 (s, 1 H) 8.15 (s, 1 H).

[0221] Step 2: Preparation of 1-(2,5-dimethoxy-4-methylphenyl)propan-2-one To a mixture of 1,4-dimethoxy-2-methyl-5-[(E)-2-nitropropa-1-enyl]benzene (2.2 g, 9.27 mmol, 1 equivalent) in AcOH (40 mL), iron (517.84 mg, 9.27 mmol, 1 equivalent) was added all at once at 20°C under N2. The mixture was stirred at 120°C for 3 hours. At completion, the mixture was filtered by suction through a moist Celite bed. The solid was washed with H2O (100 mL) and EA (100 mL). The pH was adjusted to approximately 8 by adding Na2CO3, and the mixture was extracted with EA (3 × 50 mL). The organic layer was dehydrated with MgSO4, filtered, and concentrated to obtain crude 1-(2,5-dimethoxy-4-methylphenyl)propan-2-one (1.9 g, 9.12 mmol, yield 98%) as a yellow solid. The crude product was used in the next step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3 H) 2.14 (s, 3 H) 3.60 (s, 2 H) 3.67 (s, 3 H) 3.70 (s, 3 H) 6.74 (s, 1 H) 6.80 (s, 1 H)

[0222] Step 3: Preparation of 1-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)propan-2-amine (17) To a solution of 1-(2,5-dimethoxy-4-methylphenyl)propan-2-one (600 mg, 2.88 mmol, 1 equivalent) and (2-methoxyphenyl)methaneamine (395.23 mg, 2.88 mmol, 372.86 μL, 1 equivalent) in DCE (20 mL), AcOH (346.03 mg, 5.76 mmol, 329.56 μL, 2 equivalents) under N2 was added all at once. After the addition, the mixture was stirred at this temperature for 30 minutes, and then NaBH(OAc)3 (1.22 g, 5.76 mmol, 2 equivalents) was added all at once at 20 °C. The resulting mixture was stirred at 20 °C for 16 hours. At completion, the mixture was washed with aqueous NaHCO3 solution (20 mL) and extracted with DCM (10 mL x 3). The combined organic layer was dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~55%, 10 min). Following preparative HPLC, the solution was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with EA (20 mL × 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain 1-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)propan-2-amine (420 mg, 1.52 mmol, yield 53%, purity 100%) as a yellow oil. LCMS R T = 2.068 min, MS calculated value: 329.20, [M+H] + = 330.1; 1H NMR (400 MHz, chloroform-d) δ ppm 7.12 - 7.23 (m, 1 H), 6.87 (t, J = 7.2 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.60 (s, 1 H), 3.70 - 3.89 (m, 5 H), 3.68 (s, 3 H), 3.61 (s, 3 H), 2.82 - 2.93 (m, 1 H), 2.60 - 2.75 (m, 2 H), 2.22 (s, 3 H), 1.92 - 2.16 (m, 1 H), 1.13 (d, J = 6.0 Hz, 3 H); 13C NMR (101 MHz, DMSO-d6) δ ppm 157.52, 151.36, 151.19, 129.70, 128.33, 127.84, 125.72, 124.62, 119.98, 113.74, 113.48, 109.76, 55.85, 54.72, 51.54, 46.88, 38.07, 20.23, 16.09.

[0223] (Example 17) Preparation of 2-(((1-(2,5-dimethoxy-4-methylphenyl)propan-2-yl)aminomethyl)phenol (18) [ka]

[0224] Step 1: Preparation of 2-(((1-(2,5-dimethoxy-4-methylphenyl)propan-2-yl)aminomethyl)phenol (18) To a solution of 1-(2,5-dimethoxy-4-methylphenyl)propan-2-one (560 mg, 2.69 mmol, 1 equivalent) in MeOH (10 mL), 2-(aminomethyl)phenol (331.16 mg, 2.69 mmol, 62.14 μL, 1 equivalent) was added in one step under N2. After the addition, the mixture was stirred at this temperature for 30 minutes, and then NaBH3CN (168.98 mg, 2.69 mmol, 1 equivalent) was added in one step at 20°C. The resulting mixture was stirred at 20°C for 4 hours. At completion, the reaction products were washed with aqueous NaHCO3 (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%, 10 min) to obtain 2-(((1-(2,5-dimethoxy-4-methylphenyl)propan-2-yl)aminomethyl)phenol (340 mg, 1.05 mmol, yield 39%, purity 100%, HCl) as a white solid. LCMS R T= 2.028 min, MS calculated: 315.18, [M+H] + = 316.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 10.30 (s, 1 H), 8.99 (br s, 1 H), 8.78 (br s, 1 H), 7.45 (dd, J = 7.6, 1.2 Hz, 1 H), 7.23 - 7.29 (m, 1 H), 6.99 (d, J = 8.0 Hz, 1 H), 6.85 - 6.90 (m, 1 H), 6.84 (s, 1 H), 6.76 (s, 1 H), 4.11 - 4.21 (m, 2 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.15 (dd, J = 13.2, 4.0 Hz, 1 H), 2.68 - 2.78 (m, 1 H), 2.15 (s, 3 H), 1.18 (d, J = 6.4 Hz, 3 H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 156.55, 151.51, 151.24, 131.97, 130.69, 125.49, 122.80, 119.46, 118.79, 115.92, 114.51, 113.94, 56.26, 53.79, 43.03, 33.53, 16.47, 16.05.

[0225] (Example 18) Preparation of 1-(2,5-dimethoxy-4-methylphenyl)-N-[(2-methoxyphenyl)methyl]butan-2-amine (19) [ka]

[0226] Step 1: Preparation of 1-(2,5-dimethoxy-4-methylphenyl)-N-[(2-methoxyphenyl)methyl]butan-2-amine (19) A solution of 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine (1.1 g, 4.93 mmol, 1 equivalent), 2-methoxybenzaldehyde (536.52 mg, 3.94 mmol, 0.8 equivalents), and AcOH (59.16 mg, 985.18 μmol, 56.34 μL, 0.2 equivalents) in DCE (20 mL) was stirred at 15°C for 1 hour. Then NaBH(OAc)3 (2.09 g, 9.85 mmol, 2 equivalents) was added. The mixture was stirred at 15°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%, 20 min) to obtain 1-(2,5-dimethoxy-4-methylphenyl)-N-[(2-methoxyphenyl)methyl]butan-2-amine (400 mg, 1.05 mmol, yield 21%, purity 100%, HCl) as a white solid. LCMS R T = 2.179 minutes, MS calculated: 343.46, [M+H] + = 344.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.90 - 8.78 (m, 2H), 7.50 (dd, J = 1.2, 7.6 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 4.15 (t, J = 5.2 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.67 (s, 3H), 3.26 - 3.19 (m, 1H), 3.01 (dd, J = 5.2, 13.6 Hz, 1H), 2.88 (dd, J = 8.8, 13.2 Hz, 1H), 2.13 (s, 3H), 1.67 - 1.57 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.55, 151.02, 150.75, 131.65, 130.75, 125.05, 122.19, 120.35, 119.62, 113.98, 113.41, 110.95, 58.38, 55.75, 55.73, 55.47, 43.10, 30.55, 22.48, 15.97, 9.17.

[0227] (Example 19) Preparation of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)propyl)benzonitrile (20) [ka]

[0228] Step 1: Preparation of 1-bromo-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene A mixture of 4-bromo-2,5-dimethoxybenzaldehyde (10 g, 40.80 mmol, 1 equivalent) and NH4OAc (6.29 g, 81.61 mmol, 2 equivalents) in nitroethane (52.07 g, 693.68 mmol, 49.59 mL, 17 equivalents) was stirred and heated at 115°C for 2 hours. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 60:1 to 40:1) to obtain 1-bromo-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene (12 g, 39.72 mmol, yield 97%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 8.17 (s, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.39 (s, 3H).

[0229] Step 2: Preparation of 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-one A mixture of 1-bromo-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene (9 g, 29.79 mmol, 1 equivalent) and Fe (9.98 g, 178.74 mmol, 6 equivalents) in AcOH (100 mL) was stirred and heated at 120 °C for 8 hours. Upon completion, the mixture was filtered and concentrated. The residue was basicized to pH=9 with saturated Na2CO3 aqueous solution and extracted with EA (50 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 20:1~5:1) to obtain 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-one (4.7 g, 17.21 mmol, yield 58%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.07 (s, 1H), 6.72 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.65 (s, 2H), 2.16 (s, 3H).

[0230] Step 3: Preparation of 4-acetonyl-2,5-dimethoxybenzonitrile A mixture of 1-(4-bromo-2,5-dimethoxyphenyl)propan-2-one (2.6 g, 9.52 mmol, 1 equivalent), Zn(CN)2 (782.5 mg, 6.66 mmol, 0.7 equivalents), and XPhOS-Pd-G3 (1.21 g, 1.43 mmol, 0.15 equivalents) in dioxane (30 mL) was stirred and heated at 100 °C for 12 hours. Upon completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 10:1 to 3:1) to obtain 4-acetonyl-2,5-dimethoxybenzonitrile (1.8 g, 8.21 mmol, yield 86%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.01 (s, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.74 (s, 2H), 2.22 (s, 3H).

[0231] Step 4: Preparation of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)propyl)benzonitrile (20) A solution of 4-acetonyl-2,5-dimethoxybenzonitrile (700 mg, 3.19 mmol, 1 equivalent) and (2-methoxyphenyl)methaneamine (656.40 mg, 4.79 mmol, 619.25 μL, 1.5 equivalents) in MeOH (10 mL) was stirred at 15°C for 1 hour. Then NaBH3CN (401.30 mg, 6.38 mmol, 2 equivalents) was added. The mixture was stirred at 15°C for 12 hours. At completion, the solvent was removed. The residue was dissolved in DCM (20 mL), washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%~55%, 20 min) to obtain 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)propyl)benzonitrile (340 mg, 982.10 μmol, yield 31%, purity 98.33%) as a yellow solid. LCMS R T = 1.952 min, MS calculated: 340.42, [M+H] + = 341.1; 1H NMR (400 MHz, chloroform-d) δ ppm 7.24 - 7.17 (m, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.93 - 6.90 (m, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.74 - 6.71 (m, 1H), 3.86 (s, 0.5H), 3.82 (s, 3.5H), 3.70 - 3.67 (m, 3.5H), 3.65 (s, 3.5H), 2.93 - 2.84 (m, 1H), 2.77 (dd, J = 7.6, 13.2 Hz, 1H), 2.66 (dd, J = 5.6, 12.8 Hz, 1H), 1.90 - 1.84 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H); 13¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 157.85, 155.78, 151.78, 136.48, 130.12, 128.45, 128.43, 120.47, 117.03, 114.86, 114.37, 110.34, 99.07, 56.64, 56.13, 55.25, 51.47, 47.21, 38.97, 20.70.

[0232] (Example 20) Preparation of 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (21) [ka]

[0233] Step 1: Preparation of 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (21) A solution of 4-acetonyl-2,5-dimethoxybenzonitrile (700 mg, 3.19 mmol, 1 equivalent) and 2-(aminomethyl)phenol (589.82 mg, 4.79 mmol, 1.5 equivalents) in MeOH (10 mL) was stirred at 15°C for 1 hour. Then NaBH3CN (401.30 mg, 6.39 mmol, 2 equivalents) was added. The mixture was stirred at 15°C for 12 hours. At completion, the solvent was removed. The residue was dissolved in DCM (10 mL), washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250×70mm×10μm; mobile phase: [water (0.05% NH3H2O ​​- 10mM NH4HCO3)-ACN]; B%: 32%~62%, 30 min) to obtain 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (350 mg, 1.04 mmol, yield 33%, purity 97.28%) as a yellow solid. LCMS R T = 1.840 min, MS calculated: 326.39, [M+H] += 327.1; ¹H NMR (400 MHz, chloroform-d) δ ppm 7.15 (t, J = 7.6 Hz, ¹H), 6.97 (s, ²H), 6.84 - 6.70 (m, ³H), 4.08 - 3.99 (m, ¹H), 3.97 - 3.84 (m, ⁴H), 3.76 (s, ³H), 3.12 - 3.03 (m, ¹H), 2.94 - 2.86 (m, ¹H), 2.69 (dd, J = 6.4, 12.8 Hz, ¹H), 1.20 - 1.11 (m, ³H); 13 ¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 158.12, 155.57, 151.28, 134.92, 128.63, 128.09, 122.76, 118.90, 116.58, 116.35, 114.65, 114.29, 99.36, 56.40, 55.84, 52.55, 50.11, 38.33, 20.00.

[0234] (Example 21) Preparation of 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine (22) [ka]

[0235] Step 1: Preparation of 2,5-dimethoxy-4-propylbenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent) and propylboronic acid (1.61 g, 18.36 mmol, 1.5 equivalents) in toluene (50 mL), K3PO4 (7.80 g, 36.72 mmol, 3 equivalents) and Pd(dppf)Cl2 (447.85 mg, 612.07 μmol, 0.05 equivalents) were added. The mixture was stirred at 110°C for 2 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 2,5-dimethoxy-4-propyl-benzaldehyde (2 g, 9.60 mmol, yield 79%) as a pale yellow solid.1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.42 (s, 1H), 7.29 (s, 1H), 6.81 (s, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 2.67 - 2.62 (m, 2H), 1.68 - 1.61 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H).

[0236] Step 2: Preparation of 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-propylbenzene A mixture of 2,5-dimethoxy-4-propyl-benzaldehyde (2 g, 9.60 mmol, 1 equivalent) in nitroethane (14.41 g, 192.00 mmol, 13.73 mL, 20 equivalents) was treated with NH4OAc (1.48 g, 19.20 mmol, 2 equivalents) in a single pass under N2 conditions at 20°C. The mixture was stirred and heated to 115°C for 2 hours. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-propylbenzene (1.7 g, 6.41 mmol, yield 67%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.29 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.65 - 2.60 (m, 2H), 2.43 (d, J = 0.8, 3H), 1.67 - 1.61 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0237] Step 3: Preparation of 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine (22) To a solution of 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-propylbenzene (1.7 g, 6.41 mmol, 1 equivalent) in THF (30 mL), LiAlH4 (973 mg, 25.63 mmol, 4 equivalents) was added all at once under N2 conditions at 0°C. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 4.5 hours. At completion, the reaction mixture was quenched at 0°C by adding H2O (1 mL) followed by 30% NaOH aqueous solution (1 mL) dropwise. After stirring to obtain a smooth dispersion, the solid was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%~45%, 20 min) to obtain 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine (420 mg, 1.53 mmol, yield 24%, purity 100%, HCl) as a white solid. LCMS R T =1.930 min, MS calculated value: 237.17, [M+H] + = 238.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.15 (br s, 3H), 6.78 (d, J = 2.0 Hz, 2H), 3.75 - 3.70 (m, 6H), 3.43 - 3.37 (m, 1H), 2.91 (dd, J = 5.6, 13.1 Hz, 1H), 2.69 (dd, J = 8.8, 13.2 Hz, 1H), 2.50 - 2.46 (m, 2H), 1.53 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.95 150.76, 129.51, 122.38, 113.98, 113.11, 55.84, 46.93, 34.78, 31.78, 22.77, 17.84, 13.96.

[0238] (Example 22) Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (23) [ka]

[0239] Step 1: Preparation of 2,5-dimethoxy-4-pentylbenzaldehyde A mixture of 4-bromo-2,5-dimethoxybenzaldehyde (6 g, 24.48 mmol, 1 equivalent), pentylboronic acid (4.26 g, 36.72 mmol, 1.5 equivalents), Pd(dppf)Cl2 (895.71 mg, 1.22 mmol, 0.05 equivalents), and K3PO4 (15.59 g, 73.45 mmol, 3 equivalents) in toluene (100 mL) was stirred and heated at 110 °C for 12 hours. Upon completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 50:1) to obtain 2,5-dimethoxy-4-pentylbenzaldehyde (5.1 g, 21.58 mmol, yield 88%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.4 (s, 1 H), 7.27 (s, 1 H), 6.79 (s, 1 H), 3.89 (s, 3 H), 3.82 (s, 3 H), 2.59 - 2.68 (m, 2 H), 1.52 - 1.65 (m, 2 H), 1.26 - 1.41 (m, 4 H), 0.91 (t, J = 6.8 Hz, 3 H).

[0240] Step 2: Preparation of 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-pentylbenzene A mixture of 2,5-dimethoxy-4-pentylbenzaldehyde (1.2 g, 5.08 mmol, 1 equivalent) and NH4OAc (782.87 mg, 10.16 mmol, 2 equivalents) in nitroethane (9.53 g, 126.95 mmol, 9.08 mL, 25 equivalents) was stirred at 115°C for 1 hour. Upon completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-pentylbenzene (1.2 g, 4.09 mmol, yield 81%) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.30 (s, 1H), 6.79 - 6.77 (m, 1H), 6.76 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.66 - 2.61 (m, 2H), 2.43 (s, 3H), 1.65 - 1.57 (m, 2H), 1.40 - 1.33 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H).

[0241] Step 3: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (23) A solution of 1,4-dimethoxy-2-[(E)-2-nitropropa-1-en-1-yl]-5-pentylbenzene (1.2 g, 4.09 mmol, 1 equivalent) in THF (20 mL) was cooled to 0°C. Then LiAlH4 (621.02 mg, 16.36 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.6 mL) was added. Then 0.6 mL of 30% NaOH aqueous solution was added. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%~45%, 10 min) to obtain 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (1.08 g, 4.07 mmol, yield 100%, HCl) as a white solid. LCMS R T = 2.163 minutes, MS calculated: 265.39, [M+H] + = 266.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.02 (br s, 3H), 6.78 (d, J = 6.4 Hz, 2H), 3.73 (s, 6H), 3.42 - 3.35 (m, 1H), 2.88 (dd, J = 5.6, 12.8 Hz, 1H), 2.68 (dd, J = 8.4, 13.2 Hz, 1H), 2.54 - 2.51 (m, 2H), 1.51 (td, J = 7.2, 14.8 Hz, 2H), 1.34 - 1.24 (m, 4H), 1.10 (d, J = 6.4 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.96, 150.71, 129.81, 122.22, 113.98, 113.01, 55.85, 55.82, 46.93, 34.77, 31.15, 29.57, 29.23, 21.91, 17.85, 13.88.

[0242] (Example 23) Preparation of 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile (24) [ka]

[0243] Step 1: Preparation of 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile (24) A mixture of 4-acetonyl-2,5-dimethoxybenzonitrile (700 mg, 3.19 mmol, 1 equivalent) and NH4OAc (739 mg, 9.58 mmol, 3 equivalents) in MeOH (10 mL) was stirred at 15°C for 1 hour. Then, NaBH3CN (401.3 mg, 6.39 mmol, 2 equivalents) was added, and the mixture was stirred at 15°C for 12 hours. At completion, the solvent was removed. The residue was dissolved in DCM (20 mL), washed with H2O and brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%~50%, 10 min) to obtain 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile (160 mg, 726.4 μmol, yield 23%, purity 100%) as a yellow solid. LCMS R T = 1.552 min, MS calculated: 220.27, [M+H] + = 221.1; ¹H NMR (400 MHz, chloroform-d) δ ppm 6.98 (s, 1H), 6.80 (s, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.28 - 3.19 (m, 1H), 2.77 (dd, J = 5.2, 12.8 Hz, 1H), 2.58 (dd, J = 8.0, 12.8 Hz, 1H), 1.39 - 1.31 (m, 2H), 1.13 (d, J = 6.4 Hz, 3H); 13¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 155.65, 151.49, 136.09, 116.70, 114.67, 114.34, 99.18, 56.47, 55.98, 46.90, 41.65, 23.86.

[0244] (Example 24) Preparation of 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine (25) [ka]

[0245] Step 1: Preparation of 1,4-dimethoxy-2-methyl-5-[(E)-2-nitrobuta-1-en-1-yl]benzene A mixture of 2,5-dimethoxy-4-methylbenzaldehyde (2 g, 11.10 mmol, 1 equivalent) and NH4OAc (1.71 g, 22.20 mmol, 2 equivalents) in 1-nitropropane (16.81 g, 188.7 mmol, 16.84 mL, 17 equivalents) was stirred at 115°C for 2 hours. Upon completion, the reaction mixture was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 15 / 1) to obtain 1,4-dimethoxy-2-methyl-5-[(E)-2-nitrobuta-1-en-1-yl]benzene (2.1 g, 8.36 mmol, yield 75%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.24 (s, 1H), 6.78 (d, J = 2.8 Hz, 2H), 3.82 (d, J = 8.4 Hz, 6H), 2.86 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.30 - 1.26 (m, 3H).

[0246] Step 2: Preparation of 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine (25) A solution of 1,4-dimethoxy-2-methyl-5-[(E)-2-nitrobuta-1-en-1-yl]benzene (2.7 g, 10.75 mmol, 1 equivalent) in THF (40 mL) was cooled to 0°C. Then LiAlH4 (1.63 g, 42.98 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (2 mL) was added. Then 2 mL of 30% NaOH aqueous solution was added. The mixture was stirred to make a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%, 10 min) to obtain 1-(2,5-dimethoxy-4-methylphenyl)butan-2-amine (1.4g, 5.20 mmol, yield 48%, purity 96.4%, HCl) as a white solid. LCMS R T = 1.786 min, MS calculated: 223.31, [M+H] + = 224.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.05 (br. s, 3H), 6.82 (s, 2H), 3.73 (d, J = 2.4 Hz, 6H), 3.22 (d, J = 5.6 Hz, 1H), 2.89 - 2.75 (m, 2H), 2.13 (s, 3H), 1.57 - 1.44 (m, 2H), 0.99 - 0.81 (m, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 150.96, 150.88, 124.88, 122.13, 113.93, 113.69, 55.82, 55.68, 52.22, 32.55, 24.69, 15.99, 9.45.

[0247] (Example 25) Preparation of 1-(2,5-dimethoxy-4-(phenylthio)phenyl)propan-2-amine (26) [ka]

[0248] Step 1: Preparation of 2,5-dimethoxy-4-(phenylthio)benzaldehyde To a 30 mL solution of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent), benzenethiol (2.70 g, 24.48 mmol, 2.50 mL, 2 equivalents), Pd2(dba)3 (1.68 g, 1.84 mmol, 0.15 equivalents), Xantphos (1.06 g, 1.84 mmol, 0.15 equivalents), and DIEA (7.91 g, 61.21 mmol, 10.66 mL, 5 equivalents) were added. The solution was stirred at 110°C for 3 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 40:1 to 10:1) to obtain 2,5-dimethoxy-4-(phenylthio)benzaldehyde (3 g, 10.94 mmol, yield 89%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.32 (s, 1H), 7.58 (dd, J = 3.2, 6.8 Hz, 2H), 7.50 - 7.44 (m, 3H), 7.29 (s, 1H), 6.29 (s, 1H), 3.93 (s, 3H), 3.57 (s, 3H).

[0249] Step 2: Preparation of (E)-(2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)phenyl)(phenyl)sulfan To a solution of 2,5-dimethoxy-4-(phenylthio)benzaldehyde (3 g, 10.94 mmol, 1 equivalent) in nitroethane (16.42 g, 218.71 mmol, 15.64 mL, 20 equivalents), NH4OAc (2.53 g, 32.81 mmol, 3 equivalents) was added. The solution was stirred at 110°C for 3 hours. At completion, the solvent was removed. The residue was purified by silica gel chromatography (PE:EA = 50:1 to 20:1) to obtain (E)-(2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)phenyl)(phenyl)sulfan (2.6 g, 7.85 mmol, yield 72%) as a yellow solid. 1¹H NMR (400 MHz, chloroform-d) δ ppm 8.23 ​​(s, 1H), 7.54 - 7.49 (m, 2H), 7.45 - 7.39 (m, 3H), 6.82 (s, 1H), 6.43 (s, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.44 - 2.41 (m, 3H).

[0250] Step 3: Preparation of 1-(2,5-dimethoxy-4-(phenylthio)phenyl)propan-2-amine (26) To a solution of (E)-(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)(phenyl)sulfan (2.6 g, 7.85 mmol, 1 equivalent) in THF (50 mL), LiAlH4 (1.19 g, 31.38 mmol, 4 equivalents) was added at 0 °C. The solution was then stirred at 20 °C for 30 minutes. The mixture was then stirred at 60 °C for 4 hours. At completion, the mixture was cooled to 0 °C. H2O (1.2 mL) was then added. 30% NaOH (1.2 mL) was then added. The mixture was stirred to form a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 mm × 100 mm × 10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%~45%, 25 min) to obtain 1-(2,5-dimethoxy-4-(phenylthio)phenyl)propan-2-amine (410 mg, 1.21 mmol, yield 15%, purity 100%, HCl) as a white solid. LCMS R T = 2.052 minutes, MS calculated: 303.42, [M+H] += 304.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 7.96 (br s, 3H), 7.38 - 7.22 (m, 5H), 6.99 (s, 1H), 6.75 (s, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 3.47 - 3.39 (m, 1H), 2.90 (dd, J = 6.4, 13.2 Hz, 1H), 2.75 (dd, J = 8.0, 13.2 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.67, 151.44, 134.69, 129.63, 129.36, 126.81, 125.57, 120.51, 115.14, 115.11, 56.36, 55.82, 46.79, 34.78, 18.07.

[0251] (Example 26) Preparation of 1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-amine (27) [ka]

[0252] Step 1: Preparation of benzyl(1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate A solution of benzyl (1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl) carbamate (1.5 g, 3.67 mmol, 1 equivalent) and 1-bromo-5-fluoropentane (2.48 g, 14.70 mmol, 4 equivalents) in DME (10 mL) is mixed with bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinehexafluorophosphate (41. 22 mg, 36.74 μmol, 0.01 equivalents) of dichloronickel 1,2-dimethoxyethane (4.04 mg, 18.37 μmol, 0.005 equivalents), Na2CO3 (778.79 mg, 7.35 mmol, 2 equivalents), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (4.93 mg, 18.37 μmol, 0.005 equivalents), and bis(trimethylsilyl)silyl-trimethylsilane (913.56 mg, 3.67 mmol, 1 equivalent) were added, and the reaction mixture was stirred at 25°C for 12 hours while irradiating with blue light (34 W LED). Upon completion, the mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 56%~86%; 20 min) to obtain benzyl(1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (800 mg, 1.92 mmol, yield 52%) as a yellow oily substance. 1H NMR (400 MHz, chloroform-d) δ = 7.55 - 7.22 (m, 5H), 6.79 - 6.49 (m, 2H), 5.06 (br s, 2H), 4.58 - 4.46 (m, 1H), 4.43 - 4.30 (m, 1H), 3.95 (br d, J = 6.0 Hz, 1H), 3.86 - 3.62 (m, 6H), 2.90 - 2.64 (m, 2H), 2.64 - 2.44 (m, 2H), 1.84 - 1.67 (m, 2H), 1.62 (br t, J = 7.6 Hz, 2H), 1.52 - 1.42 (m, 2H), 1.32 (br s, 1H), 1.18 (d, J = 6.4 Hz, 3H).

[0253] Step 2: Preparation of 1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-amine (27) Benzyl(1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-yl)carbamate (600 mg, 1.44 mmol, 1 equivalent) was dissolved in MeOH (10 mL) and NH3·H2O (1 mL), to which Pd(OH)2 (800 mg) was added under N2. The suspension was degassed several times under vacuum and purged with H2. The mixture was stirred at 25°C under H2 (15 psi) for 1 hour. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 15%~45%; 8 min) to obtain 1-(4-(5-fluoropentyl)-2,5-dimethoxyphenyl)propan-2-amine (320 mg, 1.13 mmol, HCl) as a white solid. LCMS R T = 2.098 min, MS calculated: 283.38, [M+H] += 284.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 8.32 (br s, 3H), 6.69 (d, J = 9.2 Hz, 2H), 4.51 (t, J = 6.4 Hz, 1H), 4.39 (t, J = 6.4 Hz, 1H), 3.80 (d, J = 8.0 Hz, 6H), 3.70 (br s, 1H), 3.18 - 3.02 (m, 1H), 2.97 - 2.83 (m, 1H), 2.66 - 2.50 (m, 2H), 1.61 (br d, J = 8.0 Hz, 4H), 1.52 - 1.43 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 151.31, 151.21, 130.97, 121.78, 114.35, 112.96, 83.34, 56.17, 55.92, 48.52, 36.56, 30.37, 30.18, 29.64, 25.10, 25.04, 18.50.

[0254] (Example 27) Preparation of 1-(2,5-dimethoxy-4-(pentylthio)phenyl)propan-2-amine (28) [ka]

[0255] Step 1: Preparation of 2,5-dimethoxy-4-(pentylthio)benzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (5 g, 20.40 mmol, 1 equivalent) and pentane-1-thiol (2.76 g, 26.52 mmol, 1.3 equivalents) in toluene (50 mL), N2-based DIEA (7.91 g, 61.21 mmol, 10.66 mL, 3 equivalents), Pd2(dba)3 (1.87 g, 2.04 mmol, 0.1 equivalent), and DPPF (1.13 g, 2.04 mmol, 0.1 equivalent) were added. The mixture was stirred and heated at 110°C for 12 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain 2,5-dimethoxy-4-(pentylthio)benzaldehyde (3.5 g, 11.31 mmol, yield 55%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 10.36 (s, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 3.91 (d, J = 11.6 Hz, 6H), 2.96 (t, J = 7.6 Hz, 2H), 1.77 (m, J = 7.2 Hz, 2H), 1.54 - 1.45 (m, 2H), 1.44 - 1.34 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0256] Step 2: Preparation of (E)-(2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)phenyl)(pentyl)sulfan To a solution of 2,5-dimethoxy-4-(pentylthio)benzaldehyde (1.7 g, 6.33 mmol, 1 equivalent) in nitroethane (9.51 g, 126.7 mmol, 9.06 mL, 20 equivalents), NH4OAc (1.46 g, 19.00 mmol, 3 equivalents) was added. The mixture was heated and stirred at 110°C for 2 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain (E)-(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)(pentyl)sulfan (0.5 g, 1.48 mmol, yield 23%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.29 (s, 1H), 6.79 (d, J = 6.4 Hz, 2H), 3.87 (d, J = 1.6 Hz, 6H), 2.95 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.74 (m, J = 7.6 Hz, 2H), 1.52 - 1.44 (m, 2H), 1.41 - 1.33 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0257] Step 3: Preparation of 1-(2,5-dimethoxy-4-(pentylthio)phenyl)propan-2-amine (28) (E)-(2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)phenyl)(pentyl)sulfan (1.3 g, 3.99 mmol, 1 equivalent) was dissolved in THF (20 mL) and LiAlH4 (606.48 mg, 15.98 mmol, 4 equivalents) was added all at once at 0°C under N2. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 12 hours. At completion, the mixture was cooled to 0°C. The reaction mixture was quenched at 0°C by adding H2O (1 mL) and 1 mL of 30% NaOH aqueous solution, then filtered and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%; 23 min) to obtain 1-(2,5-dimethoxy-4-(pentylthio)phenyl)propan-2-amine (380 mg, 1.12 mmol, yield 28%, purity 98.7%, HCl) as a white solid. LCMS R T = 2.258 min, MS calculated: 297.46, [M+H] + = 298.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.06 (br s, 3H), 6.83 (d, J = 10.8 Hz, 2H), 3.76 (d, J = 5.2 Hz, 6H), 3.33 (s, 1H), 2.93 - 2.84 (m, 3H), 2.70 (dd, J = 8.4, 13.2 Hz, 1H), 1.58 (m, J = 7.2 Hz, 2H), 1.43 - 1.25 (m, 4H), 1.11 (d, J = 6.4 Hz, 3H), 0.91 - 0.81 (m, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 151.51, 150.27, 123.95, 122.11, 114.27, 111.14, 56.21, 56.02, 46.84, 34.58, 30.54, 30.40, 28.00, 21.63, 17.86, 13.81.

[0258] (Example 28) Preparation of 1-(4-isopentyl-2,5-dimethoxyphenyl)propan-2-amine (29) [ka]

[0259] Step 1: Preparation of 4-isopentyl-2,5-dimethoxybenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (2 g, 8.16 mmol, 1 equivalent) and isopentylboronic acid (946.40 mg, 8.16 mmol, 1 equivalent) in toluene (20 mL), K3PO4 (5.20 g, 24.48 mmol, 3 equivalents) and Pd(dppf)Cl2 (298.57 mg, 408.05 μmol, 0.05 equivalents) were added. The mixture was stirred and heated at 110°C for 12 hours. At completion, the mixture was filtered, concentrated, and the solvent removed. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain 4-isopentyl-2,5-dimethoxybenzaldehyde (1.7 g, 7.19 mmol, yield 88%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.97 - 10.86 (m, 1H), 7.78 (s, 1H), 7.31 (s, 1H), 4.41 (s, 3H), 4.34 (s, 3H), 3.20 - 3.12 (m, 2H), 2.17 - 2.10 (m, 1H), 2.03 - 1.93 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H).

[0260] Step 2: Preparation of 1-isopentyl-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene To a solution of 4-isopentyl-2,5-dimethoxybenzaldehyde (1.7 g, 7.19 mmol, 1 equivalent) in 1-nitroethane (15.75 g, 209.81 mmol, 15 mL, 29.18 equivalents), NH4OAc (1.11 g, 14.38 mmol, 2 equivalents) was added. The mixture was stirred and heated at 110°C for 1 hour. At completion, the mixture was concentrated and the solvent was removed. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain 1-isopentyl-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene (1.4 g, 4.77 mmol, yield 66%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.30 (s, 1H), 6.77 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 2.67 - 2.61 (m, 2H), 2.43 (s, 3H), 1.63 (td, J = 6.6, 13.4 Hz, 1H), 1.51 - 1.46 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H).

[0261] Step 3: Preparation of 1-(4-isopentyl-2,5-dimethoxyphenyl)propan-2-amine (29) To a solution of 1-isopentyl-2,5-dimethoxy-4-[(E)-2-nitropropa-1-en-1-yl]benzene (1.4 g, 4.77 mmol, 1 equivalent) in THF (30 mL), LiAlH4 (724.52 mg, 19.09 mmol, 4 equivalents) was added at 0°C. The mixture was stirred and heated to 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then, H2O (0.7 mL) was added dropwise while stirring, followed by the dropwise addition of 30% NaOH aqueous solution (0.7 mL). The mixture was stirred to form a smooth dispersion, then filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%, 10 min) to obtain 1-(4-isopentyl-2,5-dimethoxyphenyl)propan-2-amine (350 mg, 1.13 mmol, yield 24%, purity 97.9%, HCl) as a white solid. LCMS R T = 2.264 minutes, MS calculated: 265.39, [M+H] + = 266.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.14 - 7.91 (m, 3H), 6.78 (d, J = 6.9 Hz, 2H), 3.75 - 3.71 (m, 6H), 3.42 - 3.35 (m, 1H), 2.88 (dd, J = 5.7, 13.2 Hz, 1H), 2.68 (dd, J = 8.4, 13.2 Hz, 1H), 2.56 - 2.51 (m, 2H), 1.59 - 1.48 (m, 1H), 1.43 - 1.36 (m, 2H), 1.10 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.5 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.01, 150.68, 129.97, 122.24, 114.02, 112.89, 55.90, 55.83, 46.93, 38.93, 34.77, 27.51, 27.47, 22.44, 17.84, 11.29.

[0262] (Example 29) Preparation of 1-(2,5-dimethoxy-4-(4-methylpentyl)phenyl)propan-2-amine (30) [ka]

[0263] Step 1: Preparation of benzyl 1-[2-[2,5-dimethoxy-4-[(E)-4-methylpenta-1-en-1-yl]phenyl]propan-2-yl]carbamate A mixture of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (500 mg, 1.22 mmol, 1 equivalent), [(E)-4-methylpenta-1-en-1-yl]boronic acid (235.09 mg, 1.84 mmol, 1.5 equivalents), K3PO4 (779.84 mg, 3.67 mmol, 3 equivalents), and Pd(dppf)Cl2 (179.21 mg, 244.93 μmol, 0.2 equivalents) in dioxane (20 mL) and H2O (2 mL) was degassed and then heated at 80°C under N2 for 3 hours. At completion, the mixture was filtered and concentrated. The residue was purified by preparative TLC (SiO2, PE:EA=5:1) to obtain the product benzyl 1-[2-[2,5-dimethoxy-4-[(E)-4-methylpenta-1-en-1-yl]phenyl]propan-2-yl]carbamate (340 mg, yield 67%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.40 - 7.27 (m, 5H), 6.91 (s, 1H), 6.69 - 6.61 (m, 2H), 6.23 - 6.12 (m, 1H), 5.15 - 4.97 (m, 3H), 4.08 - 3.89 (m, 1H), 3.86 - 3.67 (m, 6H), 2.88 - 2.64 (m, 2H), 2.18 - 2.07 (m, 2H), 1.73 (td, J = 6.8, 13.3 Hz, 1H), 1.17 (br d, J = 6.4 Hz, 2H), 0.95 (d, J = 6.4 Hz, 6H).

[0264] Step 2: Preparation of 1-(2,5-dimethoxy-4-(4-methylpentyl)phenyl)propan-2-amine (30) A solution of benzyl 1-[2-[2,5-dimethoxy-4-[(E)-4-methylpenta-1-en-1-yl]phenyl]propan-2-yl]carbamate (500 mg, 1.21 mmol, 1 equivalent) in THF (20 mL) was mixed with Pd(OH)2 / C under N2. The suspension was degassed several times under vacuum and purged with H2. The mixture was stirred at 20°C under H2 (15 psi) for 1 hour. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~45%; 8 min) to obtain 1-(2,5-dimethoxy-4-(4-methylpentyl)phenyl)propan-2-amine (68 mg, 243.4 μmol, yield 20%, purity 100%, HCl salt) as a white solid. LCMS R T = 2.347 minutes, MS calculated: 279.22, [M+H] + = 280.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 7.95 - 7.61 (m, 3H), 6.81 (s, 1H), 6.76 (s, 1H), 3.74 (d, J = 2.4 Hz, 6H), 3.45 - 3.36 (m, 1H), 2.85 (dd, J = 6.0, 13.2 Hz, 1H), 2.69 - 2.67 (m, 1H), 2.60 - 2.53 (m, 2H), 1.60 - 1.46 (m, 3H), 1.26 - 1.17 (m, 2H), 1.11 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 151.46, 151.21, 130.38, 122.63, 114.47, 113.52, 56.36, 56.32, 47.48, 38.84, 35.29, 30.36, 27.92, 27.73, 22.99, 18.42.

[0265] (Example 30) Preparation of 1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-amine (31) [ka]

[0266] Step 1: Preparation of benzyl(1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-yl)carbamate Benzyl (1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (500 mg, 1.22 mmol, 1 equivalent), 4-bromo-1,1,1-trifluorobutane (935.57 mg, 4.90 mmol, 4 equivalents), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinehexafluorophosphate A mixture of phosphate (13.74 mg, 12.25 μmol, 0.01 equivalent), dichloronickel 1,2-dimethoxyethane (1.35 mg, 6.12 μmol, 0.005 equivalent), Na2CO3 (259.60 mg, 2.45 mmol, 2 equivalents), dtbbpy (1.64 mg, 6.12 μmol, 0.005 equivalent), and TTMSS (304.52 mg, 1.22 mmol, 377.81 μL, 1 equivalent) in DME (4 mL) was degassed three times and purged with Ar. The mixture was then stirred at 25°C for 12 hours under an Ar atmosphere while irradiating with blue light (34 W LED). At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 52%~82%; 20 min) to obtain benzyl (1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-yl) carbamate (780 mg, crude product) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.38 - 7.29 (m, 5H), 6.63 (s, 2H), 5.05 (br s, 2H), 4.02 - 3.89 (m, 1H), 3.82 - 3.70 (m, 6H), 2.88 - 2.60 (m, 4H), 2.19 - 1.98 (m, 2H), 1.90 - 1.78 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H)

[0267] Step 2: Preparation of 1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-amine (31) To a solution of benzyl(1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-yl)carbamate (580 mg, 1.32 mmol, 1 equivalent) in MeOH (30 mL) and CH3NH2 (3 mL, 30% purity), Pd(OH)2 (1 g, 7.12 mmol, 5.40 equivalents) was added. The mixture was stirred at 15°C under H2 (15 psi) for 2 hours. At completion, the reaction mixture was filtered, and the filtrate was concentrated to obtain 1-(2,5-dimethoxy-4-(4,4,4-trifluorobutyl)phenyl)propan-2-amine (500 mg) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 6.69 - 6.62 (m, 2H), 3.78 (d, J = 1.2 Hz, 6H), 3.27 - 3.16 (m, 1H), 2.78 - 2.63 (m, 3H), 2.52 (dd, J = 8.0, 12.9 Hz, 1H), 2.19 - 2.05 (m, 2H), 1.91 - 1.80 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H) 13 ¹³C NMR (10¹ MHz, chloroform-d) δ values: 151.57, 151.17, 128.69, 127.73, 126.65, 114.04, 113.03, 56.05, 55.99, 47.30, 40.96, 33.50, 33.23, 29.28, 23.56, 22.30, 22.28.

[0268] (Example 31) Preparation of 1-(4-butoxy-2,5-dimethoxyphenyl)propan-2-amine (33) [ka]

[0269] Step 1: Preparation of 4-butoxy-2,5-dimethoxybenzaldehyde A mixture of 4-bromo-2,5-dimethoxybenzaldehyde (2 g, 8.16 mmol, 1 equivalent), butan-1-ol (1.21 g, 16.32 mmol, 1.49 mL, 2 equivalents), Pd(OAc)2 (183.22 mg, 816.09 μmol, 0.1 equivalent), t-BuXphos (693.09 mg, 1.63 mmol, 0.2 equivalents), and Cs2CO3 (7.98 g, 24.48 mmol, 3 equivalents) in toluene (20 mL) was degassed three times and purged with N2. The mixture was then stirred at 80°C under an N2 atmosphere for 16 hours. At completion, the reaction mixture was poured into H2O (20 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with brine (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain 4-butoxy-2,5-dimethoxybenzaldehyde (1 g, 4.20 mmol, yield 51%) as a yellow solid.

[0270] Step 2: Preparation of (E)-1-butoxy-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene NH4OAc (873.41 mg, 11.33 mmol, 3 equivalents) was added to a solution of 4-butoxy-2,5-dimethoxybenzaldehyde (0.9 g, 3.78 mmol, 1 equivalent) in nitroethane (10 mL). The mixture was stirred at 110 °C for 0.5 hours. At completion, the reaction was concentrated to obtain the crude product. The crude product was purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate (100:1 to 0:1) to obtain (E)-1-butoxy-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (1 g, 3.39 mmol, 90% yield) as a yellow solid.

[0271] Step 3: Preparation of 1-(4-butoxy-2,5-dimethoxyphenyl)propan-2-amine (33) A mixture of (E)-1-butoxy-2,5-dimethoxy-4-(2-nitropropa-1-en-1-yl)benzene (1 g, 3.39 mmol, 1 equivalent) in THF (10 mL) was degassed three times and purged with N2. LiAlH4 (514.06 mg, 13.54 mmol, 4 equivalents) was added at 0°C, and the mixture was then stirred at 60°C under an N2 atmosphere for 6 hours. At completion, the reaction mixture was quenched at 0°C by dropwise addition of H2O (1 mL) and 30% NaOH aqueous solution (1 mL). After solid formation, the mixture was filtered, and the filtrate was concentrated to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%; 10 min) to obtain 1-(4-butoxy-2,5-dimethoxyphenyl)propan-2-amine (520 mg, 1.84 mmol, yield 54%, purity 94.7%, HCl salt) as a white solid. 1HNMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.02 - 8.35 (m, 3 H), 6.77 - 6.84 (m, 1 H), 6.62 - 6.68 (m, 1 H), 3.93 - 4.01 (m, 2 H), 3.82 - 3.92 (m, 3 H), 3.72 - 3.78 (m, 3 H), 3.66 - 3.71 (m, 3 H), 2.80 - 2.91 (m, 1 H), 2.58 - 2.70 (m, 1 H), 1.61 - 1.75 (m, 2 H), 1.36 - 1.50 (m, 2 H), 1.05 - 1.17 (m, 3H), 0.86 - 0.98 (m, 3 H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.59, 147.99, 142.65, 116.02, 115.60, 99.32, 68.17, 56.46, 56.09, 47.05, 34.30, 30.98, 18.82, 17.77, 13.76.

[0272] (Example 32) Preparation of 1-(2,5-dimethoxy-4-(3-methoxypropyl)phenyl)propan-2-amine (35) [ka]

[0273] Step 1: Preparation of benzyl(1-(2,5-dimethoxy-4-((E)-3-methoxypropane-1-en-1-yl)phenyl)propan-2-yl)carbamate A mixture of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl) carbamate (1.5 g, 3.67 mmol, 1 equivalent) and 2-[(E)-3-methoxypropa-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.18 g, 11.02 mmol, 2.34 mL, 3 equivalents) in THF (30 mL) was added all at once under N2 conditions at 25°C to K3PO4 (1.56 g, 7.35 mmol, 2 equivalents) and BrettPhos Pd G3 (333.04 mg, 367.39 μmol, 0.1 equivalent). The mixture was stirred at 80°C for 4 hours. At completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain benzyl(1-(2,5-dimethoxy-4-((E)-3-methoxypropa-1-en-1-yl)phenyl)propan-2-yl)carbamate (600 mg, 1.50 mmol, yield 41%) as a yellow oily substance. 1 H NMR (400 MHz, chloroform-d) δ = 7.39 - 7.28 (m, 5H), 6.95 (s, 2H), 6.66 (br s, 1H), 6.27 (td, J = 6.4, 16.0 Hz, 1H), 5.05 (s, 3H), 4.12 (dd, J = 1.2, 6.4 Hz, 2H), 3.98 (br s, 1H), 3.89 - 3.69 (m, 6H), 3.40 (s, 3H), 2.73 (br d, J = 5.6 Hz, 2H), 1.18 (d, J = 6.4 Hz, 3H).

[0274] Step 2: Preparation of 1-(2,5-dimethoxy-4-(3-methoxypropyl)phenyl)propan-2-amine (35) A solution of benzyl(1-(2,5-dimethoxy-4-((E)-3-methoxypropa-1-en-1-yl)phenyl)propan-2-yl)carbamate (300 mg, 751 μmol, 1 equivalent) in THF (4 mL) was mixed with Pd(OH)2 / C under N2. The suspension was degassed several times under vacuum and purged with H2. The mixture was stirred at 25°C under H2 (15 psi) for 1 hour. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%~40%; 7 min) to obtain 1-(2,5-dimethoxy-4-(3-methoxypropyl)phenyl)propan-2-amine (151 mg, 497 μmol, yield 66%, HCl) as a white solid. LCMS R T = 1.820 min, MS calculated: 267.36, [M+H] + = 268.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 8.33 (br s, 3H), 6.70 (s, 2H), 3.79 (d, J = 5.2 Hz, 6H), 3.70 (br d, J = 1.6 Hz, 1H), 3.40 (t, J = 6.4 Hz, 2H), 3.36 (s, 3H), 3.09 (br dd, J = 6.0, 13.1 Hz, 1H), 2.90 (br dd, J = 7.6, 13.2 Hz, 1H), 2.72 - 2.58 (m, 2H), 1.85 (dd, J = 6.8, 8.4 Hz, 2H), 1.40 (br d, J = 6.4 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt) δ = 151.33, 151.29, 130.32, 122.02, 114.34, 113.08, 72.32, 58.54, 56.16, 55.90, 48.40, 36.55, 29.76, 27.00, 18.43

[0275] (Example 33) Preparation of 2-(4-hexyl-2,5-dimethoxyphenyl)ethanamine (36) [ka]

[0276] Step 1: Preparation of 4-hexyl-2,5-dimethoxybenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent) and hexylboronic acid (1.59 g, 12.24 mmol, 1 equivalent) in toluene (50 mL), Pd(dppf)Cl2 (448 mg, 0.612 mmol, 0.1 equivalent) and K3PO4 (5.2 g, 24.48 mmol, 2 equivalents) were added under N2. The mixture was stirred at 110°C for 12 hours. At completion, the mixture was filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain 4-hexyl-2,5-dimethoxybenzaldehyde (2.6 g, 10.32 mmol, yield 84%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 10.36 (s, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 3.91 (d, J = 11.6 Hz, 6H), 2.56 (t, J = 7.6 Hz, 2H), 1.77 (s, 3H), 1.54 - 1.45 (s, 6H), 0.93 (t, J = 7.2 Hz, 3H).

[0277] Step 2: Preparation of (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrovinyl)benzene To a solution of 4-hexyl-2,5-dimethoxybenzaldehyde (1 g, 3.99 mmol, 1 equivalent) in nitromethane (11.3 g, 185.12 mmol, 10 mL, 20 equivalents), NH4OAc (615.84 g, 7.99 mmol, 3 equivalents) was added. The mixture was stirred and heated at 110°C for 2 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrovinyl)benzene (1 g, 3.44 mmol, yield 84%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 8.29 (d, J = 12.8, 1H), 7.79 (d, 1H), 6.89 (d, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.63 (s, J = 8, Hz, 2H), 1.65 (m, 2H), 1.52 - 1.44 (m, 6H), 0.92 (t, J = 7.2 Hz, 3H).

[0278] Step 3: Preparation of 2-(4-hexyl-2,5-dimethoxyphenyl)ethanamine (36) (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrovinyl)benzene (1 g, 3.41 mmol, 1 equivalent) was dissolved in THF (20 mL) and LiAlH4 (517.46 mg, 13.64 mmol, 4 equivalents) was added all at once at 0°C under N2. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 11.5 hours. At completion, the mixture was cooled to 0°C. The reaction mixture was quenched at 0°C by adding H2O (1 mL) followed by 30% NaOH aqueous solution (1 mL) dropwise, then stirred, the solid was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%; 23 min) to obtain 2-(4-hexyl-2,5-dimethoxyphenyl)ethanamine (270 mg, 0.99 mmol, yield 29%, purity 97%, HCl) as a white solid. LCMS R T =2.258 min, MS calculated value: 297.46, [M+H] + = 298.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 7.89 (br. s, 3H), 6.83 (d, J = 10.8 Hz, 2H), 3.76 (d, J = 5.2 Hz, 6H), 2.89 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H), 2.51 (s, 2H), 1.48 (d, J = 7.2 Hz, 2H), 1.43 - 1.25 (d, J = 2.8 Hz, 6H),0.75(t , J = 6.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 151.51, 150.27, 123.95, 122.11, 114.27, 111.14, 56.21, 56.02, 46.84, 34.58, 30.54, 30.40, 28.00, 21.63, 17.86, 13.81.

[0279] (Example 34) Preparation of 2-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)ethaneamine (37) [ka]

[0280] Step 1: Preparation of tert-butyl(4-(4-fluorobutyl)-2,5-dimethoxyphenethyl)carbamate tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (500 mg, 1.39 mmol, 1 equivalent), 1-bromo-4-fluorobutane (860.58 mg, 5.55 mmol, 597.62 μL, 4 equivalents), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinehexafluorophosphate (15.57 A mixture of (1.52 mg, 6.94 μmol, 0.005 equivalent), dichloronickel 1,2-dimethoxyethane (1.52 mg, 6.94 μmol, 0.005 equivalent), Na2CO3 (294.22 mg, 2.78 mmol, 2 equivalents), dtbbpy (1.86 mg, 6.94 μmol, 0.005 equivalent), and TTMSS (345.13 mg, 1.39 mmol, 428.20 μL, 1 equivalent) in DME (4 mL) was degassed three times, purged with Ar, and then stirred at 25°C for 10 hours under an Ar atmosphere while irradiating with blue light (34 W LED). Upon completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 47%~77%; 20 min) to obtain tert-butyl (4-(4-fluorobutyl)-2,5-dimethoxyphenethyl)carbamate (870 mg, crude product) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 6.69 - 6.63 (m, 2H), 4.76 - 4.62 (m, 1H), 4.54 (t, J = 6.0 Hz, 1H), 4.42 (t, J = 5.6 Hz, 1H), 3.78 (d, J = 4.0 Hz, 6H), 3.40 - 3.27 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.84 - 1.64 (m, 4H), 1.44 (s, 9H)

[0281] Step 2: Preparation of 2-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)ethanamine (37) To a solution of tert-butyl(4-(4-fluorobutyl)-2,5-dimethoxyphenethyl)carbamate (750 mg, 2.11 mmol, 1 equivalent) in MeOH (20 mL), HCl / MeOH (4 M, 60 mL, 113.74 equivalents) was added at 0°C. The mixture was stirred at 15°C for 2 hours. At completion, the mixture was concentrated to obtain 2-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)ethanamine (500 mg, HCl salt) as a white solid. 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ 7.83 (br s, 3H), 6.79 (s, 2H), 4.53 - 4.49 (m, 1H), 4.41 - 4.37 (m, 1H), 3.74 (d, J = 3.2 Hz, 6H), 3.00 - 2.93 (m, 2H), 2.81 (br d, J = 8.4 Hz, 2H), 2.58 - 2.53 (m, 3H), 1.73 - 1.56 (m, 4H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ 151.33, 151.27, 129.68, 123.40, 113.86, 113.58, 83.37, 56.33, 30.04, 29.64, 28.48, 25.73.

[0282] (Example 35) Preparation of 2-(4-(butylthio)-2,5-dimethoxyphenyl)ethaneamine (38) [ka]

[0283] Step 1: Preparation of 4-(butylthio)-2,5-dimethoxybenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (5 g, 20.40 mmol, 1 equivalent) and butane-1-thiol (2.76 g, 30.60 mmol, 3.28 mL, 1.5 equivalents) in toluene (50 mL), N2-based DIEA (7.91 g, 61.21 mmol, 10.66 mL, 3 equivalents), DPPF (1.13 g, 2.04 mmol, 0.1 equivalent), and Pd2(dba)3 (1.87 g, 2.04 mmol, 0.1 equivalent) were added. The mixture was stirred and heated at 110°C for 3 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain 4-(butylthio)-2,5-dimethoxybenzaldehyde (4 g, 15.73 mmol, yield 77%) as a gray solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 10.35 (s, 1H), 7.24 (s, 1H), 6.76 (s, 1H), 3.89 - 3.92 (d, J = 12.4 Hz, 6H), 2.94 - 2.98 (t, J = 7.2 Hz, 2H), 1.72 - 1.76 (m, 2H), 1.52 - 1.55 (m, 2H), 0.95 - 0.99 (m, 2H).

[0284] Step 2: Preparation of (E)-butyl(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)sulfane To a solution of 4-(butylthio)-2,5-dimethoxybenzaldehyde (2.5 g, 9.83 mmol, 1 equivalent) in nitromethane (12.0 g, 196.6 mmol, 10.62 mL, 20 equivalents), NH4OAc (2.27 g, 29.49 mmol, 3 equivalents) was added. The mixture was stirred and heated at 110°C for 3 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1) to obtain (E)-butyl(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (1 g, 3.36 mmol, yield 34%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 8.14 (s, 1H), 7.27 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.95 - 2.98 (t, J = 14.8 Hz, 2H), 1.71 - 1.73 (m, 2H), 1.51 - 1.53 (m, 2H), 0.96 - 0.99 (t, J = 14.8 Hz, 3H).

[0285] Step 3: Preparation of 2-(4-(butylthio)-2,5-dimethoxyphenyl)ethanamine (38) To a solution of (E)-butyl(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (1 g, 3.36 mmol, 1 equivalent) in THF (20 mL), LiAlH4 (510.48 mg, 13.45 mmol, 4 equivalents) was added at 0°C under N2. The mixture was heated to 60°C and stirred at 60°C under N2 for 3 hours. At completion, the reaction mixture was quenched by adding 0.5 mL of water at 0°C and 1.5 mL of a 15% NaOH solution at 0°C, and then diluted with water (0.5 mL) at 0°C. The mixture was vigorously stirred, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%; 23 min) to obtain 2-(4-(butylthio)-2,5-dimethoxyphenyl)ethaneamine (0.26 g, 825 μmol, yield 25%, purity 97%, HCl) as a white solid. LCMS R T = 2.105 minutes, MS calculated: 269.40, [M+H] + = 270.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.02 (br s, 3H), 6.83 (d, J = 11.6 Hz, 2H), 3.76 (s, 6H), 2.83 - 2.90 (m, 6H), 1.41 - 1.54 (m, 4H), 0.88 (s, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 151.42, 150.42, 123.78, 122.74, 113.74, 111.19, 56.26, 56.11, 38.64, 30.51, 27.83, 21.42, 13.58.

[0286] (Example 36) Preparation of 2-(2,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (39) [ka]

[0287] Step 1: Preparation of (E)-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfan To a solution of 2,5-dimethoxy-4-(pentylthio)benzaldehyde (1.8 g, 6.71 mmol, 1 equivalent) in nitromethane (8.19 g, 134.14 mmol, 7.25 mL, 20 equivalents), NH4OAc (1.55 g, 20.12 mmol, 3 equivalents) was added. The mixture was stirred and heated to 110°C for 0.2 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain (E)-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfan (1 g, 3.21 mmol, yield 48%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.13 (d, J = 13.6 Hz, 1H), 7.84 (d, J = 13.6 Hz, 1H), 6.87 - 6.75 (m, 2H), 3.91 (d, J = 18.8 Hz, 6H), 2.99 - 2.92 (m, 1H), 2.96 (t, J = 7.6 Hz, 1H), 1.75 (m, J = 7.4 Hz, 2H), 1.53 - 1.33 (m, 4H), 0.96 - 0.90 (m, 1H), 0.93 (t, J = 7.2 Hz, 2H).

[0288] Step 2: Preparation of 2-(2,5-dimethoxy-4-(pentylthio)phenyl)ethanamine (39) To a solution of (E)-(2,5-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfan (1 g, 3.21 mmol, 1 equivalent) in THF (15 mL), LiAlH4 (487.54 mg, 12.85 mmol, 4 equivalents) was added all at once under N2 conditions at 0°C. The mixture was stirred at 20°C for 30 minutes, then heated to 60°C and stirred for 12 hours. At completion, the mixture was cooled to 0°C. The reaction mixture was quenched at 0°C by adding H2O (1 mL) and 30% NaOH aqueous solution (1 mL), then filtered and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×15μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%; 10 min) to obtain 2-(2,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (340 mg, 1.20 mmol, yield 37%, purity 100%, HCl) as a white solid. LCMS R T = 2.201 min, MS calculated: 283.43, [M+H] + = 284.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.01 (br s, 3H), 6.83 (d, J = 10.4 Hz, 2H), 3.76 (d, J = 6.8 Hz, 6H), 3.00 - 2.87 (m, 4H), 2.85 - 2.78 (m, 2H), 1.57 (m, J = 7.2 Hz, 2H), 1.43 - 1.35 (m, 2H), 1.33 - 1.27 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 151.35, 150.37, 123.75, 122.69, 113.67, 111.18, 56.21, 56.06, 38.57, 30.59, 30.43, 28.05, 27.78, 21.68, 13.86.

[0289] (Example 37) Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)butan-2-amine (40) [ka]

[0290] Step 1: Preparation of 4-hexyl-2,5-dimethoxybenzaldehyde 4-bromo-2,5-dimethoxybenzaldehyde (5 g, 20.4 mmol, 1 equivalent), hexylboronic acid (2.65 g, 20.4 mmol, 1 equivalent), Pd(dppf)Cl2 (746 mg, 1.02 mmol, 0.05 equivalents), and K3PO4 (8.66 g, 40.8 mmol, 2 equivalents) were degassed from toluene (50 mL) and then heated at 110°C under N2 for 12 hours. Upon completion, the mixture was filtered, concentrated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100:1 to 50:1) to obtain 4-hexyl-2,5-dimethoxybenzaldehyde (4.2 g, 16.8 mmol, yield 82%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.40 (s, 1H), 7.27 (s, 1H), 6.80 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 2.69 - 2.60 (m, 2H), 1.67 - 1.53 (m, 2H), 1.42 - 1.27 (m, 6H), 0.94 - 0.85 (m, 3H).

[0291] Step 2: Preparation of (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)benzene A mixture of 4-hexyl-2,5-dimethoxybenzaldehyde (1.8 g, 7.2 mmol, 1 equivalent) and NH4OAc (1.11 g, 14.4 mmol, 2 equivalents) in 1-nitropropane (24.9 g, 279.8 mmol, 25.0 mL, 38.9 equivalents) was heated at 115°C for 1 hour. At completion, the mixture was concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30:1) to obtain (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)benzene (1 g, 3.1 mmol, yield 43%) as a yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.26 (s, 1H), 6.78 (d, J = 15.6 Hz, 2H), 3.83 (dd, J = 1.2, 14.4 Hz, 6H), 2.87 (m, 2H), 2.69 - 2.58 (m, 1H), 2.69 - 2.58 (m, 1H), 1.67 - 1.51 (m, 3H), 1.45 - 1.25 (m, 11H), 0.97 - 0.85 (m, 3H).

[0292] Step 3: Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)butan-2-amine (40) A solution of (E)-1-hexyl-2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)benzene (1 g, 3.1 mmol, 1 equivalent) in THF (10 mL) was cooled to 0°C. Then LiAlH4 (473 mg, 12.45 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.5 mL) was added dropwise. Then 30% NaOH aqueous solution (0.5 mL) was added dropwise. After stirring until a filterable solid was formed, the mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~50%, 10 min) to obtain 1-(4-hexyl-2,5-dimethoxyphenyl)butan-2-amine (380 mg, 1.15 mmol, yield 37%, purity 100%, HCl) as a white solid. LCMS R T = 2.439 minutes, MS calculated: 293.24, [M+H] + = 294.2; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 7.96 (br s, 3H), 6.80 (d, J = 10.8 Hz, 2H), 3.73 (s, 6H), 3.33 (s, 12H), 3.28 - 3.18 (m, 1H), 2.79 (d, J = 6.8 Hz, 2H), 2.53 (s, 1H), 2.56 - 2.52 (m, 1H), 1.57 - 1.44 (m, 4H), 1.28 (s, 6H), 0.96 - 0.81 (m, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.01, 150.71, 129.78, 122.16, 114.05, 113.01, 55.85, 52.22, 32.64, 31.12, 29.67, 29.57, 28.66, 24.78, 22.08, 13.97, 9.45.

[0293] (Example 38) Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)butan-2-amine (41) [ka]

[0294] Step 1: Preparation of (E)-butyl(2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan To a solution of 4-(butylthio)-2,5-dimethoxybenzaldehyde (1.5 g, 5.90 mmol, 1 equivalent) in 1-nitropropane (10.5 g, 118 mmol, 10.5 mL, 20 equivalents), NH4OAc (1.36 g, 17.7 mmol, 3 equivalents) was added. The mixture was heated to 110°C and stirred for 3 hours. At completion, the mixture was filtered and concentrated to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain (E)-butyl(2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan (1.0 g, 3.1 mmol, yield 52%) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.24 (s, 1H), 7.27 (s, 1H), 6.79 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 2.95 - 2.98 (m, 2H), 2.85 - 2.94 (m, 2H), 1.69 - 1.75 (m, 2H), 1.50 - 1.58 (m, 2H), 1.28 - 1.32 (m, 3H), 0.95 - 0.99 (m, 3H).

[0295] Step 2: Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)butan-2-amine (41) (E)-butyl(2,5-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan (1 g, 3.1 mmol, 1 equivalent) was dissolved in THF (20 mL) and LiAlH4 (467 mg, 12.3 mmol, 4 equivalents) was added at 0°C under N2. The mixture was heated to 60°C and stirred at 60°C under N2 for 5 hours. At completion, the stirred reaction mixture was quenched by sequentially adding water (0.5 mL), a 30% NaOH solution (0.5 mL), and water (0.5 mL) at 0°C dropwise. The mixture was stirred until a smooth solid was formed, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm × 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 20%~50%, 23 min) to obtain 1-(4-(butylthio)-2,5-dimethoxyphenyl)butan-2-amine (0.32 g, 1.1 mmol, yield 35%, HCl) as a white solid. LCMS R T = 2.155 minutes, MS calculated: 297.46, [M+H] + = 298.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.05 (br s, 3H), 6.89 (s, 1H), 6.81 (s, 1H), 3.75 (s, 6H) 3.22 - 3.25 (m, 1H), 2.89 - 2.92 (m, 2H), 2.8 - 2.82 (m, 2H), 1.40 - 1.57(m, 6H), 0.87 - 0.93 (m, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 151.57, 150.23, 123. 97, 121.95, 114.36, 111.01, 56.21, 52.13, 38.64, 32.42, 30.44, 24.85, 21.37, 13.51, 9.44.

[0296] (Example 39) Preparation of 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-amine (42) [ka]

[0297] Step 1: Preparation of benzyl(1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-yl)carbamate Benzyl(1-(4-bromo-2,5-dimethoxyphenyl)butan-2-yl)carbamate (500 mg, 1.18 mmol, 1 equivalent), 1-bromo-4-fluorobutane (734 mg, 4.74 mmol, 510 uL, 4 equivalents), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+)4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridinehexafluoro A mixture of lophosphate (13.3 mg, 11.8 μmol, 0.01 equivalent), dichloronickel-1,2-dimethoxyethane (1.3 mg, 5.9 μmol, 0.005 equivalent), Na2CO3 (250.97 mg, 2.37 mmol, 2 equivalents), dtbbpy (1.6 mg, 5.9 μmol, 0.005 equivalent), and TTMSS (294 mg, 1.2 mmol, 366 μL, 1 equivalent) in DME (4 mL) was degassed three times and purged with Ar. The mixture was then stirred at 25°C for 10 hours under an Ar atmosphere while irradiating with blue light (34 W LED). At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC ([water (0.04% HCl)-ACN]; B%: 52%~82%, 20 min) to obtain benzyl (1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-yl) carbamate (610 mg, 1.5 mmol, yield 41%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.27 (s, 5H), 6.69 - 6.61 (m, 2H), 5.33 - 5.29 (m, 2H), 5.06 - 5.01 (m, 2H), 4.57 - 4.50 (m, 1H), 3.80 - 3.69 (m, 5H), 2.79 - 2.71 (m, 2H), 2.66 - 2.58 (m, 2H), 1.84 - 1.61 (m, 6H), 0.99 - 0.92 (m, 3H).

[0298] Step 2: Preparation of 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-amine (42) To a solution of benzyl(1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-yl)carbamate (510 mg, 1.22 mmol, 1 equivalent) in MeOH (30 mL) and CH3NH2 (3 mL, 30% purity), Pd(OH)2 (1 g, 7.12 mmol, 5.8 equivalents) was added. The mixture was stirred at 15°C under H2 (15 psi) for 1 hour. At completion, the reaction mixture was filtered, and the filtrate was concentrated to obtain 1-(4-(4-fluorobutyl)-2,5-dimethoxyphenyl)butan-2-amine (300 mg, 1.0 mmol, yield 83%, purity 96%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 6.70 - 6.65 (m, 2H), 4.57 - 4.51 (m, 1H), 4.45 - 4.40 (m, 1H), 3.78 (s, 6H), 3.02 - 2.93 (m, 1H), 2.88 - 2.79 (m, 1H), 2.68 - 2.60 (m, 2H), 2.52 - 2.42 (m, 1H), 1.83 - 1.74 (m, 2H), 1.71 (br dd, J = 3.2, 6.3 Hz, 2H), 1.64 - 1.48 (m, 1H), 1.48 - 1.33 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d): δ = 151.56, 151.21, 114.04, 113.06, 84.97, 83.34, 56.09, 53.15, 30.32, 30.12, 29.74, 10.63.

[0299] (Example 40) Preparation of 2-amino-3-(2,5-dimethoxy-4-pentylphenyl)propan-1-ol (43i) [ka]

[0300] Step 1: Preparation of (E)-3-(2,5-dimethoxy-4-pentylphenyl)-2-nitropropa-2-en-1-ol A mixture of 2,5-dimethoxy-4-pentylbenzaldehyde (3 g, 12.7 mmol, 1 equivalent) and 2-nitroethanol (8.09 g, 89 mmol, 6.3 mL, 7 equivalents) in AcOH (20 mL) was treated with NH4OAc (1.96 g, 25.4 mmol, 2 equivalents) and stirred at 20°C. The mixture was then heated and stirred at 90°C for 2.5 hours. The reaction mixture was partially concentrated and poured into ice water (20 mL), and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to obtain (E)-3-(2,5-dimethoxy-4-pentylphenyl)-2-nitropropa-2-en-1-ol (2g, 6.47 mmol, yield 51%) as an orange oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.46 (s, 1 H), 7.11 (s, 1 H), 6.76 (s, 1 H), 4.71 (s, 2 H), 3.86 (s, 3 H), 3.83 (s, 3 H), 2.68 - 2.60 (m, 2 H), 1.65 - 1.55 (m, 2 H), 1.42 - 1.32 (m, 4 H), 0.92 (br t, J = 6.8 Hz, 3 H).

[0301] Step 2: Preparation of (E)-tert-butyl((3-(2,5-dimethoxy-4-pentylphenyl)-2-nitroallyl)oxy)dimethylsilane (E)-3-(2,5-dimethoxy-4-pentylphenyl)-2-nitropropa-2-en-1-ol (1.5 g, 4.9 mmol, 1 equivalent) and imidazole (660 mg, 9.7 mmol, 2 equivalents) were dissolved in DCM (20 mL) and TBSCl (877 mg, 5.82 mmol, 713 μL, 1.2 equivalents) was added at 0 °C. After addition, the mixture was stirred at 20 °C for 15 hours. The mixture was filtered to remove insoluble solids. The filtrate was concentrated under vacuum to obtain a residue, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to obtain (E)-tert-butyl((3-(2,5-dimethoxy-4-pentylphenyl)-2-nitroallyl)oxy)dimethylsilane (0.8 g, 1.9 mmol, yield 39%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 8.48 (s, 1 H), 7.28 (s, 1 H), 6.75 (s, 1 H), 4.80 (s, 2 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 2.68 - 2.60 (m, 2 H), 1.66 - 1.57 (m, 2 H), 1.41 - 1.32 (m, 4 H), 0.92 (s, 9 H), 0.95 - 0.89 (m, 3 H), 0.16 (s, 6 H).

[0302] Step 3: Preparation of 2-amino-3-(2,5-dimethoxy-4-pentylphenyl)propan-1-ol (43i) A solution of (E)-tert-butyl((3-(2,5-dimethoxy-4-pentylphenyl)-2-nitroallyl)oxydimethylsilane (1.1 g, 2.6 mmol, 1 equivalent) in THF (10 mL) was degassed three times and purged with N2. LiAlH4 (394 mg, 10.4 mmol, 4 equivalents) was added to this stirred solution cooled to 0°C, and the stirred mixture was heated to 60°C for 30 minutes under an N2 atmosphere. After cooling, the mixture was quenched by sequentially adding water (0.4 mL), 15% NaOH solution (0.4 mL), and water (0.4 mL) dropwise. After stirring to obtain a smooth granular mixture, the solid was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC ([A: NH4HCO3 in 10 mM H2O; B: ACN] B%: 25%~45%, 8 min) to obtain 2-amino-3-(2,5-dimethoxy-4-pentylphenyl)propan-1-ol (300 mg, 1.05 mmol, yield 40%, purity 98%) as a grayish-white solid. LCMS R T = 2.116 minutes, MS calculated: 281.20, [M+H] + = 282.1; 1H NMR (400 MHz, chloroform-d) δ ppm 6.69 (s, 1 H), 6.65 (s, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.54 (dd, J = 4.0, 10.8 Hz, 1 H), 3.36 (dd, J = 6.4, 10.8 Hz, 1 H), 3.15 - 3.05 (m, 1 H), 2.76 (dd, J = 6.0, 13.3 Hz, 1 H), 2.65 - 2.54 (m, 3 H), 1.85 (br s, 3 H), 1.63 - 1.52 (m, 2 H), 1.41 - 1.29 (m, 4 H), 0.96 - 0.87 (m, 3 H); 13 ¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 151.39, 151.34, 130.46, 124.55, 113.99, 113.01, 66.30, 56.17, 56.12, 53.36, 35.15, 31.84, 30.22, 29.85, 22.59, 14.08.

[0303] (Example 41) Preparation of 2-(3,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (44) [ka]

[0304] Step 1: Preparation of 3,5-dimethoxy-4-(pentylthio)benzaldehyde To a mixture of 4-bromo-3,5-dimethoxybenzaldehyde (3 g, 12.2 mmol, 1 equivalent) and pentane-1-thiol (1.66 g, 15.9 mmol, 1.3 equivalents) in toluene (30 mL), DIEA (4.75 g, 36.7 mmol, 6.40 mL, 3 equivalents), DPPF (679 mg, 1.22 mmol, 0.1 equivalent), and Pd2(dba)3 (1.12 g, 1.22 mmol, 0.1 equivalent) were added all at once under N2 conditions at 20°C. The mixture was heated and stirred at 110°C for 2 hours. Upon completion, the reaction mixture was cooled to room temperature, then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:EA = 100:1 to 50:1) to obtain 3,5-dimethoxy-4-(pentylthio)benzaldehyde (3g, 11.2 mmol, yield 91%) as a brownish oily substance. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.88 (s, 1H), 7.05 - 7.00 (m, 2H), 3.92 (s, 6H), 2.90 (t, J = 7.2 Hz, 2H), 1.52 - 1.42 (m, 2H), 1.39 - 1.17 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H)

[0305] Step 2: Preparation of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfane A mixture of 3,5-dimethoxy-4-(pentylthio)benzaldehyde (3 g, 11.2 mmol, 1 equivalent) and NH4OAc (1.72 g, 22.4 mmol, 2 equivalents) in nitromethane (20.5 g, 335 mmol, 30 equivalents) was stirred at 115°C for 2 hours. Upon completion, the reaction mixture was cooled and concentrated. The residue was purified by silica gel chromatography (petroleum ether: EA = 80:1 to 60:1) to obtain (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfan (1.5 g, 4.82 mmol, yield 43%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 8.00 - 7.92 (m, 1H), 7.60 (d, J = 13.6 Hz, 1H), 6.71 (s, 2H), 3.99 - 3.91 (m, 6H), 2.97 - 2.85 (m, 2H), 1.58 - 1.47 (m, 2H), 1.41 - 1.24 (m, 4H), 0.91 - 0.82 (m, 3H)

[0306] Step 3: Preparation of 2-(3,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (44) A solution of LiAlH4 (585 mg, 15.4 mmol, 6 equivalents) in THF (60 mL) was stirred at 0°C. Then, (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(pentyl)sulfan (800 mg, 2.57 mmol, 1 equivalent) was added as a solution in THF (5 mL). The mixture was heated and stirred at 60°C for 5 hours. At completion, the mixture was cooled to 0°C. H2O (0.58 mL), 30% NaOH aqueous solution (0.58 mL), and then H2O (0.58 mL) were added dropwise to the reaction mixture. After stirring until a smooth granular solid was formed, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC ([water (0.04% HCl)-ACN]; B%: 10%~40%, 10 min) to obtain 2-(3,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (170 mg, 599 μmol, yield 12%) as a white solid. LCMS R T= 2.077 minutes, MS calculated: 283.42, [M+H] + = 284.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 8.37 (br s, 3H), 6.48 (s, 2H), 3.89 (s, 6H), 3.37 - 3.20 (m, 2H), 3.16 - 3.03 (m, 2H), 2.83 - 2.72 (m, 2H), 1.54 - 1.43 (m, 2H), 1.40 - 1.24 (m, 4H), 0.91 - 0.82 (m, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 161.26, 137.41, 104.87, 56.37, 40.83, 34.41, 34.33, 34.22, 34.07, 30.93, 29.32, 22.28, 13.99.

[0307] (Example 42) Preparation of 2-(3,5-dimethoxy-4-((4-methylpentyl)thio)phenyl)ethaneamine (45) [ka]

[0308] Step 1: Preparation of 3,5-dimethoxy-4-((4-methoxybenzyl)thio)benzaldehyde To a mixture of (4-methoxyphenyl)methanethiol (5.66 g, 36.7 mmol, 5.1 mL, 2 equivalents), 4-bromo-3,5-dimethoxybenzaldehyde (4.5 g, 18.4 mmol, 1 equivalent), and DIEA (4.75 g, 36.7 mmol, 6.4 mL, 2 equivalents) in dioxane (100 mL), Xantphos (1.06 g, 1.84 mmol, 0.1 equivalent) and Pd2(dba)3 (1.68 g, 1.84 mmol, 0.1 equivalent) were added all at once under N2 conditions at 15°C. The mixture was heated to 110°C and stirred for 3 hours. Upon completion, the reaction mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (SiO2, PE:EA = 10:1 to 0:1) to obtain 3,5-dimethoxy-4-((4-methoxybenzyl)thio)benzaldehyde (4.5 g, 14.1 mmol, yield 77%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.91 (s, 1H), 7.17 - 7.10 (m, 2H), 7.03 (s, 2H), 6.78 - 6.70 (m, 2H), 4.10 (s, 2H), 3.92 (s, 6H), 3.76 (s, 3H).

[0309] Step 2: Preparation of 4-mercapto-3,5-dimethoxybenzaldehyde To a solution of 3,5-dimethoxy-4-((4-methoxybenzyl)thio)benzaldehyde (2 g, 6.28 mmol, 1 equivalent) in DCE (10 mL), TFA (14.3 g, 125.6 mmol, 9.3 mL, 20 equivalents) was added at 0°C. The mixture was heated and stirred at 70°C for 1 hour. At completion, the solvent was removed. The crude product, 4-mercapto-3,5-dimethoxybenzaldehyde (2.07 g, crude), a black solid, was used in the next step without further purification. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.96 (s, 1H), 7.05 (s, 2H), 3.80 (s, 6H).

[0310] Step 3: Preparation of 3,5-dimethoxy-4-((4-methylpentyl)thio)benzaldehyde To a solution of crude 4-mercapto-3,5-dimethoxybenzaldehyde (1.87 g, 9.43 mmol, 1 equivalent) in DMF (100 mL), 4-methylpentylmethanesulfonate (3.40 g, 18.9 mmol, 2 equivalents) and K2CO3 (11.7 g, 84.9 mmol, 9 equivalents) were added under an N2 atmosphere. The mixture was heated and stirred at 100°C for 12 hours. Upon completion, the reaction mixture was cooled, diluted with H2O (300 mL), and extracted with EA (300 mL x 3). The combined organic layer was washed with brine (300 mL x 2), dehydrated with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to obtain 3,5-dimethoxy-4-((4-methylpentyl)thio)benzaldehyde (620 mg) as a yellow oily substance. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.94 (s, 1H), 7.08 (s, 2H), 4.02 - 3.92 (m, 6H), 3.68 - 3.61 (m, 8H), 2.96 - 2.89 (m, 2H), 1.63 - 1.54 (m, 14H), 1.32 - 1.19 (m, 15H), 0.90 (d, J = 6.4 Hz, 28H), 0.84 (d, J = 6.4 Hz, 5H).

[0311] Step 4: Preparation of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-methylpentyl)sulfan To a mixture of 3,5-dimethoxy-4-((4-methylpentyl)thio)benzaldehyde (613 mg, 2.17 mmol, 1 equivalent) in nitromethane (6.62 g, 108.5 mmol, 5.9 mL, 50 equivalents), NH4OAc (335 mg, 4.34 mmol, 2 equivalents) was added in one step at 20°C under N2. The mixture was heated, stirred at 115°C for 15 minutes, then cooled and concentrated to obtain the residue. This residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1~0:1) to obtain (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-methylpentyl)sulfan (113 mg, 313 μmol, yield 14%, crude product) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.97 (br d, J = 14.0 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.43 (td, J = 1.6, 2.8 Hz, 1H), 6.71 (s, 2H), 3.94 (s, 6H), 3.78 (br s, 2H), 2.96 - 2.84 (m, 3H), 1.60 - 1.53 (m, 5H), 1.26 (s, 3H), 0.85 (d, J = 6.4 Hz, 6H).

[0312] Step 5: Preparation of 2-(3,5-dimethoxy-4-((4-methylpentyl)thio)phenyl)ethaneamine (45) A dispersion of LiAlH4 (660 mg, 17.4 mmol, 20 equivalents) was stirred in THF (20 mL) and heated to 80°C under N2. Then, (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-methylpentyl)sulfan (283 mg, 870 μmol, 1 equivalent) from THF (5 mL) was added dropwise. The mixture was stirred at 80°C for 15 minutes. At completion, the reaction mixture was cooled and quenched by adding H2O (0.6 mL) and NaOH aqueous solution (3 M) (0.6 mL) dropwise at 0°C. After stirring to obtain a smooth dispersion, the solid was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80×40mm×3μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~33%, 7 min) to obtain the desired compound 2-(3,5-dimethoxy-4-((4-methylpentyl)thio)phenyl)ethaneamine (18 mg, 69 μmol, yield 8%, purity 89%) as a white solid. LCMS R T = 2.163 minutes, MS calculated: 297.1, [M+H] + = 298.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.10 - 7.79 (m, 3H), 6.60 - 6.51 (m, 2H), 3.87 - 3.76 (m, 6H), 3.13 - 3.00 (m, 2H), 2.92 - 2.79 (m, 2H), 2.67 (t, J = 7.2 Hz, 2H), 1.50 - 1.40 (m, 1H), 1.40 - 1.30 (m, 2H), 1.27 - 1.18 (m, 2H), 0.80 (d, J = 6.8 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 161.00, 139.52, 105.36, 56.43, 40.66, 37.68, 33.96, 33.78, 27.56, 27.35, 22.90.

[0313] Step 6: Preparation of 4-methylpentylmethanesulfonate A mixture of 4-methylpentan-1-ol (5 g, 49 mmol, 6.17 mL, 1 equivalent) and Et3N (9.9 g, 98 mmol, 13.6 mL, 2 equivalents) in 100 mL of DCM was mixed with MsCl (8.41 g, 73.4 mmol, 5.7 mL, 1.5 equivalents) dropwise at 0°C under N2. The mixture was stirred at 15°C for 12 hours, and the reaction mixture was then quenched at 15°C by adding H2O (50 mL). The product was extracted with 300 mL of DCM (100 mL x 3). The combined organic layer was washed with 300 mL of brine (100 mL x 3), dehydrated with Na2SO4, filtered, and concentrated to obtain 4-methylpentylmethanesulfonate (7.1 g, 39.4 mmol, yield 81%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 4.21 (t, J = 6.8 Hz, 2H), 3.01 (s, 3H), 1.88 - 1.68 (m, 2H), 1.65 - 1.53 (m, 1H), 1.41 - 1.22 (m, 2H), 0.91 (d, J = 6.8 Hz, 6H).

[0314] (Example 43) Preparation of 2-(4-(isopentylthio)-3,5-dimethoxyphenyl)ethaneamine (46) [ka]

[0315] Step 1: Preparation of 4-(isopentylthio)-3,5-dimethoxybenzaldehyde To a mixture of 4-bromo-3,5-dimethoxybenzaldehyde (2 g, 8.16 mmol, 1 equivalent) and 3-methylbutan-1-thiol (1.11 g, 10.6 mmol, 1.32 mL, 1.3 equivalents) in toluene (20 mL), DIEA (3.16 g, 24.5 mmol, 4.3 mL, 3 equivalents), DPPF (452 ​​mg, 817 μmol, 0.1 equivalent), and Pd2(dba)3 (747 mg, 816 μmol, 0.1 equivalent) were added in one step under N2 conditions at 20°C. The mixture was heated and stirred at 110°C for 2 hours. At completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain 4-(isopentylthio)-3,5-dimethoxybenzaldehyde (1.6 g, 5.96 mmol, yield 73%) as a brownish oily substance. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 9.94 (s, 1H), 7.20 (s, 2H), 3.89 (s, 6H), 2.90 (t, J = 7.6 Hz, 2H), 1.58 - 1.62 (m, 1H), 1.24 - 1.29 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H).

[0316] Step 2: Preparation of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(isopentyl)sulfane A mixture of 4-(isopentylthio)-3,5-dimethoxybenzaldehyde (1.8 g, 6.71 mmol, 1 equivalent) and NH4OAc (1.03 g, 13.4 mmol, 2 equivalents) in nitromethane (8.19 g, 134 mmol, 7.25 mL, 20 equivalents) was stirred and heated at 115°C for 1 hour. Upon completion, the solvent was removed to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(isopentyl)sulfan (1.17 g, 3.76 mmol, yield 56%) as a bronze-colored solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.97 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 6.71 (s, 2H), 3.92 (s, 6H), 2.92 (t, J = 8.0 Hz, 2H), 1.65 - 1.74(m, 1H), 1.37-1.43 (m, 2H), 0.87 (d, J = 6.8 Hz, 6H).

[0317] Step 3: Preparation of 2-(4-(isopentylthio)-3,5-dimethoxyphenyl)ethanamine (46) A solution of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(isopentyl)sulfan (1.17 g, 3.76 mmol, 1 equivalent) in THF (20 mL) was cooled to 0°C. LiAlH4 (570 mg, 15 mmol, 4 equivalents) was added all at once to the resulting solution under N2 at 0°C. The mixture was stirred at 0°C for 5 minutes, then heated to 60°C and stirred for 5 hours. At completion, the mixture was cooled to 0°C. H2O (0.6 mL) was then added dropwise, followed by the addition of 30% NaOH aqueous solution (0.6 mL). The resulting solid was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (HCl conditions) to obtain 2-(4-(isopentylthio)-3,5-dimethoxyphenyl)ethaneamine (210 mg, 657 μmol, yield 18%, HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.07 (br s, 3H), 6.58 (s, 2H), 3.79 (s, 6H), 3.07 (s, 2H), 2.93 - 2.82 (m, 2H), 2.73 - 2.66 (m, 2H), 1.65 (m, 1H), 1.31 - 1.20 (m, 2H), 0.81 (d, J = 6.4 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 160.45, 139.06, 107.92, 104.95, 55.97, 38.16, 33.41, 31.04, 26.52, 22.13.

[0318] (Example 44) Preparation of 2-(4-((4-fluorobutyl)thio)-3,5-dimethoxyphenyl)ethaneamine (47) [ka]

[0319] Step 1: Preparation of 4-((4-fluorobutyl)thio)-3,5-dimethoxybenzaldehyde A mixture of 4-mercapto-3,5-dimethoxybenzaldehyde (1.5 g, 7.57 mmol, 1 equivalent) and 1-bromo-4-fluorobutane (1.76 g, 11.4 mmol, 1.22 mL, 1.5 equivalents) in DMF (100 mL) was to be mixed with K₂CO₃ (10.46 g, 75.7 mmol, 10 equivalents) in one go under N₂ at 25°C. The mixture was heated to 100°C and stirred for 12 hours. At completion, the reaction mixture was diluted with H₂O (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dehydrated with Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~5:1) to obtain 4-((4-fluorobutyl)thio)-3,5-dimethoxybenzaldehyde (176 mg, 582 μmol, yield 8%, purity 90%) as a yellow oily substance. 1 H NMR (400 MHz, chloroform-d) δ = 9.96 (s, 1H), 7.13 - 7.04 (m, 2H), 4.49 (t, J = 6.0 Hz, 1H), 4.40 - 4.34 (m, 1H), 4.16 - 4.10 (m, 1H), 3.98 (s, 6H), 3.04 - 2.96 (m, 2H), 2.94 - 2.88 (m, 1H), 1.90 - 1.74 (m, 5H), 1.69 - 1.60 (m, 2H), 1.56 (br s, 2H), 1.33 - 1.21 (m, 2H).

[0320] Step 2: Preparation of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-fluorobutyl)sulfan To a mixture of 4-((4-fluorobutyl)thio)-3,5-dimethoxybenzaldehyde (200 mg, 734 μmol, 1 equivalent) in nitromethane (2.24 g, 36.7 mmol, 2 mL, 50 equivalents), NH4OAc (113 mg, 1.5 mmol, 2 equivalents) was added in one step under N2 conditions at 20°C. The mixture was heated and stirred at 115°C for 15 minutes. At completion, the solvent was removed. The residue was purified by preparative TLC (SiO2, PE:EA = 5:1) to obtain (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-fluorobutyl)sulfan (124 mg, 354 μmol, yield 48%, purity 90%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.97 - 7.84 (m, 1H), 7.52 (d, J = 13.7 Hz, 1H), 6.64 (s, 2H), 4.44 - 4.40 (m, 1H), 4.31 - 4.27 (m, 1H), 4.10 - 4.03 (m, 2H), 3.90 - 3.84 (m, 6H), 2.93 - 2.84 (m, 2H), 1.76 - 1.65 (m, 4H), 1.60 - 1.53 (m, 2H).

[0321] Step 3: Preparation of 2-(4-((4-fluorobutyl)thio)-3,5-dimethoxyphenyl)ethaneamine (47) LiAlH4 (241 mg, 6.3 mmol, 20 equivalents) was carefully added to THF (15 mL) under N2, and then heated to 80°C. A solution of (E)-(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)(4-fluorobutyl)sulfan (100 mg, 317 μmol, 1 equivalent) in THF (2 mL) was added dropwise to the LiAlH4 solution. The mixture was stirred at 85°C for 6 hours. At completion, the reaction was cooled to 0°C. H2O (0.3 mL) was added dropwise to the stirred reaction mixture at 0°C, followed by 30% NaOH (0.3 mL). After a smooth dispersion was formed, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100×25mm×3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 1%~20%, 8 min) to obtain the desired compound 2-(4-((4-fluorobutyl)thio)-3,5-dimethoxyphenyl)ethaneamine (8.5 mg, 33 μmol, yield 11%, purity 96%) as a white solid. LCMS R T = 1.827 min, MS calculated: 287.14, [M+H] + = 288.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ = 8.04 - 7.87 (m, 3H), 6.58 (s, 2H), 4.45 (br t, J = 6.0 Hz, 1H), 4.33 (br t, J = 6.0 Hz, 1H), 3.80 (s, 6H), 3.13 - 3.03 (m, 2H), 2.91 - 2.81 (m, 2H), 2.76 - 2.68 (m, 2H), 1.79 - 1.72 (m, 1H), 1.70 - 1.64 (m, 1H), 1.42 (td, J = 7.2, 14.7 Hz, 2H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ = 161.07, 139.71, 107.94, 105.43, 84.76, 83.15, 56.47, 39.13, 33.95, 33.12, 29.27, 29.07, 25.39.

[0322] (Example 45) Preparation of 4-((4-(2-aminoethyl)-2,6-dimethoxyphenyl)thio)butan-1-ol (47i) [ka]

[0323] Step 1: Preparation of 4-((4-hydroxybutyl)thio)-3,5-dimethoxybenzaldehyde A mixture of 4-bromo-3,5-dimethoxybenzaldehyde (3 g, 12.2 mmol, 1 equivalent), 4-sulfanylbutan-1-ol (1.7 g, 15.9 mmol, 1.3 equivalents), DPPF (679 mg, 1.22 mmol, 0.1 equivalent), DIEA (4.75 g, 36.7 mmol, 6.40 mL, 3 equivalents), and Pd2(dba)3 (1.12 g, 1.22 mmol, 0.1 equivalent) in toluene (20 mL) was degassed three times and purged with N2. The stirred mixture was heated and stirred at 110°C under an N2 atmosphere for 2 hours. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was treated with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (100 mL x 1), dehydrated with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 0 / 1) to obtain 4-((4-hydroxybutyl)thio)-3,5-dimethoxybenzaldehyde (2.8 g, 10.4 mmol, yield 85%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform -d) δ = 9.93 (s, 1H), 7.07 (s, 2H), 3.96 (s, 6H), 3.63 (t, J = 6.4 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 1.72 - 1.57 (m, 5H)

[0324] Step 2: Preparation of (E)-4-((2,6-dimethoxy-4-(2-nitrovinyl)phenyl)thio)butan-1-ol NH4OAc (1.78 g, 23.2 mmol, 2 equivalents) was added to a solution of 4-((4-hydroxybutyl)thio)-3,5-dimethoxybenzaldehyde (3.13 g, 11.6 mmol, 1 equivalent) in CH3NO2 (15 mL). The mixture was stirred at 115°C for 15 minutes. At completion, the solvent was removed to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 0 / 1) to obtain (E)-4-((2,6-dimethoxy-4-(2-nitrovinyl)phenyl)thio)butan-1-ol (1.09 g, 3.5 mmol, yield 30%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.96 (d, J = 13.6 Hz, 1H), 7.60 (d, J = 13.6 Hz, 1H), 6.71 (s, 2H), 3.94 (s, 6H), 3.65 (t, J = 6.4 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 1.72 - 1.65 (m, 3H), 1.65 - 1.57 (m, 3H)

[0325] Step 3: Preparation of 4-((4-(2-aminoethyl)-2,6-dimethoxyphenyl)thio)butan-1-ol (47i) (E)-4-((2,6-dimethoxy-4-(2-nitrovinyl)phenyl)thio)butan-1-ol (300 mg, 957 μmol, 1 equivalent) was dissolved in THF (15 mL) and LiAlH4 (218 mg, 5.7 mmol, 6 equivalents) was added at 0°C. The mixture was heated to 80°C and stirred at 80°C for 5 hours. At completion, the mixture was cooled to 0°C. Water (0.2 mL) was added dropwise to the reaction mixture and stirred for 5 minutes. Then 30% NaOH aqueous solution (0.2 mL) was added dropwise and stirred. After stirring, the resulting dispersion was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 5%~30%, 8 min) to obtain 4-((4-(2-aminoethyl)-2,6-dimethoxyphenyl)thio)butan-1-ol (25 mg) as a colorless oil.1 H NMR (400 MHz, methanol-d4) δ 6.54 (s, 2H), 4.86 (s, 6H), 3.87 - 3.83 (m, 6H), 3.50 (t, J = 6.4 Hz, 2H), 2.94 - 2.88 (m, 2H), 2.79 - 2.71 (m, 4H), 1.67 - 1.56 (m, 2H), 1.54 - 1.43 (m, 2H); 13 ¹³C NMR (10¹ MHz, chloroform -d) δ values: 160.80, 142.93, 107.23, 105.32, 67.50, 60.76, 56.35, 43.87, 33.62, 31.96, 26.27, 25.61.

[0326] (Example 46) Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)butan-2-amine (48) [ka]

[0327] Step 1: Preparation of (E)-butyl(2,6-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan A mixture of 4-(butylthio)-3,5-dimethoxybenzaldehyde (1.8 g, 7.1 mmol, 1 equivalent) and NH4OAc (1.09 g, 14.2 mmol, 2 equivalents) stirred in 1-nitropropane (14 mL) was degassed three times and purged with N2, and then the mixture was stirred under an N2 atmosphere at 100°C for 2 hours. At completion, the solvent was removed. The residue was purified by column chromatography to obtain (E)-butyl(2,6-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan (0.7 g, 2.0 mmol, yield 29%, purity 95%) as a yellow oil. 1¹H NMR (400 MHz, chloroform-d) δ ppm 7.99 (s, 1H), 6.61 (s, 2H), 3.92 (s, 6H), 2.92 - 2.87 (m, 4H), 1.53 - 1.40 (m, 4H), 1.32 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H).

[0328] Step 2: Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)butan-2-amine (48) A stirred solution of (E)-butyl(2,6-dimethoxy-4-(2-nitrobuta-1-en-1-yl)phenyl)sulfan (0.7 g, 2.15 mmol, 1 equivalent) in THF (10 mL) was degassed three times and purged with N2, and then LiAlH4 (327 mg, 8.6 mmol, 4 equivalents) was added at 0°C. The mixture was then heated at 60°C under an N2 atmosphere for 5 hours. At completion, the reaction mixture was quenched by adding water (0.3 mL) dropwise at 0°C, and then by adding 30% NaOH aqueous solution (0.4 mL) dropwise at 0°C. After stirring, the resulting dispersion was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~55%, 10 min) to obtain 1-(4-(butylthio)-3,5-dimethoxyphenyl)butan-2-amine (280 mg, 815 μmol, yield 38%, purity 97%, HCl) as a grayish-white solid. LCMS R T = 2.043 minutes, MS calculated: 297.46, [M+H] + = 298.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.08 (br s, 3H), 6.60 (s, 2H), 3.79 (s, 6H), 3.33 (s, 3H), 2.97 - 2.75 (m, 2H), 2.74 - 2.54 (m, 2H), 1.67 - 1.44 (m, 2H), 1.34 (s, 4H), 0.94 (t, J = 7.2 Hz, 3H), 0.88 - 0.73 (m, 3H);13 C NMR (101 MHz, DMSO-d6, HCl salt); δ ppm 160.90, 138.84, 108.46, 106.09, 56.48, 53.36, 41.24, 41.11, 38.68, 33.17, 31.68, 25.34, 21.55, 13.98, 9.90.

[0329] (Example 47) Preparation of 2-(3,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)ethaneamine (49) [ka]

[0330] Step 1: Preparation of 3,5-dimethoxy-4-pentylbenzaldehyde A mixture of 4-bromo-3,5-dimethoxybenzaldehyde (3.0 g, 12.2 mmol, 1 equivalent), K3PO4 (7.8 g, 36.7 mmol, 3 equivalents), pentylboronic acid (2.13 g, 18.4 mmol, 1.5 equivalents), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (1.01 g, 2.45 mmol, 0.2 equivalents), and Pd(OAc)2 (275 mg, 1.22 mmol, 0.1 equivalent) in toluene (25 mL) was stirred and heated at 105°C under N2 for 2 hours. The mixture was stirred at 80°C for 12 hours. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain 3,5-dimethoxy-4-pentylbenzaldehyde (2 g, 8.5 mmol, yield 69%) as a yellow oily substance. 1 ¹H NMR (400 MHz, chloroform -d): δ = 9.91 (s, 1H), 7.06 (s, 2H), 3.89 (s, 6H), 2.73 - 2.64 (m, 2H), 1.55 - 1.42 (m, 2H), 1.34 (br dd, J = 3.6, 7.2 Hz, 4H), 0.94 - 0.86 (m, 3H).

[0331] Step 2: Preparation of (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene A mixture of 3,5-dimethoxy-4-pentylbenzaldehyde (2 g, 8.5 mmol, 1 equivalent) and NH4OAc (1.30 g, 16.9 mmol, 2 equivalents) in nitromethane (15.5 g, 254 mmol, 13.7 mL, 30 equivalents) was stirred at 115°C for 2 hours. Upon completion, the reaction mixture was concentrated to obtain a residue, which was purified by silica gel chromatography (PE:EA = 80:1 to 60:1) to obtain (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene (1.7 g, 6.1 mmol, yield 72%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.97 (d, J = 13.6 Hz, 1H), 7.59 (d, J = 13.6 Hz, 1H), 6.69 (s, 2H), 3.86 (s, 6H), 2.73 - 2.59 (m, 2H), 1.52 - 1.42 (m, 2H), 1.33 (br d, J = 3.2 Hz, 4H), 0.90 (t, J = 6.8 Hz, 3H).

[0332] Step 3: Preparation of 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine A solution of (E)-1,3-dimethoxy-5-(2-nitrovinyl)-2-pentylbenzene (600 mg, 2.15 mmol, 1 equivalent) in THF (20 mL) was cooled to 0°C. Then LiAlH4 (489 mg, 12.9 mmol, 6 equivalents) was added. The mixture was stirred and then heated to 60°C for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.5 mL) was added dropwise and the mixture was stirred. Then 30% NaOH aqueous solution (0.5 mL) was added and the mixture was stirred. After stirring to make a smooth dispersion, the solid was filtered and the filtrate was concentrated to obtain 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine (500 mg, yield 89%) as a white solid. This substance was used directly in the next step.

[0333] Step 4: Preparation of 2-(3,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)ethaneamine (49) To a solution of 2-(3,5-dimethoxy-4-pentylphenyl)ethaneamine (400 mg, 1.6 mmol, 1 equivalent) and 2-methoxybenzaldehyde (65 mg, 477 μmol, 0.3 equivalents) in DCE (10 mL), AcOH (9.56 mg, 159 μmol, 0.1 equivalent) was added. The mixture was stirred at 15°C for 1 hour. Then NaBH(OAc)3 (1.01 g, 4.77 mmol, 3 equivalents) was added, and the mixture was stirred at 15°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution, stirred, and then extracted with DCM (10 mL x 2). The organic layer was washed with brine (15 mL), dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC ([water (0.04% HCl)-ACN]; B%: 24%~54%, 20 min) to obtain 2-(3,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)ethaneamine (260 mg, yield 24%, HCl) as a white solid. LCMS R T = 2.494 minutes, MS calculated: 371.51, [M+H] + = 372.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 9.54 - 9.23 (m, 2H), 7.43 - 7.30 (m, 2H), 7.03 - 6.92 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.30 (s, 2H), 4.16 (br s, 2H), 3.79 - 3.69 (m, 6H), 3.63 (s, 3H), 3.10 (br s, 4H), 2.64 - 2.51 (m, 2H), 1.50 - 1.38 (m, 2H), 1.37 - 1.24 (m, 4H), 0.89 (br t, J = 6.8 Hz, 3H); 13¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 156.66, 130.12, 129.41, 119.22, 108.53, 102.28, 53.90, 30.10, 26.95, 20.80, 20.62, 12.15.

[0334] (Example 48) Preparation of 2-(((4-(butylthio)-3,5-dimethoxyphenethyl)aminomethyl)phenol (50) [ka]

[0335] Step 1: Preparation of (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan To a mixture of 4-(butylthio)-3,5-dimethoxybenzaldehyde (3 g, 11.8 mmol, 1 equivalent) in nitromethane (13 mL), NH4OAc (1.82 g, 23.6 mmol, 2 equivalents) was added, and the mixture was heated and stirred at 115°C under an N2 atmosphere for 0.5 hours. Upon completion, the reaction mixture was concentrated to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1) to obtain (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (2.2 g, 6.66 mmol, yield 56%, purity 90%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.98 - 7.94 (d, J = 13.6 Hz, 1H), 7.62 - 7.58 (d, J = 13.6 Hz, 1H), 6.71 (s, 2H), 3.94 (s, 6H), 2.92 (t, J = 7.6 Hz, 2H), 1.53 - 1.37 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H).

[0336] Step 2: Preparation of 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine A solution of (E)-butyl(2,6-dimethoxy-4-(2-nitrovinyl)phenyl)sulfan (2 g, 6.73 mmol, 1 equivalent) in THF (10 mL) was degassed three times and purged with N2. LiAlH4 (1.02 g, 26.9 mmol, 4 equivalents) was added at 0°C, and the mixture was heated and stirred at 60°C for 5 hours under an N2 atmosphere. At completion, the reaction mixture was quenched by adding water (1 mL) dropwise at 0°C, followed by adding 30% NaOH aqueous solution (1 mL) dropwise at 0°C. After stirring to obtain a smooth dispersion, the mixture was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (0.8 g, 2.67 mmol, yield 40%, purity 90%) as a yellow oily substance. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 6.59 (s, 2H), 4.69 (s, 2H), 3.89 (s, 6H), 2.84 - 2.76 (m, 2H), 1.49 - 1.36 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H).

[0337] Step 3: Preparation of 2-(((4-(butylthio)-3,5-dimethoxyphenethyl)amino)methyl)phenol (50) A mixture of 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (0.3 g, 1.11 mmol, 1 equivalent), 2-hydroxybenzaldehyde (136 mg, 1.11 mmol, 118 uL, 1 equivalent), and NaBH3CN (105 mg, 1.67 mmol, 1.5 equivalents) in MeOH (3 mL) was degassed three times, purged with N2, and then stirred at 25°C under an N2 atmosphere for 12 hours. At completion, the reaction mixture was quenched by adding water (5 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100×25mm×3um; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%~45%, 8 min) to obtain 2-(((4-(butylthio)-3,5-dimethoxyphenethyl)amino)methyl)phenol (150 mg, 348 μmol, yield 31%, purity 96%, HCl) as a grayish-white solid. LCMS R T = 2.180 min, MS calculated: 375.52, [M+H] + = 376.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 10.25 (br s, 1H), 9.01 (br s, 2H), 7.40-7.38 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.56 (s, 2H), 4.11 (s, 2H), 3.83 (s, 6H), 3.17 (s, 2H), 3.02 - 2.91 (m, 2H), 2.72 - 2.65 (m, 2H), 1.37 - 1.28 (m, 4H), 0.84 - 0.77 (m, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 161.00, 156.52, 139.52, 132.08, 130.95, 119.56, 118.60, 115.87, 108.43, 105.33, 56.47, 47.76, 45.60, 41.35, 41.31, 41.27, 41.09, 33.18, 32.29, 31.67, 21.53, 13.98.

[0338] (Example 49) Preparation of 2-(3,5-dimethoxy-4-(pentylthio)phenyl)-N-(2-methoxybenzyl)ethaneamine (51) [ka]

[0339] Step 1: Preparation of 2-(3,5-dimethoxy-4-(pentylthio)phenyl)-N-(2-methoxybenzyl)ethanamine (51) To a solution of 2-(3,5-dimethoxy-4-(pentylthio)phenyl)ethaneamine (300 mg, 1.06 mmol, 1 equivalent) in MeOH (4 mL), Et3N (1071 mg, 10.6 mmol, 10 equivalents) was added, followed by 2-methoxybenzaldehyde (130 mg, 953 μmol, 0.9 equivalents). The mixture was stirred at 25°C for 2 hours. Then NaBH3CN (67 mg, 1.06 μmol, 1 equivalent) was added. The mixture was stirred at 25°C for 12 hours. At completion, the MeOH was removed, the reaction product was diluted in H2O (5 mL), and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC ([water (0.05% HCl)-ACN]; B%: 20%~40%, 8 min) to obtain 2-(3,5-dimethoxy-4-(pentylthio)phenyl)-N-(2-methoxybenzyl)ethaneamine (231 mg, 572 μmol, yield 48%, HCl) as a white solid. LCMS R T = 2.340 min, MS calculated: 403.22, [M+H] += 404.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 9.37 (ddd, J = 0.8, 4.8, 7.2 Hz, 2H), 7.42 - 7.29 (m, 2H), 6.96 (br t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.36 (s, 2H), 4.14 (br s, 2H), 3.83 (s, 6H), 3.68 (s, 3H), 3.12 (br s, 4H), 2.78 (t, J = 7.6 Hz, 2H), 1.60 - 1.45 (m, 2H), 1.42 - 1.17 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 161.31, 157.61, 137.88, 132.05, 131.48, 121.16, 118.00, 110.57, 109.59, 104.64, 56.38, 55.50, 47.36, 47.21, 34.07, 32.78, 30.95, 29.35, 22.31, 14.01.

[0340] (Example 50) Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (52) [ka]

[0341] Step 1: Preparation of 4-(butylthio)-3,5-dimethoxybenzaldehyde To a mixture of 4-bromo-3,5-dimethoxybenzaldehyde (3.5 g, 14.3 mmol, 1 equivalent) and butane-1-thiol (1.67 g, 18.6 mmol, 2.0 mL, 1.3 equivalents) in toluene (30 mL), DIEA (5.54 g, 43 mmol, 7.46 mL, 3 equivalents), DPPF (792 mg, 1.43 mmol, 0.1 equivalent), and Pd2(dba)3 (1.31 g, 1.43 mmol, 0.1 equivalent) were added all at once under N2 conditions at 20°C. The mixture was heated to 110°C and stirred for 2 hours. At completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to obtain the product 4-(butylthio)-3,5-dimethoxybenzaldehyde (2.5 g, 9.83 mmol, yield 69%) as a yellow oily substance. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.97 - 9.91 (m, 1H), 7.07 (s, 2H), 3.97 (s, 6H), 3.00 - 2.91 (m, 2H), 1.55 - 1.37 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H).

[0342] Step 2: Preparation of (E)-butyl(2,6-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan To a mixture of 4-(butylthio)-3,5-dimethoxybenzaldehyde (2.3 g, 9.04 mmol, 1 equivalent) in nitroethane (16.97 g, 226 mmol, 16.16 mL, 25 equivalents), NH4OAc (1.39 g, 18.1 mmol, 2 equivalents) was added in one step under N2 conditions at 20°C. The mixture was heated to 115°C and stirred for 2 hours. At completion, the solvent was removed, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to obtain the product (E)-butyl(2,6-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (2.1 g, 6.74 mmol, yield 75%) as a yellow solid. 1¹H NMR (400 MHz, chloroform-d): δ = 8.10 - 7.99 (m, 1H), 6.60 (s, 2H), 3.91 (s, 6H), 2.88 (t, J = 7.6 Hz, 2H), 2.49 (d, J = 1.2 Hz, 3H), 1.55 - 1.35 (m, 4H), 0.88 (t, J = 7.2 Hz, 3H).

[0343] Step 3: Preparation of 1-(4-butylsulfanyl-3,5-dimethoxyphenyl)propan-2-amine A solution of (E)-butyl(2,6-dimethoxy-4-(2-nitropropa-1-en-1-yl)phenyl)sulfan (1.0 g, 3.21 mmol, 1 equivalent) in THF (30 mL) was stirred and cooled to 0°C. Then LiAlH4 (488 mg, 12.9 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred for 5 hours. At completion, the reaction mixture was quenched by adding H2O (0.5 mL) dropwise at 0°C, followed by adding 30% NaOH aqueous solution (0.5 mL) dropwise. The mixture was stirred to make a smooth dispersion, then filtered, and the filtrate was concentrated to obtain 1-(4-(butylthio)-3,5-dimethoxyphenyl)propan-2-amine (1.13 g, crude) as a yellow oil. This substance was used directly in the next step.

[0344] Step 4: Preparation of 1-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (52) To a solution of 1-(4-(butylthio)-3,5-dimethoxyphenyl)propan-2-amine (540 mg, 1.91 mmol, 1 equivalent) and 2-methoxybenzaldehyde (156 mg, 1.14 mmol, 0.6 equivalents) in DCE (20 mL), AcOH (12 mg, 191 μmol, 10.9 μL, 0.1 equivalent) was added at 20°C under N2. The mixture was stirred at 20°C for 2 hours. The mixture was then treated with NaBH(OAc)3 (1.21 g, 5.72 mmol, 3 equivalents) in a single dose at 20°C under N2. The mixture was stirred at 20°C for 12 hours. At completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 25%~55%, 10 min) to obtain 1-(4-(butylthio)-3,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (337 mg, 587 μmol, yield 43%, purity 100%, HCl) as a grayish-white oily substance. LCMS R T = 2.332 minutes, MS calculated: 403.22, [M+H] + = 404.1; 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ = 9.16 - 8.92 (m, 2H), 7.54 (dd, J = 1.2, 7.5 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.55 (s, 2H), 4.28 - 4.12 (m, 2H), 3.85 - 3.78 (m, 9H), 3.49 (br d, J = 4.4 Hz, 2H), 3.26 (br dd, J = 4.4, 13.1 Hz, 1H), 2.83 - 2.64 (m, 3H), 1.37 - 1.30 (m, 4H), 1.23 (d, J = 6.4 Hz, 3H), 0.86 - 0.78 (m, 3H); 13C NMR (101 MHz, DMSO-d6, HCl salt) δ = 160.95, 158.00, 139.10, 132.01, 131.28, 120.88, 120.41, 111.57, 105.83, 56.50, 56.05, 55.01, 43.14, 39.19, 33.12, 31.67, 21.51, 16.11, 13.97.

[0345] (Example 51) Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (53) [ka]

[0346] Step 1: Preparation of 1-(4-hexyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (53) To a mixture of 1-(4-hexyl-2,5-dimethoxyphenyl)propan-2-amine (440 mg, 1.39 mmol, 1 equivalent, HCl) in MeOH (5 mL), Et3N (1.41 g, 13.9 mmol, 1.94 mL, 10 equivalents) was added until the pH of the reaction mixture was approximately 8. Then 2-methoxybenzaldehyde (171 mg, 1.25 mmol, 0.9 equivalents) was added at 20°C. The mixture was stirred for 1 hour, then treated with NaBH3CN (87.5 mg, 1.39 mmol, 1 equivalent), and stirred at 20°C for 12 hours. The reaction mixture was diluted in H2O (5 mL), concentrated, and MeOH was removed. The residue was diluted in H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 40%~70%, 10 min) to obtain 1-(4-hexyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (267 mg, 667 μmol, yield 48%) as a white solid. 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.90 - 8.51 (m, 2H), 7.49 - 7.45 (m, 1H), 7.45 - 7.40 (m, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 4.19 (s, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.38 (br s, 1H), 3.10 (dd, J = 4.4, 13.2 Hz, 1H), 2.70 (dd, J =10.4, 13.2 Hz, 1H), 1.49 d, J = 7.6 Hz, 2H), 1.27 (d, J = 2.4 Hz, 6H), 1.17 (d, J = 6.4 Hz, 3H), 0.91 - 0.81 (m, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.52, 150.84, 150.77, 131.39, 130.84, 129.96, 122.15, 120.42, 113.86, 113.09, 111.08, 55.90, 55.84, 55.57, 53.62, 33.13, 31.11, 29.65, 29.57, 28.63, 22.07, 15.67, 13.96.

[0347] (Example 52) Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (54) [ka]

[0348] Step 1: Preparation of 4-(butylthio)-2,5-dimethoxybenzaldehyde A mixture of 4-bromo-2,5-dimethoxybenzaldehyde (3 g, 12.24 mmol, 1 equivalent), butane-1-thiol (1.44 g, 15.9 mmol, 1.70 mL, 1.3 equivalents), DPPF (679 mg, 1.22 mmol, 0.1 equivalent), DIEA (4.75 g, 36.7 mmol, 6.40 mL, 3 equivalents), and Pd2(dba)3 (1.12 g, 1.22 mmol, 0.1 equivalent) in toluene (20 mL) was degassed three times and purged with N2. The resulting mixture was heated to 110°C and stirred under an N2 atmosphere for 2 hours. At completion, the reaction mixture was filtered and the filtrate was concentrated. Water (100 mL) was added to the residue, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (60 mL x 1), dehydrated with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 0 / 1) to obtain 4-(butylthio)-2,5-dimethoxybenzaldehyde (2.38 g, 9.36 mmol, yield 76%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ values: 10.37 (s, 1H), 7.25 (s, 1H), 6.78 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 2.97 (t, J = 7.2 Hz, 2H), 1.80 - 1.70 (m, 2H), 1.59 - 1.48 (m, 3H), 0.98 (t, J = 7.2 Hz, 3H).

[0349] Step 2: Preparation of (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan NH4OAc (1.44 g, 18.7 mmol, 2 equivalents) was added to a solution of 4-(butylthio)-2,5-dimethoxybenzaldehyde (2.38 g, 9.36 mmol, 1 equivalent) in nitroethane (20 mL). The mixture was heated to 110 °C and stirred for 3 hours. At completion, the solvent was removed to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (1.68 g, 5.40 mmol, yield 58%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 6.80 (d, J = 8.0 Hz, 2H), 3.87 (d, J = 1.2 Hz, 6H), 2.96 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.72 (quintet, J = 7.2 Hz, 2H), 1.57 - 1.46 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H).

[0350] Step 3: Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine A solution of (E)-butyl(2,5-dimethoxy-4-(2-nitropropane-1-en-1-yl)phenyl)sulfan (1.58 g, 5.07 mmol, 1 equivalent) in THF (20 mL) was stirred at 0°C and treated with LiAlH4 (770 mg, 20.3 mmol, 4 equivalents). After 15 minutes at 15°C, the mixture was heated to 70°C and stirred for 5 hours. At completion, the mixture was cooled to 0°C and water (1 mL) was added dropwise while stirring. After stirring for about 5 minutes, 30% NaOH aqueous solution (1 mL) was added dropwise and stirred to obtain a smooth dispersion. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine (1.56 g, crude product) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 6.84 (s, 1H), 6.68 (s, 1H), 3.87 - 3.83 (m, 3H), 3.81 - 3.77 (m, 3H), 3.28 - 3.16 (m, 1H), 2.89 (t, J = 7.2 Hz, 2H), 2.72 (dd, J = 5.2, 13.0 Hz, 1H), 2.60 - 2.47 (m, 1H), 1.68 - 1.58 (m, 2H), 1.52 - 1.43 (m, 2H), 1.13 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H).

[0351] Step 4: Preparation of 1-(4-(butylthio)-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (54) A stirred solution of 1-(4-(butylthio)-2,5-dimethoxyphenyl)propan-2-amine (400 mg, 1.41 mmol, 1 equivalent) and 2-methoxybenzaldehyde (154 mg, 1.13 mmol, 0.8 equivalents) in DCE (15 mL) was treated with AcOH (8.5 mg, 141 μmol, 8.1 μL, 0.1 equivalent). The mixture was stirred at 20°C for 1 hour. Then NaBH(OAc)3 (1.05 g, 4.94 mmol, 3.5 equivalents) was added. The mixture was stirred at 20°C for 10 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (50 mL x 2). The organic layer was dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 45%~85%, 10 min) to obtain 1-(4-(butylthio)-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)propan-2-amine (260 mg) as a yellow oily substance. 1H NMR (400 MHz, chloroform-d) δ 7.23 - 7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.81 - 6.75 (m, 2H), 6.64 (s, 1H), 3.88 - 3.61 (m, 11H), 2.88 (d, J = 7.2 Hz, 2H), 2.77 - 2.69 (m, 1H), 2.67 - 2.61 (m, 1H), 2.01 (s, 1H), 1.64 (quintet, J = 7.2 Hz, 2H), 1.47 (qd, J = 7.2, 14.8 Hz, 2H), 1.14 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d) δ values: 157.63, 151.89, 151.66, 129.90, 128.16, 126.89, 122.50, 120.19, 114.12, 113.46, 110.00, 56.40, 56.09, 54.97, 51.59, 46.89, 38.04, 32.45, 31.24, 22.03, 20.15, 13.68.

[0352] (Example 53) Preparation of 2-(((1-(2,5-dimethoxy-4-pentylphenyl)propan-2-yl)aminomethyl)phenol (55) [ka]

[0353] Step 1: Preparation of 1,4-dimethoxy-2-[(E)-2-nitropropa-1-enyl]-5-pentylbenzene To a mixture of 2,5-dimethoxy-4-pentylbenzaldehyde (2 g, 8.46 mmol, 1 equivalent) in nitroethane (15.75 g, 210 mmol, 15 mL, 25 equivalents), NH4OAc (1.30 g, 16.9 mmol, 2 equivalents) was added at 20°C. The mixture was then heated to 115°C and stirred for 1.5 hours. Upon completion, the reaction product was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 80:1 to 50:1) to obtain (E)-1,4-dimethoxy-2-(2-nitropropane-1-en-1-yl)-5-pentylbenzene (1.5 g, 5.11 mmol, yield 60%) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ ppm 8.29 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 2.70 - 2.56 (m, 2H), 2.43 (s, 4H), 1.69 - 1.55 (m, 3H), 1.45 - 1.30 (m, 5H), 0.92 (t, J = 6.8 Hz, 3H).

[0354] Step 2: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine A stirred solution of (E)-1,4-dimethoxy-2-(2-nitropropane-1-en-1-yl)-5-pentylbenzene (1.5 g, 5.11 mmol, 1 equivalent) in THF (15 mL) was cooled to 0°C, and then LiAlH4 (776 mg, 20.5 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.6 mL) was added dropwise, followed by 30% NaOH aqueous solution (0.6 mL). After stirring to make a smooth mixture, the solid was filtered, and the filtrate was concentrated to obtain 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (800 mg, 3.01 mmol, yield 59%) as a yellow oil. 1¹H NMR (400 MHz, chloroform -d) δ ppm 6.73 (s, 1H), 6.71 (s, 1H), 4.46 (s, 1H), 3.00 (m, 1H), 2.56 - 2.40 (m, 5H), 1.58 - 1.45 (m, 3H), 1.41 - 1.17 (m, 7H), 0.94 (d, J = 6.4 Hz, 3H), 0.87 (t, J = 6.8 Hz, 1H).

[0355] Step 3: Preparation of 2-(((1-(2,5-dimethoxy-4-pentylphenyl)propan-2-yl)aminomethyl)phenol (55) A solution of 1-(2,5-dimethoxy-4-pentylphenyl)propan-2-amine (522 mg, 1.97 mmol, 1 equivalent), 2-hydroxybenzaldehyde (204 mg, 1.67 mmol, 178 μL, 0.85 equivalents), and AcOH (11.8 mg, 197 μmol, 11.3 μL, 0.1 equivalent) in DCE (8 mL) was stirred at 20°C for 1 hour. Then NaBH(OAc)3 (1.04 g, 4.92 mmol, 2.5 equivalents) was added. The mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 30%~60%, 10 min) to obtain 2-(((1-(2,5-dimethoxy-4-pentylphenyl)propan-2-yl)aminomethyl)phenol (430 mg, 1.05 mmol, yield 54%, HCl) as a brown solid. 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 10.35 (s, 1H), 9.19 (d, J =4.8 Hz, 1H), 8.97 (d, J = 4.8 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 2H), 4.14 (s, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 3.44 - 3.28 (m, 3H), 3.15 (dd, J = 3.6, 12.8 Hz, 1H), 2.72 (dd, J = 10.4, 12.8 Hz, 1H), 2.52 - 2.49 (m, 2H), 1.50 (m, 2H), 1.35 - 1.21 (m, 4H), 1.16 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 156.11, 150.86, 150.76, 131.53, 130.23, 129.83, 122.42, 118.97, 118.31, 115.43, 113.81, 113.06, 55.89, 55.82, 53.26, 42.51, 33.06, 31.22, 29.64, 29.30, 21.98, 15.62, 13.94.

[0356] (Example 54) Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)butan-2-amine (56) [ka]

[0357] Step 1: Preparation of (E)-1,4-dimethoxy-2-(2-nitrobuta-1-en-1-yl)-5-pentylbenzene 2,5-Dimethoxy-4-pentylbenzaldehyde (2 g, 8.46 mmol, 1 equivalent) was mixed with 1-nitropropane (10 mL) and NH4OAc (1.30 g, 16.9 mmol, 2 equivalents) at 20°C. The mixture was then heated to 115°C and stirred for 1.5 hours. At completion, the reaction product was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 50:1) to obtain (E)-1,4-dimethoxy-2-(2-nitrobuta-1-en-1-yl)-5-pentylbenzene (1.5 g, 4.88 mmol, yield 58%) as an orange oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 10.41 (s, 1H), 8.25 (s, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 3.84 (s, 4H), 3.81 (s, 4H), 2.87 (mz, 2H), 2.69 - 2.58 (m, 3H), 1.65 - 1.54 (m, 5H), 1.36 (td, J = 3.6, 7.2 Hz, 6H), 1.33 - 1.25 (m, 1H), 0.98 - 0.88 (m, 5H).

[0358] Step 2: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine A stirred solution of (E)-1,4-dimethoxy-2-(2-nitrobuta-1-en-1-yl)-5-pentylbenzene (1.5 g, 4.88 mmol, 1 equivalent) in THF (15 mL) was cooled to 0°C, and then LiAlH4 (741 mg, 20 mmol, 4 equivalents) was added. The mixture was heated to 60°C and stirred for 5 hours. At completion, the mixture was cooled to 0°C. Then H2O (0.6 mL) was added dropwise, followed by 30% NaOH aqueous solution (0.6 mL). The mixture was stirred until a smooth dispersion was formed, the solid was filtered and concentrated to obtain 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (1 g, 3.58 mmol, yield 73%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.05 - 6.94 (m, 1H), 6.78 - 6.67 (m, 1H), 4.45 (s, 1H), 3.77 - 3.62 (m, 3H), 3.65 - 3.55 (m, 1H), 2.82 - 2.68 (m, 1H), 2.60 (dd, J = 5.6, 12.8 Hz, 1H), 2.36 (dd, J = 7.6, 12.8 Hz, 1H), 1.81 - 1.71 (m, 1H), 1.60 - 1.44 (m, 1H), 1.42 - 1.23 (m, 4H), 1.23 - 1.10 (m, 1H), 0.93 - 0.81 (m, 3H).

[0359] Step 3: Preparation of 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)butan-2-amine (56) A solution of 1-(2,5-dimethoxy-4-pentylphenyl)butan-2-amine (600 mg, 2.15 mmol, 1 equivalent), 2-methoxybenzaldehyde (220 mg, 1.61 mmol, 0.75 equivalents), and AcOH (13 mg, 215 μmol, 12.3 μL, 0.1 equivalent) in DCE (3 mL) was stirred at 20°C for 1 hour. Then, NaBH(OAc)3 (910 mg, 4.29 mmol, 2 equivalents) was added, and the mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 40%~70%, 10 min) to obtain 1-(2,5-dimethoxy-4-pentylphenyl)-N-(2-methoxybenzyl)butan-2-amine (410 mg, 940 μmol, yield 48%, HCl) as a colorless oil. 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.69 (br s, 2H), 7.49 - 7.39 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.78 (s, 2H), 4.16 (t, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.68 (s, 3H), 3.25 (d, J = 3.6 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.92 - 2.82 (m, 1H), 2.53 (s, 2H), 1.67 - 1.57 (m, 2H), 1.51 (td, J = 7.2, 14.8 Hz, 2H), 1.34 - 1.22 (m, 4H), 0.88 (td, J = 7.2, 11.6 Hz, 6H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.56, 150.89, 150.79, 131.61, 130.83, 129.97, 122.21, 120.38, 119.58, 113.84, 113.08, 110.98, 58.46, 55.92, 55.78, 55.48, 43.29, 31.15, 30.61, 29.56, 29.23, 22.51, 21.92, 13.89, 9.13.

[0360] (Example 55) Preparation of N-benzyl-2-(2,5-dimethoxy-4-propylphenyl)ethanamine (57) [ka]

[0361] Step 1: Preparation of tert-butyl(2,5-dimethoxy-4-propylphenethyl)carbamate To a mixture of tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (3.8 g, 10.6 mmol, 1 equivalent), propylboronic acid (2.78 g, 31.7 mmol, 3 equivalents), and Cs2CO3 (10.31 g, 31.7 mmol, 3 equivalents) stirred in 2-methyl-2-butanol (20 mL) and H2O (2 mL), [2-(2-aminophenyl)phenyl]-chloropalladium;bis(1-adamantyl)-butylphosphine (705 mg, 1.05 mmol, 0.1 equivalent) was added all at once under N2 at 20°C. The mixture was heated and stirred at 80°C for 12 hours. At completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain tert-butyl(2,5-dimethoxy-4-propylphenethyl)carbamate (2.2 g, 6.80 mmol, yield 65%) as a yellow oily substance. 1 H NMR (400 MHz, chloroform-d) δ = 6.66 (d, J = 7.6 Hz, 2H), 4.69 (br s, 1H), 3.84 - 3.72 (m, 6H), 3.40 - 3.28 (m, 2H), 2.82 - 2.74 (m, 2H), 2.60 - 2.50 (m, 2H), 1.60 (sxt, J = 7.6 Hz, 2H), 1.48 - 1.40 (m, 9H), 0.97 (t, J = 7.2 Hz, 3H).

[0362] Step 2: Preparation of 2-(2,5-dimethoxy-4-propylphenyl)ethaneamine To a mixture of tert-butyl(2,5-dimethoxy-4-propylphenethyl)carbamate (1.2 g, 3.71 mmol, 1 equivalent) in 12 mL of dimethyl phosphate (DCM), 2.5 mL of taffycin (TFA) was added all at once under N2 conditions at 20°C. The mixture was stirred at 20°C for 2 hours. At completion, the mixture was basicized to pH=8 with saturated sodium 2CO3 aqueous solution and extracted with 2 x 10 mL of DCM. The organic layer was dehydrated with sodium 2SO4, filtered, and concentrated to obtain 2-(2,5-dimethoxy-4-propylphenyl)ethaneamine (800 mg, yield 87%) as a brownish oil. 1H NMR (400 MHz, chloroform-d) δ = 6.71 - 6.64 (m, 2H), 4.21 (br s, 2H), 3.78 (d, J = 3.2 Hz, 6H), 3.13 - 2.98 (m, 2H), 2.87 - 2.79 (m, 2H), 2.60 - 2.50 (m, 2H), 1.67 - 1.54 (m, 2H), 1.01 - 0.90 (m, 3H).

[0363] Step 3: Preparation of N-benzyl-2-(2,5-dimethoxy-4-propylphenyl)ethaneamine (57) 2-(2,5-dimethoxy-4-propylphenyl)ethaneamine (450 mg, 2.02 mmol, 1 equivalent) and benzaldehyde (160 mg, 1.51 mmol, 153 μL, 0.75 equivalents) were stirred in DCE (5 mL), to which AcOH (0.05 mL) was added. After stirring at 20°C for 1 hour, NaBH(OAc)3 (1.28 g, 6.05 mmol, 3 equivalents) was added, and the mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80×40mm×3μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 37%~60%, 7 min) to obtain N-benzyl-2-(2,5-dimethoxy-4-propylphenyl)ethaneamine (188 mg, 600 μmol, yield 30%, HCl) as a white solid. LCMS R T = 2.277 minutes, MS calculated: 313.20, [M+H] += 314.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 9.98 (br s, 2H), 7.57 (br d, J = 7.2 Hz, 2H), 7.41 - 7.28 (m, 3H), 6.71 (s, 1H), 6.60 (s, 1H), 4.06 (br s, 2H), 3.83 - 3.63 (m, 6H), 3.22 - 3.00 (m, 4H), 2.52 (br t, J = 7.6 Hz, 2H), 1.56 (qd, J = 7.2, 15.0 Hz, 2H), 0.93 (t, J = 7.2Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 151.38, 151.10, 130.95, 130.40, 130.27, 129.32, 129.03, 122.41, 113.75, 112.82, 56.21, 55.74, 50.46, 45.33, 32.35, 27.84, 23.20, 14.07.

[0364] (Example 56) Preparation of 2-(2,5-dimethoxy-4-propylphenyl)-N-(2-fluorobenzyl)ethaneamine (58) [ka]

[0365] Step 1: Preparation of 2-(2,5-dimethoxy-4-propylphenyl)-N-(2-fluorobenzyl)ethanamine (58) 2-(2,5-dimethoxy-4-propylphenyl)ethaneamine (600 mg, 2.69 mmol, 1 equivalent) and 2-fluorobenzaldehyde (267 mg, 2.15 mmol, 0.8 equivalents) were stirred in DCE (5 mL), to which AcOH (0.05 mL) was added. After stirring at 20°C for 1 hour, NaBH(OAc)3 (1.71 g, 8.06 mmol, 3 equivalents) was added, and the mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100×25mm×3μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%~50%, 8 min) to obtain 2-(2,5-dimethoxy-4-propylphenyl)-N-(2-fluorobenzyl)ethaneamine (198 mg, 597 μmol, yield 22%, HCl) as a white solid. LCMS R T = 2.296 minutes, MS calculated: 331.19, [M+H] + = 332.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ = 9.99 (br s, 2H), 7.86 (br s, 1H), 7.38 - 7.30 (m, 1H), 7.23 - 7.17 (m, 1H), 7.08 (br t, J = 8.8 Hz, 1H), 6.78 - 6.52 (m, 2H), 4.37 - 4.09 (m, 2H), 3.72 (d, J = 19.6 Hz, 6H), 3.29 - 3.01 (m, 4H), 2.64 - 2.44 (m, 2H), 1.57 (qd, J = 7.6, 15.0Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13¹³C NMR (10¹ MHz, chloroform-d, HCl salt): δ = 162.59, 160.12, 151.39, 151.06, 132.72, 131.57, 131.49, 131.03, 125.05, 125.02, 122.23, 117.80, 117.66, 115.80, 115.59, 113.72, 112.86, 56.22, 55.80, 45.83, 43.22, 32.35, 27.99, 23.18, 14.09.

[0366] (Example 57) Preparation of 4-[2-(benzylamino)ethyl]-2,5-dimethoxybenzonitrile (59) [ka]

[0367] Step 1: Preparation of tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate Under an N2 atmosphere at 20°C, the mixture was stirred and dissolved tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (1.5 g, 4.16 mmol, 1 equivalent) and Zn(CN)2 (342.3 mg, 2.91 mmol, 185 μL, 0.7 equivalents) in dioxane (10 mL), and treated with XPhos Pd G3 (529 mg, 625 μmol, 0.15 equivalents). The mixture was then heated to 100°C and stirred for 2 hours. Upon completion, the reaction product was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1~5:1) to obtain tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate (900 mg, 2.94 mmol, yield 71%) as a yellow solid. 1¹H NMR (400 MHz, chloroform -d): δ = 6.97 (s, 1H), 6.80 (s, 1H), 4.62 (br s, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.36 (q, J = 6.4 Hz, 2H), 2.85 (br t, J = 6.8 Hz, 2H), 1.43 (s, 9H).

[0368] Step 2: Preparation of 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate (0.9 g, 2.94 mmol, 1 equivalent) was dissolved in DCM (10 mL) and treated with TFA (3.08 g, 27 mmol, 2 mL, 9.2 equivalents) at 20°C, stirring for 2 hours. Upon completion, the reaction mixture was carefully treated with saturated Na2CO3 aqueous solution until basic, and extracted with DCM (5 mL x 3). The organic layer was dehydrated with Na2SO4, filtered, and concentrated to obtain 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile (410 mg, 2.0 mmol, yield 68%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform -d) δ ppm 7.01 - 6.93 (m, 1H), 6.81 (s, 1H), 3.94 - 3.85 (m, 3H), 3.83 - 3.74 (m, 3H), 3.00 - 2.92 (m, 2H), 2.87 - 2.76 (m, 2H), 1.94 (br s, 2H).

[0369] Step 3: Preparation of 4-[2-(benzylamino)ethyl]-2,5-dimethoxybenzonitrile (59) A solution of 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile (410 mg, 2.0 mmol, 1 equivalent), benzaldehyde (169 mg, 1.6 mmol, 161 μL, 0.8 equivalents), and AcOH (12 mg, 199 μmol, 11.4 μL, 0.1 equivalents) in DCE (10 mL) was stirred at 20°C for 1 hour. Then, NaBH(OAc)3 (1.26 g, 5.96 mmol, 3 equivalents) was added, and the mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%~60%, 10 min) to obtain 4-[2-(benzylamino)ethyl]-2,5-dimethoxybenzonitrile (95 mg, 321 μmol, yield 16%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.29 (d, J = 4.4 Hz, 4H), 7.25 (s, 1H), 7.21 (td, J = 4.0, 8.4 Hz, 1H), 7.08 (s, 1H), 7.10 - 7.07 (m, 1H), 3.83 - 3.82 (m, 1H), 3.83 (s, 2H), 3.75 (s, 3H), 3.70 (s, 2H), 2.82 - 2.74 (m, 2H), 2.73 - 2.65 (m, 2H); 13 C NMR (400 MHz, DMSO-d6) δ ppm 155.66, 151.47, 141.46, 137.39, 128.52, 128.38, 126.93, 114.92, 114.90, 97.82, 56.85, 56.61, 53.17, 48.63, 31.33.

[0370] (Example 58) Preparation of 4-(2-((benzo[d][1,3]dioxol-4-ylmethyl)amino)propyl)-2,5-dimethoxybenzonitrile (60) [ka]

[0371] Step 1: Preparation of tert-butyl(1-(4-cyano-2,5-dimethoxyphenyl)propan-2-yl)carbamate A mixture of Zn(CN)2 (308 mg, 2.62 mmol, 166.2 μL, 0.7 equivalents) and tert-butyl (1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl) carbamate (1.4 g, 3.74 mmol, 1 equivalent) in dioxane (10 mL) was treated with XPhos Pd G3 (475 mg, 562 μmol, 0.15 equivalents). The mixture was stirred and heated at 100 °C for 12 hours. At completion, the reaction product was concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1~5:1) to obtain tert-butyl (1-(4-cyano-2,5-dimethoxyphenyl)propan-2-yl) carbamate (850 mg, 2.65 mmol, yield 70.93%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform -d) δ ppm 6.96 (s, 1H), 6.85 - 6.74 (m, 1H), 4.55 (s, 1H), 4.23 - 4.00 (m, 1H), 3.88 (s, 3H), 3.84 - 3.75 (m, 3H), 2.86 - 2.73 (m, 2H), 1.50 - 1.33 (m, 9H), 1.17 - 1.08 (m, 3H).

[0372] Step 2: Preparation of 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile To a stirred solution of tert-butyl(1-(4-cyano-2,5-dimethoxyphenyl)propan-2-yl)carbamate (850 mg, 2.65 mmol, 1 equivalent) in 10 mL of DCM, TFA (3.08 g, 27 mmol, 2 mL, 10 equivalents) was added at 20°C, and the mixture was stirred at 20°C for 3 hours. Upon completion, the reaction product was carefully treated with saturated aqueous Na2CO3 solution (Na2CO3 (1.5 g)) and extracted with 3 x 10 mL of DCM. The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile (410 mg, 1.86 mmol, yield 70%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.26 (d, J = 4.4 Hz, 1H), 6.99 (d, J =3.2 Hz, 1H), 4.26 - 4.08 (m, 2H), 3.91 - 3.88 (m, 4H), 3.83 - 3.77 (m, 3H), 3.40 - 3.29 (m, 1H), 1.74 (s, 2H), 1.20 - 1.16 (m, 1H), 1.19 - 1.15 (m, 3H).

[0373] Step 3: Preparation of 4-(2-((benzo[d][1,3]dioxol-4-ylmethyl)amino)propyl)-2,5-dimethoxybenzonitrile (60) A solution of 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile (230 mg, 1.04 mmol, 1 equivalent), benzo[d][1,3]dioxol-4-carbaldehyde (62.7 mg, 418 μmol, 48 μL, 0.4 equivalents), and AcOH (6.3 mg, 104 μmol, 6.0 μL, 0.1 equivalents) in DCE (5 mL) was stirred at 20°C for 1 hour. NaBH(OAc)3 (664 mg, 3.13 mmol, 3 equivalents) was added to this solution, and the mixture was stirred at 20°C for 12 hours. At completion, the mixture was basicized to pH=8 with saturated NaHCO3 aqueous solution and extracted with DCM (5 mL x 2). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (neutral conditions) to obtain 4-(2-((benzo[d][1,3]dioxol-4-ylmethyl)amino)propyl)-2,5-dimethoxybenzonitrile (50 mg, 141 μmol, yield 14%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.25 (s, 1H), 7.02 (s, 1H), 6.82 - 6.73 (m, 3H), 5.93 (d, J = 9.6 Hz, 2H), 3.81 (s, 3H), 3.70 (s, 3H), 3.70 - 3.61 (m, 2H), 2.91 - 2.74 (m, 2H), 2.54 (s, 1H), 1.82 (s, 1H), 0.95 (d, J = 6.0 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.47, 151.64, 147.01, 145.29, 136.81, 123.00, 122.23, 121.59, 117.15, 115.48, 114.92, 107.25, 56.83, 56.55, 52.18, 44.49, 38.06, 20.61.

[0374] (Example 59) Preparation of 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)propan-2-amine (61) [ka]

[0375] Step 1: Preparation of benzyl(1-(2,5-dimethoxy-4-propylphenyl)propan-2-yl)carbamate To a stirred solution of benzyl(1-(4-bromo-2,5-dimethoxyphenyl)propan-2-yl)carbamate (2 g, 4.90 mmol, 1 equivalent) in toluene (20 mL), N2 propylboronic acid (517 mg, 5.9 mmol, 1.2 equivalents), K3PO4 (3.12 g, 14.7 mmol, 3 equivalents), and Pd(dppf)Cl2 (358 mg, 490 μmol, 0.1 equivalent) were added. The mixture was heated to 110°C and stirred for 12 hours. At completion, the mixture was cooled, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain benzyl(1-(2,5-dimethoxy-4-propylphenyl)propan-2-yl)carbamate (1.3 g, 3.50 mmol, yield 71%) as a white solid. 1 H NMR (400 MHz, Chloroform-d) δ ppm 7.37 - 7.28 (m, 5H), 6.67 (s, 1H), 6.62 (s, 1H), 5.11 (s, 1H), 5.05 (s, 2H), 4.01 - 3.90 (m, 1H), 3.79 - 3.73 (m, 6H), 2.85 - 2.67 (m, 2H), 2.60 - 2.53 (m, 2H), 1.63 - 1.56 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H).

[0376] Step 2: Preparation of 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine To a solution of benzyl(1-(2,5-dimethoxy-4-propylphenyl)propan-2-yl)carbamate (1.2 g, 3.23 mmol, 1 equivalent) in THF (15 mL), Pd(OH)2 (454 mg, 323 μmol, purity 10%, 0.1 equivalent) was added. The mixture was heated to 50°C and stirred under H2 (15 psi) for 2 hours. At completion, the mixture was filtered and concentrated to obtain 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine (0.75 g, 3.16 mmol, yield 98%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 6.68 (s, 1H), 6.69 - 6.67 (m, 1H), 6.67 - 6.65 (m, 1H), 3.78 (d, J = 1.7 Hz, 4H), 3.80 - 3.75 (m, 1H), 3.24 - 3.15 (m, 1H), 2.72 (dd, J = 5.2, 13.0 Hz, 1H), 2.59 - 2.45 (m, 3H), 1.61 (m, 2H), 1.33 (s, 2H), 1.12 (d, J = 6.2 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H).

[0377] Step 3: Preparation of 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)propan-2-amine (61) A mixture of 1-(2,5-dimethoxy-4-propylphenyl)propan-2-amine (0.75 g, 3.16 mmol, 1 equivalent), 2-methoxybenzaldehyde (387.2 mg, 2.84 mmol, 0.9 equivalents), and AcOH (380 mg, 6.32 mmol, 362 uL, 2 equivalents) in 20 mL of DCE was stirred at 0°C for 1.5 hours. NaBH(OAc)3 (2.01 g, 9.48 mmol, 3 equivalents) was added, and the mixture was stirred at 0°C for 1 hour. At completion, the mixture was basicized to pH=9 with saturated Na2CO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250×50mm×10μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 30%~70%, 10 min) to obtain 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)propan-2-amine (400 mg, 1.02 mmol, yield 32%, HCl) as a white solid. LCMS R T = 2.338 minutes, MS calculated: 357.49, [M+H] += 358.1; 1H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 9.50 - 9.32 (m, 1H), 9.16 - 9.00 (m, 1H), 7.56 (dd, J = 1.6, 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 4.0 Hz, 2H), 4.16 (t, J = 4.8 Hz, 2H), 3.81 (s, 3H), 3.70 (d, J = 14.0 Hz, 5H), 3.72 (d, J = 10.8 Hz, 1H), 3.33 (d, J = 4.4 Hz, 1H), 3.17 (dd, J = 4.4, 13.0 Hz, 1H), 2.73 (dd, J = 10.0, 12.8 Hz, 1H), 2.50 - 2.46 (m, 2H), 1.53 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 157.51, 150.82, 150.78, 131.48, 130.60, 129.60, 122.46, 120.31, 119.91, 113.85, 113.16, 110.98, 55.86, 55.81, 55.52, 53.27, 42.43, 33.09, 31.72, 22.73, 15.55, 13.89.

[0378] (Example 60) Preparation of 1-(2,5-dimethoxy-4-propylphenyl)butan-2-amine (63i) [ka]

[0379] Step 1: Preparation of 2,5-dimethoxy-4-propylbenzaldehyde To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (5 g, 20.4 mmol, 1 equivalent) and propylboronic acid (2.33 g, 26.5 mmol, 1.3 equivalents) in toluene (50 mL), K3PO4 (12.99 g, 61.21 mmol, 3 equivalents) and Pd(dppf)Cl2 (746.43 mg, 1.02 mmol, 0.05 equivalents) were added. The mixture was heated to 110°C and stirred for 12 hours. At completion, the mixture was filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain 2,5-dimethoxy-4-propylbenzaldehyde (3.65 g, 17.5 mmol, yield 86%) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm: 10.88 (s, 1H), 7.74 (s, 1H), 7.27 (s, 1H), 4.37 (s, 3H), 4.30 (s, 3H), 3.14 - 3.07 (m, 2H), 2.10 (m, 2H), 1.45 (t, J = 7.4 Hz, 3H).

[0380] Step 2: Preparation of 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-en-1-yl]-5-propylbenzene A solution of 2,5-dimethoxy-4-propylbenzaldehyde (3.65 g, 17.5 mmol, 1 equivalent), 1-nitropropane (35.93 g, 403 mmol, 36 mL, 23 equivalents), and NH4OAc (2.70 g, 35 mmol, 2 equivalents) was heated to 115°C and stirred for 2 hours. Upon completion, the solvent was removed. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 4 / 1) to obtain 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-en-1-yl]-5-propylbenzene (2.0 g, 7.16 mmol, yield 41%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.26 (s, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.87 (q, J = 7.3 Hz, 2H), 2.66 - 2.58 (m, 2H), 1.69 - 1.58 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H).

[0381] Step 3: Preparation of 1-(2,5-dimethoxy-4-propylphenyl)butan-2-amine (63i) A solution of 1,4-dimethoxy-2-[(E)-2-nitrobuta-1-en-1-yl]-5-propylbenzene (2 g, 7.16 mmol, 1 equivalent) in THF (30 mL) was cooled to 0°C and treated with LiAlH4 (1.09 g, 28.6 mmol, 4 equivalents). The mixture was heated to 85°C and stirred for 6 hours. At completion, the mixture was cooled to 0°C, then stirred, and H2O (1.09 mL) was added dropwise. 30% NaOH aqueous solution (1.09 mL) was added dropwise, and stirring was continued until a smooth dispersion was formed. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100×25mm×3μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 20%~40%, 8 min) to obtain 1-(2,5-dimethoxy-4-propylphenyl)butan-2-amine (1.08 g, 3.63 mmol, yield 51%, purity 97%, HCl) as a white solid. LCMS R T = 2.107 min, MS calculated: 251.36, [M+H] += 252.1; 1H NMR (400 MHz, chloroform-d, HCl salt) δ ppm 8.46 - 8.19 (m, 3H), 6.73 (s, 1H), 6.68 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.55 - 3.43 (m, 1H), 3.08 - 2.95 (m, 2H), 2.60 - 2.50 (m, 2H), 1.88 - 1.68 (m, 2H), 1.63 - 1.57 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.3Hz, 3H); 13 ¹³C NMR (10¹ MHz, chloroform-d, HCl salt) δ ppm: 151.06, 150.89, 130.86, 121.49, 114.09, 112.77, 76.89, 55.94, 55.68, 53.80, 33.96, 32.05, 25.14, 22.85, 13.80, 9.88.

[0382] (Example 61) Preparation of 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)butan-2-amine (63) [ka]

[0383] Step 1: Preparation of 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)butan-2-amine (63) A solution of 1-(2,5-dimethoxy-4-propylphenyl)butan-2-amine (1 g, 3.98 mmol, 1 equivalent), 2-methoxybenzaldehyde (379 mg, 2.8 mmol, 0.7 equivalents), and AcOH (24 mg, 398 μmol, 23 μL, 0.1 equivalent) in DCE (20 mL) was stirred at 20°C for 2.5 hours. Then, NaBH(OAc)3 (2.11 g, 9.95 mmol, 2.5 equivalents) was added, and the mixture was stirred at 20°C for 10 hours. At completion, the mixture was basicized to pH=9 with saturated NaHCO3 aqueous solution and extracted with DCM (10 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.04% HCl)-ACN]; B%: 19%~49%, 20 min) to obtain 1-(2,5-dimethoxy-4-propylphenyl)-N-(2-methoxybenzyl)butan-2-amine (500 mg, 1.47 mmol, yield 37%, purity 100%, HCl) as a white solid. LCMS R T = 2.405 minutes, MS calculated: 371.51, [M+H] + = 372.1; ¹H NMR (400 MHz, chloroform-d, HCl salt) δ ppm 10.57 - 10.31 (m, ¹H), 7.51 - 7.38 (m, ¹H), 7.37 - 7.31 (m, ¹H), 7.20 (d, J = 7.2 Hz, ¹H), 6.95 (t, J = 7.2 Hz, ¹H), 6.83 (s, ¹H), 6.75 (d, J = 8.4 Hz, ¹H), 6.58 (s, ¹H), 4.33 (d, J = 13.6 Hz, ¹H), 4.08 - 3.96 (m, ¹H), 3.79 (s, ³H), 3.53 (s, ³H), 3.50 (s, 3H), 3.13 - 3.05 (m, 1H), 3.02 - 2.94 (m, 2H), 2.62 - 2.47 (m, 2H), 2.04 - 1.88 (m, 2H), 1.58 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H), 1.00 - 0.94 (m, 3H); 13¹³C NMR (10¹ MHz, chloroform-d, HCl salt) δ ppm: 157.28, 151.52, 150.91, 131.75, 131.21, 131.06, 121.32, 121.14, 118.30, 114.47, 112.84, 110.23, 57.49, 56.21, 55.53, 55.18, 45.40, 32.73, 32.40, 23.21, 23.18, 14.12, 10.09.

[0384] (Example 62) Preparation of 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (64) [ka]

[0385] Step 1: Preparation of tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate A solution of tert-butyl(4-bromo-2,5-dimethoxyphenethyl)carbamate (2 g, 5.55 mmol, 1 equivalent), Zn(CN)2 (456 mg, 3.89 mmol, 247 μL, 0.7 equivalents), and Xphos Pd G3 (705 mg, 833 μmol, 0.15 equivalents) in dioxane (30 mL) was heated to 100 °C and stirred for 1 hour. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 10:1~3:1) to obtain tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate (1.6 g, 5.22 mmol, yield 94%) as a white solid.

[0386] Step 2: Preparation of 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile A solution of tert-butyl(4-cyano-2,5-dimethoxyphenethyl)carbamate (1 g, 3.26 mmol, 1 equivalent) and TFA (4.62 g, 40.5 mmol, 3 mL, 12.4 equivalents) in 10 mL of DCM was stirred at 20°C for 2 hours. Upon completion, the solvent was removed. The residue was dissolved in 10 mL of DCM and basicized to pH=9 with saturated Na2CO3 aqueous solution. The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated to obtain 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile (580 mg, 2.81 mmol, yield 86%) as a yellow oil.

[0387] Step 3: Preparation of 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (64) A solution of 4-(2-aminoethyl)-2,5-dimethoxybenzonitrile (570 mg, 2.76 mmol, 1 equivalent), 2-hydroxybenzaldehyde (270.01 mg, 2.21 mmol, 234.79 uL, 0.8 equivalents), and AcOH (105 mg, 1.75 mmol, 0.1 mL) in DCE (8 mL) was stirred at 15°C for 2 hours. Then, NaBH(OAc)3 (1.17 g, 5.53 mmol, 2 equivalents) was added, and the mixture was stirred at 15°C for 12 hours. At completion, the mixture was basicized to pH=9 with saturated NaHCO3 aqueous solution and extracted with DCM (5 mL x 2). The organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Kromasil C18 (250 × 50 mm × 10 μm); mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%~60%, 10 min) to obtain 4-(2-((2-hydroxybenzyl)amino)propyl)-2,5-dimethoxybenzonitrile (217 mg, 615.3 μmol, yield 22%, purity 98.9%) as a grayish-white solid. LCMS R T = 1.879 min, MS calculated: 312.36, [M+H] += 313.1; ¹H NMR (400 MHz, chloroform-d) δ ppm 7.19-7.15 (m, ¹H), 6.99-6.97 (m, ²H), 6.83-6.76 (m, ³H), 4.00 (s, ²H), 3.89 (s, ³H), 3.79 (s, ³H), 2.95-2.87 (m, ⁴H); 13 ¹³C NMR (10¹ MHz, chloroform-d) δ ppm: 157.74, 155.65, 151.44, 136.65, 129.07, 128.35, 124.57, 118.90, 117.16, 115.78, 114.99, 114.94, 97.99, 56.83, 56.62, 50.72, 48.07, 30.73.

[0388] (Example 63) Preparation of 2-(4-(butylthio)-3,5-dimethoxy-2-methylphenyl)ethaneamine (67) [ka]

[0389] Step 1: Preparation of tert-butyl(4-(butylthio)-3,5-dimethoxyphenethyl)carbamate A stirred solution of 2-(4-(butylthio)-3,5-dimethoxyphenyl)ethanamine (3 g, 11.1 mmol, 1 equivalent), (Boc)2O (4.86 g, 22.3 mmol, 5.12 mL, 2 equivalents), and TEA (3.38 g, 33.4 mmol, 4.65 mL, 3 equivalents) in DCM (30 mL) was degassed three times, purged with N2, and then heated at 60°C for 1 hour under an N2 atmosphere. At completion, the reaction mixture was concentrated. The crude product was purified by column chromatography (SiO2, PE:EA = 100:1 to 30:1) to obtain tert-butyl(4-(butylthio)-3,5-dimethoxyphenethyl)carbamate (1.3 g, 3.52 mmol, yield 32%) as a yellow oil. 1¹H NMR (400 MHz, chloroform -d) δ ppm: 6.40 (s, 2 H), 4.61 (s, 1 H), 3.88 (s, 6 H), 3.39 (s, 2 H), 2.78 (t, J = 7.6 Hz, 4 H), 1.37 - 1.53 (m, 13 H), 0.87 (t, J = 7.2 Hz, 3 H).

[0390] Step 2: Preparation of tert-butyl(2-bromo-4-(butylthio)-3,5-dimethoxyphenethyl)carbamate To a stirred solution of tert-butyl(4-(butylthio)-3,5-dimethoxyphenethyl)carbamate (800 mg, 2.16 mmol, 1 equivalent) in ACN (8 mL), NBS (424 mg, 2.38 mmol, 1.1 equivalents) was added. The mixture was stirred at 20°C for 1 hour. At completion, the reaction mixture was quenched at 20°C by adding saturated NaHCO3 aqueous solution (10 mL). The mixture was extracted with EA (4 mL x 3), the combined organic layer was dehydrated with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain tert-butyl(2-bromo-4-(butylthio)-3,5-dimethoxyphenethyl)carbamate (800 mg, 1.78 mmol, yield 82%). 1 ¹H NMR (400 MHz, chloroform -d) δ ppm: 6.59 (s, 1 H), 4.64 (s, 1 H), 3.88 (d, J = 3.6, 6 H), 3.40 (m, 2 H), 2.964 (t, J = 7.6 Hz, 2 H), 2.86 (t, J = 7.6 Hz, 2 H), 1.37 - 1.53 (m, 13 H), 0.88 (t, J = 7.2 Hz, 3 H).

[0391] Step 3: Preparation of tert-butyl(4-(butylthio)-3,5-dimethoxy-2-methylphenethyl)carbamate A mixture of tert-butyl(2-bromo-4-(butylthio)-3,5-dimethoxyphenethyl)carbamate (700 mg, 1.56 mmol, 1 equivalent), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinane (1.18 g, 4.68 mmol, 1.31 mL, 50% purity, 3 equivalents), Pd(PPh3)4 (180.39 mg, 156.11 μmol, 0.1 equivalent), and K2CO3 (647 mg, 4.7 mmol, 3 equivalents) in dioxane (10 mL) was degassed, then heated to 110 °C and stirred under N2 for 3 hours. Upon completion, the reaction mixture was poured into H2O (20 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The crude substance was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20:1~5:1) to obtain tert-butyl(4-(butylthio)-3,5-dimethoxy-2-methylphenethyl)carbamate (480 mg, 1.25 mmol, yield 80%). 1 H NMR (400 MHz, chloroform-d) δ ppm 6.50 (s, 1 H), 4.48 - 4.70 (m, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.33 (t, J = 4.0 Hz, 2 H), 2.83 - 2.89 (m, 2 H), 2.81 (t, J = 7.2 Hz, 2 H), 2.21 (s, 3 H), 1.49 - 1.56 (m, 1 H), 1.47 - 1.57 (m, 2 H), 1.42 - 1.47 (m, 11 H), 0.88 (t, J = 7.2 Hz, 3 H).

[0392] Step 4: Preparation of 2-(4-(butylthio)-3,5-dimethoxy-2-methylphenyl)ethanamine (67) To a solution of tert-butyl(4-(butylthio)-3,5-dimethoxy-2-methylphenethyl)carbamate (480 mg, 1.25 mmol, 1 equivalent) in DCM (4 mL), TFA (2.19 g, 19.22 mmol, 1.42 mL, 15 equivalents) was added. The mixture was stirred at 15°C for 4 hours. At completion, the mixture was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80 × 40 mm × 3 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 27%~32%, 7 min) to obtain 2-(4-(butylthio)-3,5-dimethoxy-2-methylphenyl)ethaneamine (300 mg, 1.06 mmol, yield 85%, HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.43 (s, 3 H), 6.60 (s, 1 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 3.13-3.21 (m, 4 H), 2.08 - 2.19 (t, J = 7.6 Hz, 2 H), 2.24 (s, 3H), 1.34 - 1.42 (m, 4 H), 0.833 (t, J = 7.2 Hz, 3 H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 160.74, 158.72, 135.69, 122.72, 116.31, 108.64, 60.69, 56.37, 39.88, 34.01, 32.18, 31.88, 21.97, 13.73, 12.01.

[0393] (Example 64) Preparation of 2-(2-bromo-4-(butylthio)-3,5-dimethoxyphenyl)ethaneamine (67i) [ka]

[0394] Step 1: Preparation of 2-(2-bromo-4-(butylthio)-3,5-dimethoxyphenyl)ethanamine (67i) To a solution of tert-butyl(2-bromo-4-(butylthio)-3,5-dimethoxyphenethyl)carbamate (100 mg, 223 μmol, 1 equivalent) in DCM (2 mL), TFA (2.00 g, 17.5 mmol, 1.30 mL, 79 equivalents) was added. The mixture was stirred at 15°C for 4 hours. At completion, the mixture was concentrated, and the residue was purified by preparative HPLC (column: Welch Xtimate C18 100 × 25 mm × 3 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%~55%, 8 min) to obtain 2-(2-bromo-4-(butylthio)-3,5-dimethoxyphenyl)ethanamine (38 mg, 109.1 μmol, yield 49%, HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d6, HCl salt) δ ppm 8.12 (s, 3 H), 6.91 (s, 1 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 3.04 (s, 4 H), 2.08 - 2.19 (t, J = 6.8 Hz, 2 H), 1.34 - 1.41 (m, 4 H), 0.833 (t, J = 6.8 Hz, 3 H); 13 C NMR (101 MHz, DMSO-d6, HCl salt) δ ppm 159.57, 157.84, 137.91, 116.72, 110.38, 110.00, 60.31, 56.30, 38.06, 33.80, 32.94, 31.28, 21.12, 13.44.

[0395] (Example 65) Preparation of 1-(2,5-dimethoxy-3-methyl-4-pentylphenyl)propan-2-amine (68) [ka]

[0396] Step 1: Preparation of 2-hydroxy-5-methoxy-4-pentylbenzaldehyde A mixture of 2,5-dimethoxy-4-pentylbenzaldehyde (4 g, 16.9 mmol, 1 equivalent) in MeCN (50 mL) was added dropwise to a solution of MeCN (50 mL) containing AlCl3 (2.28 g, 17.1 mmol, 1.01 equivalent). The resulting mixture was stirred and heated to 45°C. Then NaI (3.81 g, 25.39 mmol, 1.5 equivalent) was added, and the mixture was vigorously stirred at 80°C for 2 hours. At completion, the reaction product was concentrated to obtain a residue. The residue was dissolved in RINKAN (30 mL) and treated with 30 mL of saturated disodium tartrate aqueous solution, stirring vigorously for about 1 hour until two distinct layers were formed. The aqueous phase was extracted with RINKAN (30 mL x 2). The combined organic layers were first washed with saturated Na2S2O3 aqueous solution (3 mL x 2), and then washed with brine (10 mL). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated to obtain 2-hydroxy-5-methoxy-4-pentylbenzaldehyde (3.70 g, 16.7 mmol, 98% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 10.78 (s, 1H), 9.84 - 9.79 (m, 1H), 6.95 - 6.87 (m, 1H), 6.85 - 6.75 (m, 1H), 3.90 - 3.79 (m, 3H), 2.71 - 2.56 (m, 2H), 1.64 - 1.52 (m, 2H), 1.39 - 1.28 (m, 5H), 0.94 - 0.85 (m, 3H).

[0397] Step 2: Preparation of 3-bromo-2-hydroxy-5-methoxy-4-pentylbenzaldehyde A solution of 2-hydroxy-5-methoxy-4-pentylbenzaldehyde (4.1 g, 18.5 mmol, 1 equivalent) and anhydrous AcONa (2.27 g, 27.7 mmol, 1.5 equivalents) in AcOH (20 mL) was stirred at 20°C. After all solids had completely dissolved, a solution of Br2 (3.10 g, 19.4 mmol, 999 μL, 1.05 equivalents) dissolved in AcOH (10 mL) was added dropwise to the phenol solution at 20°C (approximately 30 minutes), and the mixture was stirred for 2 hours. At completion, the reaction was diluted in H2O (10 mL) and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine (30 mL), dehydrated with Na2SO4, filtered, and concentrated to obtain 3-bromo-2-hydroxy-5-methoxy-4-pentylbenzaldehyde (4.8 g, 16 mmol, yield 86%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 11.41 (s, 1H), 9.79 (s, 1H), 6.99 - 6.88 (m, 1H), 3.91 - 3.79 (m, 3H), 2.98 - 2.81 (m, 2H), 1.58 - 1.47 (m, 2H), 1.45 - 1.32 (m, 4H), 0.97 - 0.87 (m, 3H).

[0398] Step 3: Preparation of 3-bromo-2,5-dimethoxy-4-pentylbenzaldehyde To a solution of 3-bromo-2-hydroxy-5-methoxy-4-pentylbenzaldehyde (4.7 g, 15.61 mmol, 1 equivalent) in DCM (100 mL), stirred at 20°C, an aqueous solution of NaOH (1.04 g, 26.06 mmol, 1.67 equivalents in H2O (35 mL)) was added under an N2 atmosphere. After vigorous stirring, Me2SO4 (3.94 g, 31.21 mmol, 2.96 mL, 2 equivalents) and methyl(trioctyl)ammonium chloride (315.35 mg, 780.28 μmol, 358.36 μL, 0.05 equivalents) were added. The mixture was stirred at 20°C for 4 hours. At completion, excess Me2SO4 was destroyed by adding 0.8 g of NaOH pellet to the vigorously stirred solution. Stirring was continued at 20°C for 10 hours. The layers were separated, and the aqueous layer was extracted with DCM (2 × 20 mL). The organic layer was dehydrated with Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain 3-bromo-2,5-dimethoxy-4-pentylbenzaldehyde. 1 ¹H NMR (400 MHz, chloroform-d): δ = 10.38 - 10.27 (m, 1H), 7.23 (s, 1H), 3.96 - 3.90 (m, 3H), 3.86 (s, 3H), 2.91 - 2.82 (m, 2H), 1.57 - 1.46 (m, 2H), 1.41 - 1.32 (m, 4H), 0.99 - 0.83 (m, 4H).

[0399] Step 4: Preparation of 2,5-dimethoxy-3-methyl-4-pentylbenzaldehyde To a stirred solution of 3-bromo-2,5-dimethoxy-4-pentylbenzaldehyde (3.9 g, 12.37 mmol, 1 equivalent) in dioxane (20 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9.32 g, 37.1 mmol, 10.4 mL, 50% purity, 3 equivalents) was added under N2. K2CO3 (5.13 g, 37.1 mmol, 3 equivalents) and Pd(PPh3)4 (1.43 g, 1.24 mmol, 0.1 equivalent) were added at 20°C, and the reaction mixture was heated to 110°C for 3 hours. Upon completion, the reaction mixture was diluted with H2O (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was washed with brine, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 50:1) to obtain 2,5-dimethoxy-3-methyl-4-pentylbenzaldehyde (1.4 g, 5.59 mmol, yield 45%) as an orange solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 10.51 - 10.40 (m, 1H), 7.27 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.85 - 2.75 (m, 2H), 2.45 - 2.34 (m, 3H), 1.64 - 1.54 (m, 2H), 1.53 - 1.43 (m, 4H), 1.10 - 0.97 (m, 3H).

[0400] Step 5: Preparation of 1,4-dimethoxy-3-methyl-5-[(E)-2-nitropropa-1-en-1-yl]-2-pentylbenzene NH4OAc (862 mg, 11.2 mmol, 2 equivalents) was added to a stirred solution of 2,5-dimethoxy-3-methyl-4-pentylbenzaldehyde (1.4 g, 5.59 mmol, 1 equivalent) in nitroethane (21 g, 280 mmol, 20 mL, 50 equivalents). The mixture was heated to 115°C and stirred for 1.5 hours. At completion, the reaction mixture was concentrated to obtain a residue, which was purified by column chromatography to obtain 1,4-dimethoxy-3-methyl-5-[(E)-2-nitropropa-1-en-1-yl]-2-pentylbenzene (1.58 g, 5.14 mmol, 92% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.26 (s, 1H), 6.65 (s, 1H), 3.83 - 3.78 (m, 3H), 3.70 - 3.61 (m, 3H), 2.70 - 2.61 (m, 2H), 2.44 (d, J = 0.8 Hz, 3H), 2.31 - 2.24 (m, 3H), 1.51 - 1.42 (m, 2H), 1.42 - 1.34 (m, 4H), 0.96 - 0.88 (m, 3H).

[0401] Step 6: Preparation of 1-(2,5-dimethoxy-3-methyl-4-pentylphenyl)propan-2-amine (68) A mixture of 1,4-dimethoxy-3-methyl-5-[(E)-2-nitropropa-1-en-1-yl]-2-pentylbenzene (500 mg, 1.63 mmol, 1 equivalent) in THF (7 mL) was cooled to 0°C. LiAlH4 (247 mg, 6.5 mmol, 4 equivalents) was added in several portions. The mixture was heated to 60°C and stirred for 2 hours. At completion, the mixture was cooled to 0°C. Water (0.25 mL) was added dropwise to the reaction mixture and stirred for 5 minutes. Then 0.25 mL of 30% NaOH aqueous solution was added. The mixture was stirred to make a smooth dispersion, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (0.05% HCl)-ACN]; B%: 25%~55%, 20 min) to obtain 1-(2,5-dimethoxy-3-methyl-4-pentylphenyl)propan-2-amine (185 mg, 662 μmol, yield 41%, HCl) as a grayish-white solid. 1 H NMR (400 MHz, DMSO - d6, HCl salt) δ = 8.22 (br s, 3H), 6.66 (s, 1H), 3.77 - 3.68 (m, 3H), 3.63 - 3.56 (m, 3H), 2.98 (dd, J = 5.2, 13.3 Hz, 1H), 2.70 (dd, J = 9.2, 13.3 Hz, 1H), 2.56 - 2.53 (m, 1H), 2.53 (br s, 1H), 2.55 - 2.51 (m, 1H), 2.15 (s, 3H), 1.36 (br d, J = 8.8 Hz, 2H), 1.33 - 1.27 (m, 4H), 1.11 (d, J = 6.4 Hz, 3H), 0.90 - 0.83 (m, 3H); 13 C NMR (101 MHz, DMSO - d6, HCl salt) δ = 153.63, 150.94, 130.21, 129.60, 127.26, 110.82, 60.96, 56.15, 47.74, 35.41, 32.02, 28.92, 26.47, 22.41, 18.30, 14.36, 12.48.

[0402] (Example 66) Preparation of 1-(2-methoxy-4-propylphenyl)propan-2-amine (69) [ka]

[0403] Step 1: Preparation of 2-methoxy-4-propylbenzaldehyde A stirred solution of 4-bromo-2-methoxybenzaldehyde (7 g, 32.55 mmol, 1 equivalent) in toluene (10 mL) was treated with K3PO4 (13.82 g, 65.1 mmol, 1 equivalent), propylboronic acid (4.29 g, 49 mmol, 1.5 equivalents), and Pd(dppf)Cl2 (2.38 g, 3.26 mmol, 0.1 equivalents) under N2. The mixture was stirred and heated at 110°C for 12 hours. At completion, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EA = 100:1 to 10:1) to obtain 2-methoxy-4-propylbenzaldehyde (3 g, 16.83 mmol, yield 52%) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.40 (s, 1 H), 7.74 - 7.72 (d, J = 8 Hz, 1 H), 6.99 - 6.97 (d, J = 8 Hz, 1 H), 6.75 (s, 1 H), 3.91 (s, 3 H), 2.62 - 2.74 (m, 2 H), 1.71 - 1.61 (m, 2 H), 0.90 (t, J = 6.8 Hz, 3 H).

[0404] Step 2: Preparation of 2-methoxy-1-[(E)-2-nitropropane-1-en-1-yl]-4-propylbenzene A mixture of 2-methoxy-4-propylbenzaldehyde (1.4 g, 7.86 mmol, 1 equivalent) and NH4OAc (606 mg, 7.86 mmol, 1 equivalent) in nitroethane (10 mL) was stirred and heated at 100°C for 1 hour. Upon completion, the solvent was removed, and the residue was purified by silica gel chromatography (PE:EA = 50:1 to 0:1) to obtain 2-methoxy-1-[(E)-2-nitropropa-1-en-1-yl]-4-propylbenzene (1 g, 4.25 mmol, yield 54%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.30 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.80...

Claims

1. structure: 【Chemistry 1】 A compound having or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable carrier.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method for treating a mental illness or disorder, wherein the method comprises the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method for treating headache or headache disorder, wherein the method comprises the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method for treating an inflammatory disease or disorder, wherein the method comprises the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method for treating high intraocular pressure, wherein the method comprises the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

7. The pharmaceutical composition according to claim 2 for use in a method for treating a mental illness or disorder.

8. The pharmaceutical composition according to claim 2 for use in a method for treating headache or headache disorder.

9. The pharmaceutical composition according to claim 2 for use in a method for treating an inflammatory disease or disorder.

10. The pharmaceutical composition according to claim 2 for use in a method for treating high intraocular pressure.

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