Novel phenylalkylamines and their use in the treatment of psychotic disorders

Abstract

The present disclosure provides phenylalkylamine compounds and their use in treating medical disorders, such as psychiatric diseases and disorders. Pharmaceutical compositions and methods of making various phenylalkylamine compounds are provided. Also disclosed herein are methods of treating a psychiatric disease or disorder, which include administering to a patient in need a therapeutically effective amount of any one of the therapeutic compounds described herein or a pharmaceutical composition containing the therapeutic compound.

Description

[0001] Public background Mental illnesses, including depression and anxiety, severely impair global health and human functioning. Despite the availability and widespread prescribing of various psychotropic medications, they fail to provide relief for many individuals. Even in those patients who do respond, changes in mood and behavior often appear slowly. In recent years, this persistent unmet need for improved pharmacological treatments for mental illnesses has led to consideration of previously criticized options. For example, classic serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT) have been considered as experimental therapies for various mental illness indications.

[0002] However, such compounds can cause strong hallucinogenic effects, suppressing normal bodily functions in individuals receiving such treatment. Therefore, due to their high potential for abuse, lack of approved medical use, and lack of proven safety, they are currently classified as Schedule I drugs under the Controlled Substances Act. These effects are largely mediated by binding to serotonin receptors. Activation of the serotonin 2A receptor (5-HT2A) is particularly important, as it is the cause of the problematic hallucinogenic activity of these compounds, but is also considered crucial to their claimed therapeutic effects. Therefore, compounds of this type that can provide therapeutic benefits while limiting hallucinogenic activity, thereby limiting the possibility of abuse and adverse reactions, would have high therapeutic value.

[0003] Public Overview This disclosure relates to compounds of formula (I): Or its pharmaceutically acceptable salt. in: R1 can be H, methyl, ethyl, -CH2-OH, -CH2-O-(methyl), -CH2F or -CH2CH2F; R2 is H, C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R6 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3, NO2, or SF5, wherein the alkyl, alkenyl, and ynyl groups are optionally substituted by one or more F groups, and wherein the cycloalkyl group is optionally substituted by one or more F groups, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl groups, or R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), NO2, or SF5 substituted with one or more F, wherein the alkyl, alkenyl, and ynyl groups are optionally substituted with one or more F, wherein the cycloalkyl group is optionally substituted with one or more F, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl, and wherein R4 is not isopropyl. R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, -S(O)(O)-(C1-C5 alkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by one or more F, or R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group is optionally substituted by one or more F groups; The condition is that when R5 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -S(O)(O)-(C1-C5 alkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, then R4 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl) Alkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl and ynyl groups are optionally substituted by one or more F groups, and wherein the cycloalkyl group is optionally substituted by one or more F groups, C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl groups, or When R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group is optionally substituted by one or more F groups, then R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), NO2, or SF5 substituted by one or more F groups, wherein the alkyl, alkenyl, and ynyl groups are optionally substituted by one or more F groups, wherein the cycloalkyl group is optionally substituted by one or more F groups, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl groups, and wherein R4 is not isopropyl. R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; Further conditions are: (a) When R2 is methyl, R3 is methyl, R4 is Cl or Br, R5 is methyl, R6 is H and R7 is H, then R1 is neither H nor methyl; (b) When R1 is H or methyl, R2 is H or methyl, R3 is H, R5 is methyl, R6 is H and R7 is H, then R4 is not Cl; (c) When R1 is H, R2 is methyl, R3 is H, R5 is CF3, R6 is H and R7 is o-methoxybenzyl, then R4 is not Br; (d) When R1 is H, R2 is H, R3 is H, R5 is Cl, R6 is H, and R7 is H or benzyl, then R4 is not cyclohexyl; and (e) When R1 is methyl, R2 is H, R3 is H, R5 is NH2, R6 is H and R7 is H, then R4 is not Cl.

[0004] In another embodiment, this disclosure relates to compounds of formula (I): Or its pharmaceutically acceptable salt. in: R1 is -CH2-OH, -CH2-O-(methyl), -CH2F, or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 is -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), CF3, CN, Br or I, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The conditions are: (a) When R1 is -CH2-OH, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl, -S-(methyl) or n-butyl; (b) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl; (c) When R1 is -CH2CH2F, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl; and (d) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is Br, R6 is methyl and R7 is H, then R4 is not methyl.

[0005] In another embodiment, this disclosure relates to compounds of formula (I): Or its pharmaceutically acceptable salt. in: R1 can be H, methyl, ethyl, n-propyl, -CH2-OH, -CH2-O-(methyl), -CH2F or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 represents C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 alkyl), -S(O)(O)-(C3-C5 alkenyl), -S(O)(O)-(C3-C5 ynyl), -S(O)(O)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 Alkyl)-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, F, Cl, Br, I, CN or NO2, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is F; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The condition is that when R1 is H, R2 is methyl, R3 is H, R4 is F and R7 is H, then R5 is not Cl or Br.

[0006] This disclosure also relates to miscellaneous compounds. Furthermore, this disclosure relates to deuterated analogs of the compounds described herein, i.e., when one or more hydrogen atoms in the alkyl moiety of the various substituents R1, R2, R3, R4, R5, R6, and R7 are replaced by deuterium.

[0007] This disclosure also relates to stereoisomers of any of the compounds of formula (I) herein or their deuterated analogs or hetero compounds, including enantiomers and diastereomers.

[0008] This disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of any one of the compounds of formula (I) herein, their deuterated analogs, and hybrid compounds, and their pharmaceutically acceptable carriers. Furthermore, this disclosure relates to a method of treating a subject with a mental illness, comprising administering to a subject requiring treatment a therapeutically effective amount of any one of the compounds of formula (I) herein, their deuterated analogs, or hybrid compounds. Brief description of the attached diagram The objects, features, and advantages of this disclosure will become apparent to those skilled in the art from the following detailed description taken in conjunction with the accompanying drawings.

[0010] Figure 1 The data collected from the Chronic Mild Stress (CMS) study testing the effects of compound 3DE2 are presented graphically. The graph shows sucrose intake levels in rats across different treatment groups administered different treatments weekly throughout the study period. Large arrows indicate weekly administration of ketamine (10 mg / kg, IP), and small arrows indicate the time of administration of compound 3DE2 (0.1–3.2 mg / kg, SC). The legend indicates the tested dose levels in parentheses.

[0011] Figure 2 The data collected from the CMS study testing the effects of compound 1AE2 are presented graphically. The graph shows sucrose intake levels in rats in each group who received different treatments weekly throughout the study period. Large arrows indicate weekly administration of ketamine (10 mg / kg, IP), and small arrows indicate the time of administration of compound 1AE2 (0.1 or 3.2 mg / kg, SC). The legend indicates the tested dose levels in parentheses.

[0012] Figure 3 The data collected from the CMS study testing the effects of compound 6CE2 are presented graphically. The graph shows sucrose intake levels in rats in each group who received different treatments weekly throughout the study period. Large arrows indicate weekly administration of ketamine (10 mg / kg, IP), and small arrows indicate the time of administration of compound 6CE2 (0.1–1.1 mg / kg, SC). The legend indicates the tested dose levels in parentheses.

[0013] Figure 4 The data collected from the CMS study testing the effects of compound 30E2 are presented graphically. The graph shows sucrose intake levels in rats in each group who received different treatments weekly throughout the study period. Large arrows indicate weekly administration of ketamine (10 mg / kg, IP), and small arrows indicate the time of administration of compound 30E2 (0.32 or 1 mg / kg, SC). The legend indicates the tested dose levels in parentheses.

[0014] This disclosure details This disclosure provides, for example, compounds as modulators of the 5-HT2A receptor (5-HT2A), their use as pharmaceutical agents, methods of their preparation, and pharmaceutical compositions containing them as active ingredients (alone or in combination with other pharmaceutical agents). Use as a medicament and / or in the preparation of medicaments for activating 5-HT2A in warm-blooded animals (e.g., humans) is also provided. Specifically, this disclosure relates to compounds for treating mental illnesses or conditions. Furthermore, this disclosure provides compounds that induce useful therapeutic effects while exhibiting reduced or no hallucinogenic effects.

[0015] Before further describing this disclosure, certain terms used in the specification, embodiments, and appended claims are collected herein. These definitions should be considered in light of the remainder of this disclosure and interpreted as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although similar or equivalent methods and materials to those described herein may be used in practice or experiment with embodiments of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety unless specific paragraphs are cited. In the event of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting.

[0016] This disclosure relates to various compounds identified as formula (I) that have the same structure, but the definitions of substituents identified as R1, R2, R3, R4, R5, R6, and R7 in one group of formula (I) compounds may be the same as or different from the definitions of the corresponding substituents in compounds of different groups of formula (I). For example, the definition of R1 in a compound of formula (I) may be the same as or different from the definition of R1 in a compound of another formula (I). To avoid confusion about which substituent definition refers to which compound of formula (I), it should be understood that each substituent refers to the compound of formula (I) drawn above.

[0017] Unless otherwise indicated or the context clearly states, reference to formula (I) generally refers to any or all compounds of formula (I), as stated above.

[0018] Unless otherwise indicated, all percentages are weight percentages.

[0019] As used herein, the term "active ingredient" refers to compounds of formula I as defined herein and miscellaneous compounds as defined herein.

[0020] "Treatment" includes any effect that leads to improvement of a condition, disease, symptom, etc., such as reduction, relief, regulation, or elimination.

[0021] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group (alkyl-O-) attached to an oxygen atom. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1-6 or 2-6 carbon atoms, referred to herein as C1-C6 alkoxy and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0022] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively. Exemplary 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0023] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon having one or more double bonds. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched hydrocarbons having 2-6, 2-4, or 2-3 carbon atoms having one double bond. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, homoallyl, etc.

[0024] The terms “aryl” and “aromatic,” used alone or as part of a larger body, such as “aralkyl,” “aralkylalkoxy,” or “aryloxyalkyl,” refer to monocyclic and bicyclic systems having a total of five to fourteen ring members, wherein at least one ring in the system is an aromatic ring and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aromatic ring.” In certain embodiments of this disclosure, “aryl” refers to aromatic ring systems including, but not limited to, phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. The scope of the term “aryl” as used herein also includes groups in which an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimide, naphthalimide, phenanthridine, or tetrahydronaphthyl.

[0025] As used herein, the term "cyano" refers to the -CN group.

[0026] As used herein, the terms "cycloalkyl" or "carbocyclic group" refer to, for example, a saturated or partially unsaturated cyclic hydrocarbon group with 3-6 or 4-6 carbon atoms, referred to herein as C3-C6 cycloalkyl or C4-C6 cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclopropyl, etc.

[0027] As used herein, the term "cycloalkylalkyl" refers to a saturated straight-chain or branched hydrocarbon substituted with, for example, a 3-6 or 4-6 carbon cyclic hydrocarbon group, either saturated or partially unsaturated. Exemplary cycloalkylalkyls include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, 2-cyclopropylethyl, etc.

[0028] As used herein, the term “halogenated” or “halogen” refers to F, Cl, Br, or I.

[0029] The terms “heteroaryl” and “heteroaryl-”, used alone or as part of a larger body, such as “heteroarylalkyl” or “heteroarylalkoxy”, refer to a group having 5 to 14 ring atoms (e.g., 5, 6, 9, or 10 ring atoms), having 6, 10, or 14 π electrons shared in the aromatic ring structure, and having one to five heteroatoms in addition to a carbon atom. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroary-” also include groups in which a heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings. Non-limiting examples include indolyl, isoindolyl, benzothiophene, benzofuranyl, dibenzofuranyl, indazole, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenthiazolyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaryl aromatic group,” wherein any of these terms includes optionally substituted rings. The term "heteroaryl" refers to an alkyl group substituted with a heteroaryl group, wherein the ring (heteroaryl or non-heteroaryl) of the alkyl and heteroaryl moieties is independently and optionally substituted.

[0030] The term "heterocyclic group" is well-known in the art and refers to a saturated or partially unsaturated 4-10 membered ring structure, including bridged or fused rings, whose ring structure comprises one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocycle can be linked to adjacent groups via carbon or nitrogen. Examples of heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azabutane, tetrahydrofuran, dihydrofuran, etc.

[0031] As used herein, the term "hydroxyl group" refers to the -OH group.

[0032] As used herein, the terms “about” or “approximately” mean within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may mean within a range of three or more standard deviations, as is customary in the art. Alternatively, “about” may mean a range not exceeding 20% ​​of a given value, not exceeding 10% of a given value, not exceeding 5% of a given value, and / or not exceeding 1% of a given value. Or, particularly for biological systems or processes, the term may mean within an order of magnitude of a value, such as within 5 times or 2 times. “About” and “approximately” are used interchangeably herein.

[0033] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans (as the case may be), will not produce adverse reactions, allergic reactions, or other harmful reactions. For human administration, the formulation should meet the sterility, pyrogenicity, and general safety and purity standards required by the relevant government regulatory agency.

[0034] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0035] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein and one or more pharmaceutically acceptable carriers.

[0036] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred. The compounds disclosed herein can be applied to mammals, such as humans, but can also be applied to other mammals, such as animals requiring veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammals receiving treatment in the methods of this disclosure are consensually mammals that require treatment for mental illness or condition.

[0037] "Regulation" includes antagonism (e.g., inhibition), excitation, partial antagonism, and / or partial excitation.

[0038] In this specification, the term "therapeuticly effective amount" refers to the amount of a test compound that will elicit a biological or medical response in a tissue, system, or animal (e.g., a mammal or a human) sought by an investigator, veterinarian, physician, or other clinician. The compounds of this disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and / or preventative effect, such as an amount that reduces symptoms of a mental illness, including, but not limited to, reducing sadness or somnolence, depressive mood, feelings of anxiety or grief, diminished interest in all or almost all activities, significantly increased or decreased appetite leading to weight gain or loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, poor concentration, and the frequency or severity of recurrent thoughts of death or suicide; or providing the desired pharmacological and / or physiological effects, such as reducing, inhibiting, or reversing one or more underlying pathophysiological mechanisms underlying neurological dysfunction, regulating dopamine levels or signaling, regulating serotonin levels or signaling, regulating norepinephrine levels or signaling, regulating glutamate or GABA levels or signaling, regulating synaptic connections or neurogenesis in specific brain regions, or combinations thereof. The precise dosage will vary depending on a number of factors, such as subject dependence variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or condition being treated, and the route of administration and the pharmacokinetics of the drug being administered.

[0039] Unless otherwise indicated, the terms "drugs" and "medicines" are synonymous.

[0040] As used herein, the terms “comprising,” “including,” “having,” or any other variations thereof are intended to cover non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to those elements and may also include other elements not expressly listed or inherent to such compositions, processes, methods, articles, or apparatuses.

[0041] Furthermore, the use of "an" or "a type" is for describing the elements and components described herein. This is done merely for convenience and to give a general concept of the scope of the invention. This description should be interpreted as including one (a type) or at least one (a type).

[0042] Furthermore, unless otherwise indicated, the singular form includes the plural form, and vice versa.

[0043] Furthermore, unless explicitly stated otherwise, "or" refers to inclusive "or," not exclusive "or." For example, condition A or B is satisfied by any of the following: A is true (or exists), and B is false (or does not exist); A is false (or does not exist), and B is true (or exists); A and B are both true (or exist).

[0044] Furthermore, as used herein, the term “and / or” is synonymous with the term “or”.

[0045] When expressing a range or list of numerical values, the implementation includes the endpoints of the range and / or list and all points in between. For example, the range of 6 to 9 includes the values ​​6 and 9 and all values ​​in between. Similarly, when a numerical value is expressed as an approximation using the prefix "approximately," it should be understood that the range of the numerical value is approximately at both endpoints, where "approximately" is as defined herein. All ranges are inclusive and composable. Furthermore, references to numerical values ​​stated in range form include every and every numerical value within that range.

[0046] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an acidic or basic group present in a compound that can be used in a composition. The basic compounds included in this composition are capable of forming a variety of salts with a wide range of inorganic and organic acids. The pharmaceutically acceptable acids that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, namely salts containing pharmaceutically acceptable anions, including but not limited to malates, oxalates, hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucaronates, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). The acidic compounds included in this composition are capable of forming a variety of salts with various inorganic and organic bases. The bases that can be used to prepare pharmaceutically acceptable basic salts of such acidic compounds are those bases that form non-toxic basic salts, i.e., salts containing pharmaceutically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, especially calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in this composition, including basic or acidic moieties, can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein can contain acidic and basic groups, for example, an amino group and a carboxylic acid group. In this case, the compound can exist as an acid addition salt, a zwitterion, or a basic salt.

[0047] The compounds disclosed herein may contain one or more chiral centers and thus may exist as stereoisomers. The term "stereoisomer" as used herein refers to all enantiomers or diastereomers. Specific stereoisomers of such compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of the substituents surrounding the carbon atom in the stereoconformation, but those skilled in the art will understand that the structure may implicitly represent a chiral center. This disclosure covers various stereoisomers of these compounds in purified form and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated in nomenclature as "(±)", but those skilled in the art will understand that the structure may implicitly represent a chiral center.

[0048] The compounds disclosed herein may contain one or more double bonds, and therefore exist as geometric isomers due to the arrangement of substituents around the carbon-carbon double bonds. (Symbols) The term indicates a bond, which can be a single, double, or triple bond as described herein. Substituents surrounding carbon-carbon double bonds are labeled as "". Z "or" E "Configuration, in which the term" Z "and" E "Used in accordance with IUPAC standards. Unless otherwise stated, descriptions of double bond structures cover..." E "and" Z "Isomers. Substituents around the carbon-carbon double bond can be alternatively called "cis" or "trans", where "cis" means the substituent is on the same side of the double bond and "trans" means the substituent is on the opposite side of the double bond.

[0049] The compounds disclosed herein may contain a carbocyclic or heterocyclic ring, and therefore exist as geometric isomers due to the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is designated as "". Z "or" E "Configuration, in which the term" Z "and" E "Used in accordance with IUPAC standards. Unless otherwise stated, descriptions of carbocyclic or heterocyclic structures cover..." Z "and" E "Isomers. Substituents around the carbocyclic or heterocyclic ring can also be referred to as "cis" or "trans", where the term "cis" indicates that the substituent is located on the same side of the ring plane and the term "trans" indicates that the substituent is located on the opposite side of the ring plane. A mixture of compounds in which the substituents are located on the same side and opposite side of the ring plane is designated as "cis / trans".

[0050] The various enantiomers and diastereomers of the compounds disclosed herein can be synthesized from commercially available starting materials containing asymmetric or stereocenters, or synthesized by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) linking a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their constituent enantiomers by well-known methods, such as chiral liquid chromatography or crystallizing the compounds in a chiral solvent. Stereoselective synthesis is a chemical or enzymatic reaction in which a single reactant forms a mixture of unequal amounts of stereoisomers in the process of creating a new stereocenter or transforming an existing stereocenter, as is well known in the art. Stereoselective synthesis encompasses 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.

[0051] In some embodiments, the compositions prepared herein may be enriched with a specific enantiomer of any compound disclosed herein (relative to the corresponding inverse enantiomer of that compound) such that the mixture is not racemic. In this case, the mixture of isomers should be understood as having an enantiomer excess and optical purity >0%. The enantiomer excess or optical purity of the isomer mixture may be, for example, >0%, >5%, >25%, >50%, >75%, >90%, >95%, >97%, >98%, or >99%. The enantiomer excess or optical purity of the isomer mixture may be, for example, 5-100%, 25-100%, 50-100%, 75-100%, 90-100%, 95-100%, 97-100%, 98-100%, or 99-100%. Therefore, for example, this document contemplates compositions comprising the S enantiomer of a compound and substantially free of the R enantiomer, or compositions comprising the R enantiomer and substantially free of the S enantiomer. Furthermore, if the compound contains more than one chiral center, the scope of this disclosure also includes compositions comprising various stereoisomers and diastereomers (including mixtures of various stereoisomers and / or diastereomers in different proportions or pharmaceutically acceptable salts thereof), and compositions comprising one or more stereoisomers and diastereomers and substantially free of each of one or more other stereoisomers and / or diastereomers. In this context, “substantially free” means that the composition contains less than, for example, 50%, 25%, 15%, 10%, 8%, 5%, 3%, 2%, or 1% of the enantiomer or diastereomer. For example, the expression “enantiomerically pure” means that the compound is substantially free of other stereoisomers, including any other enantiomers or diastereomers.

[0052] For clarity, in the context of this disclosure, the chemical structure of a compound described using a specific stereochemical orientation at any particular chiral center, as defined by wedge and dashed notation, is intended to represent a particular stereoisomer of the compound existing substantially in pure form, or a mixture of stereoisomers rich in a specific stereochemical orientation at the defined chiral center relative to a stereoisomer having an opposite orientation at the chiral center.

[0053] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and this disclosure is intended to include 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.

[0054] This disclosure also includes isotopically labeled compounds of this disclosure, which are identical to those listed herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that may be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, […]. 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, compounds disclosed herein may have one or more H atoms substituted with deuterium.

[0055] Disclosed compounds labeled with certain isotopes (e.g., using...) 3 H and 14 Those labeled with C can be used for the determination of compound and / or substrate tissue distribution. Incorporating tritium (i.e., 3 H) or carbon-14 (i.e., ... 14 C) Isotope compounds are particularly preferred due to their ease of preparation and detection. Furthermore, due to the kinetic isotope effect, heavier isotopes such as deuterium (i.e., 2 Substitution of H) can provide certain therapeutic advantages due to greater metabolic stability (e.g., prolonged in vivo half-life, reduced dose requirements, or reduced formation of one or more metabolites), and may therefore be preferred in certain situations. Isotopically labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents following steps similar to those disclosed in the examples herein.

[0056] As used in the chemical structures described herein, the symbol "D" denotes a deuterium-enriched H-site, where the isotopic composition at that site is enriched to a level higher than the natural abundance of deuterium. Therefore, the level of deuterium enrichment at such sites can be, for example, greater than 0.02%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 97%, greater than 98%, or greater than 99%.

[0057] compound I. Compounds of Group I (I) In one embodiment, this disclosure relates to compounds of formula (I). R1, R2, R3, R4, R5, R6 and R7 are as defined in this paper.

[0058] In one embodiment, R1 is H, methyl, ethyl, -CH2-OH, -CH2-O-(methyl), -CH2F, or -CH2CH2F. In another embodiment, R1 is H, methyl, or ethyl. In another embodiment, R1 is H or methyl. In another embodiment, R1 is ethyl, -CH2-OH, or -CH2-O-(methyl). In another embodiment, R1 is -CH2F or -CH2CH2F. In another embodiment, R1 is methyl or ethyl. In another embodiment, R1 is H. In another embodiment, R1 is methyl. In another embodiment, R1 is ethyl. In another embodiment, R1 is -CH2-OH. In another embodiment, R1 is -CH2-O-(methyl). In another embodiment, R1 is -CH2F. In another embodiment, R1 is -CH2CH2F.

[0059] In one embodiment, R2 is hydrogen, C1-C3 alkyl, cyclopropyl, 1- or 2-propynyl, or 1- or 2-propynyl, wherein the alkyl, propynyl, and cyclopropyl groups are unsubstituted or substituted with one or more F groups. In another embodiment, R2 is hydrogen, methyl, ethyl, or F, wherein the methyl and ethyl groups are optionally substituted with one or more F groups. In yet another embodiment, R2 is methyl, which is optionally substituted with F. In yet another embodiment, R2 is an unsubstituted methyl group.

[0060] In one embodiment, R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted with one or more F. In another embodiment, R3 is H or F. In yet another embodiment, R3 is hydrogen.

[0061] In another embodiment, R6 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted with one or more F. In another embodiment, R3 is H or F. In another embodiment, R3 is hydrogen. In another embodiment, both R3 and R6 are hydrogen.

[0062] In one embodiment, R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), - O-(C3-C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl), -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S. In another embodiment, R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.In yet another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms to which they are attached form a 5-membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In another embodiment, R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position by an F, OH, or -O-(methyl), or substituted by a methylenedioxy ring connecting the ortho and meta positions. In yet another embodiment, R7 is H, unsubstituted -CH2-(6-membered aryl), or unsubstituted -CH2-(6-membered heteroaryl). In yet another embodiment, R7 is an unsubstituted phenyl or H. In yet another embodiment, R7 is H. In yet another embodiment, R3, R6, and R7 are all hydrogen.

[0063] In one embodiment, R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups, and R4 is a C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), or -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl). -C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3 or SF5, wherein the alkyl, alkenyl or ynyl group of R4 is optionally substituted with one or more F, and wherein the cycloalkyl group of R4 is optionally substituted with one or more F, C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl. In another embodiment, R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups, and R4 is a C2-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-( R4 is a C1-C6 alkyl group, -S-(C3-C6 alkenyl group), -S-(C3-C6 alkynyl group), -S-(C3-C6 cycloalkyl group), -S-(C1-C3 alkyl group)-(C3-C5 cycloalkyl group), Cl, Br, I, CF3 or SF5, wherein the alkyl, alkenyl and alkynyl groups of R4 are optionally substituted with one or more F groups, and wherein the cycloalkyl group of R4 is optionally substituted with one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl groups.

[0064] In another embodiment, R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups, and R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), or SF5 substituted with one or more F groups, wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R4 are optionally substituted with one or more F groups, and the cycloalkyl group is optionally substituted with one or more F groups, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl, and R4 is not isopropyl. In another embodiment, R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups, and R4 is a C2 alkyl, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), or SF5 substituted with one or more F groups, wherein the alkyl, alkenyl, and ynyl groups of R4 are optionally substituted with one or more F groups, wherein the cycloalkyl group of R4 is optionally substituted with one or more F groups, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl groups, and wherein R4 is not isopropyl.

[0065] In another embodiment, R1 is as defined above, R2 is H, C1-C3 alkyl, C3 cycloalkyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl groups of R2 are optionally substituted with one or more F groups; R3 is H, methyl, ethyl, or F, wherein the methyl and ethyl groups of R3 are optionally substituted with one or more F groups; R6 is H, methyl, ethyl, or F, wherein the methyl and ethyl groups of R6 are optionally substituted with one or more F groups; R5 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, or - S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups, and R4 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl R4 is Br, I, CF3, or SF5, wherein the alkyl, alkenyl, and alkynyl groups are optionally substituted with one or more F groups, and wherein the cycloalkyl group is optionally substituted with one or more F groups, C1-C5 alkyl groups, C2-C5 alkenyl groups, or C2-C5 alkynyl groups; or R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups, and R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl group substituted with one or more F groups. R4 is a compound, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 alkynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), SF5, wherein the alkyl, alkenyl, and alkynyl groups of R4 are optionally substituted with one or more F groups, and wherein the cycloalkyl group of R4 is optionally substituted with one or more C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 alkynyl groups, and wherein R4 is not isopropyl.Furthermore, R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 alkynyl), -O-( -C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R7 are optionally substituted with one or more F atoms, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 5-6 membered ring, said ring optionally containing 1-2 heteroatoms selected from O, N, and S.

[0066] In another embodiment, R1 is as defined above, R2 is H, methyl, or ethyl, wherein the methyl and ethyl groups of R2 are optionally substituted with one or more F groups; R3 is H or F; R6 is H or F; R5 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups, and R4 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S- R4 is (C3-C6 alkynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, CF3, or SF5, wherein the alkyl, alkenyl, and alkynyl groups of R4 are optionally substituted with one or more F groups, and wherein the cycloalkyl group is optionally substituted with one or more F groups, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl groups; or alternatively, R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups and R4 is a C2 alkyl, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl group substituted with one or more F groups. The R4 group is alkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), SF5, wherein the alkyl, alkenyl, and ynyl groups of R4 are optionally substituted with one or more F groups, wherein the cycloalkyl group of R4 is optionally substituted with one or more F groups, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl groups, and wherein R4 is not isopropyl; and R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted with one or more unique F groups. The substituents are selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl of R7 are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl of R7 together with the atoms they are attached to form a 5-6 membered ring, wherein the ring optionally contains 1-2 heteroatoms selected from O, N and S.

[0067] In one embodiment, R2 is methyl. In one embodiment, R5 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups, and R4 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl). R4 is a C3-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C5 alkyl group, a C3-C6 cycloalkyl group, a Cl group, a Br group, an I group, a CF3 group, or a SF5 group, wherein the alkyl, alkenyl, or alkynyl group of R4 is optionally substituted with one or more F groups, and wherein the cycloalkyl group of R4 is optionally substituted with one or more F groups, C1-C5 alkyl groups, C2-C5 alkenyl groups, or C2-C5 alkynyl groups, and R1 is H, methyl, ethyl, or -CH2-O-(methyl); R3 is H, C1-C3 alkyl group, or C1-C3 alkyl group. R3 is alkyl or F, wherein the alkyl and cyclopropyl groups of R3 are optionally substituted with one or more F groups; R6 is H, C1-C3 alkyl, cyclopropyl, or F, and R7 is H, -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl) -O-(C3-alkenyl), -O-(C3-ynyl), -O-(C3-C5-cycloalkyl), -S-(C1-C3-alkyl), -S-(C3-alkenyl), -S-(C3-ynyl), -S-(C3-C5-cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl groups of R7 are optionally substituted with one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N and S.In one embodiment, R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups of R5 are optionally substituted with one or more F groups; R4 is a C2-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C1-C5 alkyl), or -S-(C1-C5 alkyl). R4 can be substituted with one or more F, and R3 can be substituted with one or more C1-C3 alkyl, C2-C3 alkyne, C3-C6 cycloalkyl, C1-C3 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, CF3, or SF5, wherein the alkyl, alkyne, alkyne, and cycloalkyl groups of R4 are optionally substituted with one or more F, and wherein the cycloalkyl group of R4 is optionally substituted with one or more C1-C3 alkyl, C2-C3 alkyne, or C2-C3 alkyne groups, and R1, R3, R6, and R7 are as defined herein. In one embodiment, when R2, R4, and R5 are as defined herein, R3 is H or F, and R1, R6, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined herein, R3 is H, and R1, R6, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R6 is hydrogen or F, and R1, R3, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R6 is hydrogen, and R1, R3, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is hydrogen, and R1, R3, and R6 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S, and R1, R3, and R6 are as defined herein.In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups of R7 are optionally substituted by one to three F, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S, and R1, R3, and R6 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl, and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a methylenedioxy ring, and R1, R3, and R6 are as defined herein. In yet another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position by an F, OH, or -O-(methyl) group, or substituted by a methylenedioxy ring connecting the ortho and meta positions, and R1, R5, and R6 are as defined herein.

[0068] In another embodiment, R2 is methyl, R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups, and R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3- R4 is C8-alkenyl, -S-(C3-C8-ynyl), -S-(C3-C8-cycloalkyl), -S-(C1-C5-alkyl)-(C3-C6-cycloalkyl), SF5, wherein the alkyl, alkenyl, and ynyl groups of R4 are optionally substituted with one or more F groups, wherein the cycloalkyl group of R4 is optionally substituted with one or more F groups, C1-C5-alkyl, C2-C5-alkenyl, or C2-C5-ynyl groups, wherein R4 is not isopropyl; and R1, R3, R6, and R7 are as defined herein. In another embodiment, R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group of R5 is optionally substituted with one or more F groups, and R4 is a C2 alkyl, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), or -S-(C3-C6 alkenyl) substituted with one or more F groups. R4 can be substituted with one or more F groups, including -S-(C3-C6 alkynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), or SF5, wherein the alkyl, alkenyl, and alkynyl groups of R4 are optionally substituted with one or more F groups, wherein the cycloalkyl groups of R4 are optionally substituted with one or more F groups, C1-C3 alkyl groups, C2-C3 alkenyl groups, or C2-C3 alkynyl groups, and wherein R4 is not isopropyl, and R1, R3, R6, and R7 are as defined herein. In one embodiment, when R2, R4, and R5 are as defined in this paragraph, R3 is H or F, and R1, R6, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R3 is H, and R1, R6, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R6 is hydrogen or F, and R1, R3, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R6 is hydrogen, and R1, R3, and R7 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is hydrogen, and R1, R3, and R6 are as defined herein.In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S, and R1, R3, and R6 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S, and R1, R3, and R6 are as defined herein. In another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl, and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a methylenedioxy ring, and R1, R3, and R6 are as defined herein. In yet another embodiment, when R2, R4, and R5 are as defined in this paragraph, R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position by an F, OH, or -O-(methyl) group, or substituted by a methylenedioxy ring connecting the ortho and meta positions, and R1, R5, and R6 are as defined herein.

[0069] In one embodiment, R2 is methyl, R1 is H, methyl, ethyl, or -CH2-O-(methyl); R3 is H, C1-C3 alkyl, cyclopropyl, or F, wherein the alkyl and cyclopropyl groups of R3 are optionally substituted with one or more F groups; R6 is H, C1-C3 alkyl, cyclopropyl, or F, wherein the alkyl and cyclopropyl groups of R6 are optionally substituted with one or more F groups; and R7 is H, -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl) R7 is a alkyl, alkenyl, alkynyl, or cycloalkyl group, wherein the alkyl, alkenyl, alkynyl, or cycloalkyl group of R7 is optionally substituted with one or more F atoms, and wherein any two adjacent substituents located on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S; R4 is a C2-C8 alkyl group, Br, or SF5, and R5 is a C1-C5 alkyl group, Cl, CN, NO2, CF3, SMe, or -S(O)(O)-(C1-C5 alkyl group). In another embodiment, R2 is methyl, R1 is H, methyl, or ethyl; R3 is H, C1-C3 alkyl, or F, wherein the alkyl group of R3 is optionally substituted with one or more F groups; R6 is H, C1-C3 alkyl, or F, wherein the alkyl group of R6 is optionally substituted with one or more F groups; and R7 is H, -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups of R7 are optionally substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl). -O-(C3-alkynyl), -O-(C3-C5-cycloalkyl), -S-(C1-C3-alkyl), -S-(C3-alkenyl), -S-(C3-alkynyl), -S-(C3-C5-cycloalkyl), wherein the alkyl, alkenyl, alkynyl, and cycloalkyl groups of R7 are optionally substituted with one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S; R4 is C2-C8 alkyl, Br, SF5, and R5 is C1-C5 alkyl, Cl, CN, NO2, CF3, SMe, -S(O)(O)-(C1-C5-alkyl).In another embodiment, R2 is methyl, R1 is H, methyl or ethyl; R3 is H, C1-C3 alkyl or F, wherein the alkyl group of R3 is optionally substituted with one or more F; R6 is H, C1-C3 alkyl or F, wherein the alkyl group of R6 is optionally substituted with one or more F; R7 is H; R4 is C2-C8 alkyl, Br, SF5, and R5 is C1-C5 alkyl, Cl, CN, NO2, CF3, SMe, -S(O)(O)-(C1-C5 alkyl).

[0070] All different combinations and permutations of variables R1, R2, R3, R4, R5, R6, and R7 as defined herein are embodiments of this disclosure and are within the scope of this disclosure.

[0071] This disclosure includes stereoisomers of compounds of the first formula (I).

[0072] In one embodiment, the compounds of the first group of formulas (I) are selected from the following: Or, or a pharmaceutically acceptable salt thereof.

[0073] Any of the compounds containing one or more chiral centers described above may be in their pure enantiomers (R or S) or diastereomers. In embodiments, this disclosure includes R and S stereoisomers of compounds identified as compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 17, 19, 21, 22, 24, 25, 28, 29, 30, and 32, including substantially pure forms and mixtures thereof.

[0074] The following compounds are excluded from the implementation plan: (a) When R2 is methyl, R3 is methyl, R4 is Cl or Br, R5 is methyl, R6 is H and R7 is H, then R1 is neither H nor methyl; (b) When R1 is H or methyl, R2 is H or methyl, R3 is H, R5 is methyl, R6 is H and R7 is H, then R4 is not Cl; (c) When R1 is H, R2 is methyl, R3 is H, R5 is CF3, R6 is H and R7 is o-methoxybenzyl, then R4 is not Br; (d) When R1 is H, R2 is H, R3 is H, R5 is Cl, R6 is H, and R7 is H or benzyl, then R4 is not cyclohexyl; and (e) When R1 is methyl, R2 is H, R3 is H, R5 is NH2, R6 is H and R7 is H, then R4 is not Cl.

[0075] In another embodiment, the following compounds are excluded from this disclosure: .

[0076] II. Compounds of Group II (I) In another embodiment, this disclosure relates to compounds of formula (I): Or its pharmaceutically acceptable salt. in: R1 is -CH2-OH, -CH2-O-(methyl), -CH2F, or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 is -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), CF3, CN, Br or I, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The conditions are: (a) When R1 is -CH2-OH, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl, -S-(methyl) or n-butyl; and (b) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl.

[0077] In one embodiment, R2 is a C1-C3 alkyl, cyclopropyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cyclopropyl groups are optionally substituted with one or more F groups; R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R5 is -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 alkynyl), -O-(cyclopropyl), -O-(C1-C3 alkyl)-(cyclopropyl), CF3 or CN, wherein the alkyl, alkenyl, alkynyl and cyclopropyl are optionally substituted by one or more F, and wherein the cyclopropyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R6 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups are optionally substituted by one or more F groups, and any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S. R1 and R4 are as defined herein for compounds of the second group (I).

[0078] In another embodiment of the compound of the second formula (I), R2 is methyl or ethyl, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R3 is either H or F; R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; R5 is -O-(methyl), -O-(ethyl), or CN, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R6 is either H or F; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

[0079] In one embodiment, R1 is -CH2-OH. In another embodiment, R1 is -CH2-O-(methyl). In yet another embodiment, R1 is -CH2F. In still another embodiment, R1 is -CH2CH2F. For each embodiment, R2, R3, R4, R5, R6 and R7 are as defined for compounds of formula (I) in the second group.

[0080] In one embodiment, R2 is methyl. In another embodiment, R5 is -O-(C1-C5 alkyl). In yet another embodiment, R5 is -O-(methyl). In still another embodiment, R2 is methyl and R5 is -O-(C1-C5 alkyl), for example, R5 is -O-(methyl). With respect to each embodiment, R1, R3, R4, R6 and R7 are as defined for compounds of the second group of formula (I).

[0081] In one embodiment, R3 is hydrogen. In another embodiment, R6 is H. In yet another embodiment, both R3 and R6 are hydrogen. For each embodiment, R1, R2, R4, R5, and R7 are as defined for compounds of the second group (I).

[0082] In one embodiment, R4 is a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl. In another embodiment, R4 is a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted with one to three F, and wherein the cycloalkyl is optionally substituted with one to three C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl. For each embodiment, R1, R2, R5, R6, and R7 are as defined for compounds of the second group (I).

[0083] In one embodiment, R7 is H. In another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl) and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N and S. In yet another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl, and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms to which they are attached, form a methylenedioxy ring. In yet another embodiment, R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position by an F, OH, or -O-(methyl) group, or by a methylenedioxy ring connecting the ortho and meta positions. For each embodiment, R1, R2, R3, R4, R5, and R6 are as defined for compounds of the second group of formulas (I).

[0084] This disclosure includes stereoisomers of compounds of the second formula (I). Any of the compounds containing one or more chiral centers may be either their pure enantiomers (R or S) or diastereomers.

[0085] The following are examples of compounds of the second group (I) that fall within the scope of this disclosure: Or, or a pharmaceutically acceptable salt thereof.

[0086] This disclosure includes R and S stereoisomers of compounds identified as 1A, 2A, 3A, 4A, 5A, 6A, 7A, and 8A, including substantially pure forms and mixtures thereof.

[0087] In one implementation, the following compounds are excluded: (a) R1 is -CH2-OH, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H, and R7 is H, and R4 is not methyl, -S-(methyl) or n-butyl; (b) R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is -O-(methyl), R6 is H, R7 is H, and R4 is not methyl; (c) When R1 is -CH2CH2F, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl; and (d) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is Br, R6 is methyl and R7 is H, then R4 is not methyl.

[0088] In one implementation, the following compounds are excluded: .

[0089] III. Compounds of Group III (I) In one embodiment, the compound of the third formula (I) has the following formula: Or it could be a pharmaceutically acceptable salt. in: R1 can be H, methyl, ethyl, n-propyl, -CH2-OH, -CH2-O-(methyl), -CH2F or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 represents C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 alkyl), -S(O)(O)-(C3-C5 alkenyl), -S(O)(O)-(C3-C5 ynyl), -S(O)(O)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 Alkyl)-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, F, Cl, Br, I, CN or NO2, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is F; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The condition is that when R1 is H, R2 is methyl, R3 is H, R4 is F and R7 is H, then R5 is not Cl or Br.

[0090] In one implementation, for compounds of formula (I) of group three, R2 is a C1-C3 alkyl, cyclopropyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cyclopropyl groups are optionally substituted by one or more F groups; R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R5 is -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 alkynyl), -O-(cyclopropyl), -O-(C1-C3 alkyl)-(cyclopropyl) or CN, wherein the alkyl, alkenyl, alkynyl and cyclopropyl are optionally substituted by one or more F, and wherein the cyclopropyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S. R1, R4, and R6 are as defined above for compounds of the third group (I).

[0091] In one implementation scheme R2 is methyl or ethyl, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R3 is either H or F; R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; R5 is -O-(methyl), -O-(ethyl), or CN, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S. Furthermore, R1 and R6 are as defined above for compounds of the third group (I).

[0092] In one embodiment, R1 is H or Me. In another embodiment, R1 is ethyl. In yet another embodiment, R1 is n-propyl. In still another embodiment, R1 is -CH2-OH. In yet another embodiment, R1 is -CH2-O-(methyl). Furthermore, in another embodiment, R1 is -CH2F. In yet another embodiment, R1 is -CH2CH2F. With respect to each embodiment, R2, R3, R4, R5, R6, and R7 are as defined for compounds of formula (I) in group III.

[0093] In one embodiment, R2 is a C1-C5 alkyl group, such as a C1-C3 alkyl group, for example, methyl. In one embodiment, R5 is -O-(C1-C5 alkyl), such as -O-(C1-C3 alkyl), for example, -O-(methyl). In another embodiment, R2 is a C1-C5 alkyl group, such as a C1-C3 alkyl group, for example, methyl, and R5 is -O-(C1-C5 alkyl), such as -O-(C1-C3 alkyl), for example, -O-(methyl). For each embodiment, R1, R3, R4, R6, and R7 are as defined for compounds of formula (I) in group III.

[0094] In one embodiment, R3 is H, a C1-C3 alkyl group (e.g., methyl or ethyl), or F. In another embodiment, R3 is H or F. In yet another embodiment, R3 is H. For each embodiment, R1, R2, R4, R5, R6, and R7 are as defined for compounds of formula (I) in group III.

[0095] In one embodiment, R4 is a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl. In another embodiment, R4 is a C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted with one to three F, and wherein the cycloalkyl is optionally substituted with one to three C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl. For each embodiment, R1, R2, R3, R5, R6, and R7 are as defined for compounds of formula (I) in group III.

[0096] In another embodiment, R7 is H. In another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the group consisting of halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms to which they are attached form a 5-membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S. In yet another embodiment, R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl, and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a methylenedioxy ring. In another embodiment, R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position by an F, OH, or -O-(methyl) group, or by a methylenedioxy ring connecting the ortho and meta positions. For each embodiment, R1, R2, R3, R4, R5, and R6 are as defined for compounds of formula (I) in group III.

[0097] This disclosure includes stereoisomers of compounds of the third formula (I). Any of the compounds containing one or more chiral centers may be either their pure enantiomers (R or S) or diastereomers.

[0098] The following are examples of compounds of group III (I) that fall within the scope of this disclosure: Or, or a pharmaceutically acceptable salt thereof.

[0099] This disclosure includes R and S stereoisomers of compounds 1B, 2B and 3B, including substantially pure forms and mixtures thereof.

[0100] The following compounds are excluded from this disclosure: R1 is H, R2 is methyl, R3 is H, R4 is F, R7 is H, and R5 is neither Cl nor Br.

[0101] In one implementation, the following compounds are excluded: .

[0102] IV. Miscellaneous compounds The following compounds are also considered within the scope of this disclosure: Or pharmaceutically acceptable salts thereof. Furthermore, this disclosure includes R and S stereoisomers of 12, 13, 16, 18, 31, 1C, 2C, 3C, 4C, 5C, and 6C, including substantially pure forms and mixtures thereof.

[0103] In addition, the following deuterated compounds or their pharmaceutically acceptable salts are part of this disclosure: Each deuterium-enriched H-site contains more than 0.02% deuterium. In embodiments, the deuterium level at each deuterium-enriched H-site of the compound ranges from about 0.02% to 100%. In other embodiments, the deuterium level at each deuterium-enriched H-site of the compound ranges from 50%-100%, 70%-100%, 90%-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100%, or 99%-100%. In one embodiment, each deuterium-enriched H-site contains more than 90% deuterium, and in another embodiment, each deuterium-enriched H-site contains more than 95% deuterium. Furthermore, this disclosure also includes 2D R and S stereoisomers.

[0104] In another embodiment, the following compositions comprising the S-enantiomers of the following compounds or pharmaceutically acceptable salts thereof are also contemplated within the scope of this disclosure: Optionally, the composition comprises the R-enantiomer of the same compound, provided that the composition contains more than 50% of the S-enantiomer. In another embodiment, the composition contains more than 90% of the S-enantiomer. In yet another embodiment, the composition contains more than 95% of the S-enantiomer.

[0105] The compounds in this section, including their pharmaceutically acceptable salts, are generally referred to as miscellaneous compounds. As used herein, the term "miscellaneous compound" refers to all the compounds in this section. If a single compound is mentioned in this section, it will be specifically indicated.

[0106] In the implementation scheme, the compound may be selected from any one or more of the following enantiomers: .

[0107] V. Description of the compound The compounds of formula (I) contain seven variables: R1, R2, R3, R4, R5, R6, and R7. This disclosure does not describe all combinations and permutations of these different variables with respect to the compounds of each formula (I). However, all these compounds of formula (I) and their pharmaceutically acceptable salts are part of and included within the scope of this disclosure.

[0108] Furthermore, all compounds of formula (I) and their pharmaceutically acceptable salts, as well as miscellaneous compounds and their pharmaceutically acceptable salts, contain a chiral center and can therefore exist in a variety of stereoisomers. These various stereoisomers, including enantiomers and diastereomers, existing in substantially pure forms and mixtures thereof (including racemic and non-racemic mixtures), are part of and included within the scope of this disclosure. In embodiments, any compound disclosed herein containing one or more chiral centers may be its pure enantiomer (R or S) or diastereomer.

[0109] Salts of the compounds disclosed herein 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, such as diethyl ether, or alcohol, such as ethanol, or an aqueous solvent) using conventional steps. Salts of the compounds of this disclosure can be exchanged for other salts by processing with conventional ion-exchange chromatography procedures or by reforming a free base or free acid and subsequently reacting it with an alternative acid or base, respectively.

[0110] If a specific enantiomer of the compounds of this disclosure is required, it can be generated from a mixture of the corresponding enantiomers by employing any suitable conventional method for resolving enantiomers. For example, diastereomeric derivatives (e.g., salts) can be generated by reacting a mixture of enantiomers of the compounds of this disclosure (e.g., racemic mixtures) with a suitable chiral compound (e.g., a chiral acid). The diastereomers can then be separated by any conventional means (e.g., crystallization), and the desired enantiomers can be recovered (e.g., by treatment with a base if the diastereomer is an acidic salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using various biocatalysts (e.g., see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0111] In another separation method, racemic mixtures of the disclosed compounds can be separated using chiral high-performance liquid chromatography. Alternatively, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the methods described above. If it is desired to obtain specific diastereomers, regioisomers, or geometric isomers of the disclosed compounds, chromatography, recrystallization, and other conventional separation procedures can also be used for intermediates or final products.

[0112] Pharmaceutical Compositions and Kits Another aspect of this disclosure provides pharmaceutical compositions comprising compounds and miscellaneous compounds of formula (I) disclosed herein, formulated with a pharmaceutically acceptable carrier. In particular, this disclosure provides pharmaceutical compositions comprising compounds disclosed herein, formulated with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions typically comprise a pharmaceutically acceptable carrier in which one or more active compounds are contained (e.g., dissolved, suspended, or mixed). It is well known that pharmaceutically acceptable carriers consist of one or more substances considered safe and effective. A carrier includes all components present in a pharmaceutical formulation other than the active ingredient. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, flow aids, disintegrants, fillers, and coating compositions. Suitable dosage forms for the compounds disclosed herein include, but are not limited to, oral forms such as tablets, hard or soft gelatin capsules, powders, granules, and oral solutions, syrups or suspensions, lozenges, and sublingual, buccal, intratracheal, intraocular, or intranasal forms suitable for inhalation, topical, transdermal, or parenteral forms, such as forms suitable for intravenous, arterial, intraperitoneal, intrathecal, intraventricular, intramuscular, or subcutaneous administration. In embodiments, for such parenteral administration, it may be in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salt or glucose, to make the solution isotonic with blood. If necessary, the aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9). The preparation of suitable parenteral formulations under sterile conditions can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0113] Pharmaceutical formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, intranasal, aerosol, or vapor administration, although the most suitable form of administration in any given case will depend on the extent and severity of the disease being treated and the nature of the specific compound used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral or subcutaneous administration.

[0114] The exemplary pharmaceutical compositions of this disclosure can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing one or more compounds of this disclosure as active ingredients, and mixed with an organic or inorganic carrier or excipient suitable for topical, enteral, or parenteral application. The active ingredient can be compounded, for example, with a commonly used, non-toxic, pharmaceutically acceptable carrier for use in tablets, microcapsules, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable forms. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of a disease.

[0115] To prepare solid compositions such as tablets, the major active ingredient may be mixed with a pharmaceutical carrier (e.g., a conventional tableting component, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformation composition containing a homogeneous mixture of the compounds disclosed herein or non-toxic, pharmaceutically acceptable salts thereof. When referring to these preformation compositions as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0116] In solid dosage forms intended for oral administration (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.), the compositions of this application are mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or dicalcium phosphate) and / or any of the following substances: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicate; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solvents. (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0117] Tablets can be made by compression or molding, optionally having one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium carboxymethyl starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the compositions of this application moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, can optionally be scored or prepared using coatings or shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations.

[0118] 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 compositions of this application, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene glycol and sorbitan fatty acid esters, cyclodextrins, and mixtures thereof.

[0119] In addition to the compositions of this application, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0120] Formulations for rectal or vaginal administration may be presented as suppositories prepared by mixing the composition of this application with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but liquid at body temperature, and thus will melt and release the active ingredient within the body cavity.

[0121] Dosage forms for transdermal administration of the compositions of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier and with any necessary preservatives, buffers, or propellants.

[0122] In addition to the compositions of this application, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0123] In addition to the compositions of this application, powders and aerosols may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Aerosols may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0124] The compositions and compounds disclosed herein can be alternatively administered via aerosols. This can be achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic nebulizers can be used because they minimize drug exposure to shear forces that can lead to degradation of the compounds contained in the compositions of this application. Typically, aqueous aerosols are formulated by combining an aqueous solution or suspension of the compositions of this application with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the specific requirements of the composition of this application but typically include nonionic surfactants (Tween, Pluronics, or polyethylene glycol), nontoxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids (e.g., glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0125] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a combination of the composition of this application with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersants, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersants shortly before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0126] 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 injectable organic esters (e.g., ethyl oleate and cyclodextrin). For example, appropriate flowability can be maintained by using coating materials (e.g., lecithin), by maintaining the desired particle size in the case of dispersants, and by using surfactants.

[0127] On the other hand, this disclosure provides an enteric pharmaceutical formulation comprising a compound or miscellaneous compound of formula (I) and an enteric-coated material; and a pharmaceutically acceptable carrier or excipient thereof. An enteric-coated material is a polymer that is substantially insoluble in the acidic environment of the stomach but is primarily soluble in intestinal fluid at a specific pH. The small intestine is the part of the digestive tract (intestinal tract) between the stomach and the large intestine, comprising 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, for example, enteric materials dissolve only at pH values ​​of 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 materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, methyl acrylate, copolymers of methyl methacrylate and methacrylate, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-ethyl chlorotrimethylammonium acrylate copolymers, natural resins (e.g., zein, shellac, and copalcollophorium), and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit...). L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric. The solubility of each of the above materials is known or readily determined in vitro. The foregoing is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not exhaustive and that there are other enteric-coated materials that satisfy the purposes of this disclosure.

[0128] The pharmaceutical compositions described herein may also have immediate-release, delayed-release, sustained-release, or modulated-release properties. In embodiments, pharmaceutical compositions with different drug release properties can be combined to create two-phase or three-phase release characteristics. For example, a pharmaceutical composition may have both immediate-release and sustained-release properties. In embodiments, a pharmaceutical composition may have both sustained-release and delayed-release properties. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0129] Pharmaceutical compositions may also contain one or more excipients. Excipients (also referred to as auxiliary ingredients) include any additional conventional substances in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents. Such excipients are appropriately selected relative to the intended form and route of administration and in accordance with standard pharmaceutical practice.

[0130] This disclosure also provides, for example, kits for consumers who require treatment with compounds of formula (I) and / or miscellaneous compounds. Such kits include a suitable dosage form (e.g., those described above) and instructions describing the method of using such dosage form to treat a medical condition (e.g., a mental illness or disease). The instructions instruct the user to administer the dosage form according to methods of administration known to those skilled in the art. Such kits can advantageously be packaged and sold in single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a relatively rigid sheet of material covered with a foil, preferably a transparent plastic material. During the packaging process, grooves are formed on the plastic foil. The grooves have the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed in the grooves, and the relatively rigid sheet of material is sealed to the plastic foil on the surface of the foil (opposite to the direction in which the grooves are formed). Thus, the tablets or capsules are sealed in the grooves between the plastic foil and the sheet. Preferably, the sheet is strong enough that tablets or capsules can be removed from the blister pack by manually applying pressure to the groove to create an opening in the sheet at the groove location. The tablets and capsules can then be removed through said opening.

[0131] Providing memory aids on the kit may be desirable, for example, in the form of numbers next to the tablets or capsules, according to which these numbers correspond to the dates of the treatment regimen on which the specified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, as follows: "Week 1, Monday, Tuesday, ... etc. Week 2, Monday, Tuesday, ... etc." Other variations of memory aids will be apparent. A "daily dose" can be a single tablet or capsule taken on a specified day or multiple pills or capsules. Furthermore, the daily dose of the first compound can consist of a single tablet or capsule, while the daily dose of the second compound can consist of multiple tablets or capsules, and vice versa. The memory aid should reflect this.

[0132] This article also considers methods and compositions that include or apply a second active ingredient.

[0133] Purpose and usage The compounds and hybrid compounds of formula (I) disclosed herein are agonists of the 5-HT2A receptor. In embodiments, the compounds and / or hybrid compounds of formula (I) selectively bind to and activate the 5-HT2A receptor. Activation of 5-HT2A receptors located in the cortical and subcortical structures of the brain is thought to mediate the subjective, behavioral, and psychological effects of hallucinogens in animals and humans. Therefore, these compounds and hybrid compounds of formula (I) can be used to treat mental illnesses. However, unlike other phenylalkylamine hallucinogens, the compounds and hybrid compounds of formula (I) have reduced or no hallucinogenic effects.

[0134] Another aspect of this disclosure provides a method for treating patients with diseases associated with the expression or activity of 5-HT2A. For example, one envisioned method involves administering a compound of formula (I) and / or a hybrid compound in an amount sufficient to establish effective relief of symptoms of the patient's mental illness or condition caused by 5-HT2A activation. Furthermore, treatment using a compound of formula (I) and / or a hybrid compound can also enhance neuroplasticity or neurogenesis in a 5-HT2A-dependent manner.

[0135] In some embodiments, this disclosure provides a method of treating a mental illness or condition, comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I) of this disclosure and / or a heterogeneous compound, such as any compound of formula (I) and / or a heterogeneous compound.

[0136] In some implementation schemes, mental illness or condition is selected from the following: major depressive disorder, persistent depression, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depression, and depression caused by other medical conditions.

[0137] In some implementations, the mental illness or condition is selected from the following: bipolar I disorder, bipolar II disorder, cyclothymic mood disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders caused by other medical conditions.

[0138] In some implementations, mental illness or disorder is defined as a substance-related disorder or substance use disorder.

[0139] In some implementation schemes, mental illness or condition is selected from the following: separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorder caused by other medical conditions.

[0140] In some implementations, mental illness or condition is selected from the following: obsessive-compulsive disorder and related disorders, trauma and stress-related disorders, eating and drinking disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

[0141] In some implementation schemes, mental illness is defined as neurocognitive impairment.

[0142] In some implementations, the mental illness or condition is a treatment-resistant illness or condition, such as treatment-resistant depression.

[0143] This disclosure also provides a method for enhancing the creativity or cognitive abilities of a subject, the method comprising administering to the subject a composition comprising an effective amount of a compound of formula (I) of this disclosure and / or a mixture of compounds.

[0144] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may be used to treat mental illnesses, including depression such as major depressive disorder, persistent depression, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depression, and depression caused by other medical conditions.

[0145] This document also provides compounds of formula (I) and / or miscellaneous compounds and compositions comprising them for the treatment of treatment-resistant or treatment-resistant depression, for example, patients with depression who have not responded to and / or have never responded to adequate courses of treatment with at least one or two other antidepressant compounds or therapies. As used herein, “depression” encompasses treatment-resistant depression.

[0146] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may be used to treat mental disorders, including bipolar and related disorders, such as bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders caused by other medical conditions.

[0147] In some embodiments, compounds and / or miscellaneous compounds of formula (I) and compositions comprising them can be used to treat mental illnesses, including substance-related disorders, such as preventing substance use cravings, reducing substance use cravings, and / or promoting substance use cessation or withdrawal. Substance use disorders involve the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, “substance” refers to addictive psychoactive compounds such as alcohol, caffeine, cannabis, hallucinogens, inhalers, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. For example, the methods and compositions described can be used to promote smoking cessation or opioid use cessation.

[0148] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may 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 / drug-induced anxiety disorder, and anxiety disorders caused by other medical conditions.

[0149] In some embodiments, the compounds and / or miscellaneous compounds of formula (I) and compositions comprising them may be used to treat mental disorders, including obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (trichotillomania), compulsive skin peeling (skin scratching) disorder, substance / drug-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders caused by other medical conditions.

[0150] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat mental disorders, including trauma and stress-related disorders, such as reactive attachment disorder, disinhibitory social engagement disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0151] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat mental illnesses, including eating and dietary disorders, such as anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder and avoidance / restriction food intake disorder.

[0152] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may be used to treat mental illnesses, including neurocognitive disorders, such as delirium, severe neurocognitive disorder, mild neurocognitive disorder, severe or mild neurocognitive disorder caused by Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder caused by traumatic brain injury, substance / drug-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder caused by HIV infection, severe or mild neurocognitive disorder caused by prion diseases, severe or mild neurocognitive disorder caused by Parkinson's disease, severe or mild neurocognitive disorder caused by Huntington's disease, severe or mild neurocognitive disorder caused by other medical conditions, and severe or mild neurocognitive disorder caused by multiple etiologies.

[0153] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may be used to treat mental disorders, including neurodevelopmental 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 transient tic disorder.

[0154] In some embodiments, compounds of formula (I) and compositions comprising them can be used to treat mental illnesses, including personality disorders, such as borderline personality disorder.

[0155] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them may be used to treat mental disorders, including sexual dysfunctions such as delayed ejaculation, erectile dysfunction, female orgasmic disorder, female sexual interest / arousal disorder, genital-pelvic pain / insertion disorder, male hypoactive sexual desire disorder, premature ejaculation, and substance / drug-induced sexual dysfunction.

[0156] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat mental disorders, including gender dysphoria, for example, gender dysphoria.

[0157] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat headaches or headache syndromes. In some embodiments, the headache syndrome is migraine or cluster headache.

[0158] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat inflammatory conditions. In some embodiments, the inflammatory condition is an inflammatory bowel disease, including ulcerative colitis and Crohn's disease. In some embodiments, the inflammatory condition is inflammatory bowel syndrome. In some embodiments, the inflammatory condition is an inflammation-related cardiovascular condition, such as atherosclerosis and coronary artery disease. In some embodiments, the inflammatory condition is a TNF-α-dependent inflammatory condition.

[0159] In some embodiments, compounds of formula (I) and / or miscellaneous compounds and compositions comprising them can be used to treat high intraocular pressure.

[0160] The compounds and miscellaneous compounds of formula (I) of this disclosure can be administered to patients (animals and humans) requiring such treatment at doses that provide optimal pharmaceutical efficacy. It should be understood that the dose required for any particular application will vary from patient to patient, depending not only on the specific compound of formula (I) and / or the specific compound or combination of miscellaneous compounds selected, but also on the route of administration, the nature of the disease being treated, the patient's age and condition, any concurrent medications or special diets the patient is receiving, and other factors understood by those skilled in the art. The appropriate dose is ultimately determined by the attending physician. For the treatment of the aforementioned clinical conditions and diseases, the compounds and / or miscellaneous compounds of formula (I) of this disclosure can be administered orally, subcutaneously, topically, parenterally, by inhalation spray, by vaporization, intranasally, or rectally in dosage units containing conventional, non-toxic, pharmaceutically acceptable carriers, excipients, and mediators. Parenteral administration can include subcutaneous injection, intravenous injection, intramuscular injection, or infusion techniques.

[0161] Treatment can be continued for any desired duration, whether long or short. The composition can be administered, for example, once to four or more times daily. A suitable treatment period can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about one year, or indefinite. The treatment period can be terminated when the desired effect (e.g., reduction of symptoms of the mental illness) is achieved. The treatment regimen may include a correction period, during which an amount sufficient to provide symptom relief is administered, followed by a maintenance period, during which a lower dose sufficient to prevent relapse of symptoms is administered. A suitable maintenance dose may be found to be in the lower part of the dose range provided herein, but those skilled in the art can readily determine the correction and maintenance doses for individual subjects based on the disclosure herein without requiring excessive experimentation. Maintenance doses can be used to maintain relief in subjects whose symptoms have previously been controlled by other means, including treatment with other pharmacological agents.

[0162] In some embodiments, the method includes treating a mental illness, such as depression, by administering to a patient in need a pharmaceutical composition comprising about 0.01 mg to about 400 mg of a compound of formula (I) of this disclosure and / or a miscellaneous compound. In some embodiments, the dosage range may be, 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 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, etc. mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 10 to 400 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 400 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 50 to 400 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 400 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg Examples of dosages are, for example, approximately 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.25 mg, 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.

[0163] In some embodiments, the dosage may include a range of approximately, for example, amounts of compounds of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof, such as 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 mg to 5 mg, or 0.1 mg to 1 mg. Specific examples of dosages are 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, 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 ... Doses of 1 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.

[0164] Typically, the compounds of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to patients in need at doses once daily, twice, three or four times, every other day, every three days, twice a week, once a week, twice a month, once a month, once every two months, once every three months, twice a year, or once a year. In some embodiments, the dosage is approximately, for example, 0.1-400 mg / application, 0.1-300 mg / application, 0.1-250 mg / application, 0.1-200 mg / application, 0.1-100 mg / application, 0.1-50 mg / application, or 0.1 to 25 mg / application, for example, 300 mg / application, 250 mg / application, 200 mg / application, 150 mg / application, 100 mg / application, 75 mg / application, 50 mg / application, 25 mg / application, 20 mg / application, 10 mg / application, 5 mg / application, 2.5 mg / application, 1 mg / application, 0.5 mg / application, 0.25 mg / application, or 0.1 mg / application.

[0165] In some embodiments, this disclosure includes pharmaceutical compositions of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof (at a concentration of about 0.005 mg / mL to about 500 mg / mL) for parenteral or inhalation, such as by spray or nebulizer. In some embodiments, the composition comprises a compound of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, at a concentration 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.

[0166] In some embodiments, the composition comprises a compound of formula (I) of this disclosure and / or a heterogeneous compound or a pharmaceutically acceptable salt thereof, at a concentration 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 configured to a total volume of about, for example, 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.

[0167] Typically, the dosage can be administered to the subject once, twice, three or four times daily, every other day, every three days, twice weekly, once weekly, twice monthly, once monthly, three times a year, twice a year, or once a year. In some embodiments, the compound of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to the subject once in the morning or once in the evening. In some embodiments, the compound of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to the subject once in the morning and once in the evening. In some embodiments, the compound of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to the subject at a dose of, for example, 0.5 mg / administered (e.g., 1.5 mg / day), three times daily (e.g., at breakfast, lunch, and dinner).

[0168] In some embodiments, any compound of formula (I) and / or miscellaneous compounds (or pharmaceutical compositions thereof) disclosed herein may be administered once, twice, three times, or four times daily, wherein the administration may be the same or different and independently selected from any dose provided herein. In some embodiments, any compound of formula (I) and / or miscellaneous compounds (or pharmaceutical compositions thereof) disclosed herein may be administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times per week (possibly at equal or alternating intervals), wherein the administration may be the same or different and independently selected from any dose provided herein. In some embodiments, any compound of formula (I) disclosed in this application and / or miscellaneous compounds (or pharmaceutical compositions thereof) may be administered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen times per month (possibly at equal or alternating intervals, such as once every two, three, four, or five days, or alternating between any of these intervals), wherein the administration may be the same or different and independently selected from any dose provided in this application. In some embodiments, any compound and / or miscellaneous compound (or pharmaceutical composition thereof) of formula (I) disclosed in this application may be administered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, or twenty-five times a year (possibly at equal or alternating intervals, such as once every two, three, four, or five weeks, or once or twice a month, or alternating between any of these intervals). The administration may be the same or different and is independently selected from any dose provided in this application.

[0169] In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 0.5 mg / day once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 1 mg / day once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 2.5 mg / day once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 5 mg / day once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 10 mg / day once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 15 mg / day, once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 20 mg / day, once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 25 mg / day, once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 30 mg / day, once or multiple times. In some embodiments, the compound of formula (I) of this disclosure and / or a heterologous compound or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 40 mg / day, once or multiple times. In some embodiments, a compound of formula (I) of this disclosure and / or a miscellaneous compound or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 50 mg / day, once or multiple times. In some embodiments, a compound of formula (I) of this disclosure and / or a miscellaneous compound or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 75 mg / day, once or multiple times. In some embodiments, a compound of formula (I) of this disclosure and / or a miscellaneous compound or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 100 mg / day, once or multiple times.

[0170] In some embodiments, the dosage of the compound of formula (I) and / or other compounds or pharmaceutically acceptable salts thereof is 0.0005-5 mg / kg, 0.001-1 mg / kg, 0.01-1 mg / kg or 0.1-5 mg / kg, once, twice, three or four times daily. For example, in some embodiments, the dosage 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, 5 mg / kg, once, twice, three or four times daily. In some embodiments, a total daily dose of 0.01 mg to 500 mg of a compound of formula (I) of this disclosure and / or a miscellaneous compound or a pharmaceutically acceptable salt thereof is administered to a subject once, twice, three or four times daily. In some implementations, the total dose administered to the subject over a 24-hour period 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, or 500 mg. In some implementations, the subject may start with a low dose and gradually increase the dose. In some implementations, the subject may start with a high dose and gradually decrease the dose.

[0171] In some implementations, compounds of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to patients under the supervision of a healthcare provider.

[0172] In some implementations, compounds of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to patients in clinics that specialize in providing psychoactive treatment, under the supervision of a healthcare provider.

[0173] In some embodiments, under the supervision of a healthcare provider, the compound of formula (I) of this disclosure and / or miscellaneous compounds or pharmaceutically acceptable salts thereof are administered to the patient at a higher dose intended to induce a psychedelic experience in the subject, such as 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.

[0174] In some implementations, in order to maintain the therapeutic effect on patients, high-dose administration to patients is performed regularly under the supervision of healthcare providers, for example, once 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.

[0175] In some embodiments, the compounds and / or miscellaneous compounds of formula (I) of this disclosure or their pharmaceutically acceptable salts are administered by the patient at home or otherwise without the supervision of a healthcare provider.

[0176] In some embodiments, the compounds and / or miscellaneous compounds of formula (I) of this disclosure or their pharmaceutically acceptable salts are administered by the patient at home or otherwise without the supervision of a healthcare provider at a low dose intended to be below the perceived threshold or to produce a threshold psychoactive effect, 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.

[0177] In some implementations, to maintain the therapeutic effect on patients, low-dose administration is performed regularly by the patients themselves, for example, once daily, once every other day, once every three days, twice a week, once a week, twice a month, or once a month.

[0178] In some embodiments, the compounds of formula (I) of this disclosure and / or miscellaneous compounds or their pharmaceutically acceptable salts may be administered to the patient at specific intervals, for example by inhalation or oral administration. For example, during treatment, the compounds of this disclosure may be administered to the patient at intervals such as once a year, once every 6 months, once every 4 months, once every 90 days, once every 60 days, once every 30 days, once every 14 days, once every 7 days, once every 3 days, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 5 hours, once every 4 hours, once every 3 hours, once every 2.5 hours, once every 2.25 hours, once every 2 hours, once every 1.75 hours, once every 1.5 hours, once every 1.25 hours, once every 1 hour, once every 0.75 hours, once every 0.5 hours, or once every 0.25 hours.

[0179] Universal synthesis The compounds disclosed herein are prepared using methods well-known in the art. The compounds of formula (I) described herein, as well as miscellaneous compounds, can be prepared in various ways based on the teachings contained herein and synthetic steps well-known in the art. In the following description of the synthetic methods, it should be understood that, unless otherwise stated, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and subsequent processing steps, are standard conditions for the reaction. Those skilled in the art of organic synthesis will understand that the functional groups present in various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods are indicated. The starting materials used in the examples are commercially available or readily prepared from known materials by standard methods. Example

[0180] The following non-limiting embodiments further illustrate the teachings of this disclosure.

[0181] In the following examples, several compounds were prepared in substantially enantiomerically pure form by separating racemic mixtures of the compounds themselves or synthetic intermediates (which were then converted into the compounds while retaining the same absolute stereochemistry at the chiral center) via chiral supercritical fluid chromatography (SFC). The enantiomerically pure compounds prepared in this manner are designated as enantiomer 1 (E1) or enantiomer 2 (E2), where these terms respectively denote the first and second eluted enantiomers from the illustrated chiral SFC method. However, the absolute stereochemistry of these enantiomerically pure compounds was not determined experimentally, and therefore, in the context of the examples, designating E1 or E2 as R or S stereochemistry in the drawn scheme should be considered arbitrary.

[0182] Example 1: Preparation of 1-(5-ethyl-2-methoxy-4-pentylphenyl)but-2-amine (1) hydrochloride Synthesis route: Step 1: Preparation of 2-methoxy-4-pentylbenzaldehyde Pentylboronic acid (808.93 mg, 6.98 mmol), cesium carbonate (4.55 g, 13.95 mmol), and Pd(dppf)Cl2 (340.26 mg, 465.02 µmol) were added to a solution of 4-bromo-2-methoxybenzaldehyde (1 g, 4.65 mmol) in toluene (23 mL) and water (2.3 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 13 h. After the reaction was complete, the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether and ethyl acetate gradient, eluted with 2% ethyl acetate) to give 2-methoxy-4-pentylbenzaldehyde as an oil (yield: 770 mg, 80%). 1 H NMR (400MHz, CDCl3): δ = 10.40 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.78 (s,1H), 3.91 (s, 3H), 2.63 (t, J = 7.8 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.37 - 1.28(m, 4H), 0.90 (t, J = 6.8 Hz, 3H).

[0183] Step 2: Preparation of 5-bromo-2-methoxy-4-pentylbenzaldehyde NBS (867.14 mg, 4.87 mmol) was added to a solution of 2-methoxy-4-pentylbenzaldehyde (670 mg, 3.25 mmol) in acetonitrile (7 mL). The mixture was stirred at 30 °C for 12 h. The reaction mixture was partitioned between ethyl acetate (10 mL x 3) and water (10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether and ethyl acetate gradient, eluted with 2% ethyl acetate) to give 5-bromo-2-methoxy-4-pentylbenzaldehyde as an oil (yield: 740 mg, 76%). 1 H NMR (400MHz, CDCl3): δ= 10.33 (s, 1H), 7.94 (s, 1H), 6.84 (s, 1H), 3.92 (s, 3H), 2.79 -2.70 (m, 2H), 1.69 - 1.60 (m, 2H), 1.45 - 1.36 (m, 4H), 0.97 - 0.89 (m, 3H).

[0184] Step 3: Preparation of 5-ethyl-2-methoxy-4-pentylbenzaldehyde Pd(dppf)Cl2 (200.13 mg, 273.52 µmol), diboronic acid (303.14 mg, 4.10 mmol), and cesium carbonate (2.67 g, 8.21 mmol) were added to a solution of 5-bromo-2-methoxy-4-pentylbenzaldehyde (780 mg, 2.74 mmol) in toluene (18 mL) and water (1.8 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 13 h. The reaction mixture was partitioned between ethyl acetate (10 mL x 3) and water (10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (petroleum ether and ethyl acetate gradient, eluted with 2% ethyl acetate) to give 5-ethyl-2-methoxy-4-pentylbenzaldehyde as a yellow oil (yield: 600 mg, 79.25%; purity: 84.6%). 1 H NMR (400MHz, CDCl3): δ = 10.40 (s, 1H), 7.63 (s, 1H), 6.76 (s, 1H), 3.91 (s, 3H), 2.66 - 2.57 (m, 4H), 1.65 - 1.57 (m, 2H), 1.42 -1.35 (m, 4H), 1.21 (t, J = 7.6 Hz, 3H), 0.96 - 0.90 (m, 3H).

[0185] Step 4: Preparation of (E)-1-ethyl-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-pentylbenzene Ammonium acetate (197.36 mg, 2.56 mmol) was added to a solution of 5-ethyl-2-methoxy-4-pentylbenzaldehyde (600 mg, 2.56 mmol) in 1-nitropropane (6 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h. The reaction mixture was partitioned between ethyl acetate (10 mL x 3) and water (10 mL). The combined organic fractions were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel (petroleum ether and ethyl acetate gradient, eluted with 2% ethyl acetate) to give a yellow oil. E )-1-Ethyl-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-pentylbenzene (yield: 530 mg, 67%). 1 H NMR (400MHz, CDCl3): δ = 8.25 (s, 1H), 7.11(s, 1H), 6.73 (s, 1H), 3.86 (s, 3H), 2.84 (q, J = 7.3 Hz, 2H), 2.67 - 2.59 (m,4H), 1.66 - 1.57 (m, 2H), 1.42 - 1.36 (m, 4H), 1.29 (t, J = 7.4 Hz, 3H), 1.23(t, J = 7.6 Hz, 3H), 0.96 - 0.91 (m, 3H).

[0186] Step 5: Preparation of 1-(5-ethyl-2-methoxy-4-pentylphenyl)but-2-amine(1) hydrochloride At 0℃ towards ( ELAH (263.43 mg, 6.94 mmol) was added to a solution of 1-ethyl-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-pentylbenzene (530.00 mg, 1.74 mmol) in THF (5 mL). The reaction mixture was stirred at 20 °C for 1 h. After completion, the reaction mixture was quenched at 0 °C by adding H2O (0.3 mL) and 30% NaOH aqueous solution (0.3 mL). The resulting suspension was filtered, the filter cake was washed with THF (20 mL x 3), and the filtrate was concentrated. The residue was purified by preparative-HPLC [column: Phenomenex Luna 80 mm x 30 mm, 3 µm; mobile phase: water (with HCl additive) ACN 15%–40%; run 8 min] to give 1-(5-ethyl-2-methoxy-4-pentylphenyl)but-2-amine (1) hydrochloride (1; yield 295 mg, 61%) as a white solid. LC-MS: m / z 277.4 [M+H] + ; 1 ¹H NMR (400MHz, methanol-d⁴): δ = 6.98 (s, 1H), 6.83 - 6.72 (m, 1H), 3.85 (s, 3H), 3.38 (m, 1H), 3.34 -3.31 (m, 1H), 3.00 - 2.79 (m, 2H), 2.68 - 2.55 (m, 4H), 1.61 (d, J = 7.5 Hz,4H), 1.45 - 1.34 (m, 4H), 1.20 (t, J = 7.6 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H),0.97 - 0.90 (m, 3H); 13 C NMR (101 MHz, methanol-d4): δ = 155.65, 140.87, 133.89, 131.21, 121.05, 54.43, 53.45, 32.87, 32.47, 31.68, 31.01, 25.17, 24.33, 22.25, 14.89, 13.01, 8.57.

[0187] Example 2: Preparation of 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2) hydrochloride Synthesis scheme: Step 1: Preparation of 4-chloro-3-propanol Potassium carbonate (6.0 g, 43.8 mmol), pinacol propyl borate (4.9 g, 29.2 mmol), and Pd(dppf)Cl₂-CH₂Cl₂ (0.6 g, 0.73 mmol) were added to a stirred solution of 3-bromo-4-chlorophenol (3.0 g, 14.6 mmol) in 1,4-dioxane / water (3:1, 30 mL) at room temperature under argon atmosphere. The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) and filtered through a diatomaceous earth mat. The filtrate was partitioned between ethyl acetate (50 mL) and water (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude substance was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give 4-chloro-3-propylphenol as a grayish-white solid (yield: 1.4 g, 56%). 1 H NMR (400 MHz, DMSO-d6): δ = 9.54 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.8 Hz, 1H), 2.56-2.49 (m, 2H), 1.59-1.49 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0188] Step 2: Preparation of 5-chloro-2-hydroxy-4-propylbenzaldehyde Triethylamine (2.26 mL, 16.4 mmol) was added to a stirred solution of 4-chloro-3-propylphenol (1.4 g, 8.22 mmol) in anhydrous ACN (14.0 mL) and stirred at room temperature for 15 min. Then, paraformaldehyde (1.4 g, 49.2 mmol) and magnesium chloride (1.2 g, 12.2 mmol) were added to the reaction mixture. The reaction mixture was heated to 70 °C and stirred for 15 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was partitioned between ethyl acetate (20 mL) and water (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by rapid column chromatography (silica gel; eluting with 0-10% ethyl acetate / heptane) to give 5-chloro-2-hydroxy-4-propylbenzaldehyde as a grayish-white solid (yield: 1.0 g, 66%). LC-MS: m / z 199 [M+1] + .

[0189] Step 3: Preparation of 5-chloro-2-methoxy-4-propylbenzaldehyde Potassium carbonate (1.0 g, 7.72 mmol) was added to a stirred solution of 5-chloro-2-hydroxy-4-propylbenzaldehyde (0.51 g, 2.57 mmol) in dimethylformamide (5.0 mL), followed by dropwise addition of iodomethane (155 µL, 6.42 mmol) at 0 °C. The reaction mixture was heated to 50 °C and stirred for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic fractions were washed with brine (10 mL), dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by column chromatography (silica gel; eluted with 0–15% EtOAc / heptane) to give 5-chloro-2-methoxy-4-propylbenzaldehyde as a colorless liquid (yield: 0.41 g, 75%). LC-MS: m / z 213 [M+1] + .

[0190] Step 4: ( E Preparation of 1-chloro-4-methoxy-5-(2-nitrovinyl)-2-propylbenzene Nitromethane (1.17 g, 19.3 mmol) was added to a solution of 5-chloro-2-methoxy-4-propylbenzaldehyde (0.41 g, 1.93 mmol) in acetic acid (5.0 mL) under stirring at 0 °C, followed by the addition of n-butylamine (0.7 mL, 9.65 mmol). The reaction mixture was then heated to 90 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into cold water (20 mL), the precipitate formed was filtered, washed with cold water, and dried under reduced pressure to obtain the desired yellow solid. E 1-Chloro-4-methoxy-5-(2-nitrovinyl)-2-propylbenzene (Yield: 0.38 g, 77%). 1 H NMR (400MHz, DMSO-d6): δ = 8.18‒8.10 (m, 2H), 7.92 (s, 1H), 7.15 (s, 1H), 3.93 (s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 1.64‒1.59 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[0191] Step 5: Preparation of 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2) H₂SO₄ (0.31 mL, 5.92 mmol) was added dropwise to a stirred solution of LAH solution (2.0 M, in THF; 5.96 mL, 11.93 mmol) in anhydrous THF (10 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and H₂SO₄ was added dropwise over 10 min intervals at 0 °C. E 1-Chloro-4-methoxy-5-(2-nitrovinyl)-2-propylbenzene (0.38 g, 1.49 mmol) / THF (5 mL). The reaction mixture was heated to room temperature and stirred for 2.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (10 mL), dried over anhydrous Na2SO4, and the combined organic fractions were filtered and concentrated under reduced pressure to give 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2) as a yellow gel (yield: 0.30 g, 88%), which was used directly for the next step. LC-MS: m / z 228 [M+1] +.

[0192] Step 6: Preparation of tert-butyl (5-chloro-2-methoxy-4-propylphenylethyl)carbamate Triethylamine (0.46 mL, 3.30 mmol) was added to a solution of 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2; 0.30 g, 1.32 mmol) in THF (10 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (0.45 mL, 1.98 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude compound. The crude compound was purified by rapid column chromatography (silica gel; eluted with 0–10% ethyl acetate / heptane) to give tert-butyl (5-chloro-2-methoxy-4-propylphenylethyl)carbamate as a grayish-white solid (yield: 100 mg, 23%). LC-MS: m / z 228 [M+H-100] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.08 (s, 1H), 6.89 (s, 1H), 6.80 (t, J =5.2 Hz, 1H), 3.77 (s, 3H), 3.06 (q, J = 6.4 Hz, 2H), 2.61 (t, J = 7.2 Hz, 4H),1.60‒1.54 (m, 2H), 1.37 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H).

[0193] Step 7: Preparation of 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.76 mL, 3.05 mmol) was added to a stirred solution of tert-butyl (5-chloro-2-methoxy-4-propylphenylethyl)carbamate (100 mg, 0.305 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 2-(5-chloro-2-methoxy-4-propylphenyl)ethyl-1-amine (2) hydrochloride as a grayish-white solid (yield: 31 mg, 38%). LC-MS: m / z 228 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.85 (s, 3H), 7.20 (s, 1H), 6.96 (s,1H), 3.80 (s, 3H), 2.97 (m, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.2 Hz,2H), 1.63‒1.54 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H).

[0194] Example 3: Preparation of 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-amine enantiomer 1 (3E1) hydrochloride and 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-amine enantiomer 2 (3E2) hydrochloride Synthesis scheme: Step 1: ( E Preparation of 1-bromo-2-chloro-5-methoxy-4-(2-nitroprop-1-en-1-yl)benzene Nitroethane (2.0 mL, 28.1 mmol) was added to a stirred solution of 4-bromo-5-chloro-2-methoxybenzaldehyde (see Example 4; 700 mg, 2.81 mmol) in acetic acid (10 mL) at 0 °C, followed by the addition of tert-butylamine (1.47 mL, 14.05 mmol). The mixture was then heated to 90 °C and stirred for 6 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice water (25 mL), the precipitate formed was filtered, washed with cold water (10 mL x 3), and dried under reduced pressure to obtain the desired yellow solid.E )-1-bromo-2-chloro-5-methoxy-4-(2-nitroprop-1-en-1-yl)benzene (yield: 780 g, 90%). 1 H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 3.89 (s, 3H), 2.28 (s, 3H).

[0195] Step 2: Preparation of 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine (12) AlCl3 (96.5 mg, 2.54 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 3.81 mL, 7.62 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-2-chloro-5-methoxy-4-(2-nitroprop-1-en-1-yl)benzene (780 mg, 2.54 mmol) / THF (5 mL). The reaction mixture was heated to room temperature and stirred for 2.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 10 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, and the combined organic fraction was filtered and concentrated under reduced pressure to give 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine (12) as a colloidal solid (yield: 700 mg, crude), which was used directly in the next step.

[0196] Step 3: Preparation of tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate Triethylamine (0.9 mL, 6.27 mmol) was added to a solution of 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine (700 mg, 2.51 mmol) in THF (10 mL) under stirring at 0 °C, followed by di-tert-butyl dicarbonate (0.78 mL, 3.76 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-15% ethyl acetate / heptane) to give tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 450 mg, 47%). LC-MS: m / z 379.05 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ =7.29 (s, 1H), 7.28 (s, 1H), 6.67 (d, J =9.2 Hz, 1H), 3.81 (s, 3H), 3.71-3.69 (s, 1H), 2.67 (dd, J = 13.2, 5.2 Hz, 1H),2.51-2.42 (m, 1H), 1.29 (s, 9H), 1.03 (d, J = 6.4 Hz, 3H).

[0197] Step 4: Preparation of tert-butyl (1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (437 mg, 3.57 mmol), n-butylboronic acid (426 mg, 4.75 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (38 mg, 0.105 mmol), and palladium acetate (12 mg, 0.053 mmol) were added to a stirred solution of (1-(4-bromo-5-chloro-2-methoxyphenyl)propyl-2-yl)carbamate (400 mg, 1.05 mmol) in 1,4-dioxane / water (7:3, 8 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (10 mL) and water (10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 100 mg, 27%). LC-MS: m / z 256.15 [M+1-100] + .

[0198] Step 5: (1-(4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl Through chiral SFC [Column Name: Phenomenex] ® Lux i-Amylose-3 (30 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA (70:30); flow rate: 80 mL / min; column temperature: 30℃] separation (1-(4-butyl-5-chloro-2-) methoxyphenyl)prop-2-yl)carbamate tert-butyl (100 mg) of enantiomers. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 40 mg, 40%, >99% ee; plotted as the S enantiomer, but absolute stereochemistry not determined experimentally) and enantiomer 2 of (1-(4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)carbamate (yield: 40 mg, 40%, >99% ee; plotted as the R enantiomer, but absolute stereochemistry not determined experimentally).

[0199] Enantiomer 1 of (1-(4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z 256.05 [M+1-100] + ; 1 H NMR (400 MHz, CDCl3): δ =7.08 (s, 1H),6.87 (s, 1H), 6.65 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.71-3.65 (m, 1H), 2.68-2.60 (m, 3H), 2.57-2.40 (m, 1H), 1.56-1.48 (m, 2H), 1.37-1.20 (m, 2H), 1.32(s, 9H), 1.01(d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis (column name: Phenomenex Lux i-Amylose-3 (150 mm x 4.6 mm, 3 µm); mobile phase: supercritical CO2 (80%), MeOH / IPA (20%); flow rate: 3.0 mL / min; column temperature: 30 °C, λ = 283 nm). R t = 1.70 min (enantiomer 1), 2.15 min (enantiomer 2).

[0200] Enantiomer 2 of (1-(4-butyl-5-chloro-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z 256.05 [M+1-100] + ; 1 H NMR (400 MHz, CDCl3): δ =7.08 (s, 1H),6.87 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 3.72-3.66 (m, 1H), 2.64-2.62 (m, 2H), 2.57-2.47 (m, 2H), 1.54-1.51 (m, 2H), 1.37-1.16 (m, 2H), 1.30(s, 9H), 1.01(d, J = 6.4 Hz, 3H), 0.91 (t, J= 7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis (column name: Phenomenex Lux i-Amylose-3 (150 mm x 4.6 mm, 3 µm); mobile phase: supercritical CO2 (80%), MeOH / IPA (20%); flow rate: 3.0 mL / min; column temperature: 30 °C, λ = 283 nm). R t = 1.70 min (enantiomer 1), 2.15 min (enantiomer 2).

[0201] Step 6a: Preparation of 1-(4-Butyl-5-chloro-2-methoxyphenyl)prop-2-amine (3E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.28 mL, 1.12 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate enantiomer 1 (40 mg, 0.112 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-amine enantiomer 1 (3E1) hydrochloride as a grayish-white solid (yield: 15 mg, 46%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 256.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.89 (s, 3H), 7.19 (s, 1H), 6.97 (s, 1H), 3.79 (s, 3H), 3.40 (q, J = 6.8 Hz, 1H), 2.85 (dd, J = 13.2, 6.0 Hz, 1H), 2.70-2.63 (m, 3H), 1.58-1.51 (m, 2H), 1.40-1.31 (m, 2H), 1.09 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.6 Hz, 3H).

[0202] Step 6b: Preparation of 1-(4-Butyl-5-chloro-2-methoxyphenyl)prop-2-amine (3E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.28 mL, 1.12 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate enantiomer 2 (40 mg, 0.112 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-butyl-5-chloro-2-methoxyphenyl)prop-2-amine enantiomer 2 (3E2) hydrochloride as a grayish-white solid (yield: 16 mg, 49%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 256.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.84 (s, 3H), 7.19 (s, 1H), 6.97 (s, 1H), 3.79 (s, 3H), 3.40 (q, J = 6.4 Hz, 1H), 2.84 (dd, J = 13.2, 6.0 Hz, 1H), 2.70-2.63 (m, 3H), 1.58-1.51 (m, 2H), 1.40-1.31 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0203] Example 4: Preparation of 1-(4-Butyl-5-chloro-2-methoxyphenyl)but-2-amine enantiomer 1 (4E1) hydrochloride and 1-(4-Butyl-5-chloro-2-methoxyphenyl)but-2-amine enantiomer 2 (4E2) hydrochloride Synthesis scheme: Step 1: Preparation of 4-bromo-5-chloro-2-methoxybenzaldehyde Titanium tetrachloride (7.4 mL, 68.4 mmol) was added to a solution of 2-bromo-1-chloro-4-methoxybenzene (5.0 g, 22.8 mmol) in DCM (20 mL) under stirring at -76 °C, followed by dropwise addition of dichloro(methoxy)methane (4.2 mL, 45.6 mmol) at the same temperature. The reaction mixture was stirred at -76 °C for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic fractions were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude compound. The crude compound was purified by rapid column chromatography (silica gel; eluted with 0–10% ethyl acetate / heptane) to give 4-bromo-5-chloro-2-methoxybenzaldehyde as a liquid (yield: 2.3 g, 41%). 1 H NMR (400 MHz, CDCl3): δ = 10.35 (s, 1H), 7.87 (s, 1H), 7.28 (s, 1H), 3.94 (s, 3H).

[0204] Step 2: Preparation of (E)-1-bromo-2-chloro-5-methoxy-4-(2-nitrobut-1-en-1-yl)benzene 1-Nitropropane (5.4 mL, 60.7 mmol) was added to a solution of 4-bromo-5-chloro-2-methoxybenzaldehyde (1.5 g, 6.07 mmol) in acetic acid (15 mL) under stirring at 0 °C, followed by the addition of tert-butylamine (3.55 mL, 33.3 mmol). The reaction mixture was then heated to 90 °C and stirred for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into cold water (50 mL), the precipitate formed was filtered, washed with cold water (50 mL x 2), and dried under reduced pressure to obtain the desired yellow solid. E 1-Bromo-2-chloro-5-methoxy-4-(2-nitrobut-1-en-1-yl)benzene (yield: 1.0 g, 51%). 1 H NMR (400 MHz, CDCl3): δ = 7.99 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 3.87(s, 3H), 2.79-2.71 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H).

[0205] Step 3: Preparation of 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine (13) AlCl3 (625 mg, 3.13 mmol) was added in portions to a stirred solution of LAH (2.0 M, in THF; 4.70 mL, 9.40 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-2-chloro-5-methoxy-4-(2-nitrobut-1-en-1-yl)benzene (1.0 g, 3.13 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 12 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was diluted with THF (10 mL) and stirred at room temperature for 30 min under an argon atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine (13) as a gel solid (yield: 0.87 g, 95%). LC-MS: m / z 293.9 [M+1] + .

[0206] Step 4: Preparation of tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-yl)carbamate Triethylamine (1.0 mL, 7.44 mmol) was added to a solution of 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine (0.87 g, 2.97 mmol) in THF (10 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (1.0 mL, 4.45 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by rapid column chromatography (eluting with 0–10% EtOAc / heptane) to give tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 500 mg, 42%). LC-MS: m / z 293.9 [M+1-100] + ; 1 HNMR (400 MHz, DMSO-d6): δ = 7.28 (s, 1H), 7.26 (s, 1H), 6.57 (d,J = 9.6 Hz, 1H),3.80 (s, 3H), 3.50 (br, 1H), 2.75-2.67 (m, 1H), 2.40-2.33 (m, 1H), 1.46-1.31(m, 2H), 1.27 (s, 9H), 0.83 (t, J = 7.2 Hz, 3H).

[0207] Step 5: Preparation of tert-butyl (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (476 mg, 3.45 mmol), n-butylboronic acid (466 mg, 4.6 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (41 mg, 0.115 mmol), and palladium acetate (13 mg, 0.057 mmol) were added to a stirred solution of (1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-yl)carbamate (0.45 g, 1.15 mmol) in 1,4-dioxane / water (7:3) (10 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (20 mL) and water (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude substance. The crude substance was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 140 mg, 33%). LC-MS: m / z 256 [M+1-100] + ; 1 H NMR (400 MHz, CDCl3): δ = 7.08 (s, 1H), 6.68 (s, 1H), 4.50 (d, J = 8.4 Hz,1H), 3.83 (s, 3H), 3.72 (br, 1H), 2.78-2.74 (m, 1H), 2.68 (t, J = 8.0 Hz, 2H), 2.60 (dd, J= 13.6, 8.4 Hz, 1H), 1.63-1.51 (m, 3H), 1.45-1.28 (m, 4H), 1.38 (s,9H), 0.98-0.87 (m, 6H).

[0208] Step 6: (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate tert-butyl The enantiomers of (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate (140 mg) were separated by chiral SFC [column name: Phenomenex, Lux Amylose-1 (21.2 mm x 250 mm) 5 µm; mobile phase: supercritical CO2IPA (75:25); flow rate: 70 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and freeze-dried to give enantiomer 1 of (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 60 mg, 43%; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate (yield: 50 mg, 36%; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0209] Enantiomer 1 of (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z 270 [M+H-100] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.09 (s, 1H), 6.86 (s, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.77 (s, 3H), 3.52- 3.50 (m, 1H), 2.73-2.68 (m, 1H), 2.62 (t, J = 8.0 Hz, 2H), 2.42-2.36 (m, 1H), 1.56-1.48 (m, 2H), 1.44-1.24 (m, 4H), 1.28 (s, 9H), 0.91 (t, J = 7.2 Hz, 3H), 0.85 (t, J= 7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis [column name: Phenomenex, Lux Amylose-1 (250 mm x 4.6 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.2% isopropylamine (75:25); flow rate: 3.0 mL / min; column temperature: 30 °C]. R t =1.55 min (enantiomer 1), 5.27 min (enantiomer 2).

[0210] Enantiomer 2 of (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z 270 [M+H-100] + ; 1 H NMR (400 MHz, CDCl3): δ = 7.08 (s, 1H),6.68 (s, 1H), 4.49 (br, 1H), 3.83 (s, 3H), 3.72 (br, 1H), 2.76-2.73 (m, 1H),2.68 (t, J = 8.0 Hz, 2H) 2.60 (dd, J = 13.6, 8.4 Hz, 1H), 1.62–1.51 (m, 3H), 1.50–1.38 (m, 3H), 1.38 (s, 9H), 0.98–0.88 (m, 6H). Enantiomer excess (>99%) was determined by chiral SFC [column name: Phenomenex, Lux Amylose-1 (250 mm x 4.6 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.2% isopropylamine (75:25); flow rate: 3.0 mL / min; column temperature: 30 °C]. R t =1.55 min (enantiomer 1), 5.27 min (enantiomer 2).

[0211] Step 7a: Preparation of 1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-amine enantiomer 1 (4E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.4 mL, 1.6 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate enantiomer 1 (60 mg, 0.16 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-amine enantiomer 1 (4E1) hydrochloride (yield: 50 mg, 99%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 270.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 3H), 7.22 (s, 1H), 6.96 (s, 1H), 3.79 (s, 3H), 3.26-3.23 (m, 1H), 2.77 (dd, J = 6.4, 1.6 Hz, 2H), 2.65 (t, J = 7.6Hz, 2H), 1.58-1.45 (m, 4H), 1.40-1.31 (m, 2H), 0.94-0.86 (m, 6H).

[0212] Step 7b: Preparation of 1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-amine enantiomer 2 (4E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane) (0.05 mL, 1.4 mmol) was added to a stirred solution of tert-butyl (1-(4-butyl-5-chloro-2-methoxyphenyl)but-2-yl)carbamate (50 mg, 0.14 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-2-methoxy-5-methylphenyl)but-2-amine enantiomer 2 (4E2) hydrochloride (yield: 30 mg, 59.5%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 270.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ = 7.85 (s, 3H), 7.22 (s, 1H), 6.96 (s, 1H), 3.79(s, 3H), 3.27-3.22 (m, 1H), 2.79-2.75 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.58-1.45 (m, 4H), 1.40-1.31 (m, 2H), 0.94-0.86 (m, 6H).

[0213] Example 5: Preparation of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 1 (5E1) hydrochloride and 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 2 (5E2) hydrochloride Synthesis scheme: Step 1: Preparation of (E)-1-chloro-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-propylbenzene At 0 °C, a solution of 5-chloro-2-methoxy-4-propylbenzaldehyde (see Example 2; 0.3 g, 1.41 mmol) in acetic acid (3 mL) was stirred, and 1-nitropropane (1.25 mL, 14.1 mmol) was added, followed by n-butylamine (0.73 mL, 7.05 mmol). The mixture was then heated to 90 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice water (25 mL), the precipitate formed was filtered, washed with cold water (10 mL x 3), and dried under reduced pressure to obtain the desired yellow solid. E )-1-chloro-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-propylbenzene (yield: 0.30 g, 75%), which was used directly in the next step.

[0214] Step 2: Preparation of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine (5) H₂SO₄ (310 mg, 4.20 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 1.66 mL, 8.40 mmol) in anhydrous THF (15 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E1-Chloro-4-methoxy-5-(2-nitrobut-1-en-1-yl)-2-propylbenzene (0.30 g, 1.05 mmol) / THF (5 mL). The reaction mixture was heated to room temperature and stirred for 3.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 7 mL) was added at the same temperature until no more bubbling occurred. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine (5) as a pale yellow solid (yield: 0.20 g, 74%), which was used directly in the next step.

[0215] Step 3: Preparation of tert-butyl (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate Triethylamine (0.27 mL, 1.95 mmol) was added to a solution of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine (0.20 g, 7.81 mmol) in THF (5 mL) under stirring at 0 °C, followed by di-tert-butyl dicarbonate (0.26 mL, 1.72 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-10% ethyl acetate / heptane) to give tert-butyl 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 160 mg, 57%). 1 H NMR (400 MHz, CDCl3): δ = 7.28 (s, 1H), 7.26 (s, 1H), 6.57 (d, J = 9.6 Hz, 1H), 3.80 (s, 3H), 3.53 ‒3.48 (m, 1H), 2.75 ‒ 2.67 (m, 2H), 2.40 ‒ 2.33 (m, 2H), 1.45 ‒ 1.30 (m, 3H),1.27 (s, 9H), 1.17 (s, 2H), 0.83 (t, J = 7.2 Hz, 3H).

[0216] Step 4: (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate tert-butyl ester Through chiral SFC [Column Name: Phenomenex] ® [Lux Amylose-1 (21 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / MeOH (75:25); flow rate: 70 mL / min; column temperature: 30 °C] Separation of enantiomers of (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate (160 mg). The separated fractions were concentrated under reduced pressure and freeze-dried to give enantiomer 1 of (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 57 mg, 36%, >99% ee; plotted as the S enantiomer, but absolute stereochemistry not determined experimentally) and enantiomer 2 of (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate (yield: 63 mg, 39%, >99% ee; plotted as the R enantiomer, but absolute stereochemistry not determined experimentally).

[0217] Enantiomer 1 of (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z 356.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.08 (s, 1H), 6.86 (s, 1H), 6.56 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.49 (br, 1H), 2.71 ‒2.67 (m, 1H), 2.59 (t, J = 7.2 Hz, 2H), 2.41 ‒ 2.35 (m, 1H), 1.58 ‒ 1.55 (m,2H), 1.45 ‒ 1.33 (m, 2H), 1.27 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H), 0.82 (t, J =7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis (column name: Lux Amylose-1 (4.6 mm x 250 mm) 5 µm; mobile phase: CO2 / IPA (75:25) containing 0.2% isopropylamine additive; flow rate: 3.0 mL / min; column temperature: 30 °C). Rt = 1.53 min (enantiomer 1), 5.39 min (enantiomer 2).

[0218] Enantiomer 2 of (1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z 356.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.08 (s, 1H), 6.86 (s, 1H), 6.53 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.51 ‒ 3.49 (m, 1H), 2.72‒ 2.63 (m, 1H), 2.61 (t, J = 7.2 Hz, 2H), 2.41 ‒ 2.33 (m, 1H), 1.55 ‒ 1.48 (m,2H), 1.43 ‒ 1.33 (m, 2H), 1.27 (s, 9H), 0.90 (t, J = 7.2 Hz, 3H), 0.88 (t, J =7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis (column name: Lux Amylose-1 (4.6 mm x 250 mm) 5 µm; mobile phase: CO2 / IPA (75:25) containing 0.2% isopropylamine additive; flow rate: 3.0 mL / min; column temperature: 30 °C). R t = 1.53 min (enantiomer 1), 5.37 min (enantiomer 2).

[0219] Step 5a: Preparation of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 1 (5E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.37 mL, 1.5 mmol) was added to a stirred solution of tert-butyl 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate enantiomer 1 (57 mg, 0.160 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 1 (5E1) hydrochloride (yield: 34 mg, 83%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 256.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.79 (s, 3H), 7.22 (s, 1H), 6.97(s, 1H), 3.79 (s, 3H), 3.28-3.25 (m, 1H), 2.80-2.71 (m, 2H), 2.67-2.61 (m,2H), 1.64-1.55 (m, 2H), 1.52-1.45 (m, 2H), 0.96-0.89 (m, 6H).

[0220] Step 5b: Preparation of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 2 (5E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.049 mL, 1.49 mmol) was added to a stirred solution of tert-butyl 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-yl)carbamate enantiomer 2 (63 mg, 0.177 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(5-chloro-2-methoxy-4-propylphenyl)but-2-amine enantiomer 2 (5E2) hydrochloride (yield: 37 mg, 90%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 256.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.81 (s, 3H), 7.22 (s, 1H), 6.96(s, 1H), 3.79 (s, 3H), 3.30-3.22 (m, 1H), 2.81-2.71 (m, 2H), 2.66-2.61 (m,2H), 1.63-1.54 (m, 2H), 1.52-1.45 (m, 2H), 0.95-0.89 (m, 6H).

[0221] Example 6: 1-(4-Butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 1 (6E1) hydrochloride and 1-(4-Butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 2 (6E2) hydrochloride Synthesis scheme: Step 1: Preparation of 4-bromo-2-methoxy-5-methylbenzaldehyde Potassium carbonate (3.2 g, 23.2 mmol) was added to a solution of 4-bromo-2-hydroxy-5-methylbenzaldehyde (2.0 g, 9.3 mmol) in dimethylformamide (20 mL) under stirring at 0 °C, followed by dropwise addition of iodomethane (868 µL, 14 mmol). The reaction mixture was heated to 50 °C and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic fractions were washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography using a 40 g silica gel column (eluted with 0–15% ethyl acetate / heptane) to give 4-bromo-2-methoxy-5-methylbenzaldehyde as a colorless liquid (yield: 2.0 g, 93.9%). LC-MS: m / z 230.95 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ = 10.38 (s, 1H), 7.66 (s, 1H), 7.19 (s, 1H), 3.91 (s, 3H), 2.36 (3H).

[0222] Step 2: Preparation of (E)-1-bromo-5-methoxy-2-methyl-4-(2-nitroprop-1-en-1-yl)benzene Nitroethane (2.3 mL, 43.7 mmol) was added to a solution of 4-bromo-2-methoxy-5-methylbenzaldehyde (1.0 g, 4.37 mmol) in acetic acid (10 mL) under stirring at 0 °C, followed by the addition of tert-butylamine (2.55 mL, 24 mmol). The mixture was then heated to 85 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice water (50 mL), the precipitate formed was filtered, washed with cold water (10 mL x 3), and dried under reduced pressure to obtain the desired yellow solid. E 1-Bromo-5-methoxy-2-methyl-4-(2-nitroprop-1-en-1-yl)benzene (Yield: 1.0 g, 80%). LC-MS: m / z 287.8 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1H), 7.12 (s, 2H), 3.81 (s, 3H), 2.36 (s, 6H).

[0223] Step 3: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-amine (14) AlCl3 (465 mg, 3.49 mmol) was added in portions to a stirred solution of LAH (2.0 M, in THF; 5.23 mL, 10.47 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-5-methoxy-2-methyl-4-(2-nitroprop-1-en-1-yl)benzene (1.0 g, 3.49 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 1.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, and the combined organic fraction was filtered and concentrated under reduced pressure to give 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-amine (14) as a gel solid (yield: 0.7 g, 77.6%), which was used directly in the next step.

[0224] Step 4: Preparation of tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-yl)carbamate Triethylamine (0.65 mL, 6.8 mmol) was added to a solution of 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-ylamine (14 g; 0.7 g, 2.71 mmol) in THF (10 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (0.9 mL, 4.6 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude compound. The crude compound was purified by rapid column chromatography (eluting with 0–10% ethyl acetate / heptane) to give tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 400 mg, 63%). LC-MS: m / z 258 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ = 7.02 (s, 1H), 6.98 (s, 1H), 4.59 (brs, 1H), 3.88-3.83 (br s, 1H), 3.81 (s, 3H), 2.69-2.63 (m, 2H), 2.31 (s, 3H), 1.40 (s,9H), 1.12 (d, J = 6.4 Hz, 3H).

[0225] Step 5: Preparation of tert-butyl (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (347 mg, 2.51 mmol), butylboronic acid (171 mg, 1.67 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (30 mg, 0.083 mmol), and palladium acetate (9.4 mg, 0.042 mmol) were added to a stirred solution of (1-(4-bromo-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate (0.3 g, 0.837 mmol) in 1,4-dioxane / water (3:1, 8 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (10 mL) and water (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography (eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 180 mg, 64%). 1 H NMR (400 MHz, CDCl3): δ = 6.88 (s,1H), 6.65 (s, 1H), 4.78 (br s, 1H), 3.86 (br s, 1H), 3.82 (s, 3H), 2.75-2.63(m, 2H), 2.56 (t, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.59-152 (m, 2H), 1.46-1.37(m, 2H), 1.41 (s, 9H), 1.11 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H).

[0226] Step 6: (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate tert-butyl The enantiomers of (1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-yl)carbamate (180 mg) were separated by chiral SFC [column name: Lux Amylose-1 (21.2 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA (75:25); flow rate: 70 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 50 mg, 31%, >99% ee; plotted as the S enantiomer, but absolute stereochemistry not determined experimentally) and enantiomer 2 of (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate (yield: 60 mg, 37%, >99% ee; plotted as the R enantiomer, but absolute stereochemistry not determined experimentally).

[0227] Enantiomer 1 of (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z 336.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ = 6.86 (s, 1H), 6.62(s, 1H), 4.75 (br s, 1H), 3.85 (br s, 1H), 3.80 (s, 3H), 2.69-2.61 (m, 2H),2.54 (t, J = 8.0 Hz, 2H), 2.19 (s, 3H), 1.57-1.49 (m, 2H), 1.44-1.35 (m, 2H), 1.38 (s, 9H), 1.11 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis [column name: Lux Amylose-1 (250 mm x 4.6 mm) 5 µm; mobile phase: CO2 / IPA (80:20) containing 0.2% isopropylamine additive; flow rate: 3.0 mL / min; run time: 15 min; column temperature: 30 °C]. R t = 1.67 min (enantiomer 1), 3.97 min (enantiomer 2).

[0228] Enantiomer 2 of (1-(4-butyl-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate tert-butyl ester LC-MS: m / z 336.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ = 6.89 (s, 1H), 6.64 (s, 1H), 4.68 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.69 (br s, 1H), 2.75-2.65 (m,2H), 2.54 (t, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.65–1.49 (m, 4H), 1.38 (s, 9H), 1.02–0.90 (m, 6H). Enantiomer excess (99%) was determined by chiral SFC [column name: Lux Amylose-1 (250 mm x 4.6 mm) 5 µm; mobile phase: CO2 / IPA (80:20) containing 0.2% isopropylamine additive; flow rate: 3.0 mL / min; run time: 8 min; column temperature: 30 °C]. R t = 1.79 min (enantiomer 1), 3.23 min (enantiomer 2).

[0229] Step 7a: Preparation of 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 1 (6E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.37 mL, 1.5 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-yl)carbamate enantiomer 1 (50 mg, 0.149 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 1 (6E1) hydrochloride (yield: 21 mg, 51.7%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 236.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.88 (s, 3H), 6.88 (s, 1H), 6.76(s, 1H), 3.75 (s, 3H), 3.39-3.38 (m, 1H), 2.84 (dd, J = 13.2, 5.2 Hz, 1H), 2.60(dd, J = 13.2, 8.8 Hz, 1H), 2.54-2.52 (m, 2H), 2.16 (s, 3H), 1.53-1.45 (m, 2H), 1.40-1.31 (m, 2H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0230] Step 7b: Preparation of 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 2 (6E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.45 mL, 1.79 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-yl)carbamate enantiomer 2 (60 mg, 0.179 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-2-methoxy-5-methylphenyl)prop-2-amine enantiomer 2 (6E2) hydrochloride (yield: 29 mg, 59.5%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 236.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 3H), 6.88 (s, 1H), 6.76(s, 1H), 3.75 (s, 3H), 3.41-3.38 (m, 1H), 2.84 (dd, J = 13.2, 5.2 Hz, 1H), 2.60(dd, J = 13.2, 8.8 Hz, 1H), 2.54-2.50 (m, 2H), 2.16 (s, 3H), 1.53-1.45 (m, 2H), 1.40-1.31 (m, 2H), 1.06 (d,J =6.4 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0231] Example 7: Enantiomer 1 (7E1) hydrochloride of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile and enantiomer 2 (7E2) hydrochloride of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile Synthesis scheme: Step 1: Preparation of 4-Butyl-2-methoxybenzaldehyde Potassium carbonate (7.6 g, 69.6 mmol), n-butylboronic acid (4.74 g, 46.4 mmol), and bis(diphenylphosphino)ferrocene)palladium dichloromethane dichloride complex (946 mg, 1.16 mmol) were added to a stirred solution of 4-bromo-2-methoxybenzaldehyde (5 g, 23.2 mmol) in 1,4-dioxane / water (3:1, 50 mL) at room temperature under argon atmosphere. The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 16 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (100 mL) and water (70 mL). The combined organic layers were washed with brine (70 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography (silica gel; eluting with 0-15% ethyl acetate / heptane) to give 4-butyl-2-methoxybenzaldehyde as a yellow liquid (yield: 2.0 g, 45%). LC-MS: m / z 193.10 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ = 10.41 42 (s, 1H), 7.765 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz,1H), 6.8079 (s, 1H), 3.94 (s, 3H), 2.6766 (t, J = 8.0 Hz, 2H), 1.687-1.60 (m,2H), 1.4241-1.32 (m, 2H), 0.95 96 (t, J = 7.2 Hz, 3H).

[0232] Step 2: Preparation of 5-bromo-4-butyl-2-methoxybenzaldehyde The solution of 4-butyl-2-methoxybenzaldehyde (2 g, 10.40 mmol) stirred at 0 °C was added in portions to a solution of acetonitrile (25 mL). N 5-Bromosuccinimide (973 mg, 12.48 mmol). The reaction mixture was stirred at 0 °C for 5 min, then heated to room temperature and stirred for 2 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by rapid column chromatography (silica gel; eluted with 0–10% ethyl acetate / heptane) to give 5-bromo-4-butyl-2-methoxybenzaldehyde as a grayish-white solid (yield: 1.5 g, 53.2%). 1 H NMR (400 MHz, CDCl3): δ = 10.35 (s, 1H), 7.97 (s, 1H), 6.85 (s, 1H), 3.94 (s, 3H), 2.77 (t, J = 8.0 Hz, 2H), 1.65-1.59 (m, 2H), 1.48-1.42 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H).

[0233] Step 3: Preparation of (E)-1-bromo-2-butyl-4-methoxy-5-(2-nitroprop-1-en-1-yl)benzene Nitroethane (2.9 mL, 55.3 mmol) was added to a solution of 5-bromo-4-butyl-2-methoxybenzaldehyde (1.5 g, 5.53 mmol) in acetic acid (10 mL) under stirring at 0 °C, followed by the addition of tert-butylamine (3.23 mL, 30.4 mmol). The mixture was then heated to 90 °C and stirred for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-10% ethyl acetate / heptane) to give a yellow solid ( E 1-Bromo-2-butyl-4-methoxy-5-(2-nitroprop-1-en-1-yl)benzene (yield: 1.2 g, 66%). 1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1H), 7.56 (s, 1H), 7.13 (s, 1H), 3.86 (s, 3H), 2.71 (t, J = 8.0 Hz, 2H), 2.30 (s, 3H), 1.61-1.53(m, 2H), 1.42-1.33 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0234] Step 4: Preparation of 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-amine (21) AlCl3 (487 mg, 3.66 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 5.49 mL, 10.98 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-2-butyl-4-methoxy-5-(2-nitroprop-1-en-1-yl)benzene (1.2 g, 3.66 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 1.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-amine (21) as a gel solid (yield: 1.0 g), which was used directly in the next step.

[0235] Step 5: Preparation of tert-butyl (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate Triethylamine (1.2 mL, 8.32 mmol) was added to a solution of crude 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-ylamine (1.0 g, 3.33 mmol) in THF (10 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (1.14 mL, 4.99 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0–10% ethyl acetate / heptane) to give tert-butyl (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 1.0 g, 75%). LC-MS: m / z 300.05 [M+1-100] + ; 1 H NMR (400 MHz, CDCl3): δ = 7.23 (s, 1H), 6.68 (s, 1H), 4.56 (br s, 1H), 3.87(br s, 1H), 3.81 (s, 3H), 2.68-2.65 (m, 4H), 1.42-1.38 (m, 4H), 1.38 (s, 9H),1.11 (d, J = 6.4 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H).

[0236] Step 6: Preparation of tert-butyl (1-(4-butyl-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate To a stirred solution of tert-butyl (1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate (0.3 g, 0.75 mmol) in DMF (10 mL), Zn(CN)₂ (96.8 mg, 0.82 mmol), zinc (9.8 mg, 0.15 mmol), 1,1′-ferrocene di-bis(diphenylphosphine) (41.5 mg, 0.075 mmol), and tris(dibenzylacetone)dipalladium (34 mg, 0.037 mmol) were added. The reaction mixture was purged with argon for 10 min and then heated at 120 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (500 mL) and water (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by rapid chromatography (silica gel; eluting with 0-20% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)carbamate as a yellow solid (yield: 150 mg, 58%). LC-MS: m / z 347.25 [M+1] + ; 1 H NMR (400MHz, DMSO-d6): δ = 7.39 (s, 1H), 7.00 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 3.85 (s,3H), 3.72-3.69 (m, 1H), 2.73-2.66 (m, 3H), 2.45-2.21 (m, 1H), 1.61-1.53 ​​(m,2H), 1.37-1.29 (m, 2H), 1.26 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.2Hz, 3H).

[0237] Step 7: (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl The enantiomers of (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)carbamate (150 mg) were separated by chiral SFC [column name: Diacel CHIRALPAK IC (21 mm x 250 mm) 5 µm; mobile phase: supercritical CO2:IPA (80:20); flow rate: 70 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 50 mg, 33%, >99% ee; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined) and enantiomer 2 of (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 50 mg, 33%, >99% ee; plotted as the R enantiomer, but absolute stereochemistry not experimentally determined).

[0238] (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate enantiomer 1 LC-MS: m / z 347.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.39 (s, 1H),7.00 (s, 1H), 6.66 (d, J = 9.2 Hz, 1H), 3.85 (s, 3H), 3.70 (t, J = 5.6 Hz, 1H),2.73-2.67 (m, 3H), 2.45-2.42 (m, 1H), 1.61-1.54 (m, 2H ), 1.35-1.9 (m, 1H ),1.26 (s, 9H), 1.20-1.17 (m, 1H) 1.02 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). Enantiomer excess (99%) was determined by chiral SFC analysis [column name: CHIRALPAK IC (250 mm x 4.6 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.2% isopropylamine (80:20); flow rate: 3.0 mL / min; column temperature: 30 °C]. R t = 2.61 min (enantiomer 1), 2.89 min (enantiomer 2).

[0239] Enantiomer 2 of (1-(4-butyl-5-cyano-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z 347.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.39 (s, 1H),7.00 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 3.70-3.69 (m, 1H), 2.73-2.67 (m, 3H), 2.45-2.42 (m, 1H), 1.61-1.53 ​​(m, 2H ), 1.35-1.23 (m, 11H),1.20-1.17 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.6 Hz, 3H). Enantiomer excess (99%) was determined by chiral SFC analysis [column name: CHIRALPAK IC (250 mm x 4.6 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.2% isopropylamine (80:20); flow rate: 3.0 mL / min; column temperature: 30 °C]. R t = 2.61 min (enantiomer 1), 2.87 min (enantiomer 2).

[0240] Step 8a: Preparation of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile enantiomer 1 (7E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.36 mL, 1.44 mmol) was added to a stirred solution of tert-butyl 1-1-(4-butyl-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate enantiomer 1 (50 mg, 0.114 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired yellow viscous solid of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile enantiomer 1 (7E1) hydrochloride (yield: 28 mg, 68%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 247.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.88 (br s, 3H), 7.56 (s, 1H), 7.09(s, 1H), 3.87 (s, 3H), 3.44-3.42 (m, 1H), 2.87 (dd, J = 13.6, 6.0 Hz, 1H) ,2.77-2.68 (m, 3H), 1.64-1.57 (m, 2H), 1.40-1.30 (m, 2H) , 1.10 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0241] Step 8b: Preparation of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile enantiomer 2 (7E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.36 mL, 1.44 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-butyl-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate enantiomer 2 (50 mg, 0.144 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired yellow viscous solid of 5-(2-aminopropyl)-2-butyl-4-methoxybenzonitrile enantiomer 2 (7E2) hydrochloride (yield: 21 mg, 51%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 247.20 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.90 (br s, 3H), 7.56 (s, 1H), 7.09(s, 1H), 3.87 (s, 3H), 3.44-3.42 (m, 1H), 2.87 (dd, J = 13.6, 6.0 Hz, 1H),2.77-2.62 (m, 3H), 1.64-1.57 (m, 2H), 1.40-1.34 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.6 Hz, 3H).

[0242] Example 8: Preparation of 1-(4-butyl-2-methoxy-5-nitrophenyl)prop-2-amine (8) Synthesis scheme: The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0243] Example 9: Preparation of 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (9) hydrochloride and its enantiomers 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 1 (9E1) hydrochloride and 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 2 (9E2) hydrochloride Synthesis scheme: Step 1: Preparation of 2-bromo-4-methoxy-1-(trifluoromethyl)benzene Methanol (1.17 mL, 28.8 mmol) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.15 g, 28.8 mmol) in DMF (15 mL, 90.4 mmol) at 0 °C under a nitrogen atmosphere. After the gas release ceased, the suspension was stirred at 0 °C for 20 min, and 2-bromo-4-fluoro-1-(trifluoromethyl)benzene (2.0 g, 8.23 ​​mmol) was added dropwise over 5 min. The reaction mixture was heated to room temperature and then heated at 60 °C for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-30% ethyl acetate / heptane) to give 2-bromo-4-methoxy-1-(trifluoromethyl)benzene as an oil (yield: 1.6 g, 76%). 1 H NMR (400 MHz, DMSO-d6): δ = 7.74 (d, J =8.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 3.85 (s, 3H).

[0244] Step 2: Preparation of 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde TiCl4 (1.96 mL, 17.64 mmol) was added dropwise to a solution of dichloromethoxymethane (1.05 g, 11.76 mmol) in anhydrous DCM (15 mL) under an argon atmosphere at -76 °C. After the addition was complete, 2-bromo-4-methoxy-1-(trifluoromethyl)benzene (1.5 g, 5.88 mmol) was added to the reaction mixture and stirred at -76 °C for 3 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (20 mL x 2) and water (10 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-30% ethyl acetate / heptane) to give 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde as an oil (yield: 870 mg, 52%). 1 H NMR (400 MHz, DMSO-d6): δ = 10.26 (s, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 4.04 (s, 3H).

[0245] Step 3: Preparation of (E)-1-bromo-5-methoxy-4-(2-nitroprop-1-en-1-yl)-2-(trifluoromethyl)benzene Nitroethane (2.3 mL, 30.7 mmol) was added to a stirred solution of 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde (870 mg, 3.07 mmol) in acetic acid (10 mL) at 0 °C, followed by the addition of tert-butylamine (1.77 mL, 16.88 mmol). The mixture was then heated to 90 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice water (30 mL) and extracted with DCM (50 mL x 2) and water (30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-20% ethyl acetate / heptane) to give a yellow solid ( E )-1-bromo-5-methoxy-4-(2-nitroprop-1-en-1-yl)-2-(trifluoromethyl)benzene (yield: 850 mg, 80%). 1 H NMR (400 MHz, DMSO-d6): δ= 7.96(s, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 3.97 (s, 3H), 2.27 (s, 3H).

[0246] Step 4: Preparation of 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine AlCl3 (332.5 mg, 2.5 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 3.75 mL, 7.50 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-5-methoxy-4-(2-nitroprop-1-en-1-yl)-2-(trifluoromethyl)benzene (850 mg, 2.50 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 2.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (17) as a colloidal solid (yield: 0.7 g, 90%), which was used directly in the next step.

[0247] Step 5: Preparation of tert-butyl (1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate Trimethylamine (0.485 mL, 3.36 mmol) was added to a solution of 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (0.7 g, 2.24 mmol) in THF (10 mL) under stirring at 0 °C, followed by di-tert-butyl dicarbonate (1.28 mL, 5.6 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-10% ethyl acetate / heptane) to give tert-butyl (1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 520 mg, 56%). 1 H NMR (400 MHz, DMSO-d6): δ = 7.49 (s, 1H), 7.38 (s, 1H), 6.68 ( J = 4.8 Hz, 1H), 3.88 (s, 3H), 3.74(br s, 1H), 2.74 (dd, J = 14.2, 4.4 Hz, 1H), 2.5-2.49 (m, 1H), 1.24 (s, 9H)1.05 (d, J = 4.8 Hz, 3H).

[0248] Step 6: Preparation of tert-butyl (1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (521 mg, 3.78 mmol), n-butylboronic acid (514 mg, 5.05 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (22 mg, 0.063 mmol), and palladium acetate (5.64 mg, 0.025 mmol) were added to a stirred solution of (1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate (520 mg, 1.26 mmol) in 1,4-dioxane / water (7:3, 10 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was partitioned between ethyl acetate (10 mL) and water (10 mL). The combined organic solvents were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 230 mg, 47%). LC-MS: m / z 290 [M+1-100] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.33 (s, 1H), 6.97 (s, 1H), 6.66(d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.73-3.71 (m, 1H), 2.73-2.64 (m, 3H), 2.52-2.46 (m, 1H), 1.58-1.15 (m, 2H), 1.41-1.33 (m, 2H), 1.25 (s, 9H), 1.03 (d, J =6.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H).

[0249] Step 7: Preparation of 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine(9) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.37 mL, 1.28 mmol) was added to a stirred solution of (1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate (50 mg, 0.128 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (9) hydrochloride as a grayish-white solid (yield: 20 mg, 49%). LC-MS: m / z 290 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.92 (s, 3H), 7.43 (s,1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.42-3.97 (m, 1H), 2.90 (dd, J = 13.2, 6 Hz,1H), 2.77-2.68 (m, 3H), 1.61-1.53 ​​(m, 2H), 1.43-1.34 (m, 2H), 1.10 (d, J = 6.8,3H), 0.92 (t, J = 6.8, 3H); 19 F NMR (376 MHz, DMSO-d6): δ = -56.72.

[0250] Synthesis scheme: Step 1: Enantiomers 1 and 1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl ester are enantiomers of tert-butyl ester. Preparation of enantiomer 2 of (5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate tert-butyl The enantiomers of (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate (600 mg; see Example 7) were separated by chiral SFC [column name: Lux Amylose-1 21.2 mm ID x 250 mm, 5 µm; mobile phase: supercritical CO2 (CO2: 100% IPA (70:30)); flow rate: 70 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate (a grayish-white solid; yield: 250 mg, 41.67%, >99% ee; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate (a grayish-white solid; yield: 240 mg, 40.00%, >99% ee; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0251] Enantiomer 1 of (1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z: 300.00 [M-100] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ= 7.23 (s, 1H),6.88 (s, 1H), 6.65 (d, J = 8.4 Hz 1H), 3.77 (s, 3H), 3.68-3.62 (m, 1H), 2.64-2.60 (m, 3H), 2.50-2.45 (m, 1H), 1.53-1.48 (m, 2H), 1.37-1.33 (m, 2H), 1.29(s, 9H), 1.01(d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (99.80%) was determined by chiral SFC analysis [column name: Lux Amylose-1 4.6 mm ID x 250 mm, 5µm; mobile phase: supercritical CO2 (CO2: 100% IPA (70:30)); flow rate: 3.0 mL / min; column temperature: 30℃]. R t =1.39 (enantiomer 1), 2.59 (enantiomer 2).

[0252] Enantiomer 2 of (1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl ester LC-MS: m / z: 300.05 [M+H-100] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.23 (s,1H), 6.88 (s, 1H), 6.65 (d, J = 8.4 Hz 1H), 3.77 (s, 3H), 3.70-3.66 (m, 1H), 2.64-2.60 (m, 3H), 2.50-2.45 (m, 1H), 1.53-1.47 (m, 2H), 1.37-1.33 (m, 2H),1.29 (s, 9H), 1.01 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (>99.52%) was determined by chiral SFC analysis [column name: Lux Amylose-1 4.6 mm ID x 250 mm, 5µm; mobile phase: supercritical CO2 (CO2: 100% IPA (70:30)); flow rate: 3.0 mL / min; column temperature: 30℃]. R t =1.42 (enantiomer 1), 2.59 (enantiomer 2).

[0253] Step 2a: Preparation of enantiomer 1 of (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl At room temperature, 0.1 g (0.251 mmol) of tert-butyl 1-(1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 1 was stirred and added to the mixture. nCuI (0.002 g, 0.013 mmol), ethane-1,2-diamine (0.015 g, 0.251 mmol), and NaI (0.075 g, 0.502 mmol) were added to a solution of -BuOH (2 mL). The reaction mixture was then stirred at 130 °C for 12 h. The reaction progress was monitored by LC-MS. After completion, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound. The crude compound was purified by silica gel column chromatography to give tert-butyl (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 1 (80 mg, yield: 71.60%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined) as a grayish-white solid. LC-MS: m / z: 392.23 [M+H-56] + .

[0254] Step 2b: Preparation of enantiomer 2 of (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl At room temperature, 0.1 g (0.251 mmol) of tert-butyl 1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 2 was stirred and added to a mixture of 1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 2. n CuI (0.002 g, 0.013 mmol), ethane-1,2-diamine (0.015 g, 0.251 mmol), and NaI (0.075 g, 0.501 mmol) were added to a solution of -BuOH (2 mL). The reaction mixture was then stirred at 130 °C for 12 h. The reaction progress was monitored by LC-MS. After completion, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound. The crude compound was purified by silica gel column chromatography to give tert-butyl (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 2 (85 mg, yield: 76.07%; plotted as R enantiomer, but absolute stereochemistry not determined experimentally) as a grayish-white solid. LC-MS: m / z: 392.06 [M+H-56] + .

[0255] Step 3a: Enantiomers of (1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)propyl-2-yl)carbamate tert-butyl ester Preparation of 1 (1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-3-methoxypropyl-2-yl)carbamate enantiomer 1 (grayish-white solid; yield: 60 mg, 46%; drawn as the S enantiomer, but absolute stereochemistry not experimentally determined) was synthesized from (1-(4-iodo-2,5-dimethoxyphenyl)-3-methoxypropyl-2-yl)carbamate enantiomer 1 (80 mg) according to general procedure E (see Example 61). (10 mg, yield: 14.36%). LC-MS: m / z: 290.10 [M+H-100] + .

[0256] Step 3b: Enantiomers of (1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)propyl-2-yl)carbamate tert-butyl ester Preparation of 2 (1-(4-Butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate enantiomer 2 (grayish-white solid; yield: 10 mg, 14.36%; drawn as the R enantiomer, but absolute stereochemistry not experimentally determined) was synthesized from (1-(4-iodo-2,5-dimethoxyphenyl)-3-methoxyprop-2-yl)carbamate enantiomer 2 (85 mg) according to general procedure E (see Example 61). (Yield: 10 mg, 14.36%). LC-MS: m / z: 290.10 [M+H-100] + .

[0257] Step 4a: 1-(4-Butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 1 (9E1) hydrochloride preparation HCl solution (4.0 M, in 1,4-dioxane; 0.02 mL, 0.078 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate enantiomer 1 (10 mg, 0.026 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (2.0 mL) to give 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 1 (9E1) hydrochloride (yield: 5 mg, 59.77%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z: 290.30 [M+1] + ; 1 H NMR (400 MHz, DMSO- d6 ): δ= 7.81(s, 3H),7.43 (s, 1H), 7.07 (s,1H), 3.86 (s, 3H), 3.43-3.38 (m, 1H), 2.90-2.85 (m, 1H), 2.77-2.73 (m, 1H),2.71-2.67 (m, 2H), 1.61-1.53 ​​(m, 2H), 1.43-1.35 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.32 Hz, 3H). 19F-NMR (376 MHz, DMSO-d6): δ -56.72 (s).

[0258] Step 4b: 1-(4-Butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 2 (9E2) hydrochloride preparation HCl solution (4.0 M, in 1,4-dioxane; 0.02 mL, 0.078 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate enantiomer 2 (10 mg, 0.026 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (2.0 mL) to give 1-(4-butyl-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine enantiomer 1 (9E2) hydrochloride (yield: 4 mg, 47.82%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z: 290.25 [M+1] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ= 7.86(s, 3H),7.43 (s, 1H), 7.07 (s,1H), 3.86 (s, 3H), 3.44-3.38 (m, 1H), 2.91-2.86 (m, 1H), 2.77-2.74 (m, 1H),2.72-2.67 (m, 2H), 1.61-1.53 ​​(m, 2H), 1.43-1.33 (m, 2H), 1.10 (d, J= 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). 19F-NMR (376 MHz, DMSO-d6): δ -56.71 (s).

[0259] Example 10: Preparation of 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 1 (10E1) hydrochloride and 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 2 (10E2) hydrochloride Synthesis scheme: Step 1: Preparation of tert-butyl (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate Zinc difluoride (260 mg, 2.55 mmol) was added to a stirred solution of tert-butyl (1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate (see Example 7; 600 mg, 1.27 mmol) in DMSO (6 mL) at 0 °C, followed by CuI (241 mg, 1.27 mmol). The mixture was then heated to 150 °C and stirred for 12 h. The reaction progress was monitored by LC-MS. After completion, the reaction mixture was concentrated and purified by rapid column chromatography followed by preparative HPLC [column: X-Bridge C8; 19 mm x 250 mm, 5 µm; gradient: acetonitrile / 0.1% formic acid aqueous solution (2% - 98%); flow rate: 18 ml / min; run time: 22 min] to obtain the desired white solid (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate tert-butyl ester (yield: 78 mg, 16.6%). 1 H NMR (400 MHz, DMSO-d6): δ= 7.04 (s, 1H), 6.77 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.69 (br s, 1H), 2.66-2.60 (m, 2H), 2.36 (s, 3H), 1.54-1.47 (m, 2H), 1.35-1.34 (m, 2H), 1.32 (s, 9H), 1.23-1.18 (m, 2H), 1.00 (d, J = 6.4 Hz, 3H), 0.90(t, J = 7.2 Hz, 3H).

[0260] Step 2: Enantiomer 1 of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)tert-butyl carbamate Preparation of enantiomer 2 of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate tert-butyl The enantiomers of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate (78 mg) were separated by chiral SFC [column name: Daicel, CHIRALPAK IG (30 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA (80:20); flow rate: 70 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and freeze-dried to give enantiomer 1 of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 15 mg, 38%, >98% ee; plotted as the S enantiomer, but absolute stereochemistry not determined experimentally) and enantiomer 2 of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate (yield: 14 mg, 36%, >98% ee; plotted as the R enantiomer, but absolute stereochemistry not determined experimentally).

[0261] (1-(4-Butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)tert-butyl carbamate enantiomer 1. LC-MS: m / z 368.05 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.04 (s, 1H), 6.77 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H), 3.70-3.67 (m, 1H), 2.67-2.62 (m,4H), 2.37 (s, 3H), 1.53-1.47 (m, 2H), 1.36-1.19 (m, 2H), 1.30 (s, 9H), 1.00(d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). Enantiomer excess (98.7%) was determined by chiral SFC analysis [Column name: Chiralpak IG (250 mm x 4.6 mm) 5 µm; Mobile phase: supercritical CO2 / 100% IPA (80:20); Flow rate: 3.0 mL / min; Column temperature: 30 °C]. R t =2.13 min (enantiomer 1), 3.51 min (enantiomer 2).

[0262] (1-(4-Butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)tert-butyl carbamate enantiomer 2. LC-MS: m / z 368.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.05 (s, 1H), 6.78 (s, 1H), 6.64 (d, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.70 (br, 1H), 2.67-2.62 (m, 2H), 2.51-2.50 (m, 2H), 2.37 (s, 3H), 1.51-1.49 (m, 2H), 1.34-1.19 (m, 2H), 1.30(s, 9H), 1.00 (d, J = 5.6 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). Enantiomer excess (98.7%) was determined by chiral SFC analysis [Column name: Chiralpak IG (250 mm x 4.6 mm) 5 µm; Mobile phase: supercritical CO2 / 100% IPA (80:20); Flow rate: 3.0 mL / min; Column temperature: 30 °C]. R t =1.99 min (enantiomer 1), 3.57 min (enantiomer 2).

[0263] Step 3a: Preparation of 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 1 (10E1) hydrochloride Preparation HCl solution (4.0 M, in 1,4-dioxane; 0.1 mL, 0.40 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate 1 (0.015 g, 0.004 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 1 (10E1) hydrochloride (yield: 10 mg, 80%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 268.20 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ = 7.84 (br s, 3H),7.08 (s, 1H), 6.86 (s, 1H), 3.77 (s, 3H), 3.72-3.67 (m, 1H), 3.46-3.34 (m,2H), 2.85 (dd, J = 13.2, 6.0 Hz, 1H), 2.71-2.64 (m, 3H), 2.39 (s, 3H), 1.56-1.49 (m, 2H), 1.39-1.30 (m, 2H), 1.1 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0264] Step 3b: (1-(4-Butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 2 (10E2) hydrochloride synthesis HCl solution (4.0 M, in 1,4-dioxane; 0.1 mL, 0.381 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate enantiomer 2 (14 mg, 0.003 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-amine enantiomer 2 (10E2) hydrochloride (yield: 4 mg, 35%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 268.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.80 (br s, 2H),7.08 (s, 1H), 6.86 (s, 1H), 3.77 (s, 3H), 3.41-3.39 (m, 1H), 2.84 (dd, J =13.2, 6 Hz, 1H), 2.71-2.63 (m, 3H), 2.39 (s, 3H), 1.56-1.49 (m, 2H), 1.39-1.32 (m, 2H), 1.10 (d, J= 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0265] Example 11: 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 1 (11E1) hydrochloric acid Preparation of salt and 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 2 (11E2) hydrochloride Synthesis scheme: Step 1: Preparation of (E)-1-bromo-5-methoxy-2-methyl-4-(2-nitrobut-1-en-1-yl)benzene 1-Nitropropane (4.0 mL, 43.7 mmol) was added to a solution of 4-bromo-2-methoxy-5-methylbenzaldehyde (see Example 6; 1.0 g, 4.37 mmol) in acetic acid (10 mL) under stirring at 0 °C, followed by the addition of tert-butylamine (2.55 mL, 24 mmol). The mixture was then heated to 90 °C and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice water (25 mL), the precipitate formed was filtered, washed with cold water (10 mL x 3), and dried under reduced pressure to obtain the desired yellow solid. E 1-Bromo-5-methoxy-2-methyl-4-(2-nitrobut-1-en-1-yl)benzene (yield: 1.0 g, 76%). LC-MS: m / z 301 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ = 8.07 (s,1H), 7.11 (s, 2H), 3.86 (s, 3H), 2.77 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.25(t, J = 7.2 Hz, 3H).

[0266] Step 2: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine AlCl3 (443 mg, 3.33 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 4.99 mL, 9.99 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E1-Bromo-5-methoxy-2-methyl-4-(2-nitrobut-1-en-1-yl)benzene (1.0 g, 3.33 mmol) / THF (10 mL). The reaction mixture was heated to room temperature and stirred for 1.5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, and the combined organic fraction was filtered and concentrated under reduced pressure to give 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine (19) as a colloidal solid (yield: 0.560 g, 61%), which was used directly in the next step.

[0267] Step 3: Preparation of tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-yl)carbamate Triethylamine (0.7 mL, 5.14 mmol) was added to a solution of 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine (19 g; 0.56 g, 2.05 mmol) in THF (10 mL) under stirring at 0 °C, followed by di-tert-butyl dicarbonate (0.7 mL, 3.04 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by rapid column chromatography (silica gel; eluting with 0-10% ethyl acetate / heptane) to give tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 500 mg, 71%). LC-MS: m / z 273 [M+H-100] + ; 1 H NMR (400 MHz, CDCl3): δ =6.99 (s, 1H), 6.98 (s, 2H), 4.46(s, 1H), 3.79 (s, 3H), 3.68 (s, 1H), 2.73-2.63 (m, 2H), 2.29 (s, 3H), 1.54-1.49 (m, 2H), 1.36 (s, 9H), 0.95-0.91 (t, J = 7.2 Hz, 3H).

[0268] Step 4: Preparation of tert-butyl (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (552 mg, 4.0 mmol), n-propylboronic acid (235 mg, 2.68 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (98 mg, 0.13 mmol), and palladium acetate (15 mg, 0.067 mmol) were added to a stirred solution of (1-(4-bromo-2-methoxy-5-methylphenyl)but-2-yl)carbamate (0.50 g, 1.34 mmol) in 1,4-dioxane / water (3:1, 8 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (10 mL) and water (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 150 mg, 33%). LC-MS: m / z 316.15 [M+1] + ; 1 H NMR (400MHz, CDCl3): δ = 6.87 (s, 1H), 6.61 (s, 1H), 4.64 (s, 1H), 3.79 (s, 3H), 3.67(br s, 1H), 2.69-2.63 (m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.62-1.47 (m, 2H), 1.36 (s, 9H), 1.44-1.31 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H), 0.91(t, J = 7.6 Hz, 3H).

[0269] Step 5: Enantiomers 1 and 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate tert-butyl ester Preparation of enantiomer 2 of (2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate tert-butyl ester Through chiral SFC [Column Name: Phenomenex] ®[Lux Amylose-1 21.2 mm ID x 250 mm, 5µm; mobile phase: supercritical CO2 (CO2: 100% IPA (75:25)); flow rate: 70 mL / min; column temperature: 30℃] Separation of enantiomers of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate (150 mg). The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 60 mg, 40%, >99% ee; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined) and enantiomer 2 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate as a grayish-white solid (yield: 50 mg, 33%, >99% ee; plotted as the R enantiomer, but absolute stereochemistry not experimentally determined).

[0270] Enantiomer 1 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z 336.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ= 6.89 (s, 1H), 6.64(s, 1H), 4.64 (br s, 1H), 3.81 (s, 3H), 3.68 (br s, 1H), 2.70-2.69 (m, 2H),2.54 (t, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.64-1.51 (m, 2H), 1.46-1.37 (m, 1H), 1.41 (s, 9H), 0.99 (t, J = 7.2 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H). Enantiomer excess was determined by chiral SFC analysis (99%). [Column name: Lux Amylose-1 (4.6 mm x 250 mm) 5 µm; Mobile phase: CO2 / IPA (80:20) with 0.2% isopropylamine additive; Flow rate: 3.0 mL / min; Column temperature: 30 °C] R t = 2.00 min (enantiomer 1), 2.61 min (enantiomer 2).

[0271] Enantiomer 2 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate tert-butyl ester LC-MS: m / z 336.1 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ =6.89 (s, 1H), 6.64(s, 1H), 4.65 (s 1H), 3.81 (s, 3H), 3.68 (br s, 1H), 2.70-2.69 (m, 2H), 2.54(t, J = 8.0 Hz, 2H), 2.21 (s, 3H), 1.64-1.51 (m, 2H), 1.44-1.53 ​​(m, 1H), 1.51(s, 9H), 0.99 (t, J = 8 Hz , 3H), 0.95 (m, J = 8 Hz, 3H). Enantiomer excess was determined by chiral SFC (99%) [Column name: Lux Amylose-1 (4.6 mm x 250 mm) 5 µm; Mobile phase: CO2 / IPA (80:20) with 0.2% isopropylamine additive; Flow rate: 3.0 mL / min; Column temperature: 30 °C]; R t = 2.00 min (enantiomer 1), 2.61 min (enantiomer 2).

[0272] Step 6a: Preparation of 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 1 (11E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.37 mL, 1.5 mmol) was added to a stirred solution of tert-butyl 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate enantiomer 1 (50 mg, 0.149 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 1 (11E1) hydrochloride (yield: 25 mg, 61%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 236.3 [M+H] + ; 1 H NMR (400 MHZ, DMSO-d6): δ= 7.81 (s, 3H), 6.92 (s, 1H), 6.76 (s,1H), 3.75 (s, 3H), 3.22-3.21 (m, 1H), 2.78-2.68 (m, 2H), 2.52-2.50 (m, 2H), 2.16 (s, 3H), 1.57-1.42 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H), 0.91 (t, J = 6.8 Hz, 3H).

[0273] Step 6b: Preparation of 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 2 (11E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.049 mL, 1.49 mmol) was added to a stirred solution of tert-butyl 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate enantiomer 2 (50 mg, 0.149 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(2-methoxy-5-methyl-4-propylphenyl)but-2-amine enantiomer 2 (11E2) hydrochloride (yield: 35 mg, 86%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 236.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.82 (s, 3H), 6.91 (s, 1H), 6.76(s, 1H), 3.75 (s, 3H), 3.27-3.20 (m, 1H), 2.78-2.67 (m, 1H), 2.52-2.50 (m,2H), 2.16 (s, 3H), 1.58-1.40 (m, 4H), 0.94 (t, J = 6.8 Hz, 3H), 0.89 (t, J = 6.8Hz, 3H).

[0274] Example 12: Preparation of 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine (12) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine(12) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.33 mL, 1.32 mmol) was added to a stirred solution of tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate (see Example 3; 50 mg, 0.132 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-amine (12) hydrochloride as a grayish-white solid (yield: 34 mg, 82%). LC-MS: m / z 278.00 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.90 (s, 3H), 7.45 (s,1H), 7.38 (s, 1H), 3.82 (s, 3H), 3.42-3.39 (m, 1H), 2.84 (dd, J = 13.6, 6.0 Hz, 1H), 2.71 (dd, J = 13.6, 6.0 Hz, 1H), 1.11 (d, J = 6.8 Hz, 3H).

[0275] Example 13: 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine (13) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine(13) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.32 mL, 1.27 mmol) was added to a stirred solution of tert-butyl (1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-yl)carbamate (see Example 4; 50 mg, 0.127 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-bromo-5-chloro-2-methoxyphenyl)but-2-amine (13) hydrochloride as a grayish-white solid (yield: 40 mg, 95%). LC-MS: m / z 292.00 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.90 (s, 3H), 7.48 (s,1H), 7.37 (s, 1H), 3.82 (s, 3H), 3.28-3.23 (m, 1H), 2.85-2.73 (m, 2H), 1.55-1.47 (m, 2H), 0.92 (d, J = 7.6 Hz, 3H).

[0276] Example 14: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-amine (14) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-amine(14) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.35 mL, 1.39 mmol) was added to a stirred solution of tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-yl)carbamate (see Example 6; 50 mg, 0.139 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-bromo-2-methoxy-5-methylphenyl)prop-2-amine (14) hydrochloride as a grayish-white solid (yield: 35 mg, 85%). LC-MS: m / z 258.15 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 3.78 (s, 3H), 3.42-3.35 (m, 1H), 2.85 (dd, J = 13.6, 6.0Hz, 1H), 2.65 (dd, J = 13.6, 8.4 Hz, 1H), 2.26 (s, 3H), 1.09 (d, J = 6.4 Hz, 3H).

[0277] Example 15: Preparation of 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 1 (15E1) hydrochloride and 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 2 (15E2) hydrochloride Synthesis scheme: Steps 1-3: Preparation of tert-butyl (1-(4-bromo-5-iodo-2-methoxyphenyl)prop-2-yl)carbamate (1-(4-bromo-5-iodo-2-methoxyphenyl)propyl-2-yl)tert-butyl carbamate was synthesized from 3.0 g of 4-bromo-5-iodo-2-methoxybenzaldehyde via a three-step reaction according to general step A (see Example 61). Yield: 800 mg, 19% (by 3 steps). 1 H NMR (400 MHz, CDCl3): δ= 7.52 (s, 1H), 7.08 (s, 1H), 3.95-3.87 (m, 1H), 3.80 (s, 3H), 2.65-2.58 (m, 2H), 1.38 (s, 9H), 1.10 (d, J =6.64 Hz, 3H).

[0278] Step 4: Preparation of tert-butyl (1-(4-bromo-5-iodo-2-methoxyphenyl)prop-2-yl)carbamate (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)tert-butyl carbamate was synthesized from (1-(4-bromo-5-iodo-2-methoxyphenyl)prop-2-yl)tert-butyl carbamate according to general procedure D (see Example 61). White solid; yield: 100 mg, 25%. LC-MS: m / z: 368.90 [M+H] + .

[0279] Step 5: (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate tert-butyl ester The enantiomers of (100 mg) tert-butyl carbamate were separated by chiral SFC [Column name: CHIRALPAK IC 21.0 mm ID x 250 mm, 5 µm; Mobile phase: supercritical CO2 (CO2: ACN (90:10) containing 0.1% ammonium hydroxide), Flow rate: 70 mL / min; Column temperature: ambient temperature]. The separated fractions were concentrated under reduced pressure and freeze-dried to give enantiomer 1 of (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate (yield: 40 mg, 40%, >99% ee; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate (grayish-white solid; yield: 45 mg, 45%, >99% ee; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0280] Enantiomer 1 of (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)tert-butyl carbamate LC-MS: m / z: 368.90 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H),7.41 (s, 1H), 6.68 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 1H), 2.74-2.71(m, 1H), 2.47-2.41 (m, 1H), 1.26 (s, 9H), 1.05 (d, J = 6.4 Hz, 3H). Enantiomer excess (98.98%) was determined by chiral SFC analysis [Column name: Chiralpak IC 4.6 mm ID x 250 mm, 5µm; Mobile phase: supercritical CO2 (CO2:100% ACN (75:25)); Flow rate: 3.0 mL / min; Column temperature: 35℃]. R t =2.34 (enantiomer 1), 3.03 (enantiomer 2).

[0281] Enantiomer 2 of (1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)tert-butyl carbamate LC-MS: m / z: 368.95 [M+H]+ ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1H),7.41 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 1H), 2.73-2.70(m, 1H), 2.47-2.42 (m, 1H), 1.26 (s, 9H), 1.05 (d, J = 6.4 Hz, 3H). Enantiomer excess (87.30%) was determined by chiral SFC analysis [Column name: Chiralpak IC 4.6 mm ID x 250 mm, 5µm; Mobile phase: supercritical CO2 (CO2:100% ACN (75:25)); Flow rate: 3.0 mL / min; Column temperature: 35℃]. R t =2.34 (enantiomer 1), 3.04 (enantiomer 2).

[0282] Step 6a: Preparation of 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 1 (15E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.135 mL, 0.54 mmol) was added to a stirred solution of tert-butyl 1-1-bromo-2-methoxyphenyl)carbamate enantiomer 1 (40 mg, 0.108 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 1 (15E1) as hydrochloride (yield: 26 mg, 83%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z: 269.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6): δ = 7.92 (br s, 3H), 7.75 (s, 1H), 7.50 (s, 1H), 3.91 (s, 3H), 3.43-3.41 (m, 1H), 2.89-2.84 (m, 1H), 2.76-2.71 (m, 1H), 1.12(d,J = 6.5 Hz, 3H).

[0283] Step 6b: Preparation of 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 2 (15E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.17 mL, 0.69 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-bromo-5-cyano-2-methoxyphenyl)prop-2-yl)carbamate enantiomer 2 (45 mg, 0.138 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 5-(2-aminopropyl)-2-bromo-4-methoxybenzonitrile enantiomer 2 (15E2) as hydrochloride (yield: 28 mg, 77%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z: 269.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 3H), 7.75 (s, 1H), 7.50 (s, 1H), 3.91(s, 3H), 3.45-3.40 (m, 1H), 2.89-2.84 (m, 1H), 2.76-2.71 (m, 1H), 1.12 (d, J =6.5 Hz, 3H).

[0284] Example 16: Preparation of 1-(4-bromo-2-methoxy-5-nitrophenyl)prop-2-amine (16) Synthesis scheme: The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0285] Example 17: Preparation of 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (17) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine(17) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.24 mL, 0.97 mmol) was added to a stirred solution of (1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-yl)carbamate (see Example 9; 40 mg, 0.097 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-bromo-2-methoxy-5-(trifluoromethyl)phenyl)prop-2-amine (17) hydrochloride as a grayish-white solid (yield: 24 mg, 71%). LC-MS: m / z 312.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.90 (s, 3H), 7.64 (s, 1H), 7.47 (s, 1H), 3.90 (s, 3H), 3.46-3.37 (m, 1H), 2.89 (dd, J =13.2, 6.8 Hz, 1H), 2.79 (dd, J = 13.6, 7.2 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H); 19 FNMR (376 MHz, DMSO-d6): δ = -59.6.

[0286] Example 18: Preparation of 1-(4-bromo-2-methoxy-5-(methylthio)phenyl)prop-2-amine (18) Synthesis scheme: The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0287] Example 19: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine (19) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine(19) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.27 mL, 1.07 mmol) was added to a stirred solution of tert-butyl (1-(4-bromo-2-methoxy-5-methylphenyl)but-2-yl)carbamate (see Example 11; 40 mg, 0.107 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-bromo-2-methoxy-5-methylphenyl)but-2-amine (19) hydrochloride as a grayish-white solid (yield: 29 mg, 87%). LC-MS: m / z 272.10 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.93 (s, 3H), 7.19(s, 1H), 7.17 (s, 1H), 3.79 (s, 3H), 3.26-3.21 (m, 1H), 2.76 (d, J = 5.6 Hz, 2H), 2.26 (s, 3H), 1.52-1.45 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0288] Example 20: Preparation of 2-(4-bromo-2-methoxy-5-methylphenyl)ethyl-1-amine (20) hydrochloride Synthesis scheme: Step 1: (E)-1-Bromo-5-methoxy-2-methyl-4-(2-nitrovinyl)benzene Preparation Nitromethane (1.3 mL, 35.2 mmol) was added to a solution of 4-bromo-2-methoxy-5-methylbenzaldehyde (0.8 g, 3.52 mmol) in acetic acid (10 mL) under stirring at 0 °C, followed by the addition of n-butylamine (1.4 mL, 19.3 mmol). The reaction mixture was then heated to 90 °C and stirred for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured into ice water (15 mL), the precipitate formed was filtered off, washed with cold water (10 mL x 3), and dried under reduced pressure to give (E)-1-bromo-5-methoxy-2-methyl-4-(2-nitrovinyl)benzene as a yellow solid (yield: 0.7 g, 73%). 1 H NMR (400MH Z , DMSO-d6): δ = 8.16-8.08 (s, 2H), 7.83 (s, 1H), 7.04 (s, 1H), 3.93 (s, 3H), 2.30 (s, 3H).

[0289] Step 2: 2-(4-bromo-2-methoxy-5-methylphenyl)ethyl-1-amine Preparation AlCl3 (342 mg, 2.57 mmol) was added in portions to a stirred solution of LAH solution (2.0 M, in THF; 4 mL, 7.72 mmol) in anhydrous THF (15 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E 1-Bromo-5-methoxy-2-methyl-4-(2-nitrovinyl)benzene (0.7 g, 2.57 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 6 mL) was added at the same temperature until no more bubbles were formed. The reaction mixture was diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF, dried over anhydrous Na2SO4, and the combined organic fraction was filtered and concentrated under reduced pressure to give a crude product, which was used directly for the next step without further characterization.

[0290] Step 3: Preparation of tert-butyl (4-bromo-2-methoxy-5-methylphenethyl)carbamate Triethylamine (0.83 mL, 6.1 mmol) was added to a solution of 2-(4-bromo-2-methoxy-5-methylphenyl)ethyl-1-amine (0.6 g, 2.45 mmol) in THF (6 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (0.84 mL, 3.67 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (18 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel rapid column chromatography (eluting with 0–10% ethyl acetate / heptane) to give tert-butyl (4-bromo-2-methoxy-5-methylphenylethyl)carbamate (yield: 300 mg, 34%). LC-MS: m / z 244 [M+H-100] + ; 1H NMR (400 MHz, DMSO- d 6 ): δ = 7.11 (s, 1H),7.05 (s, 1H), 6.82 (t, J = 5.4 Hz, 1H), 3.76 (s, 3H), 3.09-3.04 (m, 2H), 2.59 (t, J = 7.4 Hz, 2H), 2.23 (s, 3H), 1.35 (s, 9H).

[0291] Step 4: Preparation of 2-(4-bromo-2-methoxy-5-methylphenyl)ethyl-1-amine (20) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.36 mL, 1.45 mmol) was added to a stirred solution of tert-butyl (4-bromo-2-methoxy-5-methylphenylethyl)carbamate (100 mg, 0.29 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (3.0 mL) to give 2-(4-bromo-2-methoxy-5-methylphenyl)ethyl-1-amine (20) hydrochloride (yield: 21 mg, 60%). LC-MS: m / z: 244.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.84 (br s, 3H),7.18 (s, 1H), 7.15 (s, 1H), 3.79 (s, 3H), 2.94(t, J = 8.0 Hz, 2H), 2.78 (t, J = 8.0 Hz, 2H), 2.25 (s, 3H).

[0292] Example 21: Preparation of 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-amine (21) hydrochloride Synthesis scheme: Step 1: Preparation of 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-amine (21) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.185 mL, 0.74 mmol) was added to a stirred solution of (1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate (see Example 7; 30 mg, 0.074 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-amine (21) hydrochloride as a grayish-white solid (yield: 15 mg, 69%). LC-MS: m / z 300.15 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.89 (br s, 3H),7.34 (s, 1H), 6.98 (s, 1H), 3.79 (s, 3H), 3.39 (br s, 1H), 2.84 (dd, J = 13.6,6.0 Hz, 1H), 2.69-2.63 (m, 3H), 1.57-1.50 (m, 2H), 1.41-1.31 (m, 2H), 1.08(d, J = 6.4 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0293] Example 22: Preparation of 1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 1 (22E1) hydrochloride and 1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 2 (22E2) hydrochloride Synthesis scheme: Step 1: Preparation of tert-butyl (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate To a stirred solution of (1-(4-butyl-2-methoxy-5-(methylthio)phenyl)prop-2-yl)carbamate (synthesized as described in 1AE1 / 1AE2; 0.15 g, 0.42 mmol) in DCM (5 mL), m-chloroperoxybenzoic acid (≤77%, 0.28 g, 1.26 mmol) was added. The mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with DCM (10 mL), washed with sodium carbonate solution (3 x 5 mL), and then washed with brine (10 mL). The organic fraction was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by silica gel rapid column chromatography (eluting with 0-10% ethyl acetate / heptane) to give tert-butyl (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate as a grayish-white solid (yield: 120 mg, 74%). 1 H NMR (400 MHz, DMSO-d6): δ= 7.69 (s, 1H), 6.98 (s, 1H), 6.70 (d, J = 9.2 Hz1H), 3.87 (s, 3H), 3.80-3.72 (m, 1H), 3.18 (s, 3H), 2.97-2.89 (m, 2H), 2.70-2.50 (m, 2H), 1.61-1.58 (m, 2H), 1.41-1.36 (m, 2H), 1.27 (s, 9H), 1.00 (d, J =6 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0294] Step 2: Enantiomers of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)propyl-2-yl)carbamate Preparation of 1 and enantiomer 2 of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate tert-butyl Preparation The enantiomers of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate (110 mg) were separated by chiral SFC [column name: CHIRALCEL OX-H 30.0 mm ID x 250 mm, 5 µm; mobile phase: supercritical CO2 (CO2:100% IPA (75:25)); flow rate: 90 mL / min; column temperature: 35 °C]. The separated fractions were concentrated under reduced pressure and freeze-dried to give enantiomer 1 of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate (a grayish-white solid; yield: 45 mg, 40.91%, >99% ee; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate (a grayish-white solid; yield: 45 mg, 40.91%, >99% ee; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0295] (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)propyl-2-yl)tert-butyl carbamate enantiomer 1 LC-MS: m / z: 417.20 [M+18] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.61 (s, 1H), 6.98 (s, 1H), 6.70 (d, J = 8.4 Hz 1H), 3.87 (s, 3H), 3.73-3.71 (m, 1H), 3.09(s, 3H), 2.93-2.88 (m, 2H), 2.70-2.50 (m, 2H), 1.62-1.56 (m, 2H), 1.41-1.33(m, 2H), 1.27 (s, 9H), 1.00 (d, J = 6.4 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). Enantiomer excess (99.94%) was determined by chiral SFC analysis [Column name: Chiralcel OX-3 4.6 mm ID x 150 mm, 3µm; Mobile phase: supercritical CO2 (CO2: IPA (80:20) containing 0.1% isopropylamine); Flow rate: 3.0 mL / min; Column temperature: 35℃]. R t=2.26 min (enantiomer 1), 3.78 min (enantiomer 2).

[0296] (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)propyl-2-yl)tert-butyl carbamate enantiomer 2 LC-MS: m / z: 417.2 [M+18] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.62 (s, 1H), 6.98 (s, 1H), 6.70 (d, J = 8.4 Hz 1H), 3.87 (s, 3H), 3.75-3.71 (m, 1H), 3.09(s, 3H), 2.93-2.88 (m, 2H), 2.70-2.56 (m, 2H), 1.64-1.56 (m, 2H), 1.41-1.33(m, 2H), 1.27 (s, 9H), 1.00 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (99.91%) was determined by chiral SFC analysis [Column name: Chiralcel OX-3 4.6 mm ID x 150 mm, 3µm; Mobile phase: supercritical CO2 (CO2: IPA (80:20) containing 0.1% isopropylamine); Flow rate: 3.0 mL / min; Column temperature: 35℃]. R t =2.26 min (enantiomer 1), 3.78 min (enantiomer 2).

[0297] Step 3a: 1-(4-Butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 1 (22E1) hydrochloride preparation HCl solution (4.0 M, in 1,4-dioxane; 0.28 mL, 1.13 mmol) was added to a stirred solution of (1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate tert-butyl ester enantiomer 1 (45 mg, 0.113 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 1 (22E1) hydrochloride (yield: 28 mg, 74%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z: 300.25 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.87(s, 3H), 7.67 (s, 1H), 7.08 (s,1H), 3.89 (s, 3H), 3.41-3.36 (m, 1H), 3.14 (s, 3H), 2.95-2.89 (m, 2H), 2.87-2.73 (m, 2H), 1.66-1.59 (m, 2H), 1.45-1.34 (m, 2H), 1.11 (d, J = 6.52 Hz, 3H), 0.93 (t, J = 7.32 Hz, 3H).

[0298] Step 3b: 1-(4-Butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 2 (22E2) hydrochloride preparation HCl solution (4.0 M, in 1,4-dioxane; 0.28 mL, 1.13 mmol) was added to a stirred solution of tert-butyl 1-(1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-yl)carbamate enantiomer 2 (45 mg, 0.113 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 1-(4-butyl-2-methoxy-5-(methanesulfonyl)phenyl)prop-2-amine enantiomer 2 (22E2) hydrochloride (yield: 28 mg, 74%; plotted as R enantiomer, but absolute stereochemistry not determined experimentally). LC-MS: m / z: 300.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ= 7.89(br s, 3H),7.67 (s, 1H), 7.08(s, 1H), 3.89 (s, 3H), 3.41-3.39 (m, 1H), 3.14 (s, 3H), 2.96-2.86 (m, 3H),2.79-2.73 (m, 1H), 1.66-1.59 (m, 2H), 1.45-1.36 (m, 2H), 1.12 (d, J = 6.52 Hz, 3H), 0.93 (t, J = 7.32 Hz, 3H).

[0299] Example 23: 2-(5-bromo-2-methoxy-4-(pentafluoro-λ) 6 Preparation of 1-thioalkyl)phenyl)ethyl-1-amine (23) Synthesis scheme: The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0300] Example 24: Preparation of 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 1 (24E1) hydrochloride and 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 2 (24E2) hydrochloride Synthesis scheme: Step 1: Preparation of tert-butyl (1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (232 mg, 1.68 mmol), n-propylboronic acid (193 mg, 2.2 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (20 mg, 0.056 mmol), and palladium acetate (6.0 mg, 0.028 mmol) were added to a stirred solution of (1-(4-bromo-2-methoxy-5-methylphenyl)propyl-2-yl)carbamate (see Example 6; 0.20 g, 0.56 mmol) in 1,4-dioxane / water (7:3, 6 mL), at room temperature. The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (10 mL) and water (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 100 mg, 56%). LC-MS: m / z 322.10 [M+1] + .

[0301] Step 2: (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)carbamate tert-butyl The enantiomers of (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)carbamate (100 mg) were separated by chiral SFC [column name: Daicel Chiralpak AD-H (21 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA (80:20); flow rate: 60 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 40 mg, 40%; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)carbamate (yield: 40 mg, 40%; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0302] Enantiomer 1 of (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)tert-butyl carbamate LC-MS: m / z 322.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3): δ= 6.86 (s, 1H), 6.63(s, 1H), 4.77 (br s, 1H), 3.84 (br s, 1H), 3.79 (s, 3H), 2.70-2.61 (m, 2H),2.52 (t, J = 8 Hz, 2H), 2.20 (s, 3H), 1.63-1.57 (m, 2H), 1.38 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H).

[0303] Enantiomer excess (99%) was determined by chiral SFC analysis (column name: Chiralpak AD-H (4.6 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.1% NH4OH (80:20); flow rate: 3.0 mL / min; column temperature: 30 °C). R t = 1.55 min (enantiomer 1), 3.23 min (enantiomer 2).

[0304] Enantiomer 2 of (1-(2-methoxy-5-methyl-4-propylphenyl)propyl-2-yl)tert-butyl carbamate m / z 322.2 [M+H-100] + ; 1 H NMR (400 MHz, CDCl3): δ= 6.86 (s, 1H), 6.63 (s,1H), 4.77 (br s, 1H), 3.85 (br s, 1H), 3.80 (s, 3H), 2.73-2.61 (m, 2H), 2.52(t, J = 8 Hz, 2H), 2.19 (s, 3H), 1.63-1.55 (m, 2H), 1.38 (s, 9H), 1.11 (d, J =6.8 Hz, 3H), 0.96 (t, J= 7.2 Hz, 3H). Enantiomer excess (99%) was determined by chiral SFC analysis (column name: Chiralpak AD-H (4.6 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.1% NH4OH (80:20); flow rate: 3.0 mL / min; column temperature: 30 °C). R t = 1.57 min (enantiomer 1), 3.29 min (enantiomer 2).

[0305] Step 3a: Preparation of 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 1 (24E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.30 mL, 1.20 mmol) was added to a stirred solution of tert-butyl 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-yl)carbamate enantiomer 1 (40 mg, 0.12 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 1 (24E1) hydrochloride (yield: 24 mg, 75%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 222.3 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.89 (s, 3H), 6.89 (s, 1H), 6.76 (s, 1H), 3.75 (s, 3H), 3.42-3.33 (m, 1H), 2.85 (dd, J = 13.2, 5.2 Hz, 1H), 2.60(dd, J = 13.2, 8.8 Hz, 1H), 2.52-2.49 (m, 2H), 2.17 (s, 3H), 1.58-1.49 (m, 2H),1.06 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H).

[0306] Step 3b: Preparation of 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 2 (24E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.30 mL, 1.20 mmol) was added to a stirred solution of tert-butyl 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-yl)carbamate enantiomer 2 (40 mg, 0.12 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired off-white solid of 1-(2-methoxy-5-methyl-4-propylphenyl)prop-2-amine enantiomer 2 (24E2) hydrochloride (yield: 29 mg, 90%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 222.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.87 (s, 3H), 6.89 (s, 1H), 6.76 (s, 1H), 3.75 (s, 3H), 3.42-3.33 (m, 1H), 2.85 (dd, J = 13.2, 5.2 Hz, 1H), 2.61(dd, J = 13.2, 8.4 Hz, 1H), 2.52-2.49 (m, 2H), 2.17 (s, 3H), 1.58-1.49 (m, 2H),1.06 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 7.2 Hz, 3H).

[0307] Example 25: Preparation of 1-(4,5-dibutyl-2-methoxyphenyl)prop-2-amine (25) Synthesis scheme: Step 1: Preparation of tert-butyl (1-(4,5-dibutyl-2-methoxyphenyl)propyl-2-yl)carbamate Under argon atmosphere at room temperature, potassium carbonate (109 mg, 0.792 mmol), n-butylboronic acid (135 mg, 1.32 mmol), 1-[1-adamantyl(butyl)phosphino]adamantane (18.9 mg, 0.0528 mmol), and palladium acetate (5.93 mg, 0.026 mmol) were added to a stirred solution of (1-(4-bromo-5-chloro-2-methoxyphenyl)prop-2-yl)carbamate (see Example 3; 0.1 g, 0.264 mmol) in 1,4-dioxane / water (7:3, 5 mL). The reaction mixture was purged with argon for 10 min and then heated at 100 °C for 24 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (10 mL) and water (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by rapid chromatography (silica gel; eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(4,5-dibutyl-2-methoxyphenyl)propyl-2-yl)carbamate as a grayish-white solid (yield: 50 mg, 46.14%). LC-MS: m / z 330.20 [M+1-56] + ; 1 H NMR (400 MHz, CDCl3): δ = 6.84 (s, 1H), 6.67 (s, 1H), 6.62 (d, J =8.4 Hz, 1H), 3.73 (s, 3H), 3.70-3.65 (m, 1H), 2.55-2.44 (m, 6H), 1.53-1.42(m, 4H), 1.40-1.18 (m, 4H), 0.96 (d, J = 7.2 Hz, 3H), 0.93-0.92 (m, 6H).

[0308] Step 2: Preparation of 1-(4,5-dibutyl-2-methoxyphenyl)prop-2-amine(25) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.16 mL, 0.66 mmol) was added to a stirred solution of 1-(4,5-dibutyl-2-methoxyphenyl)prop-2-yl)carbamate (50 mg, 0.132 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4,5-dibutyl-2-methoxyphenyl)prop-2-amine (25) hydrochloride as a grayish-white solid (yield: 27 mg, 65%). LC-MS: m / z 278.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 8.0 (s, 3H), 6.88 (s, 1H), 6.76 (s, 1H), 3.76 (s, 3H), 3.40-3.34 (m, 1H), 2.86 (dd, J = 13.2, 5.6 Hz, 1H),2.68-2.47 (m, 5H), 1.55-1.50 (m, 4H), 1.49-1.28 (m, 4H), 1.07 (d, J = 6.4 Hz, 3H), 0.94-0.87 (m, 6H).

[0309] Example 26: Preparation of 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26) hydrochloride Synthesis scheme: Step 1: Preparation of 2-bromo-4-methoxy-1-propoxybenzene Cs₂CO₃ (9.63 g, 29.6 mmol) was added to a stirred solution of 2-bromo-4-methoxyphenol (2.0 g, 9.85 mmol) in DMF (20 mL) under a nitrogen atmosphere at 0 °C. After the gas release ceased, the suspension was stirred at 0 °C for 10 min, followed by dropwise addition of 1-iodopropane (1.44 mL, 14.8 mmol) over 5 min. The reaction mixture was heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by rapid column chromatography (silica gel; eluting with 0–30% ethyl acetate / heptane) to give 2-bromo-4-methoxy-1-propoxybenzene as a grayish-white solid (yield: 2.2 g, 91%). 1 H NMR (400MHz, CDCl3): δ = 7.11 (d, J = 2.8 Hz, 1H), 6.85-6.77 (m, 2H), 3.93 (t, J = 6.4 Hz,2H), 1.87-1.78 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H).

[0310] Step 2: Preparation of 4-bromo-2-methoxy-5-propoxybenzaldehyde TiCl4 (2.73 mL, 24.5 mmol) was added dropwise to a solution of dichloromethoxymethane (1.88 g, 16.3 mmol) in anhydrous DCM (20 mL) at -78 °C under an argon atmosphere. After the addition was complete, 2-bromo-4-methoxy-1-propoxybenzene (2.0 g, 8.16 mmol) was added to the reaction mixture and stirred at -78 °C for 3 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was quenched with saturated NH4Cl solution (10 mL) and extracted with DCM (20 mL x 2) and water (10 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude substance was purified by rapid column chromatography (silica gel; eluted with 0-30% ethyl acetate / heptane) to give 4-bromo-2-methoxy-5-propoxybenzaldehyde as a grayish-white solid (yield: 1.5 g, 60%). 1 H NMR (400 MHz, CDCl3): δ= 10.38 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 1.89-1.80 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H).

[0311] Step 3: (E)-1-bromo-5-methoxy-4-(2-nitrovinyl)-2-propoxybenzene preparation Nitromethane (1.08 mL, 18.3 mmol) was added to a stirred solution of 4-bromo-2-methoxy-5-propoxybenzaldehyde (500 mg, 1.83 mmol) at 0 °C, followed by ammonium acetate (212 mg, 2.75 mmol). The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice water (10 mL) and extracted with DCM (20 mL x 2). The organic solvent was washed with water (10 mL), then with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by rapid column chromatography (silica gel; eluted with 0-20% ethyl acetate / heptane) to give a yellow solid. E 1-Bromo-5-methoxy-4-(2-nitrovinyl)-2-propoxybenzene (Yield: 350 mg, 60%). 1 H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 13.6 Hz, 1H), 7.85 (d, J = 13.6 Hz, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 1.91-1.82(m, 2H), 1.07 (t, J = 7.6 Hz, 3H).

[0312] Step 4: Preparation of 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26) Sulfuric acid (443 mg, 4.44 mmol) was added dropwise to a stirred solution of LAH solution (2.0 M, in THF; 4.44 mL, 8.88 mmol) in anhydrous THF (30 mL) at 0 °C under an argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min and added dropwise over 10 min intervals at 0 °C. E1-Bromo-5-methoxy-4-(2-nitrovinyl)-2-propoxybenzene (350 mg, 1.11 mmol) / THF (10 mL). The reaction mixture was then heated to room temperature and stirred for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to 0 °C and THF / water (1:1, 14 mL) was slowly added at the same temperature until no more bubbles were added. The reaction mixture was then diluted with THF (10 mL) and stirred at room temperature for 30 min under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, washed with THF (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26) as a colloidal solid (yield: 0.35 g), which was used directly in the next step.

[0313] Step 5: Preparation of tert-butyl (2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl)carbamate Trimethylamine (0.427 mL, 3.04 mmol) was added to a solution of 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26; 350 mg, 1.21 mmol) in THF (10 mL) under stirring at 0 °C, followed by the addition of di-tert-butyl dicarbonate (0.442 mL, 1.82 mmol). The reaction mixture was then heated to room temperature and stirred for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (silica gel; eluted with 0–10% ethyl acetate / heptane) to give tert-butyl (2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl)carbamate as a grayish-white solid (yield: 370 mg, 78%). LC-MS: 331.90 [M+1-56] + .

[0314] Step 6: Preparation of 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.45 mL, 1.80 mmol) was added to a stirred solution of tert-butyl (2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl)carbamate (70 mg, 0.18 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 2-(4-bromo-2-methoxy-5-propoxyphenyl)ethyl-1-amine (26) hydrochloride as a grayish-white solid (yield: 35 mg, 60%). LC-MS: m / z 288.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.88 (s, 3H), 7.19 (s, 1H), 6.98(s, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 2.97 (br s, 2H), 2.83-2.79 (m,2H), 1.77-1.68 (m, 2H), 1.0 (t, J = 7.2 Hz, 3H).

[0315] Example 27: Preparation of 2-(4-bromo-5-butyl-2-methoxyphenyl)ethyl-1-amine (27) Synthesis scheme: The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0316] Example 28: Preparation of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine (28) hydrochloride and its enantiomers 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine enantiomer 1 (28E1) hydrochloride and 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine enantiomer 2 (28E2) hydrochloride Synthesis scheme: Step 1: Preparation of tert-butyl (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate (1-(5-bromo-4-butyl-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl ester (see Example 7; 0.6 g, 1.50 mmol) was stirred at 0 °C. n NaI (450 mg, 3.0 mmol) was added to a solution of -BuOH (6.0 mL), followed by CuI (14.25 mg, 0.075 mmol) and ethylene-1,2-diamine (0.01 mL, 1.50 mmol). The mixture was then heated to 130 °C and stirred for 12 h. The reaction progress was monitored by LC-MS. After completion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to obtain the desired brown solid of tert-butyl (1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate (yield: 100 mg, 14%). LC-MS: m / z 448 [M+1] + ; 1 H NMR (400 MHz, CDCl3): δ = 7.48 (s, 1H), 6.69 (s, 1H), 4.57 (br s, 1H), 3.87 (br s, 1H), 3.80(s, 3H), 2.66-2.62 (m, 4H), 1.58-1.51 (m, 2H), 1.44-1.38 (m, 2H), 1.38 (s,9H), 1.10 (d, J = 6.4 Hz, 3H), 0.96 (t, J = 7.6 Hz, 3H).

[0317] Step 1a: Preparation of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine(28) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.17 mL, 0.67 mmol) was added to a stirred solution of (1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-yl)carbamate (30 mg, 0.067 mmol) in DCM (2.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine (28) hydrochloride as a grayish-white solid (yield: 17 mg, 66%). LC-MS: m / z: 348.05 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.83 (s, 3H),7.54 (s, 1H), 6.97 (s,1H), 3.78 (s, 3H), 3.38-3.36 (br s, 1H), 2.80 (dd, J = 13.2, 6.0 Hz, 1H), 2.67-2.61 (m, 3H), 1.55-1.47 (m, 2H), 1.44-1.34 (m, 2H), 1.08 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H).

[0318] Step 2: Enantiomers 1 and 2-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl ester Preparation of enantiomer 2 of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-yl)carbamate tert-butyl The enantiomers of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-yl)carbamate (120 mg) were separated by chiral SFC [column name: Lux Amylose-1 (21.2 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.1% NH4OH (70:30); flow rate: 60 mL / min; column temperature: 30 °C]. The desired fractions were combined, concentrated under reduced pressure, and lyophilized to give enantiomer 1 of 1-(5-bromo-4-butyl-2-methoxyphenyl)prop-2-yl)carbamate (yield: 40 mg, 33%, >99% ee; plotted as...). S Enantiomers, but absolute stereochemistry not experimentally determined) and tert-butyl carbamate enantiomer 2 (yield: 38 mg, 32%, >99% ee; plotted as... R Enantiomers, but absolute stereochemistry has not been experimentally determined.

[0319] Enantiomer 1 of 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate tert-butyl. LC-MS: m / z: 392.05 [M+H-56] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ= 7.45 (s, 1H), 6.87 (s, 1H), 6.65-6.62 (m, 1H), 3.76 (s, 3H), 3.66-3.65 (m, 1H), 3.16 (d, J= 5.2 Hz, 1H),2.66-2.57 (m, 3H), 2.50-2.45 (m, 2H), 1.51-1.44 (m, 2H), 1.37-1.29 (m, 9H),0.99 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (>99%) was determined by chiral SFC analysis [column name: LuxAmylose-1 (4.6 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.1% NH4OH (70:30); flow rate: 3.0 mL / min; column temperature: 35 °C]. R t = 1.74 min (enantiomer 1), 2.71 min (enantiomer 2).

[0320] Enantiomer 2 of 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate. LC-MS: m / z: 392.00 [M+H-56] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ= 7.45 (s, 1H), 6.87 (s, 1H), 6.64-6.62 (m, 1H), 3.76 (s, 3H), 3.66-3.65 (m, 1H), 3.16 (d, J = 5.2 Hz, 1H),2.66-2.57 (m, 3H), 2.50-2.45 (m, 2H), 1.51-1.44 (m, 2H), 1.37-1.29 (m, 9H),0.99 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H). Enantiomer excess (99.52%) was determined by chiral SFC analysis [column name: LuxAmylose-1 (4.6 mm x 250 mm) 5 µm; mobile phase: supercritical CO2 / IPA containing 0.1% NH4OH (70:30); flow rate: 3.0 mL / min; column temperature: 35 °C]. R t = 1.81 min (enantiomer 1), 2.67 min (enantiomer 2).

[0321] Step 2a: Preparation of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine enantiomer 1 (28E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.11 mL, 0.445 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 1 (40 mg, 0.089 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and the solid was washed with diethyl ether (2.0 mL) to give 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-amine enantiomer 1 (28E1) hydrochloride (18 mg, yield: 60%); plotted as... S Enantiomers, but absolute stereochemistry not experimentally determined. LC-MS: m / z: 348.05 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6 ): δ= 7.87(s, 3H), 7.54 (s, 1H), 6.69 (s, 1H), 3.78 (s,3H), 3.37-3.36 (m, 1H), 2.83-2.79 (m, 1H), 2.67-2.61 (m, 3H), 1.54-1.47 (m,2H), 1.41-1.32 (m, 2H), 1.08 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.28 Hz, 3H).

[0322] Step 2b: Preparation of 1-(4-butyl-5-iodo-2-methoxyphenyl)prop-2-amine enantiomer 2 (28E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.11 mL, 0.445 mmol) was added to a stirred solution of tert-butyl 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-yl)carbamate enantiomer 2 (38 mg, 0.085 mmol) in DCM (1.0 mL) at 0 °C. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and the solid was washed with diethyl ether (2.0 mL) to give 1-(4-butyl-5-iodo-2-methoxyphenyl)propyl-2-amine enantiomer 2 (28E2) hydrochloride (18 mg, yield: 60%).R Enantiomers, but absolute stereochemistry not experimentally determined. LC-MS: m / z: 348.05 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6 ): δ= 7.87(s, 3H),7.54 (s, 1H), 6.69 (s, 1H), 3.78 (s,3H), 3.37-3.36 (m, 1H), 2.83-2.79 (m, 1H), 2.67-2.61 (m, 3H), 1.54-1.47 (m,2H), 1.41-1.32 (m, 2H), 1.08 (d, J = 6.4 Hz, 3H), 0.93 (t, J = 7.28 Hz, 3H).

[0323] Example 29: Preparation of 5-(2-aminopropyl)-2-butyl-4-methoxyaniline (29) The compound was synthesized according to the general steps described above, with modifications to the specific steps provided in other examples, and other transformation methods known in the art.

[0324] Example 30: Preparation of 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile enantiomer 1 (30E1) hydrochloride and 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile enantiomer 2 (30E2) hydrochloride Synthesis scheme: Step 1: Preparation of 2-methoxy-4-propylbenzaldehyde 2-Methoxy-4-propylbenzaldehyde (grayish-white solid, yield: 3.0 g, 72%) was synthesized from 5.0 g of 4-bromo-2-methoxybenzaldehyde according to general procedure C (see Example 61). LC-MS: m / z 176.10 [M+H] + .

[0325] Step 2: Preparation of 5-bromo-2-methoxy-4-propylbenzaldehyde NBS (3.34 g, 18.8 mmol) was added fractionally to a solution of 2-methoxy-4-propylbenzaldehyde (2.8 g, 15.71 mmol) in acetonitrile (20 mL) under stirring at 0 °C. The reaction mixture was then stirred at 0 °C for 5 min, followed by heating to room temperature and stirring for 2 h. After the reaction was complete, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 5-bromo-2-methoxy-4-propylbenzaldehyde (yield: 3.2 g, 79%), which was used directly in the next step without further purification. LC-MS: m / z 255.95 [M+H] + .

[0326] Steps 3-5: Preparation of tert-butyl (1-(5-bromo-2-methoxy-4-propylphenyl)but-2-yl)carbamate (1-(5-bromo-2-methoxy-4-propylphenyl)but-2-yl)tert-butyl carbamate (grayish-white solid, yield: 3.2 g, 64%, by 3 steps) was synthesized from 3.2 g of 5-bromo-2-methoxy-4-propylbenzaldehyde according to general step A (see Example 61). LC-MS: m / z 300.10 [M+H-100] + .

[0327] Step 6: Preparation of tert-butyl (1-(5-cyano-2-methoxy-4-propylphenyl)but-2-yl)carbamate The stirred solution of tert-butyl (1-(5-bromo-2-methoxy-4-propylphenyl)but-2-yl)carbamate (500 mg, 1.24 mmol), zinc cyanide (161 mg, 1.37 mmol), and zinc (29.32 mg, 0.24 mmol) in DMF (5 mL) was degassed and purged three times with nitrogen. 1,1′-ferrocene diyl-bis(diphenylphosphine) (69 mg, 0.12 mmol) and Pd2(dba)3 (56 mg, 0.06 mmol) were added to the reaction mixture. The resulting reaction mixture was then stirred at 120 °C for 12 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel rapid column chromatography (eluting with 0-30% ethyl acetate / heptane) to give tert-butyl (1-(5-cyano-2-methoxy-4-propylphenyl)but-2-yl)carbamate as a yellow solid (yield: 150 mg, 35%). LC-MS: m / z 347.2 [M+H]+ .

[0328] Step 7: Enantiomers 1 and 2-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)tert-butyl carbamate Preparation of enantiomer 2 of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)carbamate tert-butyl The enantiomers of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)carbamate (100 mg) were separated by chiral SFC [column name: CHIRALPAK IC 21.2 mm ID x 250 mm, 5 µm; mobile phase: supercritical CO2 (CO2: methanol containing 0.1% ammonium hydroxide (90:10)); flow rate: 50 mL / min; column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)carbamate (yield: 33 mg, 33%, 98.96% ee; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)carbamate (yield: 35 mg, 35%, 98% ee; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally).

[0329] Enantiomer 1 of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)tert-butyl carbamate LC-MS: m / z: 347.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.40 (s, 1H),7.00 (s, 1H), 6.57 (d, J = 9.20 Hz, 1H), 3.86 (s, 3H), 3.52 (m, 1H), 2.78-2.68 (m, 2H), 2.42-2.34 (m, 2H), 1.65-1.58 (m, 2H), 1.45-1.32 (m, 2H), 1.26 (s, 9H), 1.16-0.93 (m, 6H). Enantiomer excess (98.9%) was determined by chiral SFC analysis [column name: CHIRALPAK IC-3 4.6 mm ID x 150 mm, 3 µm; mobile phase: supercritical CO2 (CO2: MeOH (80:20) containing 0.2% diethylamine); flow rate: 2.5 mL / min; column temperature: 35℃]. R t= 2.49 min (enantiomer 1), 3.62 min (enantiomer 2).

[0330] Enantiomer 2 of (1-(5-cyano-2-methoxy-4-propylphenyl)-but-2-yl)tert-butyl carbamate LC-MS: m / z 347.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ = 7.40 (s, 1H),7.00 (s, 1H), 6.57 (d, J = 9.20 Hz, 1H), 3.86 (s, 3H), 3.53-3.51 (m, 1H), 2.78-2.68 (m, 2H), 2.42-2.36 (m, 2H), 1.65-1.60 (m, 2H), 1.45-1.32 (m, 2H), 1.26 (s, 9H), 0.93-0.83 (m, 6H). Enantiomer excess (98.9%) was determined by chiral SFC analysis [column name: CHIRALPAK IC-3 4.6 mm ID x 150 mm, 3 µm; mobile phase: supercritical CO2 (CO2: MeOH (80:20) containing 0.2% diethylamine); flow rate: 2.5 mL / min; column temperature: 35℃]. ；R t = 2.49 min (enantiomer 1), 3.23 min (enantiomer 2).

[0331] Step 8a: Preparation of 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile (30E1) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.24 mL, 0.95 mmol) was added to a stirred solution of tert-butyl 1-1-aminobutylcarbamate enantiomer 1 (33 mg, 0.095 mmol) in DCM (2.0 mL) at 0 °C. After addition, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile enantiomer 1 (30E1) hydrochloride (yield: 19 mg, 71%; plotted as R enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 247.2 [M+H] + ;1 HNMR (400 MHz, DMSO- d 6 ): δ = 7.85 (s, 3H),7.59 (s, 1H), 7.09 (s, 1H), 3.87 (s,3H), 3.29-3.25 (m, 1H), 2.85-2.71 (m, 4H), 1.70-1.61 (m, 2H), 1.53-1.46 (m,2H), 0.95-0.89 (m,6H).

[0332] Step 8b: Preparation of 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile (30E2) hydrochloride HCl solution (4.0 M, in 1,4-dioxane; 0.25 mL, 1.0 mmol) was added to a stirred solution of tert-butyl 1-carbamate enantiomer 2 (35 mg, 0.10 mmol) in DCM (2.0 mL) at 0 °C. After addition, the reaction mixture was heated to room temperature and stirred for 1 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was concentrated under reduced pressure and washed with diethyl ether (5.0 mL) to give the desired 5-(2-aminobutyl)-4-methoxy-2-propylbenzonitrile enantiomer 2 (30E2) hydrochloride (yield: 21 mg, 74%; plotted as the S enantiomer, but absolute stereochemistry not experimentally determined). LC-MS: m / z 247.2 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6 ): δ = 7.82 (s, 3H), 7.59 (s, 1H), 7.09 (s, 1H), 3.87 (s,3H), 3.30-3.24 (m, 1H), 2.85-2.75(m, 4H), 1.70-1.61 (m, 2H), 1.53-1.46 (m,2H), 0.95-0.89 (m,6H).

[0333] Example 31: Preparation of 5-(2-aminobutyl)-2-bromo-4-hydroxybenzonitrile enantiomer 1 (31E1) hydrochloride and 5-(2-aminobutyl)-2-bromo-4-hydroxybenzonitrile enantiomer 2 (31E2) hydrochloride Synthesis scheme: Step 1: Preparation of 4-bromo-5-iodo-2-methoxybenzaldehyde Silver sulfate (5.2 g, 16.68 mmol) and iodine (4.2 g, 16.68 mmol) were added to a stirred solution of 4-bromo-2-methoxybenzaldehyde (3 g, 13.9 mmol) in methanol (45 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL). The organic extract was washed with saturated sodium thiosulfate solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel rapid column chromatography (eluting with 0–10% ethyl acetate / heptane) to give 4-bromo-5-iodo-2-methoxybenzaldehyde as a grayish-white solid (yield: 4.0 g, 84%). 1 H NMR (400 MHZ, DMSO-d6): δ= 10.17 (s, 1H), 8.035 (s, 1H), 7.65 (s, 1H), 3.93 (s, 3H).

[0334] Steps 2-4: Preparation of tert-butyl (1-(4-bromo-5-iodo-2-methoxyphenyl)but-2-yl)carbamate (1-(4-bromo-5-iodo-2-methoxyphenyl)but-2-yl)tert-butyl carbamate (yield: 500 mg, 12% (by 3 steps)) was synthesized from 3-bromo-5-iodo-2-methoxybenzaldehyde (3.0 g) via general step A (see Example 61). LCMS: m / z 383.85 [M+H-100] + ; 1 H NMR (400 MHZ, DMSO-d6): δ= 7.56 (s, 1H), 7.23 (s, 1H), 6.57 (d, J = 9 Hz, 1H), 3.78 (s, 3H), 3.47-3.43 (m, 1H), 2.70-2.66 (m,1H), 2.36-2.31 (m, 1H), 1.44-1.39 (m, 2H), 1.37(s, 9H), 0.82 (t, J = 7.4 Hz, 3H).

[0335] Step 5: Preparation of tert-butyl (1-(4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)carbamate CuCN (130 mg, 1.13 mmol) was added to a stirred solution of tert-butyl (1-(4-bromo-5-iodo-2-methoxyphenyl)but-2-yl)carbamate (0.5 g, 1.03 mmol) in dry DMF (8 mL) at room temperature. The reaction mixture was heated at 110 °C for 12 h. The reaction progress was monitored by LC-MS and TLC. After completion, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL) and water (15 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (eluting with 0–30% ethyl acetate / heptane) to give tert-butyl (1-(4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)carbamate (yield: 150 mg, 38%). LCMS: m / z 383.00 [M+H-100] + ; 1 H NMR (400 MHZ, DMSO-d6): δ= 7.5 (s, 1H),7.40 (s,1H), 6.57 (d, J 0.84 (t, J = 7.3 Hz, 3H).

[0336] Step 6: (1-(4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)tert-butyl carbamate enantiomers 1 and (1- Preparation of enantiomer 2 of (4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)carbamate tert-butyl ester The enantiomers of (150 mg) tert-butyl carbamate were separated by chiral SFC [Column name: CHIRALPAK IC 21.0 mm ID x 250 mm, 5 µm; Mobile phase: supercritical CO2 (CO2: ACN (90:10) containing 0.1% ammonium hydroxide); Flow rate: 70 mL / min; Column temperature: 30 °C]. The separated fractions were concentrated under reduced pressure and lyophilized to give enantiomer 1 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate (yield: 30 mg, 40%, >99% ee; plotted as the S enantiomer, but the absolute stereochemistry was not determined experimentally) and enantiomer 2 of (1-(2-methoxy-5-methyl-4-propylphenyl)but-2-yl)carbamate (yield: 28 mg, 37%, >99% ee; plotted as the R enantiomer, but the absolute stereochemistry was not determined experimentally).

[0337] Enantiomer 1 of (1-(4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z: 383.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.53 (s, 1H),7.40 (s, 1H), 6.57 (d, J 0.84 (t, J =7.6 Hz, 3H). Enantiomer excess (99%) was determined by chiral SFC analysis [Column name: Chiralpak IC 4.6 mm ID x 250 mm, 5 µm; Mobile phase: supercritical CO2 (CO2: 100% ACN (75:25)); Flow rate: 3.0 mL / min; Column temperature: 35 °C]. R t = 2.38 min (enantiomer 1), 2.97 min (enantiomer 2).

[0338] Enantiomer 2 of (1-(4-bromo-5-cyano-2-methoxyphenyl)but-2-yl)tert-butyl carbamate LC-MS: m / z: 383.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 7.53 (s, 1H),7.40 (s, 1H), 6.57 (d, J 0.84 (t, J =7.6 Hz, 3H). Enantiomer excess (98.02%) was determined by chiral SFC analysis [Column name: Chiralpak IC 4.6 mm ID x 250 mm, 5 µ...

Claims

1. Compounds of formula (I): Or its pharmaceutically acceptable salt. in: R1 can be H, methyl, ethyl, -CH2-OH, -CH2-O-(methyl), -CH2F or -CH2CH2F; R2 is H, C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R6 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3, NO2, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl, or R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), NO2, or SF5 substituted with one or more F, wherein the alkyl, alkenyl, and ynyl groups are optionally substituted with one or more F, wherein the cycloalkyl group is optionally substituted with one or more F, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl, and wherein R4 is not isopropyl. R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, -S(O)(O)-(C1-C5 alkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, wherein the alkyl, alkenyl, alkynyl and cycloalkyl are optionally substituted by one or more F, or R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group is optionally substituted by one or more F groups; The condition is that when R5 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -S(O)(O)-(C1-C5 alkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, then R4 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl) Alkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl and ynyl groups are optionally substituted by one or more F groups, and wherein the cycloalkyl group is optionally substituted by one or more F groups, C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl groups, or When R5 is F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group is optionally substituted by one or more F groups, then R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), NO2, or SF5 substituted by one or more F groups, wherein the alkyl, alkenyl, and ynyl groups are optionally substituted by one or more F groups, wherein the cycloalkyl group is optionally substituted by one or more F groups, C1-C5 alkyl, C2-C5 alkenyl, or C2-C5 ynyl groups, and wherein R4 is not isopropyl. R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; Further conditions are: (a) When R2 is methyl, R3 is methyl, R4 is Cl or Br, R5 is methyl, R6 is H and R7 is H, then R1 is neither H nor methyl; (b) When R1 is H or methyl, R2 is H or methyl, R3 is H, R5 is methyl, R6 is H and R7 is H, then R4 is not Cl; (c) When R1 is H, R2 is methyl, R3 is H, R5 is CF3, R6 is H and R7 is o-methoxybenzyl, then R4 is not Br; (d) When R1 is H, R2 is H, R3 is H, R5 is Cl, R6 is H, and R7 is H or benzyl, then R4 is not cyclohexyl; and (e) When R1 is methyl, R2 is H, R3 is H, R5 is NH2, R6 is H and R7 is H, then R4 is not Cl.

2. The compound according to claim 1, wherein: R2 is H, C1-C3 alkyl, cyclopropyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cyclopropyl groups are optionally substituted by one or more F groups; R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R6 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with one or more F groups. And R4 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; Alternatively, R5 may be F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group may optionally be substituted with one or more F groups. And R4 is a C2 alkyl, C3-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl, and wherein R4 is not isopropyl; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

3. The compound according to claim 1, wherein: R2 is H, methyl, or ethyl, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R3 is either H or F; R6 is either H or F; R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C3-C5 cycloalkyl, or -S(O)(O)-(C1-C5 alkyl), wherein the alkyl, alkenyl, alkynyl, and cycloalkyl groups are optionally substituted with one or more F groups. And R4 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; Alternatively, R5 may be F, Cl, Br, I, -S-(C1-C5 alkyl), CN, or NO2, wherein the alkyl group may optionally be substituted with one or more F groups. And R4 is a C2 alkyl, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl, and wherein R4 is not isopropyl; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

4. The compound according to any one of claims 1-3, wherein R2 is methyl.

5. The compound according to any one of claims 1-4, wherein R3 and R6 are both H.

6. The compound according to any one of claims 1-5, wherein: R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, or C3-C5 cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally substituted with one or more F groups. And R4 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one to three F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; Alternatively, R5 may be F, Cl, Br, I, -S-(C1-C5 alkyl) or CN, wherein the alkyl group may optionally be substituted with one or more F groups. R4 is a C2 alkyl, C3-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), NO2, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted with one to three Fs, wherein the cycloalkyl is optionally substituted with one or more C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl, and wherein R4 is not isopropyl.

7. The compound according to any one of claims 1-5, wherein: R5 is a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, or C3-C5 cycloalkyl, wherein the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally substituted with one or more F groups. And R4 is C2-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I, CF3, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one to three F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; Alternatively, R5 may be F, Cl, Br, I, -S-(C1-C5 alkyl) or CN, wherein the alkyl group may optionally be substituted with one or more F groups. R4 is a C2 alkyl, C3-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), NO2, or SF5, wherein the alkyl, alkenyl, ynyl, and cycloalkyl are optionally substituted with one to three Fs, wherein the cycloalkyl is optionally substituted with one or more C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 ynyl, and wherein R4 is not isopropyl.

8. The compound according to any one of claims 1-7, wherein R7 is H.

9. The compound according to any one of claims 1-7, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

10. The compound according to any one of claims 1-7, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl) and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N and S.

11. The compound according to any one of claims 1-7, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms to which they are attached form a methylenedioxy ring.

12. The compound according to any one of claims 1-7, wherein R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position with an F, OH or -O-(methyl) ring, or substituted with a methylenedioxy ring connecting the ortho and meta positions.

13. The compound according to any one of claims 1-12, wherein R1 is H or methyl.

14. The compound according to any one of claims 1-12, wherein R1 is ethyl, -CH2-OH or -CH2-O-(methyl).

15. The compound according to claim 1, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

16. Compounds selected from: Or its pharmaceutically acceptable salt.

17. Compounds of formula (I) Or its pharmaceutically acceptable salt. in: R1 is -CH2-OH, -CH2-O-(methyl), -CH2F, or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 is -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), CF3, CN, Br or I, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The conditions are: (a) When R1 is -CH2-OH, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl, -S-(methyl) or n-butyl; (b) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl; (c) When R1 is -CH2CH2F, R2 is methyl, R3 is H, R5 is -O-(methyl), R6 is H and R7 is H, then R4 is not methyl; and (d) When R1 is -CH2-OH, R2 is methyl, R3 is methyl, R5 is Br, R6 is methyl and R7 is H, then R4 is not methyl.

18. The compound according to claim 17, wherein: R2 is a C1-C3 alkyl, cyclopropyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cyclopropyl groups are optionally substituted by one or more F groups; R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R5 is -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 alkynyl), -O-(cyclopropyl), -O-(C1-C3 alkyl)-(cyclopropyl), CF3 or CN, wherein the alkyl, alkenyl, alkynyl and cyclopropyl are optionally substituted by one or more F, and wherein the cyclopropyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R6 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

19. The compound according to claim 17, wherein: R2 is methyl or ethyl, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R3 is either H or F; R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; R5 is -O-(methyl), -O-(ethyl), or CN, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R6 is either H or F; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

20. The compound according to any one of claims 17-19, wherein R2 is methyl and R5 is -O-(methyl).

21. The compound according to any one of claims 17-20, wherein R3 and R6 are both H.

22. The compound according to any one of claims 17-21, wherein R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl.

23. The compound according to any one of claims 17-21, wherein R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one to three F, and wherein the cycloalkyl is optionally substituted by one to three C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl.

24. The compound according to any one of claims 17-23, wherein R7 is H.

25. The compound according to any one of claims 17-23, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

26. The compound according to any one of claims 17-23, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl) and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N and S.

27. The compound according to any one of claims 17-23, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms to which they are attached form a methylenedioxy ring.

28. The compound according to any one of claims 17-23, wherein R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position with an F, OH or -O-(methyl), or substituted with a methylenedioxy ring connecting the ortho and meta positions.

29. The compound according to any one of claims 17-28, wherein R1 is -CH2-OH.

30. The compound according to any one of claims 17-28, wherein R1 is -CH2-O-(methyl).

31. The compound according to any one of claims 17-28, wherein R1 is -CH2F.

32. The compound according to any one of claims 17-28, wherein R1 is -CH2CH2F.

33. The compound according to claim 17, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

34. Compounds of formula (I) Or its pharmaceutically acceptable salt. in: R1 can be H, methyl, ethyl, n-propyl, -CH2-OH, -CH2-O-(methyl), -CH2F or -CH2CH2F; R2 is a C1-C5 alkyl, C3-C5 cycloalkyl, C3-C5 alkenyl or C3-C5 ynyl, wherein the alkyl, alkenyl or ynyl group is optionally substituted by one or more F groups; R3 is H, C1-C3 alkyl, cyclopropyl or F, wherein the alkyl and cyclopropyl groups are optionally substituted by one or more F groups; R4 is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 ynyl, C3-C8 cycloalkyl, -(C1-C5 alkyl)-(C3-C6 cycloalkyl), -S-(C1-C8 alkyl), -S-(C3-C8 alkenyl), -S-(C3-C8 ynyl), -S-(C3-C8 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C6 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R5 represents C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C5 alkyl)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 alkyl), -S(O)(O)-(C3-C5 alkenyl), -S(O)(O)-(C3-C5 ynyl), -S(O)(O)-(C3-C5 cycloalkyl), -S(O)(O)-(C1-C5 Alkyl)-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3-C5 cycloalkyl), -O-(C1-C5 alkyl)-(C3-C5 cycloalkyl), NH2, NH(C1-C5 alkyl) or N(C1-C5 alkyl)2, F, Cl, Br, I, CN or NO2, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C5 alkyl, C2-C5 alkenyl or C2-C5 ynyl; R6 is F; R7 is H, -CH2-(aryl), or -CH2-(heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 ynyl, C3-C5 cycloalkyl, -O-(C1-C5 alkyl), -O-(C3-C5 alkenyl), -O-(C3-C5 ynyl), -O-(C3- -C5 cycloalkyl), -S-(C1-C5 alkyl), -S-(C3-C5 alkenyl), -S-(C3-C5 ynyl) and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein any two adjacent substituents on the aryl or heteroaryl groups together with the atoms they are attached to form a 4-6 membered ring, wherein the ring is optionally intercalated with 1-3 heteroatoms selected from O, N and S; The condition is that when R1 is H, R2 is methyl, R3 is H, R4 is F and R7 is H, then R5 is not Cl or Br.

35. The compound according to claim 34, wherein: R2 is a C1-C3 alkyl, cyclopropyl, C3 alkenyl, or C3 alkynyl, wherein the alkyl, alkenyl, alkynyl, and cyclopropyl groups are optionally substituted by one or more F groups; R3 is H, methyl, ethyl, or F, wherein methyl and ethyl are optionally substituted by one or more F; R5 is -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 alkynyl), -O-(cyclopropyl), -O-(C1-C3 alkyl)-(cyclopropyl) or CN, wherein the alkyl, alkenyl, alkynyl and cyclopropyl are optionally substituted by one or more F, and wherein the cyclopropyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, C3-C5 cycloalkyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(C3-C5 cycloalkyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(C3-C5 cycloalkyl), wherein the alkyl, alkenyl, ynyl, and cycloalkyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

36. The compound according to claim 34, wherein: R2 is methyl or ethyl, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R3 is either H or F; R4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -(C1-C3 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C6 alkyl), -S-(C3-C6 alkenyl), -S-(C3-C6 ynyl), -S-(C3-C6 cycloalkyl), -S-(C1-C3 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl; R5 is -O-(methyl), -O-(ethyl), or CN, wherein the methyl and ethyl groups are optionally substituted with one or more F groups; R7 is H, -CH2-(6-membered aryl), or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 ynyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(C3 alkenyl), -O-(C3 ynyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), -S-(C3 alkenyl), -S-(C3 ynyl), and -S-(cyclopropyl), wherein the alkyl, alkenyl, ynyl, and cyclopropyl groups are optionally substituted by one or more F groups, and wherein any two adjacent substituents located on the aryl or heteroaryl group, together with the atoms they are attached to, form a 5-6 membered ring, wherein the ring is optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

37. The compound according to any one of claims 34-36, wherein R2 is methyl and R5 is -O-(methyl).

38. The compound according to any one of claims 34-37, wherein R3 is H.

39. The compound according to any one of claims 34-38, wherein R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), F, Cl, Br, I, CN, NO2 or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one or more F, and wherein the cycloalkyl is optionally substituted by one or more C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl.

40. The compound according to any one of claims 34-38, wherein R4 is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C3-C5 cycloalkyl, -(C1-C2 alkyl)-(C3-C5 cycloalkyl), -S-(C1-C4 alkyl), -S-(C3-C4 alkenyl), -S-(C3-C4 ynyl), -S-(C3-C5 cycloalkyl), -S-(C1-C2 alkyl)-(C3-C5 cycloalkyl), Cl, Br, I or SF5, wherein the alkyl, alkenyl, ynyl and cycloalkyl are optionally substituted by one to three F, and wherein the cycloalkyl is optionally substituted by one to three C1-C3 alkyl, C2-C3 alkenyl or C2-C3 ynyl.

41. The compound according to any one of claims 34-40, wherein R7 is H.

42. The compound according to any one of claims 34-40, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, NO2, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl), -O-(cyclopropyl), -S-(C1-C3 alkyl), and -S-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-6 membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N, and S.

43. The compound according to any one of claims 34-40, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, C1-C3 alkyl, cyclopropyl, -O-(C1-C3 alkyl) and -O-(cyclopropyl), wherein the alkyl and cyclopropyl groups are optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms they are attached to form a 5-membered ring, said ring optionally intercalated with 1-2 heteroatoms selected from O, N and S.

44. The compound according to any one of claims 34-40, wherein R7 is -CH2-(6-membered aryl) or -CH2-(6-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally substituted by one or more substituents independently selected from: halogen, CN, OH, methyl and -O-(methyl), wherein the methyl group is optionally substituted by one to three F groups, and wherein any two adjacent substituents on the aryl or heteroaryl group together with the atoms to which they are attached form a methylenedioxy ring.

45. The compound according to any one of claims 34-40, wherein R7 is -CH2-(6-membered aryl), wherein the aryl group is optionally substituted at the ortho position with an F, OH or -O-(methyl), or substituted with a methylenedioxy ring connecting the ortho and meta positions.

46. ​​The compound according to any one of claims 34-45, wherein R1 is H or Me.

47. The compound according to any one of claims 34-45, wherein R1 is an ethyl group.

48. The compound according to any one of claims 34-45, wherein R1 is n-propyl.

49. The compound according to any one of claims 34-45, wherein R1 is -CH2-OH.

50. The compound according to any one of claims 34-45, wherein R1 is -CH2-O-(methyl).

51. The compound according to any one of claims 34-45, wherein R1 is -CH2F.

52. The compound according to any one of claims 34-45, wherein R1 is -CH2CH2F.

53. The compound according to claim 34, wherein the compound is selected from: Or its pharmaceutically acceptable salt.

54. Compounds selected from: Or its pharmaceutically acceptable salt.

55. Compounds having the following structures: Or its pharmaceutically acceptable salt.

56. Compounds having the following structures: Or its pharmaceutically acceptable salt. Each deuterium-enriched H-site contains more than 0.02% deuterium.

57. The compound of claim 56, wherein each deuterium-enriched H-site is more than 90% deuterium.

58. The compound of claim 56, wherein each deuterium-enriched H-site is more than 95% deuterium.

59. Compounds selected from: Or its pharmaceutically acceptable salt.

60. The compound according to any one of claims 1 to 59, wherein it is in the S-enantiomer form.

61. The compound according to any one of claims 1 to 59, wherein it is in the form of an R-enantiomer.

62. The compound according to claim 60 or 61, wherein the compound is substantially enantiomerically pure.

63. The compound according to claim 60 or 61, optionally comprising the compound in the form of opposite enantiomers, provided that the compound contains >50% of the indicated enantiomer and <50% of the opposite enantiomer.

64. A composition comprising the following S-enantiomers: It may optionally contain the R-enantiomer form of the same compound, provided that the composition contains more than 50% of the S-enantiomer form.

65. The composition according to claim 64, wherein it contains more than 90% of the S-enantiomer form.

66. The composition according to claim 64, wherein it contains more than 95% of the S-enantiomer form.

67. Compounds selected from: 。 68. A pharmaceutical composition comprising a compound according to any one of claims 1-63 or a composition according to any one of claims 64-67, and a pharmaceutically acceptable carrier.

69. A method of treating a mental illness or condition, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1-63 or a composition according to any one of claims 64-67.

70. The method of claim 69, wherein the mental illness or condition is selected from depression and bipolar disorder.

71. The method of claim 69, wherein the mental illness or condition is depression.

72. The method of claim 69, wherein the mental illness or condition is treatment-resistant depression.

73. The method of claim 69, wherein the mental illness or condition is selected from major depressive disorder, persistent depression, postpartum depression, premenstrual anxiety disorder, seasonal affective disorder, psychotic depression, disruptive mood disorder, substance / drug-induced depression, and depression caused by other medical conditions.

74. The method of claim 69, wherein the mental illness or condition is selected from bipolar I disorder, bipolar II disorder, cyclothymic mood disorder, substance / drug-induced bipolar and related disorders, and bipolar and related disorders caused by other medical conditions.

75. The method of claim 69, wherein the mental illness or condition is a substance-related disorder.

76. The method of claim 69, wherein the mental illness or condition is a substance use disorder.

77. The method of claim 69, wherein the mental illness or condition is anxiety disorder.

78. The method of claim 69, wherein the mental illness or condition is selected from obsessive-compulsive disorder and related disorders, trauma and stress-related disorders, eating and drinking disorders, borderline personality disorder, attention deficit / hyperactivity disorder, and autism spectrum disorder.

79. A method of treating headache or headache syndrome, comprising administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1-63 or the composition according to any one of claims 64-67.

80. A method of treating an inflammatory disease or condition, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1-63 or a composition according to any one of claims 64-67.

81. A method for treating high intraocular pressure, comprising administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1-63 or the composition according to any one of claims 64-67.

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