A kind of aromatic heterocyclic compound and its preparation method and use

Abstract

The present invention belongs to the pharmaceutical field, and provides an aryl heterocyclic compound and a preparation method and use thereof, wherein the structural formula is shown in formula (I). The compound provided by the present invention has a monoamine system regulating effect, and has binding activity to monoamine transporter proteins and G protein-coupled receptors such as 5-hydroxytryptamine receptors, dopamine receptors, and trace amine receptors. Such compounds have the potential to be applied to the treatment of various diseases, including but not limited to depression, anxiety, schizophrenia, attention deficit disorder, obesity, pain, and neurodegenerative diseases.

Description

Technical Field

[0001] The present invention relates to the fields of pharmaceutical chemistry and pharmacotherapy. Specifically, the present invention relates to a series of cyclopentadiene compounds represented by general formula I and stereoisomers, a preparation method thereof, a chiral separation method, a pharmaceutical composition containing the compound and its use. The compound represented by general formula I provided by the present invention has a high binding activity with monoamine transporters. Therefore, the cyclopentadiene compounds of the present invention can be used to prevent or treat mental diseases such as schizophrenia, depression, anxiety, etc. Background Art

[0002] Mental illness refers to a disease in which the brain of the human body is disturbed due to various biological, psychological and social environmental factors, resulting in varying degrees of disorders in mental activities such as cognition, emotion, will and behavior. Usually, mental illnesses include schizophrenia, depression, anxiety, attention deficit disorder, avolition, autism, etc. One of the main causes is the imbalance of monoamine neurotransmitters such as norepinephrine and dopamine in the brain, which causes serious harm to both the patient and society.

[0003] Take depression as an example. Its prevalence among adults has reached 10% to 20%, making it the fourth largest disease affecting global public health security. According to the latest statistics, the number of depression patients in my country has reached more than 90 million, and the incidence rate is increasing year by year while showing a trend of younger age. Depression has the characteristics of complex mechanisms, many subtypes, difficult diagnosis and large individual differences among patients, which brings great challenges to the treatment of depression. Existing antidepressants are mainly designed and developed based on the monoamine neurotransmitter hypothesis. The drugs work by increasing the level of monoamine transmitters in the synaptic cleft or enhancing related nervous system functions. At present, the first-line clinical antidepressants are mainly selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine dual reuptake inhibitors (SNRIs). These drugs have been proven to have side effects such as lack of pleasure, cognitive impairment and sexual dysfunction in long-term clinical practice, and they are slow to take effect and have high inefficiency in treatment, which is not conducive to patients' confidence in treatment, and even has the problem of increased suicide risk in adolescent patients.

[0004] Studies have shown that adding 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) triple reuptake inhibitors (TRIs) that inhibit dopamine transporters to SNRIs can improve patients' symptoms such as lack of pleasure, and have the advantages of faster onset and better efficacy. Therefore, TRIs are considered to be an important direction for developing new antidepressant drugs by optimizing monoamine strategies. Based on the regulatory effect of TRIs on monoamine transmitters in the brain, it is also widely used in the treatment of diseases such as schizophrenia, anxiety, attention deficit disorder, autism, obesity, and neuropathic pain. In addition, other receptors in the monoaminergic system, such as 5-HT receptors or DA receptors, are regulated to balance neurotransmitters in the brain, which has a therapeutic effect on mental illness and other related diseases. Summary of the invention

[0005] The first object of the present invention is to provide a cyclopentadiene compound having monoamine transporter protein binding activity, including stereoisomers or pharmaceutically acceptable salts, prodrugs or solvates thereof. Such compounds can be used for preventing, diagnosing and treating central nervous system diseases such as schizophrenia, depression, anxiety, attention deficit disorder, pain, neurodegenerative diseases, and obesity and obesity-related diseases.

[0006] The second object of the present invention is to provide a method for preparing the above-mentioned annular compound.

[0007] The third object of the present invention is to provide a method for chiral separation of the above-mentioned cyclopentane compound.

[0008] The fourth object of the present invention is to provide a pharmaceutical composition of the annular compound represented by general formula I, its stereoisomers, and pharmaceutically acceptable salts, prodrugs or solvates thereof.

[0009] In order to achieve the purpose of the present invention, the following technical solutions are adopted:

[0010] The present invention provides a compound as shown in formula (I),

[0011]

[0012] Ring A is selected from 5-7 membered heteroaryl or aryl, wherein the 5-7 membered heteroaryl or aryl is optionally substituted by 1-3 halogen, amino, hydroxy, C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl or trifluoromethyl;

[0013] m is 1, 2 or 3; preferably, m is 1 or 2;

[0014] n is 1, 2 or 3; preferably, n is 1 or 2;

[0015] R 1 and R2 each independently represents (i) hydrogen, C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered cycloalkyl, C5-C 10 Aryl or 5-10 membered aralkyl;

[0016] The C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, 3-5-membered cycloalkyl may be optionally substituted by 1-3 halogens, amino, or 3-5-membered cycloalkyl; the C5-C 10 The aryl or 5-10 membered aralkyl group is optionally substituted by 1-3 halogens, amino, C1-C4 alkyl, C1-C3 alkoxy or trifluoromethyl groups;

[0017] or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted by benzyl or C1-C4 alkyl; the benzyl group is optionally substituted by 1-3 halogens, amino, nitro, hydroxyl or C1-C4 alkyl;

[0018] R 3 and R 4 Each is independently (i) hydrogen, C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered cycloalkyl, 5-10 membered aryl or heteroaryl, 5-10 membered aralkyl or heteroaralkyl;

[0019] The C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, 3-5 membered cycloalkyl is optionally substituted by 1-3 halogens or amino groups, and the 5-10 membered aryl or heteroaryl, 5-10 membered aralkyl or heteroaralkyl is optionally substituted by 1-3 halogens, amino groups, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, or phenyl groups;

[0020] or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group, and the 3-6 membered cycloalkyl group is optionally substituted by 1-3 halogens or amino groups.

[0021] In some embodiments, Ring A is selected from thiophene, furan or benzene ring optionally substituted with 1-2 halogen, amino, hydroxy, C1-C4 alkyl, C1-C3 alkoxy, C2-C4 alkenyl or trifluoromethyl.

[0022] In some embodiments, the structural unit of Ring A dihydropyran has the following structure:

[0023]

[0024] R 7 is hydrogen, halogen, C1-C4 alkyl or C1-C3 alkoxy;

[0025] R 8 and R 9 Independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy or hydroxy.

[0026] In some embodiments, the structural unit of ring A dihydropyran is selected from the following structures:

[0027]

[0028] In some embodiments, R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl, C1-C3 alkoxy, 3-5 membered cycloalkyl or methylcyclopropyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are connected, they form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl; preferably, the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine.

[0029] In some embodiments, R 1 and R 2 are each independently H, -CH3, -CH2CH3 or -CH2CH2CH3; or

[0030] Structural unit selection since:

[0031]

[0032] In some embodiments, R 3 and R 4 Each is independently (i) hydrogen, C1-C4 alkyl, 3-5 membered cycloalkyl, phenyl or naphthyl; the phenyl or naphthyl may be optionally substituted by 1-3 halogens, amino, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl or phenyl;

[0033] or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group.

[0034] In some embodiments, R 3 and R 4 Each is independently (i) hydrogen, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, or selected from the following structures:

[0035]

[0036] or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group.

[0037] In some embodiments of the present invention, formula (I) has the following structure:

[0038]

[0039] in:

[0040] R 5 and R 6 are each independently (i) hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 6-10 membered aromatic group;

[0041] R 7 Selected from hydrogen, halogen or C1-C4 alkyl.

[0042] wherein R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl or methylcyclopropyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl groups;

[0043] Preferably, the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine.

[0044] In some embodiments, (Ia) and (Ib) have the following structures: R 1 and R 2 are each independently hydrogen, methyl, ethyl, n-propyl or methylcyclopropyl; or the structural unit Selected from:

[0045]

[0046] Structural unit Selected from:

[0047]

[0048] In some embodiments of the present invention, formula (I) has the following structure:

[0049]

[0050] in:

[0051] R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl groups;

[0052] Preferably, the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;

[0053] R 5 and R 6 are each independently (i) hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 6-10 membered aromatic group;

[0054] R 7 Selected from hydrogen, halogen, C1-C4 alkyl.

[0055] Preferably, Ic is selected from: R 1 and R 2 are independently hydrogen, C1-C4 alkyl; R 5 and R 6 are each independently (i) hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 6-10 membered aromatic group; R 7 It's hydrogen.

[0056] More preferably, Ic is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 5 and R 6 are each independently hydrogen, methyl, methoxy, trifluoromethyl or halogen; R 7 It's hydrogen.

[0057] In some embodiments of the present invention, formula (I) has the following structure:

[0058]

[0059] in:

[0060] R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms, wherein the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl groups;

[0061] Preferably, the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;

[0062] R 3 and R 4 Each independently represents (i) hydrogen, C1-C4 alkyl, 3-5 membered cycloalkyl, wherein the C1-C4 alkyl, 3-5 membered cycloalkyl may be optionally substituted by 1-3 halogens, amino, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl or phenyl; or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group;

[0063] R 7 Selected from hydrogen, halogen, C1-C4 alkyl.

[0064] Preferably, Id is selected from: R 1 and R 2 are independently hydrogen, C1-C4 alkyl; R 3 and R 4 are each independently (i) hydrogen, C1-C4 alkyl or 3-5 membered cycloalkyl; or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group; R 7 It's hydrogen.

[0065] More preferably, Id is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 3 and R 4 are each independently (i) hydrogen, methyl, ethyl, isopropyl or cyclopropylmethyl; or (ii) R 3 and R 4 Together with the carbon atom to which they are attached, they form a cyclopropyl, cyclobutyl or cyclopentyl group; R 7 It's hydrogen.

[0066] In some embodiments of the present invention, formula (I) has the following structure:

[0067]

[0068] in:

[0069] R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl groups;

[0070] Preferably, the 5-7 membered heteroaromatic ring containing 1-2 nitrogen atoms includes tetrahydropiperidine and tetrahydropiperazine;

[0071] R 5 and R 6 are each independently (i) hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 6-10 membered aromatic group;

[0072] R 8 and R 9 Each is independently hydrogen, C1-C4 alkyl, alkoxy or hydroxy.

[0073] Preferably, Ie is selected from: R 1 and R 2 are each independently hydrogen or C1-C4 alkyl; R 5 and R 6 are each independently (i) hydrogen, halogen, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl, trifluoromethoxy, phenyl or 5-10 membered aralkyl; or (ii) R 5 and R 6 Together with the carbon atoms to which they are attached, they form a 6-10 membered aromatic group; R 8 and R 9 Each is independently hydrogen, C1-C4 alkyl, alkoxy or hydroxy.

[0074] More preferably, Ie is selected from: R 1 and R 2 are each independently hydrogen, methyl, ethyl or n-propyl; R 5 and R 6 are each independently hydrogen, methyl, methoxy, trifluoromethyl or halogen; R 8 and R 9Each is independently hydrogen, methyl, methoxy or hydroxy.

[0075] In some embodiments of the present invention, formula (I) has the following structure:

[0076]

[0077] in:

[0078] R1 and R2 are each independently (i) hydrogen, C1-C4 alkyl; or (ii) R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic group containing 1-2 nitrogen atoms, including but not limited to tetrahydropiperidine, tetrahydropiperazine, etc., wherein the 5-7 membered heterocyclic group containing 1-2 nitrogen atoms may be optionally substituted by a benzyl group; the benzyl group may be optionally substituted by 1-3 halogens, amino, nitro, hydroxyl, or C1-C4 alkyl;

[0079] R 3 and R 4 Each independently represents (i) hydrogen, C1-C4 alkyl, 3-5 membered cycloalkyl, wherein the C1-C4 alkyl, 3-5 membered cycloalkyl may be optionally substituted by 1-3 halogens, amino, C1-C4 alkyl, C1-C3 alkoxy, trifluoromethyl or phenyl; or (ii) R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 3-6 membered cycloalkyl group;

[0080] R 8 and R 9 Each is independently hydrogen, C1-C4 alkyl, alkoxy or hydroxy.

[0081] Preferably, If is selected from: R 1 and R 2 are independently hydrogen, methyl, ethyl, or n-propyl; R 3 and R 4 are each independently (i) hydrogen, methyl, ethyl, isopropyl, cyclopropylmethyl; or (ii) R 3 and R 4 Together with the carbon atom to which they are attached, they form a cyclopropyl, cyclobutyl or cyclopentyl group; R 8 and R 9 It is hydrogen, methyl, methoxy, and hydroxyl.

[0082] The present invention discloses the use of the compound as shown in Formula I and its stereoisomers, and pharmaceutically acceptable salts in the preparation of drugs for preventing, treating and diagnosing depression, anxiety, schizophrenia, attention deficit disorder, obesity, neuropathic pain and neurodegenerative diseases. The compound as shown in Formula I and its stereoisomers involved in the present invention have been proved by biological activity tests to have monoamine transporter proteins and GPCR receptor binding activity such as 5-hydroxytryptamine receptors and dopamine receptors, wherein the monoamine transporter is selected from one or more proteins of 5-hydroxytryptamine transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

[0083] In the present invention,

[0084] The hydrogen described in the present invention includes various isotopes of hydrogen, such as deuterium and tritium;

[0085] The term "hydrocarbon" (whether used alone or as part of another group) refers to any structure containing carbon atoms and hydrogen atoms;

[0086] The term "alkyl" refers to a linear or branched saturated hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents, including but not limited to methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, tert-butyl;

[0087] The term "cycloalkyl" is used to refer to non-aromatic carbocyclic groups, including cyclized alkyl groups, which may include bicyclic or polycyclic ring systems; the cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decahydronaphthalene, and adamantyl;

[0088] The term "heterocyclic group" is used to represent a non-aromatic carbocyclic ring containing heteroatoms N, O, S, including but not limited to tetrahydropyrrole, tetrahydropyridine, tetrahydropyrazine;

[0089] The term "alkoxy" is used to denote an -O-alkoxy group;

[0090] The term "aryl" refers to a monocyclic aromatic group and / or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring; the aromatic group includes, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl and biphenyl;

[0091] The term "heteroaryl" refers to a monocyclic heteroaryl containing heteroatoms N, O, S and / or a polycyclic monovalent heteroaryl containing at least one aromatic hydrocarbon ring; the heteroaryl includes but is not limited to thiophene, furan, pyrrole;

[0092] The term "halogen" is used to refer to fluorine, chlorine, bromine and iodine;

[0093] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Suitable non-toxic acids include inorganic and organic acids, but are not limited to, for example, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, succinic acid, succinic acid, vinylsulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, epoxypropionic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, galactaric acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, and the like.

[0094] The term "solvate" refers to a compound or salt thereof provided by the present invention that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0095] The term "stereoisomer" includes all enantiomerically / stereomerically pure and enantiomerically / stereomerically enriched compounds of the invention.

[0096] Dashed and bold lines in chemical formulae are used to represent chemical structures with one or more stereocenters and indicate the absolute stereochemistry of the stereocenter in the chemical structure.

[0097] In the present invention, the bonds depicted in the structural formula do not represent preferred stereostructures; chemical structures containing one or more stereocenters include all possible stereoisomeric forms and mixtures thereof.

[0098] In the present invention, the compound of formula I is prepared by the following synthetic route, which is only an exemplary description of the present invention and is not intended to limit the present invention.

[0099] Synthesis of compounds of formula Ia:

[0100]

[0101] The reaction steps are as follows:

[0102] i. Compound 1 is used as a raw material and reacted with the corresponding halogenated aromatic hydrocarbon to generate compound 2.

[0103] ii. Compound 2 is reduced with lithium aluminum hydride to obtain compound 3.

[0104] iii. Compound 3 reacts with the corresponding amine reagent to generate compound 4.

[0105] iv. Compound 4 reacts with the corresponding halogenated hydrocarbon to generate compound 5.

[0106]

[0107] v. Compound 3 reacts with the corresponding amine reagent to produce compound 6.

[0108]

[0109] vi. Compound 3 reacts with a primary amine reagent to generate compound 7.

[0110] vii. Compound 7 reacts with the corresponding halogenated hydrocarbon to produce compound 8.

[0111]

[0112] viii. Compound 7 reacts with the corresponding aromatic substituted halogenated hydrocarbon to produce compound 9.

[0113]

[0114] ix. Compound 10 is used as a raw material and reacted with the corresponding bromothiophene to generate compound 11.

[0115] x. Compound 11 is reduced with lithium aluminum hydride to obtain compound 12.

[0116] xi. Compound 12 reacts with the corresponding amine reagent to generate compound 13.

[0117] Synthesis of compounds of formula Ib:

[0118]

[0119] The reaction steps are as follows:

[0120] xii. Compound 14 is used as a raw material and reacted with the corresponding halogenated aromatic hydrocarbon to produce compound 15.

[0121] xiii. Compound 15 is reduced with lithium aluminum hydride to obtain compound 16.

[0122] xiv. Compound 16 reacts with the corresponding amine reagent to generate compound 17.

[0123]

[0124] xv. Compound 16 reacts with TBSCl to generate compound 18.

[0125] xvi. Compound 18 reacts with corresponding reagents under the action of n-BuLi to obtain compound 19.

[0126] xvii. Compound 19 reacts with a corresponding amine reagent to generate compound 20.

[0127] Synthesis of compounds of formula Ic:

[0128]

[0129] The reaction steps are as follows:

[0130] xviii. Compound 10 is used as a raw material and reacted with bromofuran to generate compound 21.

[0131] xix. Compound 21 is reduced with lithium aluminum hydride to obtain compound 22.

[0132] xx. Compound 22 reacts with the corresponding amine reagent to obtain compound 23.

[0133] Synthesis of compound of formula Id:

[0134]

[0135] The reaction steps are as follows:

[0136] xxi. Compound 1 is used as a raw material and reacted with the corresponding halogenated aliphatic hydrocarbon to obtain compound 24.

[0137] xxii. Compound 24 is reduced with lithium aluminum hydride to give compound 25.

[0138] xxiii. Compound 25 reacts with a corresponding amine reagent to give compound 26.

[0139]

[0140] The reaction steps are as follows:

[0141] xxiv. Compound 27 is used as a raw material and reacted with the corresponding halogenated aliphatic hydrocarbon to obtain compound 28.

[0142] xxv. Compound 28 is hydrolyzed to give compound 29.

[0143] xxvi. Compound 29 is reduced with lithium aluminum hydride to give compound 30.

[0144] xxvii. Compound 30 reacts with a corresponding amine reagent to give compound 31.

[0145] Synthesis of compounds of formula Ie:

[0146]

[0147] The reaction steps are as follows:

[0148] xxviii. Compound 32 is used as a raw material and reacted with the corresponding halogenated aromatic hydrocarbon to produce compound 33.

[0149] xxix. Compound 33 is reacted with lithium aluminum hydride to obtain compound 34.

[0150] xxx. Compound 34 reacts with the corresponding amine reagent to give compound 35.

[0151]

[0152] xxxi. Compound 36 is used as a raw material and reacted with the corresponding halogenated aromatic hydrocarbon to obtain compound 37.

[0153] xxxii. Compound 37 is reduced to give compound 38.

[0154] xxxiii. Compound 38 is reduced with lithium aluminum hydride to give compound 39.

[0155] xxxiv. Compound 39 reacts with a corresponding amine reagent to give compound 40.

[0156] Synthesis of compounds of formula If:

[0157]

[0158] xxxv. Compound 41 is used as a starting material and reacted with the corresponding halogenated aliphatic hydrocarbon to obtain compound 42.

[0159] xxxvi. Compound 42 is hydrolyzed to give compound 43.

[0160] xxxvii. Compound 43 is reduced with lithium aluminum hydride to give compound 44.

[0161] xxxviii. Compound 44 reacts with a corresponding amine reagent to give compound 45.

[0162] The compound as shown in formula I and its stereoisomers provided by the present invention have monoamine transporter protein binding activity, wherein the monoamine transporter is selected from one or more proteins of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), and can be used for the prevention, diagnosis and treatment of central nervous system diseases such as schizophrenia, depression, attention deficit disorder, neuropathic pain, neurodegenerative diseases, as well as obesity and obesity-related diseases. DETAILED DESCRIPTION

[0163] The present invention is further described below with reference to the embodiments, but these embodiments do not limit the scope of the present invention.

[0164] Instruments used for experiments and sample analysis:

[0165] 1 HNMR was measured on a Varian Mercury plus 400 NMR spectrometer. 13CNMR was measured on a Bruker 600MHz nuclear magnetic resonance instrument. LS-MS was measured by an Agilent 1100Series LC / MSD1946D mass spectrometer. Special chemical reagents were purchased from reagent companies such as Exploration, Bid, Anaiji, Sigma, Alfa, Acros and Adamas. General chemical reagents were purchased from Sinopharm Shanghai Chemical Reagent Company. The main solvents include petroleum ether, ethyl acetate, dichloromethane, methanol, etc., which were purchased from Sinopharm Group and are all synthetic grade. Column chromatography silica gel uses chemically pure silica gel from Huanghai Chemical Plant, generally 200-300 mesh. The reagent treatment method refers to Purification of Laboratory Chemicals (1988 edition).

[0166] Example

[0167] Example 1: N-methyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0168]

[0169] Synthesis route:

[0170]

[0171] Reagents and conditions: (i) EtMgCl, (iPr)2NH, THF, 50℃, 3h; Pd(tBu3P)2, THF, 60℃, 3h; (ii) LiAlH4, THF, rt, 3h; (iii) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0172] Reaction steps:

[0173] i. Add 1.0g 3-thiopheneacetic acid (7.04mmol, 1.0eq) to a 100mL three-necked flask, add 10mL anhydrous tetrahydrofuran to completely dissolve the solid, replace the flask with nitrogen three times, and then add 70mg diisopropylamine (0.70mmol, 0.1eq) to the solution. Slowly drop 8.8mL Grignard reagent ethylmagnesium chloride (2.4M in THF, 21.12mmol, 3.0eq) in an ice bath. A large amount of bubbles are generated during the dropwise addition, and heat is released violently. After the addition is completed, the above mixture is stirred at 50°C for 3 hours and then cooled to room temperature. 1.3 g of bromobenzene (8.45 mmol, 1.2 eq) and 107 mg of tri-tert-butylphosphine palladium (0.21 mmol, 0.03 eq) were dissolved in 10 mL of anhydrous tetrahydrofuran and added to a flask. The mixture was heated to 60 °C and stirred for 3 hours. The system was cooled to room temperature. A 2N hydrochloric acid solution was slowly added to the flask to adjust the pH to 4-6. A large amount of solid precipitated. The solid was filtered out. The filtrate was extracted with ethyl acetate (30 mL x 3) and water (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a black oily substance. The filtrate was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-20 / 1) to obtain 1.0 g of yellow oily substance 2-A, with a yield of 65%. ESI-MS (MH) - :217.2.

[0174] ii. 150 mg 2-A (0.49 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, and 10 mL dry tetrahydrofuran was added to completely dissolve it. The system was replaced with nitrogen three times, and 0.6 mL lithium aluminum hydride (2.5 M in THF, 1.47 mmol, 3.0 eq) was slowly added dropwise to the flask under an ice-water bath. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated. NaOH solution (1 mol / L) was slowly added dropwise to form a large amount of precipitate, and the filtrate was filtered to obtain the filtrate, and the filter cake was washed with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (20 mL x 3) and water (10 mL), and the obtained organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 104 mg of light yellow oil 3-A, with a yield of 78%. ESI-MS (M+H) + :205.2.

[0175] iii. 100 mg 3-A (0.36 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, 5 mL of anhydrous 1,4-dioxane was added to dissolve it, and then 128 mg of methylaminoacetaldehyde dimethyl acetal (1.08 mmol, 3.0 eq) and 286 mg of trifluoromethanesulfonic acid (1.8 mmol, 5.0 eq) were added to the flask. The mixture was stirred at 80 ° C for 3 hours, and then 1N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 10-11, and extracted with ethyl acetate (20 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-10 / 1) to obtain 84 mg of yellow oil 4-A, yield: 66%.

[0176] iv. 1 H NMR (400MHz, CDCl3) δ7.26–7.18(m,3H),7.14–1.04(m,3H),6.54(d,J=4.9Hz,1H),5.28(d,J=8.8Hz,1H),4.22(dd,J=11.2 ,5.3Hz,1H),4.13–4.08(m,1H),3.62(t,J=10.2Hz,1H),3.46(d,J=12.6Hz,1H),3.17(dd,J=12.3,9.9Hz,1H),2.78(s,3H). 13 CNMR(151MHz, CDCl3)δ141.37,139.48,138.24,136.97,130.84,128.05,127.90,127.57,126.97,126.84,126.65 ,126.39,123.97,123.76,120.67,118.56,70.08,69.94,68.82,53.37,42.45,41.65,33.73,29.08.ESI-MS(M+H) + :260.1.HMRS:calc.for C 15 H 17 NOS([M+H] + )260.1104, found 260.1112.

[0177] Example 2: N-methyl-1-(4-(4-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0178]

[0179] Synthesis route and reaction steps:

[0180] Referring to step i-iii described in Example 1, bromobenzene in step i was replaced by 4-methylbromobenzene to obtain a yellow oil 4-B with a total yield of 23.4%. 1 H NMR (400MHz, CDCl3) δ7.15–7.09(m,3H),7.07–7.02(m,2H),6.57(d,J=5.1Hz,1H),5.10–4.98(m,1H),4.23(dd ,J=11.1,5.6Hz,1H),4.18–4.09(m,1H),3.60(t,J=10.5Hz,1H),3.06–2.89(m,2H),2.52(s,3H),2.33(s,3H). 13 C NMR (151MHz, CDCl3) δ137.21,137.04,136.07,135.16,128.66,127.81,126.55,122.39,74.07,71.23,56.86,42.82,35.84,20.43.ESI-MS(M+H) + :274.1.HMRS:calc.for C 16 H 19 NOS([M+H] + )274.1260, found 274.1265.

[0181] Example 3: 1-(4-(4-methoxyphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine

[0182]

[0183] Synthesis route and reaction steps:

[0184] Referring to steps i-iii described in Example 1, bromobenzene in step i was replaced by 4-methoxybromobenzene to obtain yellow oil 4-C with a total yield of 22.8%. 1H NMR (400MHz, CDCl3) δ7.15(d,J=4.9Hz,1H),7.02(d,J=8.5Hz,2H),6.82(d,J=8.6Hz,2H),6.58(d,J=5.0Hz,1H),5.22(d,J=8.1Hz,1H) ,4.22(dd,J=11.2,5.5Hz,1H),4.17–4.06(m,1H),3.78(s,3H),3.64–3.56(m,1H),3.40–3.33(m,1H),3.18–3.07(m,1H),2.74(s,3H). 13 C NMR (151MHz, CDCl3) δ158.35,139.01,134.78,132.22,128.87,123.60,122.30,113.32,73.89,70.77,55.00,54.63,41.91,35.47.ESI-MS(M+H) + :290.1.HMRS:calc.for C 16 H 19 NO2S([M+H] + )290.1209, found 290.1216.

[0185] Example 4: N-methyl-1-(4-(4-(trifluoromethyl)phenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0186]

[0187] Synthesis route and reaction steps:

[0188] Referring to steps i-iii described in Example 1, bromobenzene in step i was replaced by 4-trifluoromethylbromobenzene to obtain yellow oil 4-D with an overall yield of 19.2%. 1 H NMR (400MHz, CDCl3) δ7.56(d,J=8.1Hz,2H),7.27(d,J=8.0Hz,3H),7.14(d,J=5.1Hz,1H),6.53(d,J=5.1Hz, 1H),5.03(t,J=5.6Hz,1H),4.30–4.20(m,2H),3.61(td,J=12.2,5.4Hz,1H),3.04–2.94(m,3H),2.52(s,3H). 13C NMR (151MHz, CDCl3) δ144.35,135.78,135.74,128.27,127.91,126.12,124.93,122.95,74.13,70.58,56.91,56.72,43.04,35.86.ESI-MS(M+H) + :328.1.HMRS:calc.for C 16 H 16 F3NOS([M+H] + )328.0977, found 328.0984.

[0189] Example 5: N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine

[0190]

[0191] Synthesis route and reaction steps:

[0192] Referring to step i-iii described in Example 1, 3,4-dichloroiodobenzene was used to replace the bromobenzene in step i to obtain yellow oil 4-E with a total yield of 14.5%. ESI-MS (M+H) + :328.0.HMRS:calc.for C 15 H 15 Cl2NOS328.0324, found328.0329.

[0193] Example 6: Separation of cis and trans isomers of N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine (4-E)

[0194] Separation method:

[0195]

[0196] After the separated 4-E was dissolved in methanol, it was separated by CombiFlash using a C18 column, and the elution solvent was set to methanol / water = 1 / 100 to 100 / 1. The collected fractions were tested for purity by HPLC, and then the fractions with a purity of >95% were combined to obtain two groups of products. The solvents were removed under reduced pressure to obtain oily substances. The product part with a large amount was named 4-E-1, and the part with a small amount was named 4-E-2; then the components that were not successfully separated were repeated with the above operation to separate again, and finally the products were obtained as transparent oily substances 4-E-1 (yield: 72%) and 4-E-2 (5%) as light yellow oily substances. It was confirmed by H-NMR that 4-E-1 was in the trans configuration and 4-E-2 was in the cis configuration.

[0197] 4-E-1: trans-N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine

[0198] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.2Hz,1H),7.27–7.23(m,2H),7.18(d,J=4.9Hz,1H),7.00(d,J=8.2Hz,1H),6 .68(d,J=5.0Hz,1H),4.99–4.88(m,1H),4.10–3.99(m,2H),3.93–3.84(m,1H),3.07–2.96(m,2H),2.53(s,3H). 13 C NMR (151MHz, CDCl3) δ143.64,135.96,134.99,132.39,132.28,130.74,130.56,130.34,130.25,130.14,127.67,127.62, 127.10,126.53,126.48,124.67,124.59,124.17,74.30,73.88,73.71,70.61,70.33,60.89,57.02,41.78,41.68,36.22.

[0199] 4-E-2: cis-N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine

[0200] 1H NMR (400MHz, CDCl3) δ7.36(d,J=8.2Hz,1H),7.25(s,1H),7.14(d,J=5.0Hz,1H),7.03–6.96(m,1H),6.54(d,J=5.1Hz,1H),5. 00(t,J=5.1Hz,1H),4.22(dd,J=11.2,5.5Hz,1H),4.16–4.08(m,1H),3.63–3.48(m,1H),2.96(d,J=5.8Hz,2H),2.51(s,3H). 13 CNMR (151MHz, CDCl3) δ141.13,136.22,136.09,131.17,130.59,130.40,127.92,126.69,123.80,74.41,71.00,57.00,42.94,36.31.

[0201] Example 7: Chiral Resolution of trans-N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine (4-E-1)

[0202] Split method:

[0203]

[0204] 4-E-1A: N-methyl-1-((4S,7S)-4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine

[0205] 300 mg 4-E-1 (0.92 mmol, 1.0 eq) was dissolved in 30 mL of anhydrous ethanol. 395 mg L-(-)-dibenzoyltartaric acid (1.1 mmol, 1.2 eq) in ethanol (30 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours until a large amount of solid precipitated. The mixture was heated to 70°C until the solid was completely dissolved. The solution was stirred at 70°C for 30 minutes and then slowly cooled at a rate of 5°C / 10 min. During the cooling process, the solution was observed to see if it became turbid. If so, the solution was stirred at this temperature for about 2 hours. The solution was cooled to room temperature at a rate of 5°C / 10 min. The solid was filtered and weighed to be 408 mg after drying (yield: 65 %), the obtained solid was added with 50 mL of methanol, heated to 70°C to completely dissolve the solid, the solution was cooled at a rate of 5°C / 10 min, and the supersaturation point of the solution was observed. If a small amount of solid precipitated, the temperature was maintained and stirred until the amount of precipitated solid no longer increased, then the temperature was further lowered to room temperature, filtered, and dried to obtain a solid. The solid was added to a system of 30 mL of ethyl acetate and 20 mL of water, and 1 N sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to 11-12, and then stirred at room temperature for 20 minutes. After standing and stratification, an organic phase was obtained, and the aqueous phase was extracted with ethyl acetate (20 mL x2). After the organic phases were combined, saturated brine (20 mL) was added for washing, dried, and concentrated to obtain 68 mg of optically pure transparent oily substance 4-E-1A, with a total yield of 23%. Chiral HPLC analysis showed that ee% = 98.6%, and the compound was determined to have a (S, S) configuration by single crystal diffraction.

[0206] 4-E-1B: N-methyl-1-((4R,7R)-4-(3,4-dichlorophenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)-methylamine

[0207] 300 mg 4-E-1 (0.92 mmol, 1.0 eq) was dissolved in 30 mL anhydrous ethanol, and 395 mg D-(-)-dibenzoyltartaric acid (1.1 mmol, 1.2 eq) in ethanol (30 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours until a large amount of solid precipitated. The mixture was heated to 70 ° C until the solid was completely dissolved. The solution was stirred at 70 ° C for 30 minutes and then slowly cooled at a rate of 5 ° C / 10 min. During the cooling process, the solution was observed to see if it became turbid. If it became turbid, the temperature was maintained and stirred for about 2 hours. The temperature was further cooled to room temperature at a rate of 5 ° C / 10 min. The solid was filtered and weighed to be 408 mg after drying (yield: 65 %), the obtained solid was added with 50 mL of methanol, heated to 70°C to completely dissolve the solid, the solution was cooled at a rate of 5°C / 10 min, and the supersaturation point of the solution was observed. If a small amount of solid precipitated, the temperature was maintained and stirred until the amount of precipitated solid no longer increased, then the temperature was further lowered to room temperature, filtered, and dried to obtain a solid. The solid was added to a system of 30 mL of ethyl acetate and 20 mL of water, and 1 N sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to 11-12, and then stirred at room temperature for 20 minutes. After standing and stratification, an organic phase was obtained, and the aqueous phase was extracted with ethyl acetate (20 mL x2). After the organic phases were combined, saturated brine (20 mL) was added for washing, dried, and concentrated to obtain 54 mg of optically pure transparent oily substance 4-E-1B, with a total yield of 18%. Chiral HPLC analysis showed that ee% = 98.0%, and the compound was determined to have a (R, R) configuration by single crystal diffraction.

[0208] Example 8: N-methyl-1-(4-(naphthalen-1-yl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0209]

[0210] Synthesis route and reaction steps:

[0211] Referring to steps i-iii described in Example 1, 1-bromonaphthalene was used to replace bromobenzene in step i to obtain yellow oil 4-F with a total yield of 14.3%. 1H NMR(400MHz, CDCl3)δ7.88(t,J=7.3Hz,2H),7.76(d,J=8.1Hz,1H),7.55–7.42(m,5H),7.06(s,1H),4.93–4.89(m,1H),4.11–4.05 (m,1H),3.64(td,J=11.2,3.4Hz,1H),3.13(dd,J=12.4,2.8Hz,1H),3.04(dd,J=12.4,8.6Hz,1H),2.70–2.61(m,1H),2.56(s,3H). 13 C NMR (151MHz, CDCl3) δ136.94,134.95,133.04,132.49,131.64,130.71,128.33,128.10,1 27.74,125.85,125.41,125.38,124.55,116.75,63.63,55.87,35.80,25.77.ESI-MS(M+H) + :310.1.HMRS:calc.for C 19 H 19 NOS([M+H] + )310.1260, found310.1269.

[0212] Example 9: N-methyl-1-(4-(naphthalen-2-yl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0213]

[0214] Synthesis route and reaction steps:

[0215] Referring to steps i-iii described in Example 1, 2-bromonaphthalene was used to replace bromobenzene in step i to obtain yellow oil 4-G with a total yield of 19.0%. 1 H NMR (400MHz, CDCl3) δ8.00–7.87(m,5H),7.68–7.63(m,1H),7.57–7.50(m,2H),7.35(s,1H),5.13–5.06(m,1H),4.3 3–4.25(m,1H),3.79–3.64(m,2H),3.42(dd,J=13.0,8.6Hz,1H),3.24–3.13(m,1H),2.97–2.88(m,1H),2.81(s,3H). 13C NMR (151MHz, CDCl3) δ140.25,136.57,134.98,132.60,132.16,129.65,129.12,128.78,1 28.05,127.80,127.54,127.31,119.70,73.10,65.63,53.93,34.07,28.19.ESI-MS(M+H) + :310.1.HMRS:calc.for C 19 H 19 NOS([M+H] + )310.1260, found 310.1271.

[0216] Example 10: N-methyl-1-(4-(3-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0217]

[0218] Synthesis route and reaction steps:

[0219] Referring to step i-iii described in Example 1, 3-methyl iodobenzene was used to replace bromobenzene in step i to obtain yellow oil 4-H with a total yield of 13.6%. ESI-MS (M+H) + :274.1.HMRS:calc.for C 16 H 19 NOS([M+H] + )274.1260, found 274.1265.

[0220] Example 11: Separation of cis and trans isomers of N-methyl-1-(4-(3-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (4-H)

[0221]

[0222] As described in Reference Example 7, 4-H was separated to obtain pale yellow oily matter 4-H-1 (yield: 78.6%) and pale yellow oily matter 4-H-2 (yield: 5.7%). H-NMR confirmed that 4-H-1 was trans-configuration and 4-H-2 was cis-configuration.

[0223] 4-H-1: trans-N-methyl-1-(4-(3-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0224] 1H NMR (400MHz, CDCl3) δ7.20(t,J=7.5Hz,1H),7.11(d,J=4.9Hz,1H),7.07(d,J=7.4Hz,1H),6.96(d,J=9.3Hz,2H),6.58(d,J=4.9Hz,1H ),5.03(s,1H),4.25(dd,J=11.1,5.6Hz,1H),4.17–4.10(m,1H),3.62(t,J=10.6Hz,1H),3.03–2.95(m,2H),2.53(s,3H),2.32(s,3H). 13 C NMR (151MHz, CDCl3) δ140.63,138.19,137.68,135.78,129.23,128.45,12 7.83,127.21,125.61,123.00,74.70,71.82,57.48,43.79,36.49,21.41.

[0225] 4-H-2: cis-N-methyl-1-(4-(3-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0226] 1 H NMR (400MHz, CDCl3) δ7.17(dd,J=9.0,6.2Hz,2H),7.04(d,J=8.1Hz,1H),7.00–6.93(m,2H),6.71(d ,J=5.0Hz,1H),4.97(s,1H),4.08(s,2H),3.94(s,1H),3.08–2.96(m,2H),2.53(s,3H),2.31(s,3H). 13 C NMR (151MHz, CDCl3) δ143.24,137.97,136.18,135.79,128.91,128.29,12 7.51,127.46,125.31,123.38,74.38,70.50,57.49,42.58,36.46,21.49.

[0227] Example 12: N-methyl-1-(4-(2-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0228]

[0229] Synthesis route and reaction steps:

[0230] Referring to step i-iii described in Example 1, 2-methyl iodobenzene was used to replace bromobenzene in step i to obtain yellow oil 4-I with a total yield of 15.7%. ESI-MS (M+H) + :274.1.HMRS:calc.for C 16 H 19 NOS([M+H] + )274.1260, found 274.1262.

[0231] Example 13: Separation of cis and trans isomers of N-methyl-1-(4-(2-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (4-I)

[0232]

[0233] As described in Reference Example 7, 4-I was separated to obtain pale yellow oil 4-I-1 (yield: 81.2%) and pale yellow oil 4-I-2 (yield: 2.8%). H-NMR confirmed that 4-I-1 was trans-configuration and 4-I-2 was cis-configuration.

[0234] 4-I-1: trans-N-methyl-1-(4-(2-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0235] 1 H NMR (400MHz, CDCl3) δ7.22–7.08(m,4H),6.94(d,J=7.3Hz,1H),6.54(d,J=4.8Hz,1H),5.04(s,1H),4.46(d,J=7.4Hz ,1H),4.26(dd,J=11.2,5.5Hz,1H),3.59(t,J=10.7Hz,1H),3.00(qd,J=12.4,5.8Hz,2H),2.54(s,3H),2.40(s,3H). 13 C NMR (151MHz, CDCl3) δ138.58,137.85,136.39,135.78,130.50,128.29,12 7.09,126.84,126.26,123.07,74.79,70.59,57.51,39.79,36.52,19.52.

[0236] 4-I-2: cis-N-methyl-1-(4-(2-methylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0237] 1H NMR (400MHz, CDCl3) δ7.19(t,J=4.7Hz,2H),7.10(dt,J=14.8,7.2Hz,2H),6.84(d,J=7.6Hz,1H),6.66(d,J=5.0Hz,1H) ,5.01(d,J=5.5Hz,1H),4.25(s,1H),4.04(ddd,J=14.0,11.3,3.5Hz,2H),3.07–3.03(m,2H),2.54(s,3H),2.42(s,3H). 13 C NMR (151MHz, CDCl3) δ140.80,136.38,135.82,135.07,130.31,128.79,12 7.40,126.61,126.04,123.53,74.15,68.94,57.12,38.57,36.26,19.66.

[0238] Example 14: N-methyl-1-(4-(3-trifluoromethylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0239]

[0240] Synthesis route and reaction steps:

[0241] Referring to step i-iii described in Example 1, 3-trifluoromethyl iodobenzene was used to replace bromobenzene in step i to obtain yellow oil 4-J with a total yield of 11.8%. ESI-MS (M+H) + :328.1.HMRS:calc.for C 16 H 16 F3NOS([M+H] + )328.0977, found 328.0980.

[0242] Example 15: Separation of cis and trans isomers of N-methyl-1-(4-(3-trifluoromethylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (4-J)

[0243]

[0244] As described in Reference Example 7, 4-J was separated to obtain pale yellow oil 4-J-1 (yield: 71.0%) and pale yellow oil 4-J-2 (yield: 3.0%). H-NMR confirmed that 4-J-1 was trans-configuration and 4-J-2 was cis-configuration.

[0245] 4-J-1: trans-N-methyl-1-(4-(3-trifluoromethylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0246] 1 H NMR (400MHz, CDCl3) δ7.52(s,1H),7.43(d,J=4.1Hz,2H),7.34(s,1H),7.15(d,J=4.5Hz,1H),6.54(t, J=4.7Hz,1H),5.04(d,J=4.4Hz,1H),4.33–4.18(m,2H),3.70–3.55(m,1H),2.99(s,2H),2.53(s,3H). 13 C NMR (151MHz, CDCl3) δ141.89,136.42,131.96,130.99 (q, J=32.1Hz),129.11,126 .71,125.24,124.98,124.06,123.64,123.18,74.74,71.31,57.37,43.68,36.49.

[0247] 4-J-2: cis-N-methyl-1-(4-(3-trifluoromethylphenyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0248] 1 H NMR (400MHz, CDCl3) δ7.51–7.39(m,4H),7.20(s,1H),6.70(s,1H),4.97(s,1H),4.11(s,2H),4.03(s,1H),3.03(s,2H),2.54(s,3H). 13 C NMR (151MHz, CDCl3) δ144.40,136.35,135.11,131.64,129.10,128.87,12 7.15,126.72,124.91,124.01,123.59,74.64,70.50,57.48,42.36,36.49.

[0249] Example 16: N-methyl-N-ethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0250]

[0251] Synthetic route

[0252]

[0253] Reagents and conditions: (iv) Na2CO3, DMF, 90℃, 2h.

[0254] Reaction steps:

[0255] (iv) 90 mg of compound 3 (0.35 mmoL, 1.0 eq), 56.6 mg of ethyl bromide (0.52 mmoL, 1.5 eq), 111.3 mg of sodium carbonate (1.05 mmoL, 3.0 eq) and 3 mL of N,N-dimethylformamide were added to a 25 mL eggplant-shaped flask in sequence, heated to 90°C, reacted for 2 h, ethyl acetate / water (2:1) was added to the reaction solution to dilute (10 mL), extracted and separated to obtain an organic phase, which was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain 75 mg of yellow oil 5-A, with a yield of 75.2%. ESI-MS (M+H + ): m / z 288.1, HMRS:calc.for C 17 H 21 NOS([M+H] + )288.1417, found 288.1420.

[0256] Example 17: Separation of cis and trans isomers of N-methyl-N-ethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (5-A)

[0257]

[0258] As described in Reference Example 7, 5-A was separated to obtain pale yellow oil 5-A-1 (yield: 69.3%) and pale yellow oil 5-A-2 (yield: 18.7%). H-NMR confirmed that 5-A-1 was trans-configuration and 5-A-2 was cis-configuration.

[0259] 5-A-1: trans-N-methyl-N-ethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0260] 1H NMR(400MHz, CDCl3)δ7.29(dd,J=14.6,7.2Hz,2H),7.25(s,1H),7.16(d,J=7.2Hz ,2H),7.10(d,J=5.0Hz,1H),6.56(d,J=4.9Hz,1H),4.98(t,J=6.1Hz,1H),4.29(dd ,J=11.0,5.6Hz,1H),4.20(d,J=9.9Hz,1H),3.62(t,J=10.6Hz,1H),2.81(dd,J=1 2.6,7.3Hz,1H),2.61(dt,J=14.0,7.0Hz,3H),2.39(s,3H),1.12(t,J=7.0Hz,3H). 13 CNMR (151MHz, CDCl3) δ140.29,136.49,135.94,127.99,127.96,126.42,126.12,123.12,73.09,71.63,62.17,51.59,43.33,41.55,11.41.

[0261] 5-A-2: cis-N-methyl-N-ethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0262] 1 H NMR (400MHz, CDCl3) δ7.28(t,J=5.3Hz,2H),7.24–7.13(m,4H),6.71(d,J=4.4Hz,1H),4.95(s,1H),4.16–4.04(m,2H),3.96( s,1H),2.88(dd,J=12.4,7.4Hz,1H),2.73(dd,J=12.4,5.6Hz,1H),2.64(d,J=6.6Hz,2H),2.42(s,3H),1.13(t,J=6.9Hz,3H). 13 C NMR (151MHz, CDCl3) δ143.55,136.14,135.83,128.36,128.20,127.09,126.58,124.15,73.20,70.70,62.52,52.14,42.60,42.03,11.81.

[0263] Example 18: N-methyl-N-n-propyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0264]

[0265] Synthesis route and reaction steps:

[0266] Referring to step iv described in Example 16, bromopropane was used to replace bromoethane to obtain yellow oil 5-B with a total yield of 73.7%. ESI-MS (M+H + ): m / z 302.2, HMRS:calc.for C 18 H 23 NOS([M+H] + )302.1573, found302.1574.

[0267] Example 19: Separation of cis and trans isomers of N-methyl-N-n-propyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (5-B)

[0268]

[0269] As described in Reference Example 7, 5-B was separated to obtain pale yellow oil 5-B-1 (yield: 64.3%) and pale yellow oil 5-B-2 (yield: 10.1%). H-NMR confirmed that 5-B-1 was trans-configuration and 5-B-2 was cis-configuration.

[0270] 5-B-1: trans-N-methyl-N-propyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0271] 1 H NMR(400MHz, CDCl3)δ7.33–7.23(m,3H),7.16(d,J=7.0Hz,2H),7.11–7.07(m,1H), 6.55(dd,J=4.6,3.0Hz,1H),4.97(s,1H),4.28(ddd,J=10.6,5.4,2.9Hz,1H),4.20 (d,J=9.6Hz,1H),3.62(td,J=10.9,2.7Hz,1H),2.85–2.76(m,1H),2.70–2.62(m,1 H),2.51–2.44(m,2H),2.39(s,3H),1.62–1.52(m,2H),0.93(td,J=7.2,2.7Hz,3H). 13C NMR (151MHz, CDCl3) δ140.91,136.98,136.66,128.59,128.54,127.00,126.62,123.76,73.69,72.23,63.34,60.52,43.93,42.79,20.24,11.93.

[0272] 5-B-2: cis-N-methyl-N-n-propyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0273] 1 H NMR(400MHz, CDCl3)δ7.26(s,2H),7.18(dd,J=18.9,11.8Hz,4H),6.77–6.65(m,1H),4.94(s,1H),4.10(p,J=11.4H z,2H),3.95(s,1H),2.87(s,1H),2.75(s,1H),2.51(s,2H),2.43(s,3H),1.59(s,2H),0.93(dd,J=7.1,4.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ143.55,136.19,135.79,128.38,128.20,127.05,126.59,124.24,73.12,70.72,62.99,60.31,42.59,29.70,19.93,11.84.

[0274] Example 20: N,N-dimethyl-1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0275]

[0276] Synthesis route:

[0277]

[0278] Reagents and conditions:(v)CF3SO3H,1,4-dioxane,80℃,3h.

[0279] Reaction steps:

[0280] v. 100 mg 3-A (0.36 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, 5 mL of anhydrous 1,4-dioxane was added to dissolve it, and then 68 mg of dimethylaminoacetaldehyde dimethyl acetal (0.55 mmol, 1.5 eq) and 108 mg of trifluoromethanesulfonic acid (0.72 mmol, 2.5 eq) were added to the flask. The mixture was heated and stirred at 80° C. for 3 hours. The mixture was adjusted to pH 10-11 by adding 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate (20 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol=50 / 1-10 / 1) to obtain 49.5 mg of yellow oil 6-A, yield: 39%. 1 H NMR (400MHz, CDCl3) δ7.33–7.22(m,4H),7.17–7.11(m,3H),6.56(d,J=5.1Hz,1H),5.24(t,J=5.2Hz,1H),4.28(dd, J=11.2,5.7Hz,1H),4.22–4.14(m,1H),3.65(t,J=10.6Hz,1H),2.95–2.89(m,2H),2.60(s,6H),2.52–2.41(m,1H). 13 C NMR(151MHz, CDCl3)δ140.55,137.85,135.01,128.60(t,J=15.6Hz),128.69,128.62 ,128.49,128.21,127.22,127.14,123.88,71.91,64.17,45.56,43.76.ESI-MS(M+H) + :274.1.HMRS:calc.forC 16 H 19 NOS([M+H] + )274.1260, found 274.1265.

[0281] Example 21: 1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)pyrrolidine

[0282]

[0283] Synthesis route:

[0284]

[0285] Reagents and conditions: (vi) CF3SO3H, 1,4-dioxane, 80℃, 5h; (vii) K2CO3, KI, CH3CN, MW, 120℃, 1h.

[0286] Reaction steps:

[0287] vi. 100 mg 3-A (0.36 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, 5 mL of anhydrous 1,4-dioxane was added to dissolve it, and then 58 mg of aminoacetaldehyde dimethyl acetal (0.55 mmol, 1.5 eq) and 108 mg of trifluoromethanesulfonic acid (0.72 mmol, 2.5 eq) were added to the flask. The mixture was heated and stirred at 80° C. for 3 hours. The mixture was adjusted to pH 10-11 by adding 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate (20 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-10 / 1) to obtain 43.2 mg of yellow oil 7-A, yield: 36%. 1 H NMR (400MHz, CDCl3) δ7.31–7.16(m,3H),7.17–7.07(m,3H),6.53(d,J=5.0Hz,1H),5.23(s,1H),5.13(d,J=7.3Hz,1 H),4.20(dd,J=11.2,5.4Hz,1H),4.13–4.03(m,1H),3.61(t,J=10.3Hz,1H),3.43–3.25(m,1H),3.21–3.00(m,1H). 13 C NMR (151MHz, CDCl3) δ140.41,138.48,134.73,132.48,129.32,128.57,128.52,128.13, 127.31,127.11,124.01,73.94,72.14,70.56,44.89,43.18,42.21,29.70.ESI-MS(M+H) + :246.1.HMRS:calc.for C 14 H 15 NOS([M+H] + )246.0947, found 246.0948.

[0288] vii. Add 90 mg (0.36 mmoL, 1.0 eq) 7-A, 86 mg 1,4-dibromobutane (0.40 mmoL, 1.1 eq), 150 mg potassium carbonate (1.09 mmoL, 3.0 eq) and 7 mg potassium iodide into a microwave tube, and then add 3 mL acetonitrile. After stirring, seal the tube and react at 120°C in a microwave for 1 h. Filter the reaction solution, concentrate the filtrate and separate it by silica gel column chromatography (PE / EA=10 / 1) to obtain 20 mg of light yellow oily liquid 8-A, with a yield of 19.6%. 1 H NMR (400MHz, CDCl3) δ7.34–7.27(m,3H),7.17(d,J=6.9Hz,2H),7.11(d,J=4.8Hz,1H),6.56(d,J=5.1Hz,1H),5.04(s,1H),4.3 0(dd,J=11.2,5.7Hz,1H),4.23–4.14(m,1H),3.63(t,J=10.7Hz,1H),2.92(dt,J=21.6,10.8Hz,2H),2.72(s,4H),1.85(s,4H). 13 C NMR (151MHz, CDCl3) δ140.88,137.13,136.39,128.60,128.56,127.03,126.81,123.71,74.38,72.12,61.65,54.55,43.90,23.69.ESI-MS(M+H) + :300.1.HMRS:calc.for C 18 H 21 NOS([M+H] + )300.1417, found 300.1417.

[0289] Example 22: 1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperidine

[0290]

[0291] Synthesis route and reaction steps:

[0292] Referring to step vii described in Example 21, 1,5-dibromopentane was used to replace 1,4-dibromobutane to obtain a light yellow oil 8-B with a yield of 39.4%. 1H NMR (400MHz, CDCl3) δ7.31 (dd, J=11.0, 4.3Hz, 2H), 7.26 (d, J=7.2Hz, 1H), 7.16 (d, J= 7.8Hz,2H),7.10(d,J=5.0Hz,1H),6.55(d,J=5.1Hz,1H),4.99(t,J=6.6Hz,1H),4.27( dd,J=11.0,5.7Hz,1H),4.22–4.15(m,1H),3.61(t,J=10.6Hz,1H),2.76(dd,J=12.5, 6.2Hz,1H),2.63–2.55(m,3H),2.52(s,2H),1.70–1.63(m,4H),1.48(d,J=5.3Hz,2H). 13 C NMR (151MHz, CDCl3) δ140.94,136.99,136.76,128.59,128.53,126.98,126 .50,124.07,73.25,72.27,64.18,55.30,43.94,25.94,24.37.ESI-MS(M+H) + :314.2.HMRS:calc.for C 19 H 23 NOS([M+H] + )314.1573, found 314.1573.

[0293] Example 23: 1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)azepane

[0294]

[0295] Synthesis route and reaction steps:

[0296] Referring to step vii described in Example 21, 1,6-dibromohexane was used to replace 1,5-dibromopentane to obtain a light yellow oil 8-C with a yield of 33.4%. ESI-MS (M+H) + :328.2.HMRS:calc.for C 19 H 23 NOS([M+H] + )328.1730, found 328.1726.

[0297] Example 24: Separation of cis and trans isomers of 1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)azepane (8-C)

[0298]

[0299] As described in Reference Example 7, 8-C was separated to obtain pale yellow oil 8-C-1 (yield: 71.8%) and pale yellow oil 8-C-2 (yield: 16.0%). H-NMR confirmed that 8-C-1 was trans-configuration and 8-C-2 was cis-configuration.

[0300] 8-C-1: trans-1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)azepane

[0301] 1 H NMR (400MHz, CDCl3) δ7.28(dd,J=16.0,6.7Hz,3H),7.17(d,J=6.7Hz,2H),7.09(s,1H),6.55(d,J=4.2Hz,1H),4.89(s,1H),4 .33–4.12(m,2H),3.62(t,J=10.4Hz,1H),2.92(t,J=16.4Hz,1H),2.82(s,4H),2.73–2.64(m,1H),1.76(s,2H),1.66(s,6H). 13 CNMR (151MHz, CDCl3) δ140.95,136.97,136.58,128.61,128.53,126.98,126.30,124.17,73.92,72.35,62.80,56.14,44.01,28.24,27.14.

[0302] 8-C-2: cis-1-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)azepane

[0303] 1 H NMR (400MHz, CDCl3) δ7.30 (s, 1H), 7.17 (d, J = 6.3Hz, 4H), 7.11 (s, 1H), 6.70 (s, 1H), 4.8 1(s,1H),4.10(s,2H),3.95(s,1H),3.00(s,1H),2.83(s,5H),1.77(s,2H),1.67(s,6H). 13 C NMR (151MHz, CDCl3) δ128.62,128.55,128.35,128.19,127.01,126.53,124.58,124.18,72.33,71.05,62.83,56.24,43.98,42.66,28.36,27.13.

[0304] Example 25: 1-Benzyl-4-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0305]

[0306] Synthesis route:

[0307]

[0308] Reagents and conditions: (viii)NaHCO3, EtOH, 90℃, 2.5h.

[0309] Reaction steps:

[0310] viii. 80 mg 7-A (0.33 mmoL, 1 eq) and 3 mL of anhydrous ethanol were added to a 15 mL sealed tube, and then 92 mg N-benzyl-bis-o-chloroethylamino hydrochloride (0.34 mmoL, 1.05 eq) and 97 mg of sodium bicarbonate (1.16 mmoL, 3.5 eq) were added thereto. The tube was sealed and reacted at 90 ° C for 2.5 h. The filtrate was filtered to obtain a filtrate. The filtrate was dried and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 70 mg of a yellow oil 9-A, with a yield of 53.3%. 1 H NMR (400MHz, CDCl3) δ7.34 (s, 6H), 7.26 (d, J = 6.0Hz, 2H), 7.16 (d, J = 5.7Hz, 2H), 7.10 (s, 1H), 6. 56(s,1H),5.00(s,1H),4.31–4.22(m,1H),4.18(s,1H),3.64–3.53(m,3H),2.84–2.56(m,10H). 13 C NMR (151MHz, CDCl3) δ140.27,136.31,136.12,128.61,127.97,127.94,127.60,126 .40,125.97,123.37,72.52,71.60,62.80,62.47,53.18,52.46,43.31.ESI-MS(M+H) + :405.2.HMRS:calc.forC 25 H 28 N2OS([M+H] + )405.1995, found 405.2001.

[0311] Example 26: 1-p-Fluorobenzyl-4-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0312]

[0313] Synthesis route and reaction steps:

[0314] Referring to step viii described in Example 25, N-benzyl-bis-o-chloroethylamine was used to replace N-p-fluorobenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-B in a yield of 14.2%. 1 H NMR (400MHz, CDCl3) δ7.34–7.26(m,5H),7.13(dd,J=20.7,5.8Hz,3H),7.00(t,J=7.2Hz,2H),6.56(d,J =5.0Hz,1H),5.00(s,1H),4.30–4.15(m,2H),3.60(t,J=10.6Hz,1H),3.52(s,2H),2.84–2.53(m,10H). 13 C NMR (151MHz, CDCl3) δ 162.02 (d, J = 244.8Hz), 161.21, 140.81, 136.96, 136.60, 133.70, 130.70 (d, J = 7.7Hz), 128. 57,127.03,126.62,123.98,115.02(d,J=21.1Hz),73.05,72.21,63.35,62.19,53.66,52.91,43.88.ESI-MS(M+H) + :423.2.HMRS:calc.for C 25 H 27 FN2OS([M+H] + )423.1901, found 423.1912.

[0315] Example 27: 1-p-methoxybenzyl-4-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0316]

[0317] Synthesis route and reaction steps:

[0318] Referring to step viii described in Example 25, N-p-methoxybenzyl-bis-o-chloroethylamine was used to replace N-benzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-C in a yield of 52.1%. 1H NMR (400MHz, CDCl3) δ7.32–7.25(m,5H),7.14(d,J=21.4Hz,3H),6.87(d,J=7.4Hz,2H),6.56(s,1H),4.99(s ,1H),4.24(dd,J=21.5,16.8Hz,2H),3.80(s,3H),3.60(t,J=10.4Hz,1H),3.52(s,2H),2.86–2.52(m,10H). 13 C NMR (151MHz, CDCl3) δ158.83,140.82,136.96,136.61,130.56,128.58,128.56,127.03,126 .62,123.98,113.63,73.06,72.21,63.34,62.34,55.26,53.56,52.84,43.88.ESI-MS(M+H) + :435.2.HMRS:calc.for C 26 H 30 N2O2S([M+H] + )435.2101,found435.2114.

[0319] Example 28: 1-(4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0320]

[0321] Synthesis route and reaction steps:

[0322] Referring to step viii described in Example 25, N-benzyl-bis-o-chloroethylamine was used to replace N-p-trifluoromethylbenzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-D in a yield of 51.1%. 1 H NMR (400MHz, CDCl3) δ7.58(d,J=6.7Hz,2H),7.49(s,2H),7.34–7.28(m,3H),7.14(d,J=19.3 Hz,3H),6.57(s,1H),5.03(s,1H),4.24(d,J=31.1Hz,2H),3.61(s,3H),2.86–2.58(m,10H). 13C NMR (151MHz, CDCl3) δ140.76,137.07,136.49,129.32,128.58,127.06,126.69, 125.23,123.99,73.00,72.18,63.29,62.36,53.62,52.96,43.86.ESI-MS(M+H) + :473.2.HMRS:calc.forC 26 H 27 F3N2OS([M+H] + )473.1869, found 473.1880.

[0323] Example 29: 1-p-nitrobenzyl-4-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0324]

[0325] Synthesis route and reaction steps:

[0326] Referring to step viii described in Example 25, N-p-nitrobenzyl-bis-o-chloroethylamine was used to replace N-benzyl-bis-o-chloroethylamine hydrochloride to obtain yellow oil 9-E in a yield of 51.7%. 1 H NMR (400MHz, CDCl3) δ8.20(s,2H),7.55(s,2H),7.32(d,J=4.3Hz,3H),7.17(s,3H),6.57(s ,1H),5.06(s,1H),4.23(d,J=26.4Hz,2H),3.68(d,J=25.0Hz,3H),2.73(d,J=82.6Hz,10H). 13 C NMR (151MHz, CDCl3) δ147.19,146.36,140.71,137.11,136.37,129.55,128.57,127.07, 126.71,123.99,123.56,72.96,72.15,63.25,62.06,53.65,53.00,43.84.ESI-MS(M+H) + :450.2.HMRS:calc.forC 25 H 27 N3O3S([M+H] + )450.1846, found 450.1862.

[0327] Example 30: 1-p-aminobenzyl-4-((4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methyl)piperazine

[0328]

[0329] Synthesis route:

[0330]

[0331] Reaction steps:

[0332] 150 mg 9-E (0.33 mmol, 1.0 eq) was placed in a 25 mL eggplant-shaped bottle, 5 mL methanol was added to dissolve it, the eggplant-shaped bottle was replaced with argon three times, 30 mg Pd / C (20 wt%) was added, and the reaction was carried out for 2 h before filtering. The filtrate was dried by rotary evaporation, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol = 70 / 1) to obtain 80 mg yellow oil 9-F, with a yield of 65.9%. 1 HNMR (400MHz, CDCl3) δ7.27(dd,J=14.7,6.0Hz,3H),7.19–7.08(m,5H),6.65(t,J=9.7Hz,2H),6.56(dd,J=11. 4,4.8Hz,1H),4.98(s,1H),4.30–4.15(m,2H),3.66–3.56(m,3H),3.45(d,J=11.3Hz,2H),2.83–2.51(m,10H). 13 C NMR (151MHz, CDCl3) δ145.39,140.85,136.88,136.72,130.44,128.58,128.54,127.00, 126.57,123.99,114.88,73.07,72.22,63.38,62.64,53.75,52.88,43.88.ESI-MS(M+H) + :420.2.HMRS:calc.for C 25 H 27 N3O3S([M+H] + )420.2104, found 420.2116.

[0333] Example 31: N-methyl-1-(2-methyl-4-phenyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0334]

[0335] Synthesis route:

[0336]

[0337] Reagents and conditions: (ix) EtMgCl, (iPr)2NH, THF, 50℃, 3h; Pd(tBu3P)2, THF, 60℃, 3h; (x) LiAlH4, THF, rt, 3h; (xi) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0338] Reaction steps:

[0339] ix. Add 1.0 g 3,4-dichlorophenylacetic acid (4.88 mmol, 1.0 eq) to a 100 mL three-necked flask, add 10 mL anhydrous tetrahydrofuran to completely dissolve the solid, replace the flask with nitrogen three times, and then add 50 mg diisopropylamine (0.49 mmol, 0.1 eq) to the solution. Slowly drop 4.5 mL Grignard reagent ethylmagnesium chloride (2.7 M in THF, 12.19 mmol, 3.0 eq) in an ice bath. During the dropwise addition, a large amount of bubbles are generated and heat is released violently. After the addition is completed, the above mixture is stirred at 50°C for 3 hours and then cooled to room temperature. 1.7 g 4-bromo-2-methylthiophene (9.76 mmol, 2 eq) and 50 mg tri-tert-butylphosphine palladium (0.1 mmol, 0.02 eq) were dissolved in 10 mL anhydrous tetrahydrofuran and added to a flask. The temperature was raised to 60° C. and stirred for 3 hours. The system was cooled to room temperature. 2N hydrochloric acid solution was slowly added dropwise to the flask to adjust the pH to 4-6. A large amount of solid precipitated. The solid was filtered out, and the filtrate was extracted with ethyl acetate (30 mL x 3) and water (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a black oil, which was separated using silica gel column chromatography (dichloromethane / methanol=50 / 1-20 / 1) to obtain 540 mg of yellow oil 11-A, with a yield of 36.8%. 1 H NMR (400MHz, CDCl3) δ10.78(s,1H),7.37(d,J=10.2Hz,3H),7.08(d,J=6.1Hz,2H),3.56(s,3H).ESI-MS(MH) - :299.0.

[0340] x. Add 540 mg 11-A (1.8 mmol, 1.0 eq) into a 50 mL round-bottom flask, add 20 mL dry tetrahydrofuran to completely dissolve it, replace the system with nitrogen three times, slowly drop 2.2 mL lithium aluminum hydride (2.5 M in THF, 5.4 mmol, 3.0 eq) into the flask under an ice-water bath, remove the ice bath after the addition is complete, stir and react at room temperature for 3 hours, add sodium sulfate decahydrate into the flask to quench the reaction solution until no obvious bubbles are generated, slowly drop NaOH solution (1 mol / L) into it until a large amount of precipitate is generated, filter to obtain the filtrate, and wash the filter cake with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (20 mL x 3) and water (10 mL), and the obtained organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 337 mg of light yellow oil 12-A, with a yield of 65.5%. 1 H NMR (400MHz, CDCl3) δ7.34 (dd, J=34.0, 20.9Hz, 2H), 7.10 (d, J=6.2Hz, 1H), 6.8 1(s,1H),6.57(s,1H),4.06(dd,J=25.4,7.7Hz,3H),2.44(s,3H).ESI-MS(M+H) + :287.0.

[0341] xi. 150 mg of 12-A (0.52 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, and 5 mL of anhydrous 1,4-dioxane was added to dissolve it. Then 187 mg of methylaminoacetaldehyde dimethyl acetal (1.56 mmol, 3 eq) and 390 mg of trifluoromethanesulfonic acid (2.6 mmol, 5 eq) were added to the flask. The mixture was stirred at 80°C for 3 hours, and 1N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 10-11. The reaction solution was extracted with ethyl acetate (10 mL x 3) and water (5 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-10 / 1) to obtain 58 mg of yellow oil 13-A, yield: 32.4%. 1HNMR (400MHz, CDCl3) δ7.35(t,J=10.3Hz,1H),7.27(d,J=14.6Hz,1H),7.00(d,J=8.2Hz,1H),6.18(s,1H),4.94(s,1H ),4.19(dd,J=10.8,4.8Hz,1H),4.04(s,1H),3.56(t,J=10.3Hz,1H),2.91(t,J=9.3Hz,2H),2.51(s,3H),2.38(s,3H). 13 C NMR (151MHz, CDCl3) δ140.72,137.61,135.21,133.38,131.95,130.40,129.89, 129.76,127.32,124.05,73.79,70.39,56.61,42.27,35.87,14.60.ESI-MS(M+H) + :342.0.

[0342] Example 32: N-methyl-1-(7-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0343]

[0344] Synthesis route:

[0345]

[0346] Reagents and conditions: (xii) EtMgCl, (iPr)2NH, THF, 50℃, 3h; Pd(tBu3P)2, THF, 60℃, 3h; (xiii) LiAlH4, THF, rt, 3h; (xiv) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0347] Reaction steps:

[0348] xii. Add 1.0 g of 2-thiopheneacetic acid (7.04 mmol, 1.0 eq) to a 100 mL three-necked flask, add 10 mL of anhydrous tetrahydrofuran to completely dissolve the solid, replace the flask with nitrogen three times, and then add 70 mg of diisopropylamine (0.70 mmol, 0.1 eq) to the solution. Slowly drop 8.8 mL of Grignard reagent ethylmagnesium chloride (2.4 M in THF, 21.12 mmol, 3.0 eq) in an ice bath. During the dropwise addition, a large amount of bubbles are generated and heat is released violently. After the addition is completed, the above mixture is stirred at 50°C for 3 hours and then cooled to room temperature. 1.3 g of bromobenzene (8.45 mmol, 1.2 eq) and 107 mg of tri-tert-butylphosphine palladium (0.21 mmol, 0.03 eq) were dissolved in 10 mL of anhydrous tetrahydrofuran and added to a flask. The temperature was raised to 60 ° C and stirred for 3 hours. The system was cooled to room temperature. 2N hydrochloric acid solution was slowly added to the flask to adjust the pH to 4-6. A large amount of solid precipitated. The solid was filtered out. The filtrate was extracted with ethyl acetate (30 mL x 3) and water (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a black oil. It was separated using silica gel column chromatography (dichloromethane / methanol = 50 / 1-20 / 1) to obtain 580 mg of yellow oil 15-A, with a yield of 38%. ESI-MS (MH) - :217.2.

[0349] xiii. Add 150 mg of 15-A (0.49 mmol, 1.0 eq) into a 50 mL round-bottom flask, add 10 mL of dry tetrahydrofuran to completely dissolve it, replace the system with nitrogen three times, slowly drop 0.6 mL of lithium aluminum hydride (2.5 M in THF, 1.47 mmol, 3.0 eq) into the flask under an ice-water bath, remove the ice bath after the addition is complete, stir and react at room temperature for 3 hours, add sodium sulfate decahydrate into the flask to quench the reaction solution until no obvious bubbles are generated, slowly drop NaOH solution (1 mol / L) into it until a large amount of precipitate is generated, filter to obtain the filtrate, and wash the filter cake with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (20 mL x 3) and water (10 mL), and the obtained organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 93 mg of light yellow oil 16-A, with a yield of 62%. ESI-MS (M+H) + :205.2.

[0350] xiv. 100 mg of 16-A (0.36 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, and 5 mL of anhydrous 1,4-dioxane was added to dissolve it. Then, 128 mg of methylaminoacetaldehyde dimethyl acetal (1.08 mmol, 3.0 eq) and 286 mg of trifluoromethanesulfonic acid (1.8 mmol, 5.0 eq) were added to the flask. The mixture was stirred at 80° C. for 3 hours, and 1N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 10-11. The mixture was extracted with ethyl acetate (20 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-10 / 1) to obtain 50 mg of yellow oil 17-A, yield: 34%. 1 H NMR (400MHz, CDCl3) δ7.33–7.26(m,3H),7.21–7.16(m,3H),6.82(d,J=5.2Hz,1H),5.09(d,J=8.5Hz,1H),4. 33–4.22(m,2H),3.72–3.61(m,1H),3.38(dd,J=12.7,2.6Hz,1H),3.04(dd,J=12.6,8.9Hz,1H),2.68(s,3H). 13 C NMR (151MHz, CDCl3) δ140.43,139.71,133.58,128.66,128.56,128.48,127.96,127.62,12 4.92,122.64,77.24,77.03,76.82,72.56,70.89,54.16,43.02,41.93,35.05.ESI-MS(M+H) + :260.1.HMRS:calc.for C 15 H 17 NOS([M+H] + )260.1104, found 260.1110.

[0351] Example 33: N-methyl-1-(7-(4-methylphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0352]

[0353] Synthesis route and reaction steps:

[0354] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced with 4-methylbromobenzene to obtain a yellow oil 17-B with an overall yield of 17.0%. 1 H NMR (400MHz, CDCl3) δ7.16(d,J=5.2Hz,1H),7.15–7.10(m,4H),6.82(d,J=5.2Hz,1H),4.99–4.94(m,1H),4.30–4.2 1(m,2H),3.70–3.61(m,1H),3.09(dd,J=12.3,2.9Hz,1H),2.91(dd,J=12.4,8.4Hz,1H),2.52(s,3H),2.34(s,3H). 13 C NMR (151MHz, CDCl3) δ139.35,137.79,137.18,135.57,129.30,128.36,127. 87,124.20,122.92,74.67,71.39,55.73,43.00,36.18,21.07.ESI-MS(M+H) + :274.1.HMRS:calc.forC 16 H 19 NOS([M+H] + )274.1260, found 274.1262.

[0355] Example 34: N-methyl-1-(7-(4-methoxyphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0356]

[0357] Synthesis route and reaction steps:

[0358] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced by 4-methoxybromobenzene to obtain a yellow oil 17-C with an overall yield of 16.1%. 1 H NMR (400MHz, CDCl3) δ7.14(dd,J=10.1,6.9Hz,3H),6.84(d,J=8.6Hz,2H),6.81(d,J=5.2Hz,1H),4.98(d,J=8.3Hz,1H),4. 30–4.15(m,2H),3.78(s,3H),3.68–3.54(m,1H),3.14(dd,J=12.4,2.6Hz,2H),2.92(dd,J=12.5,8.5Hz,1H),2.54(s,3H). 13C NMR (151MHz, CDCl3) δ158.83,132.23,132.03,129.52,129.08,127.49,124 .01,114.03,71.63,71.26,55.28,55.04,42.52,34.96,29.71.ESI-MS(M+H) + :290.1.HMRS:calc.for C 16 H 19 NO2S([M+H] + )290.1209, found 290.1213.

[0359] Example 35: N-methyl-1-(7-(4-trifluoromethylphenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0360]

[0361] Synthesis route and reaction steps:

[0362] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced with 4-trifluoromethylbromobenzene to obtain a yellow oil 17-D with an overall yield of 15.0%. 1 H NMR (400MHz, CDCl3) δ7.58(d,J=8.1Hz,2H),7.35(d,J=8.0Hz,2H),7.20(d,J=5.2Hz,1H),6.85(d,J=5.2Hz,1H),5.00–4.96(m,1H),4.39–4.3 4(m,1H),4.28(dd,J=11.1,5.2Hz,1H),3.68(dd,J=11.0,8.8Hz,1H),3.07(dd,J=12.6,2.9Hz,1H),2.93(dd,J=12.5,8.4Hz,1H),2.53(s,3H). 13 C NMR (151MHz, CDCl3) δ144.49,136.70,135.74,129.22,129.01,128.19,127.73,124. 95,124.92,124.37,123.89,122.56,74.39,69.98,55.14,42.52,35.78.ESI-MS(M+H) + :328.1.HMRS:calc.for C 16 H 16 F3NOS([M+H] +)328.0977, found 328.0989.

[0363] Example 36: N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0364]

[0365] Synthesis route and reaction steps:

[0366] Referring to steps xii-xiv described in Example 32, 3,4-dichloroiodobenzene was used to replace the bromobenzene in step xii to obtain a yellow oil 17-E with a total yield of 9.8%. ESI-MS (M+H) + :328.0.HMRS:calc.for C 15 H 15 Cl2NOS([M+H] + )328.0324, found 328.0329.

[0367] Example 37: Separation of cis and trans isomers of N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine (17-E)

[0368]

[0369] As described in Reference Example 7, 17-E was separated to give pale yellow oil 17-E-1 (yield: 62%) and pale yellow oil 17-E-2 (yield: 3%). H-NMR confirmed that 17-E-1 was trans-configured and 17-E-2 was cis-configured.

[0370] 17-E-1: trans-N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0371] 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.2Hz,1H),7.26(d,J=6.2Hz,1H),7.17(d,J=4.9Hz,1H),7.00(d,J=8.2Hz,1H),6.56(d,J=4.9 Hz,1H),5.11–5.02(m,1H),4.24(dd,J=11.3,5.7Hz,1H),4.19–4.08(m,1H),3.63–3.54(m,1H),3.06–2.97(m,2H),2.56(s,3H). 13C NMR (151MHz, CDCl3) δ141.14,136.22,136.08,132.67,131.17,130.58,130.39,127.92,126.69,123.80,74.39,70.98,56.95,42.93,36.28.

[0372] 17-E-2: cis-N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0373] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.2Hz,1H),7.29–7.21(m,2H),7.02(d,J=8.2Hz,1H),6.81(d,J=5.4 Hz,1H),5.15(d,J=10.1Hz,1H),4.08–3.91(m,3H),3.55(d,J=11.5Hz,1H),3.18(s,1H),2.80(s,3H). 13 C NMR (151MHz, CDCl3) δ137.40,133.03,131.85,130.99,130.22,127.66,126.15,123.03,71.80,71.13,69.29,52.85,41.35,33.94.

[0374] Example 38: Chiral Resolution of trans-N-methyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine (17-E-1)

[0375]

[0376] 17-E-1A: N-methyl-1-((4R,7R)-7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0377] 17-E-1B: N-methyl-1-((4S,7S)-7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0378] As described in Reference Example 8, 17-E-1 was split to give a transparent oily substance 17-E-1A (yield: 30.6%), chiral HPLC analysis showed ee% = 95.4%, and the compound was determined to have a (R, R) configuration by single crystal diffraction; a transparent oily substance 17-E-1B (yield: 25.8%), chiral HPLC analysis showed ee% = 96%, and the configuration was determined to be (S, S) type.

[0379] Example 39: N-methyl-1-(7-(1-naphthyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0380]

[0381] Synthesis route and reaction steps:

[0382] Referring to steps xii-xiv described in Example 32, 1-bromonaphthalene was used to replace the bromobenzene in step xii to obtain a yellow oil 17-F with an overall yield of 14.7%. 1 H NMR (400MHz, CDCl3) δ7.88–7.83(m,1H),7.77–7.71(m,1H),7.55–7.43(m,2H ),7.39–7.29(m,2H),7.19–7.11(m,1H),6.85(dd,J=9.7,5.2Hz,1H),5.02(d ,J=8.2Hz,1H),4.41(dd,J=11.0,5.0Hz,1H),4.25–4.12(m,1H),3.82(s,1H) ,3.14–3.06(m,1H),2.96(dd,J=12.4,8.5Hz,1H),2.52(s,3H),2.23(s,1H). 13 C NMR (151MHz, CDCl3) δ138.18,136.25,135.87,133.34,131.07,130.30,128.61,127.39,126.94,126.40,125 .75,125.13,124.87,123.93,123.61,122.50,76.82,74.62,69.71,68.68,55.60,55.35,35.92.ESI-MS(M+H) + :310.2.HMRS:calc.for C 19 H 19 NOS([M+H] + )310.1260, found310.1268.

[0383] Example 40: N-methyl-1-(7-(2-naphthyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0384]

[0385] Synthesis route and reaction steps:

[0386] Referring to steps xii-xiv described in Example 32, 2-bromonaphthalene was used to replace bromobenzene in step xii to obtain a yellow oil 17-G with an overall yield of 12.5%. 1 H NMR (400MHz, CDCl3) δ7.84–7.77(m,3H),7.74(s,1H),7.50–7.43(m,2H),7.30( dd,J=8.5,1.1Hz,1H),7.18(d,J=5.2Hz,1H),6.86(d,J=5.2Hz,1H),5.02–4.98( m,1H),4.51–4.45(m,1H),4.34(dd,J=11.1,5.4Hz,1H),3.79(dd,J=10.9,9.7H z,1H),3.10(dd,J=12.5,2.8Hz,1H),2.94(dd,J=12.4,8.3Hz,1H),2.53(s,3H). 13 C NMR (151MHz, CDCl3) δ138.15,137.73,135.65,132.78,132.21,127.74,127.15,127.08,126.83,1 25.71,125.61,125.46,125.30,123.66,122.45,74.60,70.59,55.49,42.97,35.92.ESI-MS(M+H) + :310.2.HMRS:calc.for C 19 H 19 NOS([M+H] + )310.1260, found310.1271.

[0387] Example 41: 1-(7-(Naphthalen-2-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0388]

[0389] Synthesis route and reaction steps:

[0390] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced by 2-bromonaphthalene, and methylaminoacetaldehyde dimethyl acetal was replaced by aminoacetaldehyde dimethyl acetal to obtain yellow oil 17-H. The total yield was 9.9%. 1 HNMR (400MHz, CDCl3) δ7.83–7.78(m,3H),7.74(s,1H),7.49–7.45(m,2H),7.30(d,J=8.4Hz,1H),7.19(d,J=5.1Hz,1H),6.84(d,J=5.2Hz,1H) ,4.87–4.83(m,1H),4.51–4.45(m,1H),4.34(dd,J=11.1,5.4Hz,1H),3.80(t,J=10.4Hz,1H),3.26–3.18(m,1H),3.05(dd,J=13.6,6.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ138.87,137.61,135.25,132.79,132.23,127.76,127.16,127.0 9,126.87,125.70,125.64,125.34,123.83,122.39,70.66,45.81,43.03.ESI-MS(M+H) + :296.1.HMRS:calc.for C 18 H 17 NOS([M+H] + )296.1104,found296.1114.

[0391] Example 42: N,N-dimethyl-1-(7-(naphthalen-2-yl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0392]

[0393] Synthesis route and reaction steps:

[0394] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced by 2-bromonaphthalene, and dimethylaminoacetaldehyde dimethyl acetal in step xiv was replaced by aminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-I with a total yield of 11.3%. 1HNMR (400MHz, CDCl3) δ7.82–7.77(m,3H),7.74(s,1H),7.49–7.45(m,2H),7.30(d,J=9.6Hz,1H),7.17(d,J=5.2Hz,1H),6.92(d,J=5. 2Hz,1H),5.01–4.97(m,1H),4.52–4.45(m,1H),4.38(dd,J=11.1,5.5Hz,1H),3.78(t,J=10.3Hz,1H),2.77–2.70(m,2H),2.40(s,6H). 13 CNMR(151MHz, CDCl3)δ139.18,138.85,137.08,133.77,133.19,128.70,128.14,128.06,127.83, 126.80,126.71,126.58,126.27,124.35,123.81,74.38,71.74,64.59,46.44,43.91.ESI-MS(M+H) + :324.2.HMRS:calc.for C 20 H 21 NOS([M+H] + )324.1417, found324.1424.

[0395] Example 43: 1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0396]

[0397] Synthesis route and reaction steps:

[0398] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced with 3,4-dichloroiodobenzene, and methylaminoacetaldehyde dimethyl acetal in step xiv was replaced with aminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-J with a total yield of 11.1%. 1H NMR(400MHz, CD3ODδ7.45(d,J=8.3Hz,1H),7.35(dd,J=11.7,3.3Hz,2H),7.12(dd,J=8.3,1.6Hz,1H),6.61(d,J=5.1Hz,1H),5.19(d,J=8.2Hz,1H),4.29 (dd,J=11.2,5.4Hz,1H),4.24–4.16(m,1H),3.69(dd,J=11.0,8.7Hz,1H),3. 37(dd,J=13.3,2.9Hz,1H),3.31–3.28(m,1H),3.16(dd,J=13.3,8.5Hz,1H). 13 C NMR (151MHz, CD3OD) δ140.22,136.06,131.62,130.63,129.20,128.93,128.76,126.69,125.18,123.06,71.02,68.22,42.92,40.74.ESI-MS(M+H) + :314.2.HMRS:calc.for C 14 H 13 Cl2NOS([M+H] + )314.0168,found314.0174.

[0399] Example 44: N,N-dimethyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0400]

[0401] Synthesis route and reaction steps:

[0402] Referring to steps xii-xiv described in Example 32, bromobenzene in step xii was replaced with 3,4-dichloroiodobenzene, and methylaminoacetaldehyde dimethyl acetal in step xiv was replaced with dimethylaminoacetaldehyde dimethyl acetal to obtain a yellow oil 17-K with a total yield of 8.7%. 1H NMR (400MHz, CDCl3) δ7.91(s,1H),7.46(d,J=8.3Hz,1H),7.35–7.31(m,2H),7.13(dd,J=8.2,1.6Hz,1H),6.60(d,J=5.1Hz,1H),5.30 (t,J=6.3Hz,1H),4.29(dd,J=11.2,5.4Hz,1H),4.24–4.16(m,1H),3.70(dd,J=11.1,8.6Hz,1H),3.17(d,J=6.5Hz,3H),2.71(s,6H). 13 C NMR (151MHz, CDCl3) δ140.69,136.32,135.11,132.00,130.45,130.04,129.93,129. 79,127.35,125.71,123.61,72.89,70.92,64.28,45.40,45.03,42.43.ESI-MS(M+H) + :342.1.HMRS:calc.for C 16 H 17 Cl2NOS([M+H] + )342.0481,found342.0490.

[0403] Example 45: N-cyclopropanecarbonyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0404]

[0405] Synthesis route and reaction steps:

[0406]

[0407] 1.0 g of compound 17-J (3.19 mmol, 1.0 eq) was added to a 100 mL three-necked flask, and 20 mL of dichloromethane was added to dissolve it. Then 484 mg of triethylamine (4.79 mmol, 1.5 eq) was added thereto, and 400 mg of cyclopropanecarbonyl chloride (3.83 mmol, 1.2 eq) was slowly added under ice bath. After removing the ice bath, the above mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water (5 mL x 3) and then dried over anhydrous sodium sulfate, filtered and concentrated to obtain an oily substance, which was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 20 / 1) to obtain 868 mg of yellow oily substance 17-L, with a yield of 69%. 1H NMR (400MHz, CDCl3) δ7.40(d,J=8.2Hz,1H),7.33(s,1H),7.21(d,J=4.1Hz,1H),7. 07(d,J=8.1Hz,1H),6.89(d,J=4.3Hz,1H),6.15(s,1H),4.89(d,J=7.5Hz,1H),4.2 6(m,4.32-4.18,2H),4.15–3.98(m,1H),3.64(t,J=11.3Hz,1H),3.40–3.25(m,1H) ,1.37(s,1H),1.25(s,1H),1.06–0.91(m,2H),0.76(d,J=7.1Hz,2H).ESI-MS(M+H) + :382.0.

[0408] Example 46: N-cyclopropylmethyl-1-(7-(3,4-dichlorophenyl)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0409]

[0410] Synthesis route and reaction steps:

[0411]

[0412] 200 mg 17-L (0.52 mmol, 1.0 eq) was added to a 25 mL round-bottom flask, and 5 mL dry tetrahydrofuran was added to completely dissolve it. The system was replaced with nitrogen three times, and 1.6 mL lithium aluminum hydride (1M in THF, 1.56 mmol, 3.0 eq) was slowly added dropwise to the flask under an ice-water bath. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated. NaOH solution (1 mol / L) was slowly added dropwise to it until a large amount of precipitate was generated. The filtrate was filtered and the filter cake was washed with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (10 mL x 3) and water (15 mL). The obtained organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 115 mg of light yellow oil 17-M, with a yield of 60%. 1H NMR (400MHz, CDCl3) δ7.30–7.24(m,2H),7.19(d,J=6.9Hz,2H),7.13(d,J=5.2 Hz,1H),6.85–6.79(m,1H),6.05(s,1H),4.85(d,J=7.9Hz,1H),4.30–4.19(m, 2H),4.12–4.00(m,1H),3.65(t,J=8.8Hz,1H),3.36–3.26(m,1H),1.34–1.28( m,2H),0.96–0.87(m,2H),0.86–0.76(m,2H),0.74–0.64(m,2H).ESI-MS(M+H) + :368.1.

[0413] Example 47: N-methyl-1-(2-methyl-7-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methanamine

[0414]

[0415] Synthesis route:

[0416]

[0417] Reagents and conditions: (xv)TBSCl, imidazole, dichloromethane, rt, 2h; (xvi) n-BuLi, CH3I, THF, -78℃~rt, 3h; (xvii) CF3SO3H, 1,4-dioxane, 80℃, 5h;

[0418] Reaction steps:

[0419] xv. 300 mg of 16-A (1.47 mmol, 1.0 eq) was added to a 25-caliber flask, and 5 mL of dichloromethane was added to dissolve it. Then, 200 mg of imidazole (2.94 mmol, 2.0 eq) and 264 mg of tert-butyldimethylsilyl chloride (1.76 mmol, 1.2 eq) were added thereto. The mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added dropwise to the mixture to quench it. The mixture was extracted with dichloromethane (10 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The mixture was concentrated to obtain a yellow oil, which was then separated by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 1) to obtain 420 mg of a transparent oil 18-A, with a yield of 90%. 1H NMR (400MHz, CDCl3) δ7.29–7.25(m,4H),7.23–7.17(m,1H),7.13(dd,J=5.1,1.1Hz,1H),6.89(dd,J=5.0,3.6Hz,1H),6.83–6.7 9(m,1H),4.31(t,J=6.6Hz,1H),4.06(ddd,J=25.6,9.8,6.6Hz,2H),0.80(s,9H),0.08(d,J=4.6Hz,6H).ESI-MS(M+H)+:319.1.

[0420] xvi. 100 mg of 18-A (0.31 mmol, 1.0 eq) was added to a 25 mL flask, and 5 mL of dry tetrahydrofuran was added to dissolve it. 0.4 mL of n-butyl lithium (2.4 M in THF, 0.93 mmol, 3.0 eq) was slowly added to the solution at -78°C. After stirring for 30 minutes, a tetrahydrofuran solution of 89 mg of iodomethane (0.63 mmol, 2.0 eq) was added to the above solution. After the addition, stirring was maintained at -78°C for 1 hour, and then the temperature was slowly raised to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride was slowly added to the above mixture to quench it, and extracted with ethyl acetate (10 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated using silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 60 / 1) to obtain 68 mg of a transparent oily substance 19-A, with a yield of 66%. 1 H NMR (400MHz, CDCl3) δ7.33 (dq, J=9.6, 7.2Hz, 6H), 6.42–6.36 (m, 1H), 6.30 (dd ,J=3.8,1.8Hz,1H),4.24–3.99(m,3H),0.91(s,9H),0.03(s,5H).ESI-MS(M+H) + :333.1.

[0421] xvii. 100 mg of 19-A (0.30 mmol, 1.0 eq) was added to a 25 mL round-bottom flask, and 5 mL of anhydrous 1,4-dioxane was added to dissolve it. Then, 107 mg of methylaminoacetaldehyde dimethyl acetal (0.90 mmol, 3.0 eq) and 238 mg of trifluoromethanesulfonic acid (1.5 mmol, 5.0 eq) were added to the flask. The mixture was stirred at 80° C. for 5 hours, and 1N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 10-11. The mixture was extracted with ethyl acetate (10 mL x 3) and water (10 mL). The organic phases were combined, washed with saturated brine (15 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 10 / 1) to obtain 22 mg of yellow oil 20-A, with a yield of 27%. 1 H NMR (400MHz, CDCl3) δ7.31–7.22(m,3H),7.19–7.12(m,2H),6.46(s,1H),5.33(d,J=9.6Hz,1H),4.2 8–4.13(m,2H),3.76–3.65(m,1H),3.52–3.41(m,1H),3.16–3.03(m,1H),2.78(s,3H),2.37(s,3H). 13 C NMR (151MHz, CDCl3) δ140.73,139.72,137.09,132.37,128.56,128.34,127.46 ,120.58,70.97,70.26,52.20,42.51,33.76,29.70,15.25,1.02.ESI-MS(M+H) + :274.1.HMRS:calc.for C 16 H 19 NOS([M+H] + )274.1260, found 274.1266.

[0422] Example 48: N-methyl-1-(2-fluoro-7-phenyl-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)-methylamine

[0423]

[0424] Synthesis route and reaction steps:

[0425] Referring to steps xv-xvii described in Example 47, iodomethane in step xvi was replaced by N-fluorobisbenzenesulfonamide (NFSI) to obtain yellow oil 20-B in an overall yield of 4.8%. 1H NMR (400MHz, CDCl3) δ7.32–7.26(m,3H),7.20–7.12(m,2H),6.22(s,1H),5.25(d,J=9.2Hz,1H),4.27(dd,J= 10.8,4.8Hz,1H),4.19–4.11(m,1H),3.79–3.70(m,1H),3.41–3.32(m,1H),3.14–3.04(m,1H),2.76(s,3H). 13 CNMR(151MHz, CDCl3)δ186.49,139.86,128.76,128.32,127.83,70.48,51.94,41.66,33.78,31.93,29.71,29.37,22.70,14.13.ESI-MS(M+H) + :278.1.HMRS:calc.for C 15 H 16 FNOS([M+H] + )278.1010, found 278.1022.

[0426] Example 49: N-methyl-1-(4-(3,4-dichlorophenyl)-4,7-dihydro-5H-furo[2,3-c]pyran-7-yl)methanamine

[0427]

[0428] Synthesis route:

[0429]

[0430] Reagents and conditions: (xvii) EtMgCl, (iPr)2NH, THF, 50℃, 3h; Pd(tBu3P)2, THF, 60℃, 3h; (xix) LiAlH4, THF, rt, 3h; (xx) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0431] Reaction steps:

[0432] xviii. Add 1.0 g of 3,4-dichlorophenylacetic acid (4.88 mmol, 1.0 eq) to a 100 mL three-necked flask, add 10 mL of anhydrous tetrahydrofuran to completely dissolve the solid, replace the flask with nitrogen three times, and then add 50 mg of diisopropylamine (0.49 mmol, 0.1 eq) to the solution. Slowly drop 4.5 mL of Grignard reagent ethylmagnesium chloride (2.7 M in THF, 12.19 mmol, 3.0 eq) in an ice bath. During the dropwise addition, a large amount of bubbles are generated and heat is released violently. After the addition is completed, the above mixture is stirred at 50°C for 3 hours and then cooled to room temperature. 1.4 g 3-bromofuran (9.76 mmol, 2 eq) and 50 mg tri-tert-butylphosphine palladium (0.1 mmol, 0.02 eq) were dissolved in 10 mL anhydrous tetrahydrofuran and added to a flask. The temperature was raised to 60° C. and stirred for 3 hours. The system was cooled to room temperature. 2N hydrochloric acid solution was slowly added dropwise to the flask to adjust the pH to 4-6. A large amount of solid precipitated. The solid was filtered out, and the filtrate was extracted with ethyl acetate (30 mL x 3) and water (20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a black oil, which was separated using silica gel column chromatography (dichloromethane / methanol=50 / 1-20 / 1) to obtain 353 mg of yellow oil 21-A, with a yield of 26.2%. 1 H NMR (400MHz, CDCl3) δ11.33(s,1H),7.42(dd,J=8.7,7.8Hz,4H),7.20(d,J=7.3Hz,1H),6.34(s,1H),4.83(s,1H).ESI-MS(MH) - :269.0.

[0433] xix. Add 353 mg 21-A (1.3 mmol, 1.0 eq) into a 50 mL round-bottom flask, add 20 mL dry tetrahydrofuran to completely dissolve it, replace the system with nitrogen three times, slowly drop 1.6 mL lithium aluminum hydride (2.5 M in THF, 3.9 mmol, 3.0 eq) into the flask under an ice-water bath, remove the ice bath after the addition is complete, stir and react at room temperature for 3 hours, add sodium sulfate decahydrate into the flask to quench the reaction solution until no obvious bubbles are generated, slowly drop NaOH solution (1 mol / L) into it until a large amount of precipitate is generated, filter to obtain the filtrate, and wash the filter cake with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (20 mL x 3) and water (10 mL), and the obtained organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 250 mg of a light yellow oil 22-A, with a yield of 74.7%. 1H NMR (400MHz, CDCl3) δ7.40(d,J=8.2Hz,3H),7.34(d,J=12.7Hz,2H),7.12(d,J=7.5Hz,1H),6.26(s,1H),4.01(d,J=3.1Hz,3H).ESI-MS(M+H) + :257.0.

[0434] xx. 100 mg of 22-A (0.40 mmol, 1.0 eq) was added to a 50 mL round-bottom flask, and 10 mL of anhydrous 1,4-dioxane was added to dissolve it. Then 144 mg of methylaminoacetaldehyde dimethyl acetal (1.20 mmol, 3 eq) and 300 mg of trifluoromethanesulfonic acid (2.0 mmol, 5 eq) were added to the flask. The mixture was stirred at 80°C for 3 hours, and 1N sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction solution to 10-11. The mixture was extracted with ethyl acetate (10 mL x 3) and water (5 mL). The organic phases were combined, washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and filtered. The concentrated phase gave a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1-10 / 1) to give 40 mg of brown oil 23-A, with a yield of 32.4%. 1 H NMR (400MHz, CDCl3) δ7.37(d,J=7.3Hz,2H),7.23(s,1H),7.00(d,J=7.9Hz,1H),6.10(s,1H),5.13(s,1H), 4.25–4.04(m,2H),3.55(d,J=12.1Hz,1H),3.51–3.43(m,1H),3.31–3.19(m,1H),2.76(s,3H).ESI-MS(M+H) + :312.1.

[0435] Example 50: N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0436]

[0437] Synthesis route:

[0438]

[0439] Reagents and conditions: (xxi)EtMgCl, (iPr)2NH,THF,50℃,3h; Pd(tBu3P)2,THF,60℃,3h; (xxii)LiAlH4,THF,rt,1h; (xxiii)CF3SO3H,1,4-dioxane,80℃,3h.

[0440] Reaction steps:

[0441] xxi. Add 1.0 g of 3-thiopheneacetic acid (7.0 mM, 1.0 eq) into a 100 mL three-necked flask, add 10 mL of anhydrous tetrahydrofuran to completely dissolve the solid, replace the flask with argon three times, add 0.1 mL of diisopropylamine (0.7 mM, 0.1 eq) to the solution, and slowly add 6.6 mL of ethylmagnesium chloride (2.7 M in THF, 17.6 mM, 2.5 eq) dropwise to the above solution under an ice bath. A large amount of bubbles are generated during the addition, and heat is released violently. The above mixture was stirred at room temperature for 3 hours, then 2 g of iodomethane (14.1 mM, 2.0 eq) and 71.5 mg of di-tri-tert-butylphosphine palladium (0.14 mM, 0.02 eq) were dissolved in 10 mL of anhydrous tetrahydrofuran and added to the flask, the temperature was raised to 60 ° C and stirred for 3 hours, the system was cooled to room temperature, 2N hydrochloric acid solution was slowly added to the flask to adjust the pH to 4-6, a large amount of solid precipitated, and the solid was removed by diatomaceous earth filtration. The filtrate was extracted with ethyl acetate (50 mL x 3) and water (40 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to obtain 730 mg of yellow oily liquid 24-A, with a yield of 33.2%. ESI-MS (MH) - :155.0.

[0442] xxii. 730 mg 24-A (4.7 mM, 1.0 eq) was added to a 100 mL eggplant-shaped flask, and 30 mL THF was added to completely dissolve it. After argon replacement, 14 mL LiAlH4 THF solution (1.0 Min THF, 14.0 mM, 3.0 eq) was slowly added dropwise under an ice bath. The reaction was allowed to react for 1 h at room temperature. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated. Then 1 N sodium hydroxide aqueous solution was slowly added dropwise until a large amount of precipitation was generated. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (30 mL × 3) and water (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a yellow oil. After silica gel column chromatography (PE / EA = 10 / 1), 550 mg of light yellow oily liquid 25-A was obtained. The yield was 82.8%. ESI-MS (M+H) + :143.0.1 H NMR (400MHz, CDCl3) δ7.27(s,1H),7.05–6.94(m,2H),3.61(d,J=6.1Hz,2H),3.02(dd,J=12.8,6.4Hz,1H),2.11(s,1H),1.25(d,J=6.5Hz,3H).

[0443] xxiii. 400 mg 25-A (2.82 mM, 1.0 eq) was added to a 50 mL eggplant-shaped bottle, 20 mL of anhydrous 1,4-dioxane was added to dissolve it, 1.0 g of methylaminoacetal dimethanol (8.45 mM, 3.0 eq) and 2.1 g of trifluoromethanesulfonic acid (14.1 mM, 5.0 eq) were added thereto, the mixture was stirred at 80°C for 3 h, 1 N sodium hydroxide aqueous solution was added to adjust the pH of the reaction solution to 10-11, and the mixture was extracted with ethyl acetate (30 mL x 3) and water (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily substance, and the obtained oily substance was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1-50 / 1) to obtain 457 mg of a yellow oily substance 26-A, yield: 82.8%. ESI-MS (M+H) + :198.1.HMRS:calc.for C 10 H 15 NOS([M+H] + )198.0947,found198.0946.

[0444] Example 51: Separation of cis and trans isomers of N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine (26-A)

[0445]

[0446] The separated 457 mg 26-A was dissolved in methanol and separated by CombiFlash using a C18 column. The elution solvent was set to methanol / H2O = 1 / 100 to 100 / 1 to obtain two groups of light yellow oils. The structure was identified by H-NMR, confirming that 55 mg of trans-configuration 26-A-1 (yield: 12.0%) and 180 mg of cis-configuration 26-A-2 (yield: 39.4%) were obtained.

[0447] 26-A-1: trans-N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0448] 1H NMR (400MHz, CDCl3) δ7.21(d,J=3.7Hz,1H),6.90(dd,J=16.2,4.3Hz,1H),5.17(d,J=9.2Hz,1H),4.12(dd,J=11.0,4.8Hz,1H),3.81(dd,J=44.9,10 .2Hz,1H),3.46(t,J=15.4Hz,1H),3.35(t,J=10.1Hz,1H),3.26–3.10(m, 1H), 2.88 (d, J = 10.6Hz, 4H), 1.23 (d, J = 6.7Hz, 1H), 1.13 (d, J = 6.7Hz, 2H). 13 C NMR (151MHz, CDCl3) δ140.50,140.28,129.26,129.07,125.96,125.40,123.85,69 .62,69.41,68.26,68.20,53.40,53.13,33.78,33.69,30.19,30.02,18.24,15.46

[0449] 26-A-2: cis-N-methyl-1-(4-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0450] 1 H NMR (400MHz, CDCl3) δ7.17(s,1H),6.90(d,J=25.2Hz,1H),4.90(s,1H),4.21–3.79(m,1H),3.34(t,J=10.4H z,1H),3.05–2.76(m,3H),2.51(d,J=3.6Hz,3H),2.07(s,1H),1.27(d,J=6.8Hz,1H),1.16(d,J=6.7Hz,2H). 13 C NMR (151MHz, CDCl3) δ139.05,138.98,133.99,133.72,125.93,125.04,122.58 ,73.85,73.61,70.59,69.21,56.79,56.73,35.79,30.58,30.43,19.44,15.50.

[0451] Example 52: N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0452]

[0453] Synthesis route and reaction steps:

[0454] Referring to step xxi-xxiii described in Example 50, iodoethane was used to replace iodomethane in step xxi to obtain yellow oil 26-B with a total yield of 5.7%. ESI-MS (M+H) + :212.1.HMRS:calc.for C 11 H 17 NOS([M+H] + )212.1104, found 212.1105.

[0455] Example 53: Separation of cis and trans isomers of N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0456]

[0457] As described in Reference Example 51, 26-B was separated to give pale yellow oil 26-B-1 (yield: 24.7%) and pale yellow oil 26-B-2 (yield: 23.3%). H-NMR confirmed that 26-B-1 was trans-configuration and 26-B-2 was cis-configuration.

[0458] 26-B-1: trans-N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0459] 1 H NMR (400MHz, CDCl3) δ7.33–7.12(m,1H),6.91(d,J=14.0Hz,1H),5.17(s,1H),4.08(d,J=59.4Hz,1H),3.87–3.40(m, 2H),3.19(s,1H),2.96–2.75(m,4H),2.57(s,1H),1.72(d,J=49.6Hz,1H),1.36(d,J=81.9Hz,1H),1.03–0.89(m,3H). 13 C NMR (151MHz, CDCl3) δ139.29,139.18,129.53,129.45,126.68,125.74,123.66,123.56,69.62 ,69.30,66.80,66.54,53.55,53.08,36.98,36.37,33.77,33.72,26.28,24.30,11.23,10.63.

[0460] 26-B-2: cis-N-methyl-1-(4-ethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0461] 1 H NMR(400MHz, CDCl3)δ7.15(s,1H),6.96–6.76(m,1H),4.87(s,1H),4.25–3.91(m,1H),3.85–3.40(m,1H),3.0 0–2.81(m,3H),2.50(s,3H),1.78(s,1H),1.72–1.62(m,1H),1.54–1.21(m,1H),0.98(dt,J=14.7,7.2Hz,3H). 13 C NMR (151MHz, CDCl3) δ138.52,138.50,135.00,127.19,125.87,122.98,122.86,74.52,74 .25,68.50,67.68,57.66,57.36,38.06,37.40,36.50,36.45,27.55,24.87,12.10,11.30.

[0462] Example 54: N-methyl-1-(4-isopropyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0463]

[0464] Synthesis route and reaction steps:

[0465] Referring to steps xxi-xxiii described in Example 50, 2-iodopropane was used to replace the iodomethane in step xxi to obtain a yellow oil 26-C with an overall yield of 2.3%. 1 H NMR(400MHz, CDCl3)δ7.15(s,1H),6.91(d,J=4.5Hz,1H),4.88(s,1H),4.12–4.03(m,1H),3.70–3 .62(m,1H),2.90(s,2H),2.82(s,1H),2.50(s,3H),1.01(d,J=7.0Hz,3H),0.85(d,J=6.5Hz,3H). 13 C NMR (151MHz, CDCl3) δ136.88,134.90,125.70,122.10,73.27,64.02,56.62,41.22,35.78,29.13,19.86,17.66.ESI-MS(M+H) + :226.1.

[0466] Example 55: N-methyl-1-(4,4-dimethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-7-yl)methanamine

[0467]

[0468] Synthesis route:

[0469]

[0470] Reagents and conditions: (xxiv) NaH, DMSO, rt, 3h; (xxv) 4.0N LiOH (aq), 100℃, 15h; (xxvi) LiAlH4, THF, rt, 3h; (xxvii) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0471] Reaction steps:

[0472] xxiv. 500 mg of 3-thiopheneacetonitrile (4.1 mM, 1.0 eq) was added to a 50 mL eggplant-shaped bottle, and then 15 mL of dimethyl sulfoxide was added to dissolve it. After replacing the argon gas, 400 mg of sodium hydrogen (10.0 mM, 2.5 eq) was added to the eggplant-shaped bottle in batches. After the addition was completed, the reaction was stirred at room temperature for 30 min; 1.16 g of iodomethane (8.2 mM, 2.0 eq) was added to the above reaction system, and the reaction was continued at room temperature for 3 h. 5 mL of H2O was slowly added to quench the reaction, and then ethyl acetate (50 mL x 2) and water (15 mL) were added for extraction. The organic phase was washed with water (30 mL x 3) and saturated brine, and then dried and concentrated to obtain an oily liquid. After separation by silica gel column chromatography (PE / EA=30 / 1), 520 mg of colorless oily liquid 28-A was obtained, with a yield of 84.7%. ESI-MS (M+H) + :152.0. 1 H NMR (400MHz, CDCl3) δ7.36–7.17(m,2H),7.08(d,J=22.4Hz,1H),1.64(dd,J=39.3,25.8Hz,6H).

[0473] xxv. 530 mg (3.5 mM, 1.0 eq) of 28-A was placed in a 100 mL eggplant-shaped bottle, 28 mL of 4.0 N lithium hydroxide solution was added, and the mixture was refluxed at 100 ° C for 15 h, then cooled to room temperature, 200 mL of dilute hydrochloric acid was added to the reaction solution, and then extracted with ethyl acetate (75 mL x 3), the organic phases were combined, washed with water (100 mL x 3) and saturated brine, and the organic phases were dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 600 mg of white solid 29-A, yield: 100%. ESI-MS (MH) - :169.0

[0474] xxvi. 600 mg 29-A (3.5 mM, 1.0 eq) was added to a 100 mL eggplant-shaped flask, and 30 mL THF was added to completely dissolve it. After argon replacement, 10.5 mL LiAlH4 THF solution (1.0 Min THF, 10.5 mM, 3.0 eq) was slowly added dropwise under an ice bath. The reaction was allowed to react for 1 h at room temperature. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated. Then 1 N sodium hydroxide aqueous solution was slowly added dropwise until a large amount of precipitation was generated. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (30 mL × 3) and water (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a yellow oil. After silica gel column chromatography (PE / EA = 10 / 1), 357 mg of light yellow oily liquid 30-A was obtained. The yield was 64.5%. ESI-MS (M+H) + :157.0. 1 H NMR (400MHz, CDCl3) δ7.31(s,1H),7.07(s,2H),3.55(s,2H),1.42(s,1H),1.32(s,6H).

[0475] xxvii. 357 mg 30-A (2.3 mM, 1.0 eq) was added to a 50 mL eggplant-shaped bottle, and 20 mL of anhydrous 1,4-dioxane was added to dissolve it. 821 mg methylaminoacetal dimethanol (6.9 mM, 3.0 eq) and 1.7 g trifluoromethanesulfonic acid (11.5 mM, 5.0 eq) were added thereto. The mixture was stirred and reacted at 80° C. for 3 h. 1 N sodium hydroxide aqueous solution was added to adjust the pH of the reaction solution to 10-11. The mixture was extracted with ethyl acetate (30 mL x 3) and water (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 50 / 1) to obtain 51.7 mg of light yellow oil 31-A, with a yield of 10.6%. 1H NMR (400MHz, CDCl3) δ7.15(d,J=4.6Hz,1H),6.93(d,J=4.9Hz,1H),4.89(d,J=4.5Hz,1H),3.72(d,J=11.1H z,1H),3.47(t,J=20.3Hz,1H),2.95(d,J=6.9Hz,2H),2.52(s,3H),2.17(s,1H),1.27(s,3H),1.19(s,3H). 13 CNMR(151MHz, CDCl3)δ143.24,132.90,124.10,122.72,75.19,73.93,56.79,35.76,33.56,27.68,24.36.ESI-MS(M+H) + :212.1.

[0476] HMRS:calc.for C 11 H 17 NOS([M+H] + )212.1104, found 212.1105.

[0477] Example 56: N-methyl-1-(5'H,7'H-spiro[cyclopropane-1,4'-thieno[2,3-c]pyran]-7'-yl)methanamine

[0478]

[0479] Synthesis route and reaction steps:

[0480] Referring to steps xxiv-xxvii described in Example 55, 1-bromo-2-chloroethane (1.0 eq) was used to replace iodomethane (2.0 eq) in step xxiv to obtain a light yellow oil 31-B. The total yield was 4.6%. 1 H NMR (400MHz, CDCl3) δ7.12 (s, 1H), 6.48 (s, 1H), 5.00 (s, 1H), 3.99 (d, J = 9.9Hz, 1 H),3.63–3.36(m,1H),2.98(s,2H),2.53(s,3H),1.98(s,1H),1.05–0.83(m,4H). 13 C NMR (151MHz, CDCl3) δ138.71,133.76,122.93,121.25,74.18,71.86,56.54,35.80,18.72,16.28,10.35.ESI-MS(M+H) + :210.1.HMRS:calc.for C 11H 15 NOS([M+H] + )210.0947, found 210.0945.

[0481] Example 57: N-methyl-1-(5'H,7'H-spiro[cyclobutane-1,4'-thieno[2,3-c]pyran]-7'-yl)methanamine

[0482]

[0483] Synthesis route and reaction steps:

[0484] Referring to steps xxiv-xxvii described in Example 55, 1,2-dibromopropane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxiv to obtain a light yellow oil 31-C. The total yield was 22.5%. 1 H NMR (400MHz, CDCl3) δ7.17(d,J=11.3Hz,2H),4.88(s,1H),4.17(d,J=11.2Hz,1H),3.65(d,J =10.8Hz,1H),2.91(s,2H),2.50(s,3H),2.43–2.35(m,1H),2.20(s,2H),2.06–1.96(m,4H). 13 C NMR (151MHz, CDCl3) δ142.49,133.99,125.11,123.53,74.51,73.62,57.30,39.96,36.37,34.15,30.28,15.68.ESI-MS(M+H) + :224.1.HMRS:calc.for C 12 H 17 NOS([M+H] + )224.1104, found224.1106.

[0485] Example 58: N-methyl-1-(5'H,7'H-spiro[cyclopentane-1,4'-thieno[2,3-c]pyran]-7'-yl)methanamine

[0486]

[0487] Synthesis route and reaction steps:

[0488] Referring to steps xxiv-xxvii described in Example 55, 1,3-dibromobutane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxiv to obtain a light yellow oil 31-D. The total yield was 18.5%. 1H NMR (400MHz, CDCl3) δ7.16(s,1H),6.90(s,1H),4.94(s,1H),3.77(d,J=11.1Hz,1H),3.47(d,J= 10.8Hz,1H),2.99(d,J=12.7Hz,1H),2.76(s,2H),2.56(s,3H),1.73(dd,J=121.4,54.9Hz,8H). 13 C NMR (151MHz, CDCl3) δ143.37,132.44,124.38,122.88,73.16,72.61,56.26,44.41,38.60,35.47,35.39,25.03,24.60.ESI-MS(M+H) + :238.1.HMRS:calc.for C 13 H 19 NOS([M+H] + )238.1260, found238.1261.

[0489] Example 59: 1-(4-(3,4-dichlorophenyl)-8-methoxyisochroman-1-yl)-N-methylmethylamine (Compound 35-A), 1-(4-(3,4-dichlorophenyl)-6-methoxyisochroman-1-yl)-N-methylmethylamine (Compound 35-B)

[0490]

[0491] Synthesis route:

[0492]

[0493] Reagents and conditions: (xxviii)EtMgCl, (iPr)2NH,THF,50℃,3h; Pd(tBu3P)2,THF,60℃,3h; (xxix)LiAlH4,THF,rt,3h; (xxx)CF3SO3H,1,4-dioxane,100℃,24h.

[0494] Reaction steps:

[0495] xxviii. 1.0g 3,4-Dichlorophenylacetic acid(4.9mmol, 1.0eq) was added to a 100mL three-necked flask, 10mL of anhydrous tetrahydrofuran was added to completely dissolve the solid, the flask was replaced with nitrogen three times, 50mg of diisopropylamine (0.49mmol, 0.1eq) was added to the solution. 6.1mL of Grignard reagent ethylmagnesium chloride (2.4M in THF, 14.7mmol, 3.0eq) was slowly added dropwise under an ice bath, a large number of bubbles were generated during the addition, and heat was released violently. The above mixture was stirred at 50°C for 3 hours, then cooled to room temperature, 1.37g 3-methoxyiodobenzene (5.9mmol, 1.2eq) and 75mg tri-tert-butylphosphine palladium (0.15mmol, 0.03eq) were dissolved in 10mL anhydrous tetrahydrofuran and added to the flask, the temperature was raised to 60°C and stirred for 3 hours, the system was cooled to room temperature, 2N hydrochloric acid solution was slowly added dropwise to the flask to adjust the pH to 4-6, a large amount of solid precipitated, the solid was filtered out, ethyl acetate (30mL x 3) and water (20mL) were added to the filtrate for extraction, the organic phases were combined, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to obtain a black oil, which was separated using silica gel column chromatography (dichloromethane / methanol = 50 / 1-20 / 1) to obtain 903mg of yellow oil 33-A, yield: 59%. ESI-MS (MH) + :278.9.

[0496] xxix. 900 mg 33-A (3.22 mmol, 1.0 eq) was added to a 100 mL round-bottom flask, and 30 mL dry tetrahydrofuran was added to completely dissolve it. The system was replaced with nitrogen three times, and 3.9 mL lithium aluminum hydride (2.5 M in THF, 9.68 mmol, 3.0 eq) was slowly added dropwise to the flask under an ice-water bath. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated. NaOH solution (1 mol / L) was slowly added dropwise to it until a large amount of precipitate was generated. The filtrate was filtered and the filter cake was washed with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (20 mL x 3) and water (15 mL), and the obtained organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 696 mg of light yellow oil 34-A, yield: 73%. 1 H NMR (400MHz, CDCl3) δ7.45–7.32(m,2H),7.28(d,J=3.2Hz,1H),7.20–7.06(m,3H ),6.96–6.84(m,2H),4.12(d,J=3.2Hz,3H),3.81(d,J=3.2Hz,3H).ESI-MS(M+H) +:297.1.

[0497] xxx. 500 mg 34-A (1.69 mmol, 1.0 eq) was added to a 100 mL sealed tube, 30 mL of anhydrous 1,4-dioxane was added to dissolve it, 402 mg of methylaminoacetaldehyde dimethyl acetal (3.4 mmol, 2.0 eq) and 760 mg of trifluoromethanesulfonic acid (5.07 mmol, 3.0 eq) were added to the flask, the sealed tube was sealed and heated at 100°C with stirring for 24 hours, the mixture was adjusted to pH 10-11 with 1N sodium hydroxide aqueous solution, extracted with ethyl acetate (20 mL x 3) and water (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1-10 / 1) to obtain 71 mg 35-A (yield: 12%) and 124 mg 35-B (yield: 21%), all were yellow oils.

[0498] 35-A: 1-(4-(3,4-dichlorophenyl)-8-methoxyisochroman-1-yl)-N-methylmethanamine

[0499] 1 H NMR (400MHz, CDCl3) δ7.28–7.12(m,3H),6.91(dd,J=19.6,8.2Hz,1H),6.76(d,J=8.0Hz,1H),6.56–6.49(m,1H),5.40 –5.19(m,1H),4.21–4.08(m,1H),3.84(s,3H),3.80–3.64(m,2H),3.60–3.45(m,2H),3.35–3.15(m,1H),2.75(s,3H). 13 C NMR (151MHz, CDCl3) δ155.51,155.36,143.01,141.58,137.26,132.68,132.46,131.23,130.95,130.77,130.61,130 .44,130.39,129.08,128.21,128.03,121.96,108.90,68.25,65.97,55.40,49.77,42.84,33.26,33.15.ESI-MS(M+H) + :352.1.

[0500] 35-B: 1-(4-(3,4-dichlorophenyl)-6-methoxyisochroman-1-yl)-N-methylmethanamine

[0501] 1H NMR (400MHz, CDCl3) δ7.33–7.27(m,1H),7.19–7.15(m,1H),7.03(dd,J=8.6,3.6Hz ,1H),6.93–6.88(m,1H),6.79(dd,J=8.6,2.6Hz,1H),6.40–6.36(m,1H),5.22(d,J= 8.4Hz,1H),4.12(dd,J=11.2,4.2Hz,1H),4.08–4.02(m,1H),3.67(s,2H),3.65(dd, J=7.4,4.0Hz,1H),3.46–3.35(m,1H),3.31–3.17(m,1H),2.71(s,3H).ESI-MS(M+H) + :352.1.

[0502] Example 60: 1-(4-(3,4-dichlorophenyl)-8-methylisochroman-1-yl)-N-methylmethanamine

[0503]

[0504] Synthesis route and reaction steps:

[0505] Referring to steps xxviii-xxx described in Example 59, 3-methyl iodobenzene was used to replace 3-methoxy iodobenzene in step xxviii to obtain yellow oil 35-C in an overall yield of 9.3%. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=8.2Hz,1H),7.23–7.19(m,1H),7.08–7.04(m,2H),6.97(d,J=8.4Hz,1H),6.77(s,1H),5.31(d,J=10. 2Hz,1H),4.06–4.00(m,2H),3.97–3.89(m,1H),3.52(d,J=13.2Hz,1H),3.15(t,J=12.0Hz1H),2.77(s,3H),2.25(s,3H).ESI-MS(M+H) + :336.1.

[0506] Example 61: 1-(4-(3,4-dichlorophenyl)-6-methylisochroman-1-yl)-N-methylmethanamine

[0507]

[0508] Synthesis route and reaction steps:

[0509] Referring to steps xxviii-xxx described in Example 59, 3-methyl iodobenzene was used to replace 3-methoxy iodobenzene in step xxviii to obtain yellow oil 35-D in an overall yield of 8.4%. 1 H NMR(400MHz, CDCl3)δ7.35–7.28(m,1H),7.21(s,1H),7.08–7.01(m,3H),6 .94(d,J=8.3Hz,1H),6.75–6.71(m,1H),5.48(d,J=9.6Hz,1H),4.23(dd,J= 11.4,3.9Hz,1H),4.13–4.05(m,1H),3.82(dd,J=11.5,6.6Hz,1H),3.43(d ,J=11.9Hz,1H),3.27–3.17(m,1H),2.78(s,3H),2.26(s,3H).ESI-MS(M+H) + :336.1.

[0510] Example 62: 1-(4-(3,4-dichlorophenyl)-7-methylisochroman-1-yl)-N-methylmethanamine

[0511]

[0512] Synthesis route and reaction steps:

[0513] Referring to steps xxviii-xxx described in Example 59, 3-methoxyiodobenzene in step xxviii was replaced by 4-methyliodobenzene to obtain yellow oil 35-E in an overall yield of 11.2%. 1 H NMR(400MHz, CDCl3)δ7.37–7.29(m,1H),7.26(s,1H),7.17(s,1H),7.04–6 .98(m,1H),6.94–6.90(m,1H),6.78(d,J=8.0Hz,1H),5.27(d,J=9.6Hz,1H ),4.19(dd,J=11.2,4.8Hz,1H),4.15–4.08(m,1H),4.04–3.99(m,1H),3.7 8–3.69(m,1H),3.25–3.14(m,1H),2.80(s,3H),2.31(s,3H).ESI-MS(M+H) + :336.1.

[0514] Example 63: 1-(4-(3,4-dichlorophenyl)-6,8-dimethylisochroman-1-yl)-N-methylmethanamine

[0515]

[0516] Synthesis route and reaction steps:

[0517] Referring to steps xxviii-xxx described in Example 59, 3,5-dimethyliodobenzene was used to replace 3-methoxyiodobenzene in step xxiv to obtain yellow oil 35-F. The total yield was 14.5%. 1 H NMR (400MHz, CDCl3) δ13.60–13.56(m,1H),7.29(s,1H),7.26–7.21(m,1H),7.16(s,1H),6.94–6.88(m,2H),6.62(s,1H),5.49(d,J=9.2H z,1H),4.29–4.20(m,1H),4.02–3.93(m,1H),3.92–3.83(m,1H),3.35–3.20(m,2H),2.82(s,3H),2.28(s,3H),2.23(s,3H).ESI-MS(M+H) + :350.2.

[0518] Example 64: 1-(7,9-dimethyl-5-phenyl-1,3,4,5-tetrahydrobenzo[C]oxepin-1-yl)-N-methylmethanamine

[0519]

[0520] Synthesis route:

[0521]

[0522] Reagents and conditions: (xxxi) Ag2CO3, Pd(OAc)2, AcOH, 100℃, 6~30h; (xxxii) L-proline, CHCl3, rt, 16h; (xxxiiii) LiAlH4, 0℃, 2h; (xxxiv) CF3SO3H, 1,4-dioxane, 80℃, 16h.

[0523] Reaction steps:

[0524] xxxi. 134 mg of phenylpropanaldehyde (1.0 mmol, 1.0 eq) was dissolved in 3 mL of glacial acetic acid and added to a sealed tube. 331 mg of silver carbonate (1.2 mmol, 1.2 eq), 580 mg of 3,5-dimethyliodobenzene (2.5 mmol, 2.5 eq) and 22 mg of palladium acetate (0.1 mmol, 10 mol%) were added thereto. The mixture was heated to 100° C. in a sealed tube and stirred for 6 hours. The mixture was cooled to room temperature and filtered. The mixture was concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain 156 mg of a transparent oil 37-A, with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ9.55 (d, J=8.0Hz, minor CHO), 9.51 (d, J=8.0Hz, 1H, major CHO),7.50–7.41(m,3H,ArH),7.39–7.36(m,1H,ArH),7.33–7.28(m,2H,ArH),7.11(s,minor ArH),7.08(s,1H,major ArH),6.97(s,2H,major ArH),6.92(s,1H,minor ArH),6.59(d,J=8.0Hz,1H,major CH),6.57(d,J=8.0Hz,minor CH),2.35(s,2H,CH3),2.30(s,6H,CH3).ESI-MS(M+H) + :237.1.

[0525] xxxii. 540 mg 37-A (2.29 mmol, 1.0 eq) was dissolved in 20 mL chloroform and added to a round-bottom flask, and then 26 mg L-proline (0.23 mmol, 0.1 eq) and 872 mg dihydropyridine 1149-23-1 (3.45 mmol, 1.5 eq) were added thereto. The mixture was stirred at room temperature for 16 hours, and a 2N aqueous sodium hydroxide solution was added and stirred at room temperature for 30 minutes to hydrolyze the dihydropyridine 1149-23-1 and then dissolved in the aqueous phase. The organic phase was separated, and the solvent was removed under reduced pressure to obtain an oily substance. 270 mg of yellow oily substance 38-A was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1), and the yield was 54%.

[0526] xxxiii. Add 270 mg 38-A (1.13 mmol, 1.0 eq) into a 25 mL round-bottom flask, add 10 mL dry tetrahydrofuran to completely dissolve it, replace the system with nitrogen three times, slowly drop 1.4 mL lithium aluminum hydride (2.5 M in THF, 3.39 mmol, 3.0 eq) into the flask under an ice-water bath, remove the ice bath after the addition is complete, stir and react at room temperature for 2 hours, add sodium sulfate decahydrate into the flask to quench the reaction solution until no obvious bubbles are generated, slowly drop NaOH solution (1 mol / L) into it until a large amount of precipitate is generated, filter to obtain the filtrate, and wash the filter cake with ethyl acetate. The obtained filtrate was extracted with ethyl acetate (10 mL x 3) and water (15 mL), and the obtained organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 239 mg of light yellow oil 39-A, with a yield of 73%. ESI-MS (M+H) + :241.3.

[0527] xxxiv. 200 mg of 39-A (0.83 mmol, 1.0 eq) was added to a 48 mL sealed tube, and 10 mL of anhydrous 1,4-dioxane was added to dissolve it. Then 196 mg of methylaminoacetaldehyde dimethyl acetal (1.66 mmol, 2.0 eq) and 373 mg of trifluoromethanesulfonic acid (2.49 mmol, 3.0 eq) were added to the flask. After the sealed tube was sealed, it was heated and stirred at 100°C for 24 hours. The mixture was adjusted to pH 10-11 by adding 1N sodium hydroxide aqueous solution, and extracted with ethyl acetate (15 mL x 3) and water (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The obtained oil was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1-10 / 1) to obtain 88 mg of light yellow foamy solid 40-A, yield: 36%. 1 H NMR (400MHz, CDCl3) δ10.19(s,1H),9.19(s,1H),7.45–7.20(m,6H),6.82(s,1H),6.23(s,1H),5.77(d,J=9.6Hz,1H),4.81(d,J= 9.2Hz,1H),4.19–3.97(m,1H),3.69–3.55(m,1H),3.55–3.40(m,2H),3.32–3.17(m,1H),2.95(s,3H),2.39(s,3H),2.08(s,3H). 13C NMR (151MHz, CDCl3) δ141.89,141.69,138.05,135.76,130.43,129.44,129.07,128.48 ,127.13,126.74,63.58,52.11,50.67,42.63,33.74,33.24,21.02,20.37.ESI-MS(M+H) + :296.2.

[0528] Example 65: 1-(7-methoxy-5-phenyl-1,3,4,5-tetrahydrobenzo[C]oxepin-1-yl)-N-methylmethanamine

[0529]

[0530] Synthesis route and reaction steps:

[0531] Referring to steps xxxi-xxxiv described in Example 64, 3,5-dimethyliodobenzene in step xxxi was replaced with 3-methoxyiodobenzene to obtain a yellow oil 40-B with an overall yield of 14.5%. 1 H NMR(400MHz, CDCl3)δ7.35(t,J=7.2Hz,2H),7.31–7.24(m,2H),7.18(d,J=7.6Hz,2H ),6.96(d,J=8.4Hz,1H),6.61(d,J=8.4Hz,1H),6.13(s,1H),5.23(d,J=10.6Hz,1H), 4.46(d,J=10.2Hz,1H),4.36–4.25(m,1H),4.18(t,J=11.4Hz,1H),3.61(s,1H),3.6 0(s,3H),3.40(t,J=11.3Hz,1H),2.87(s,3H),2.36–2.19(m,1H),2.10–1.99(m,1H). 13 C NMR (151MHz, CDCl3) δ159.27,147.46,143.33,129.44,128.70,128.60,126.77,124.99,11 6.14,109.74,74.31,72.72,55.00,52.07,48.13,35.45,33.98,29.70,1.03.ESI-MS(M+H) + :298.2.

[0532] Example 66: 1-((4,4-dimethyl)-8-methoxyisochroman-1-yl)-N-methylmethanamine (Compound 45-A), 1-((4,4-dimethyl)-6-methoxyisochroman-1-yl)-N-methylmethanamine (Compound 45-B)

[0533]

[0534] Synthesis route:

[0535]

[0536] Reagents and conditions: (xxxv) NaH, DMSO, rt, 3h; (xxxvi) 4.0N LiOH (aq), 100℃, 15h; (xxxvii) LiAlH4, THF, rt, 1h; (xxxviii) CF3SO3H, 1,4-dioxane, 80℃, 3h.

[0537] Reaction steps:

[0538] xxxv. 1 g of 3-methoxybenzeneacetonitrile (6.8 mM, 1.0 eq) was added to a 100 mL two-necked bottle, and then 30 mL of dimethyl sulfoxide was added to dissolve it. After replacing the argon gas, 680 mg of sodium hydrogen (17.0 mM, 2.5 eq) was added to the eggplant-shaped bottle in batches. After the addition was completed, the reaction was stirred at room temperature for 30 min. 1.93 g of iodomethane (13.6 mM, 2.0 eq) was added to the above reaction system. After continuing to react at room temperature for 3 h, 10 mL of H2O was slowly added to quench the reaction. Ethyl acetate (75 mL x 2) and water (30 mL) were added for extraction. The organic phase was washed with water (50 mL x 3) and saturated brine, dried and concentrated to obtain an oily liquid. After separation by silica gel column chromatography (PE / EA=30 / 1), 1.1 g of colorless oily liquid 42-A was obtained. The yield was 84.7%. ESI-MS (M+H) + :176.0. 1 H NMR (400MHz, CDCl3) δ7.31(t,J=7.9Hz,1H),7.08–6.98(m,2H),6.85(d,J=5.8Hz,1H),3.83(s,3H),1.71(s,6H).

[0539] xxxvi. 1.9 g (10.9 mM, 1.0 eq) of 42-A was placed in a 250 mL eggplant-shaped bottle, 86 mL of 4.0 N lithium hydroxide solution was added, and the mixture was refluxed at 100 ° C for 15 h, then cooled to room temperature, 300 mL of dilute hydrochloric acid was added to the reaction solution, and then extracted with ethyl acetate (150 mL x 3), the organic phases were combined, washed with water (150 mL x 3) and saturated brine, and the organic phases were dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 2.1 g of white solid 43-A, yield: 100%. ESI-MS (MH) - :193.0. 1 H NMR (400MHz, CDCl3) δ7.25(d,J=7.4Hz,1H),7.01–6.93(m,2H),6.80(d,J=8.0Hz,1H),3.80(s,3H),1.58(s,6H).

[0540] xxxvii. 2.1 g of 43-A (10.9 mM, 1.0 eq) was added to a 250 mL eggplant-shaped flask, and 100 mL of THF was added to completely dissolve it. After argon replacement, 21.8 mL of LiAlH4 THF solution (1.0 Min THF, 21.8 mM, 2.0 eq) was slowly added dropwise under an ice bath, and the reaction was allowed to react at room temperature for 1 h. Sodium sulfate decahydrate was added to the flask to quench the reaction solution until no obvious bubbles were generated, and then 1 N sodium hydroxide aqueous solution was slowly added dropwise until a large amount of precipitation was generated. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (50 mL × 3) and water (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a yellow oil, which was separated by silica gel column chromatography (PE / EA = 10 / 1) to obtain 1.82 g of colorless oily liquid 44-A, with a yield of 93.0%. ESI-MS (M+H) + :181.0. 1 H NMR (400MHz, CDCl3) δ7.26(d,J=3.1Hz,1H),7.01–6.88(m,2H),6.76(d,J=7.2Hz,1H),3.81(s,3H),3.59(s,2H),1.32(s,6H).

[0541] xxxviii. 1.82 g of 44-A (10.0 mM, 1.0 eq) was added to a 250 mL eggplant-shaped bottle, 100 mL of anhydrous 1,4-dioxane was added to dissolve it, 3.57 g of methylaminoacetal dimethanol (30 mM, 3.0 eq) and 7.5 g of trifluoromethanesulfonic acid (50.0 mM, 5.0 eq) were added thereto, and the mixture was stirred at 80 ° C for 3 h, 1 N sodium hydroxide aqueous solution was added to adjust the pH of the reaction solution to 10-11, and ethyl acetate (50 mL x 100 mL) was added after drying. 3) and water (30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oil. The oil was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 50 / 1) to obtain 2.7 g of crude product, and then separated by reverse phase column chromatography (methanol / H2O = 1 / 100 to 100 / 1) to obtain 150 mg of light yellow oily liquid 45-A (yield: 6.3%) and 1.1 g of light yellow powdery solid 45-B (yield: 47.4%).

[0542] 45-A: 1-(8-methoxy-4,4-dimethylisochroman-1-yl)-N-methylmethanamine

[0543] 1 H NMR (400MHz, CDCl3) δ7.25(s,1H),6.96(d,J=6.2Hz,1H),6.69(d,J=6.4Hz,1H),5.22(d,J=7.4Hz,1H),3. 85–3.62(m,5H),3.51(d,J=11.0Hz,1H),3.22(s,1H),3.02(s,1H),2.90(s,3H),1.23(s,3H),1.17(s,3H). 13 C NMR (151MHz, CDCl3) δ155.14,145.24,128.90,119.20,117.94,107.80,71.29,68.14,55.33,50.39,33.71,33.33,27.72,25.91.ESI-MS(M+H) + :236.2.HMRS:calc.for C 14 H 21 NO2([M+H] + )236.1645, found236.1647.

[0544] 45-B: 1-(6-methoxy-4,4-dimethylisochroman-1-yl)-N-methylmethanamine

[0545] 1H NMR (400MHz, CDCl3) δ6.97(d,J=8.2Hz,1H),6.85(s,1H),6.72(d,J=8.3Hz,1H),5.10(d,J=9.6Hz,1H),3.78(s,3H),3.6 8(d,J=11.2Hz,1H),3.52(t,J=17.1Hz,2H),3.15(d,J=8.6Hz,1H),2.90(s,3H),2.58(s,1H),1.26(s,3H),1.16(s,3H). 13 C NMR (151MHz, CDCl3) δ159.24,145.07,125.32,122.89,111.86,111.62,73.39,71.22,55.26,53.67,34.16,33.77,27.93,25.99.ESI-MS(M+H) + :236.2.HMRS:calc.for C 14 H 21 NO2([M+H] + )236.1645, found 236.1647.

[0546] Example 67: 1-(8-Methoxy-4-methylisochroman-1-yl)-N-methylmethanamine

[0547]

[0548] Synthesis route and reaction steps:

[0549] Referring to steps xxxv-xxxviii described in Example 66, the amount of NaH in step xxxv was adjusted to 1.5 eq and the amount of iodomethane was adjusted to 1.05 eq to obtain yellow oil 45-C with a total yield of 1.7%. ESI-MS (M+H) + :222.1. 1 H NMR (400MHz, CDCl3) δ7.17(d,J=7.7Hz,1H),6.87–6.67(m,2H),5.07(dd,J=3.9,3.1Hz,1H),4.02(d,J=8.2Hz, 1H),3.80(d,J=16.6Hz,3H),3.51(s,1H),3.04–2.80(m,3H),2.51(d,J=16.8Hz,3H),1.26(s,3H).ESI-MS(M+H) + :222.1.

[0550] Example 68: 1-(6-methoxy-4-methylisochroman-1-yl)-N-methylmethanamine

[0551]

[0552] Synthesis route and reaction steps:

[0553] Referring to steps xxxv-xxxviii described in Example 66, the amount of NaH in step xxxv was adjusted to 1.5 eq and the amount of iodomethane was adjusted to 1.05 eq to obtain yellow oil 45-D with a total yield of 11.9%. ESI-MS (M+H) + :222.1. 1 H NMR (400MHz, CDCl3) δ7.00(d,J=8.1Hz,1H),6.75(dd,J=21.3,13.1Hz,2H),4.85(dd,J=23.3,6.5Hz,1H),4.05(dd,J=10.9,4.3Hz,1H ),3.81(d,J=12.7Hz,4H),3.51–3.39(m,1H),2.93(dd,J=21.2,9.0Hz,2H),2.49(s,3H),1.35(d,J=6.9Hz,1H),1.24(d,J=6.8Hz,2H).

[0554] Example 69: 1-(8'-methoxyspiro[cyclopropane-1,4'-isobenzodihydrofuran]-1'-yl)-N-methylmethanamine

[0555]

[0556] Synthesis route and reaction steps:

[0557] Referring to steps xxxv-xxxviii described in Example 66, 1-bromo-2-chloroethane (1.0 eq) was used to replace iodomethane (2.0 eq) in step xxxv to obtain yellow oil 45-E. The total yield was 1.42%. 1 H NMR (400MHz, CDCl3) δ7.15(s,1H),6.66(d,J=7.3Hz,1H),6.35(s,1H),5.23(s,1H),4.06(d,J=11.5Hz,1H),3.81( s,3H),3.48(s,1H),3.29(d,J=11.2Hz,1H),3.05(s,2H),2.52(d,J=10.4Hz,3H),1.12(s,1H),1.02–0.77(m,3H). 13C NMR (151MHz, CDCl3) δ155.38,140.09,127.80,124.51,113.58,107.12,71.69,67.39,55.25,52.23,35.84,18.90,18.60,12.29.ESI-MS(M+H) + :234.1.HMRS:calc.for C 14 H 19 NO2([M+H] + )234.1489, found 234.1489.

[0558] Example 70: 1-(6'-methoxyspiro[cyclopropane-1,4'-isobenzodihydrofuran]-1'S-yl)-N-methylmethanamine

[0559]

[0560] Synthesis route and reaction steps:

[0561] Referring to steps xxxv-xxxviii described in Example 66, 1-bromo-2-chloroethane (1.0 eq) was used to replace iodomethane (2.0 eq) in step xxxv to obtain yellow oil 45-F in an overall yield of 4.26%. 1 H NMR (400MHz, CDCl3) δ7.01(d,J=8.3Hz,1H),6.70(d,J=6.8Hz,1H),6.26(s,1H),5.05(d,J=6.7Hz,1H),3.87–3.74(m,4H) ,3.58(d,J=11.3Hz,1H),3.11(d,J=10.8Hz,1H),3.06–2.97(m,1H),2.56(s,3H),1.05(s,1H),0.97(s,2H),0.85(s,1H). 13 C NMR (151MHz, CDCl3) δ158.84,140.45,128.06,125.30,110.89,107.20,75.17,71.06,55.81,55.24,36.02,19.13,17.73,13.53.ESI-MS(M+H) + :234.1.HMRS:calc.for C 14 H 19 NO2([M+H] + )234.1489, found 234.1489.

[0562] Example 71: 1-(6'-methoxyspiro[cyclopropane-1,4'-isobenzodihydrofuran]-1'R-yl)-N-methylmethanamine

[0563]

[0564] Synthesis route and reaction steps:

[0565] Referring to steps xxxv-xxxviii described in Example 66, 1-bromo-2-chloroethane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow powdery solid 45-G. The total yield was 13.4%. 1 H NMR (400MHz, CDCl3) δ6.99(d,J=8.0Hz,1H),6.69(s,1H),6.25(d,J=1.8Hz,1H),5.21(d,J=7.8Hz,1H),3.73(d ,J=10.7Hz,4H),3.65–3.53(m,2H),3.25(s,1H),2.90(d,J=24.2Hz,4H),0.96(d,J=12.6Hz,3H),0.81(s,1H). 13 C NMR (151MHz, CDCl3) δ159.53,140.51,125.40,124.53,111.30,107.58,71.46,70.49,55.26,53.49,34.16,18.81,17.08,13.71.ESI-MS(M+H) + :234.1.HMRS:calc.for C 14 H 19 NO2([M+H] + )234.1489, found 234.1489.

[0566] Example 72: 1-(8'-methoxyspiro[cyclobutano-1,4'-isobenzodihydrofuran]-1'-yl)-N-methylmethanamine

[0567]

[0568] Synthesis route and reaction steps:

[0569] Referring to steps xxxv-xxxviii described in Example 66, 1,3-dibromopropane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow oil 45-H in an overall yield of 1.88%. ESI-MS (M+H) + :248.2. 1H NMR (400MHz, CDCl3) δ7.30(d,J=8.0Hz,1H),7.21(d,J=7.3Hz,1H),6.72(d,J=7.7Hz,1H),5.20(d,J=9.1Hz,1H),3.90(t ,J=13.6Hz,1H),3.82(s,4H),3.68(s,1H),3.17(s,1H),2.88(s,3H),2.29(d,J=26.8Hz,1H),2.21(s,3H),2.02(s,4H).

[0570] Example 73: 1-(6'-methoxyspiro[cyclobutano-1,4'-isobenzodihydrofuran]-1'S-yl)-N-methylmethanamine

[0571]

[0572] Synthesis route and reaction steps:

[0573] Referring to steps xxxv-xxxviii described in Example 66, 1,3-dibromopropane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow oil 45-I with a total yield of 2.93%. ESI-MS (M+H) + :248.2. 1 H NMR (400MHz, CDCl3) δ7.11(s,1H),6.97(d,J=7.5Hz,1H),6.74(d,J=8.0Hz,1H),4.86(s,1H),4.08(d,J=11.2Hz,1H),3.83(d,J=1.8Hz,3H),3.69(d ,J=11.2Hz,1H),2.97(d,J=12.2Hz,1H),2.86(t,J=9.4Hz,1H),2.48(d,J= 1.7Hz,3H),2.42(d,J=9.0Hz,1H),2.23(s,2H),2.06(s,3H),1.93(s,1H).

[0574] Example 74: 1-(6'-methoxyspiro[cyclobutano-1,4'-isobenzodihydrofuran]-1'R-yl)-N-methylmethanamine

[0575]

[0576] Synthesis route and reaction steps:

[0577] Referring to steps xxxv-xxxviii described in Example 66, 1,3-dibromopropane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow oil 45-J with a total yield of 17.3%. ESI-MS (M+H) + :248.2. 1 H NMR (400MHz, CDCl3) δ7.10(s,1H),6.97(d,J=7.9Hz,1H),6.74(d,J=7.7Hz,1H),5.09(d,J=9.3Hz,1H),4.04(d,J=11.3Hz,1H),3.82(s,3H),3.70(d, J=11.2Hz,1H),3.53(s,1H),3.09(s,1H),2.87(s,3H),2.67(s,1H),2.33( d,J=9.2Hz,1H),2.19(d,J=7.6Hz,2H),1.99(d,J=6.6Hz,2H),1.87(s,1H).

[0578] Example 75: 1-(8'-methoxyspiro[cyclopenta-1,4'-isobenzodihydrofuran]-1'-yl)-N-methylmethanamine

[0579]

[0580] Synthesis route and reaction steps:

[0581] Referring to steps xxxv-xxxviii described in Example 66, 1,4-dibromobutane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow oil 45-K in an overall yield of 1.45%. 1 H NMR (400MHz, CDCl3) δ7.21(d,J=6.2Hz,1H),6.91(s,1H),6.68(s,1H),5.11(d,J=6.3Hz,1H),3.80(s,3H),3.65(d, J=11.3Hz,1H),3.45(d,J=11.3Hz,1H),3.09(d,J=11.1Hz,1H),3.00–2.88(m,1H),2.53(s,3H),1.96–1.62(m,8H). 13 C NMR (151MHz, CDCl3) δ155.13,145.72,127.78,123.59,118.06,107.25,71.21 ,68.37,55.18,52.61,44.84,40.09,37.70,35.76,26.52,26.03.ESI-MS(M+H) +:262.2.HMRS:calc.for C 16 H 23 NO2([M+H] + )262.1802, found 262.1803.

[0582] Example 76: 1-(6'-methoxyspiro[cyclopenta-1,4'-isobenzodihydrofuran]-1'-yl)-N-methylmethanamine

[0583]

[0584] Synthesis route and reaction steps:

[0585] Referring to steps xxxv-xxxviii described in Example 66, 1,4-dibromobutane (1.0 eq) was used to replace methyl iodide (2.0 eq) in step xxxv to obtain yellow oil 45-L in an overall yield of 9.74%. 1 H NMR(400MHz, CDCl3)δ6.96(s,1H),6.83–6.58(m,2H),4.86(s,1H),3.81–3.59(m,4H),3. 45(s,1H),2.93(d,J=32.0Hz,2H),2.47(d,J=14.0Hz,3H),1.85(dd,J=75.3,32.4Hz,8H). 13 C NMR (151MHz, CDCl3) δ158.45,145.75,127.49,125.02,111.35,111.19,75.11 ,71.51,56.74,55.17,45.30,40.27,37.50,36.43,26.38,25.89.ESI-MS(M+H) + :262.2.HMRS:calc.for C 16 H 23 NO2([M+H] + )262.1802, found 262.1803.

[0586] Example 77: 1-((4,4,6-Trimethylisochroman-1-yl)-N-methylmethanamine

[0587]

[0588] Synthesis route and reaction steps:

[0589] Referring to steps xxxv-xxxviii described in Example 66, 3-methylbenzeneacetonitrile was used to replace 3-methoxybenzene isocyanide in step xxxv to obtain yellow oil 45-M in an overall yield of 33.4%. 1 H NMR (400MHz, CDCl3) δ7.14(s,1H),6.96(d,J=6.0Hz,2H),5.01(d,J=8.5Hz,1H),3.68(d,J=11.1Hz,1H),3.51(d,J=11.1H z,1H),3.30(d,J=12.4Hz,1H),3.02(t,J=11.0Hz,1H),2.68(s,3H),2.32(s,3H),1.28(s,3H),1.19(s,3H).ESI-MS(M+H) + :220.2.

[0590] Example 78: 1-(4,4-Dimethyl-6-hydroxyisochroman-1-yl)-N-methylmethanamine

[0591]

[0592] Synthesis route:

[0593]

[0594] Reaction steps: 200 mg 45-B (0.85 mmol, 1.0 eq) was dissolved in 10 mL dichloromethane, added to a 25 mL two-necked bottle, and after replacing argon, 3.75 mL BBr3 dichloromethane solution (17% in CH2Cl2, 2.55 mmol, 3.0 eq) was slowly added to the solution under ice bath conditions. After reacting for 20 min under ice bath, the reaction solution was slowly added to a large amount of ice water to quench. Then, it was extracted with ethyl acetate (25 mL x 3), and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (DCM / MeOH=20 / 1) to obtain 76 mg of white solid 45-B, with a yield of 40.4%. 1H NMR (400MHz, CD3OD) δ6.92(d,J=8.0Hz,1H),6.78(d,J=16.3Hz,1H),6.63(d,J=7.3Hz,1H),4.84(d,J=8.4Hz,1H),3.69(t,J=14.1Hz,1H) ,3.49(s,1H),3.04(t,J=14.5Hz,1H),2.91(d,J=10.6Hz,1H),2.49(d,J=16.9Hz,3H),1.29(s,3H),1.19(d,J=17.1Hz,3H).ESI-MS(M+H) + :222.3

[0595] Example 79: Monoamine transporter binding protein binding activity test of aryl annular compounds (I):

[0596] This part of the biological activity test was completed at Shanghai WuXi AppTec Pharmaceuticals Co., Ltd. (hereinafter referred to as WuXi AppTec). The cell lines stably expressing SERT, NET and DAT established by WuXi AppTec, as well as the reuptake experimental methods developed and established, were used for sample testing. The positive references for each target were: BTCP for DAT, Nisoxetine for NET, and Citalopram for SERT, which were provided by WuXi AppTec. The inhibition rate of the test compound on the three transporters of SERT, NET and DAT at the specified concentration was calculated to calculate the IC 50 The specific experimental process is as follows:

[0597] 1. Cell culture

[0598] 1) Thaw cells and culture for 3 to 4 days.

[0599] 2) The cells were passaged and cultured in the incubator for another 3 days.

[0600] 3) The cells were digested with trypsin-EDTA and collected after centrifugation at 1000 rpm for 5 minutes.

[0601] 4) Redisperse the cell pellet in 10 mL of growth medium. Use a sterile pipette to pipette up and down to remove clumps. TM Count cells to determine cell viability.

[0602] 5) Dilute the cell suspension to 1 M cells / ml (20,000 cells per 20 μl well) using culture medium and seed into a 384-well cell plate.

[0603] 6) Place the plate in a 37°C / 5% CO2 incubator for 16-20 hours.

[0604] (II) Transporter testing

[0605] 1) Using the Bravo automated liquid handling platform (hereinafter referred to as Bravo), the reference compound solution with a maximum concentration of 2 μM was diluted in a 4-fold concentration gradient using an assay buffer (20 mM HEPES in HBSS, containing 0.1% BSA), in duplicate; the test compound was diluted in a 3-fold concentration gradient to obtain 10 different concentrations of the test compound solution with a maximum concentration of 6 μM, with two samples for each concentration.

[0606] 2) Use Washer (750rpm, 15s) aspirates the medium from the wells and transfers 25μL / well of compound dilution to the cell plate by Bravo. Note: For high control wells, add 25μL of assay buffer containing BSA (containing 0.2% DMSO); for low control wells, add 25μL of 2μM reference compound dilution solution.

[0607] 3) Centrifuge at 300 rpm for 15 seconds and then incubate at 37°C for 30 minutes.

[0608] 4) After incubation with the compound, add 25uL of dye solution to each well and incubate at 37°C for 30 minutes.

[0609] 5) Use The multi-mode plate reader reads the plate information and calculates the corresponding inhibition rate.

[0610] Some activity test results are shown in the following table:

[0611] Table 1 In vitro triple reuptake inhibition activity test results of compounds (I)

[0612]

[0613]

[0614]

[0615] Example 80: Monoamine transporter binding protein binding activity test of aryl annular compounds (II):

[0616] This part of the biological activity test was completed at Shanghai WuXi AppTec Pharmaceuticals Co., Ltd. The method was the same as Example 79, and the inhibition rate of the three transporters of SERT, NET and DAT was tested at a specified concentration. Some of the test results are shown in the following table:

[0617] Table 2 In vitro triple reuptake inhibition activity test results of compounds (II)

[0618]

[0619]

[0620]

[0621] Example 81: Monoamine transporter binding protein binding activity test of aryl annular compounds (III):

[0622] This part of the biological activity test was completed at Shanghai WuXi AppTec Pharmaceuticals Co., Ltd. (hereinafter referred to as WuXi AppTec). The method was the same as Example 79, and the inhibition rate of the three transporters of SERT, NET and DAT was tested by the compound at a specified concentration. The results are shown in the following table:

[0623] Table 3 In vitro triple reuptake inhibition activity test results of compounds (III)

[0624]

[0625]

[0626] *********.

Claims

1. A compound represented by formula (Ia), (Ib), (Ic), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, In formula (Ia), (Ib) and (Ic), n=1, m=1; R 1 and R 2 are each independently hydrogen, methyl, ethyl, propyl or methylcyclopropyl; or R 1 and R 2 Together with the nitrogen atoms to which they are attached, they form R 5 and R 6 are each independently (i) hydrogen, methyl, -OCH3, trifluoromethyl, halogen; or (ii) R 5 and R 6 Together with the carbon atom to which they are attached they form a phenyl group; R 7 is selected from hydrogen, methyl or F.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 5 and R 6 are independently hydrogen, methyl, methoxy, trifluoromethyl or Cl or R 5 and R 6 Combined into phenyl; R 7 It is hydrogen, methyl, and F.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

5. A pharmaceutical composition, characterized in that It comprises an effective therapeutic amount of an active ingredient and a pharmaceutically acceptable excipient or carrier; The active ingredient is selected from: The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof.

6. Use of the compound as claimed in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a monoamine transporter protein modulator: The monoamine transporter protein is selected from one or more of serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET).

7. Use of the compound as claimed in claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing, treating or diagnosing depression, anxiety, schizophrenia, attention deficit disorder, obesity, pain or neurodegenerative diseases.

Images