Fluorine-substituted cyclopropylamine compounds and their preparation, pharmaceutical compositions and uses

Abstract

The present invention provides compounds of general formula I, their racemates, R-isomers, S-isomers, pharmaceutically acceptable salts and mixtures thereof, methods for preparing them, pharmaceutical compositions containing such compounds and their use as lysine-specific demethylase 1 (LSD1) inhibitors. The present invention provides the use of fluorine-substituted cyclopropylamine compounds of general formula I in the treatment of cancer. [Formula 1]

Description

Detailed Description of the Invention [Technical field]

[0001] The present invention relates to the fields of medicinal chemistry and therapeutics, and in particular to fluorine-substituted cyclopropylamine compounds, methods for their preparation, pharmaceutical compositions containing such compounds and their use as lysine-specific demethylase 1 (LSD1) inhibitors, particularly for the preparation of drugs for treating diseases such as cancer, leukemia, etc. [Background technology]

[0002] Epigenetics is a subfield of genetics that studies the heritable change in gene expression through reversible modifications to nucleotides or chromosomes, on the premise that the DNA sequence of genes remains unchanged. The regulatory mechanisms of epigenetics mainly include DNA methylation, histone modification, non-coding RNA action, etc. In most cases, epigenetic information is accumulated through changes in the chemical modifications of cytosine and histones, and these changes in chemical structure regulate the structure of chromatin. Normal epigenetic processes have an important role in vital activities such as embryonic development and cell differentiation. Research has proven that the occurrence of many diseases is related to abnormalities in epigenetic modifications. In recent years, epigenetics has become the focus of research in biology, medicine and other fields, and related research on epigenetics is of great significance in the process of preventing and treating many diseases in mankind.

[0003] LSD1 (also called BHC110, p110b and NPAO) was identified by Shi's research team in 2004, and its structure is highly conserved from yeast to humans. In cells, the demethylation ability of LSD1 has a high degree of gene, substrate and environment specificity, and gene expression at different gene sites produces different (and therefore opposite) effects. Studies have found that LSD1 plays an important role in promoting normal cell differentiation, but it has also been found that LSD1 exerts an unjustified inhibitory effect on downstream abnormal gene targets of genetic damage that leads to leukemia through abnormal recruitment (e.g. MLL-AF9). In such cases, LSDD1 maintains the activity conferred on leukemia stem cells (LSCs) by the initial damage, and the downstream cellular effects of LSD1 are also significantly different from normal cellular conditions. In normal hematopoiesis, no changes in gene expression are observed at the level of the initial hematopoietic stem cells (HSCs), which is consistent with the observation of a completely opposite result of LSD1 depletion resulting in a reduction in blood cells. Therefore, LSD1 may be a potential drug target for treating leukemia if it can produce controllable, reversible toxicity in normal haematopoietic cells.

[0004] The development of small molecule LSD1 inhibitors with novel structures has important research significance for the study of the treatment of diseases such as malignant tumors and leukemia. Summary of the Invention

[0005] One object of the present invention is to provide a fluorine-substituted cyclopropylamine compound represented by the general formula I, its medicamentous salt, racemate, R-isomer, S-isomer or mixtures thereof.

[0006] Another object of the present invention is to provide a method for preparing the fluorine-substituted cyclopropylamine compound represented by the above general formula I.

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the fluorine-substituted cyclopropylamine compounds represented by the above general formula I, its medicament salts, racemates, R-isomers, S-isomers or mixtures thereof.

[0008] Yet another object of the present invention is to provide a lysine-specific demethylase 1 (LSD1) inhibitor, comprising one or more selected from the group consisting of fluorine-substituted cyclopropylamine compounds represented by the above general formula I, their pharmaceutical salts, racemates, R-isomers, S-isomers, and mixtures thereof.

[0009] Yet another object of the present invention is to provide a use of the fluorine-substituted cyclopropylamine compound represented by the above general formula I, its pharmaceutical salt, racemate, R-isomer, S-isomer or mixture thereof in the manufacture of a drug for treating malignant tumor diseases associated with lysine-specific demethylase 1 (LSD1) inhibitors, such as cancer, leukemia and the like.

[0010] Yet another object of the present invention is to provide a method for treating malignant tumor diseases, such as cancer, leukemia, etc., associated with lysine-specific demethylase 1 (LSD1) inhibitors, comprising administering to a patient in need of such treatment one or more of the fluorine-substituted cyclopropylamine compounds represented by the above general formula I, its medicamentous salt, racemate, R-isomer, S-isomer, or mixtures thereof.

[0011] In accordance with the above objective, the present invention provides a fluorine-substituted cyclopropylamine compound having a structure represented by the following general formula I, and its racemate, R-isomer, S-isomer, pharma- ceutically acceptable salt, or mixture thereof:

[0012] [ka] General formula I (wherein A is selected from a substituted or unsubstituted benzene ring or a substituted or unsubstituted C5-C12 aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the substituted benzene ring or substituted aromatic heterocycle contains 1 to 3 substituents in each ring.

[0013] Here, the substituents in the substituted benzene ring or substituted aromatic heterocycle are hydrogen, a hydrogen isotope, a halogen, a C1 to C12 linear or branched alkyl group substituted with 1 to 3 halogens or an unsubstituted one, a C1 to C12 linear or branched alkoxy group substituted with 1 to 3 halogens or a phenyl group or an unsubstituted one, a C2 to C12 linear or branched unsaturated hydrocarbon group substituted with 1 to 3 halogens or an unsubstituted one, a C3 to C6 cycloalkyl group substituted with 1 to 3 halogens or an unsubstituted one, a C1 to C6 linear or branched alkyl group substituted with a C1 to C6 alkoxy group, a C1 to C6 linear or branched alkyl group substituted with a C3 to C6 cycloalkyl group, a hydroxy group, a cyano group, a nitro group, a C1 to C6 linear or branched hydroxyalkyl group, or a mercapto group.

[0014] Alternatively, any two substituents in the substituted benzene ring or substituted aromatic heterocycle may be linked together with the adjacent carbon atom or heteroatom to form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O and S, and the 5- to 7-membered heterocycle may be substituted with a substituent selected from hydrogen, a hydrogen isotope, a halogen, a C1-C6 linear or branched alkyl group substituted with 1 to 3 halogens or an unsubstituted group, a C1-C6 linear or branched alkoxy group substituted with 1 to 3 halogens or an unsubstituted group, or a hydroxy group.

[0015] Each R1 is independently selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, hydrogen, a substituted or unsubstituted C1-C6 alkyl group, -SO2Ra, -NC(O)Ra, -CH2C(O)ORa, -C(O)ORa, -C(O)Ra, -C(O)NRaRb, -NRcRd, a substituted or unsubstituted amino group, urea, amide, sulfamide, a substituted or unsubstituted aralkyl group, and a substituted or unsubstituted heteroaralkyl group.

[0016] Each Ra is independently a hydrogen atom, a phenyl group, a phenylmethyl group, a 3,5-dimethylisoxazol-4-yl group, a 1,2-dimethyl-1H-imidazol-4-yl group, a C3-C7 cycloalkyl group, a C1-C6 alkyl group, a C1-C4 alkoxy group, a C1-C3 alkylamino group, or -NHPh.

[0017] Rb is hydrogen or a C1-C3 alkyl group, or, when attached to the same atom, Ra together with Rb form a 5- or 6-membered heterocycloalkyl ring. Rc and Rd are each independently selected from hydrogen, a C1-C3 linear or branched alkyl group, a C3-C5 cycloalkyl group, a C1-C3 alkoxy group, a 4- to 6-membered heterocyclic group, a C1-C3 alkyl acyl group, a C5-C7 aryl acyl group, a benzyl group, and a C5-C7 aryl group, the C1-C3 linear or branched alkyl group being optionally substituted with one or more groups selected from a methylsulfonyl group, a C1-C3 alkoxy group, and a C1-C3 alkoxycarbonyl group, and the heterocyclic group contains one heteroatom selected from oxygen, sulfur, and nitrogen.

[0018] R2 is hydrogen or COOH. R3 is a C1-C4 alkyl group, an acyl group, -C(O)CF3 or hydrogen. W is -(CH2) 1-4 or -CH(Re)(CH2) 0-3 where Re is CN or a C1-C4 alkyl group.

[0019] Y is N or C. X is N or C. Z is 0 or (CH2)q, where q is 0 to 2, and when q is 0, Z represents a bond.

[0020] n is 0 to 3. The condition is that if Z is 0, then Y is N and X is C. And the proviso is that when X is C, at least one of the R groups connected to X is not hydrogen. In another preferred embodiment, when X is N, only one R1 is linked to X.

[0021] In another preferred embodiment, W is -CH2-. In another preferred embodiment, Z is (CH2)q, where q is 1. In another preferred embodiment, X is C, and at least one of R1 linked to X is -NRcRd, where Rc and Rd are each independently selected from hydrogen, a C1-C3 linear or branched alkyl group, a C3-C5 cycloalkyl group, a C1-C3 alkoxy group, a 4-6 membered heterocyclic group, a C1-C3 alkyl acyl group, a C5-C7 aryl acyl group, a benzyl group, and a C5-C7 aryl group, the C1-C3 linear or branched alkyl group may be substituted with one or more groups selected from a methylsulfonyl group, a C1-C3 alkoxy group, and a C1-C3 alkoxycarbonyl group, and the heterocyclic group contains one heteroatom selected from oxygen, sulfur, and nitrogen.

[0022] In another preferred embodiment, X is N and at least one of R1 linked to X is selected from a substituted or unsubstituted aryl group, a heteroaryl group, an aralkyl group, and a heteroaralkyl group.

[0023] In another preferred embodiment, X is N, and at least one of R1 linked to X is selected from a substituted or unsubstituted aryl C1-C4 alkyl group, and a heteroaryl C1-C4 alkyl group.

[0024] In another preferred embodiment, the compound has a structure represented by general formula (1R,2S)-Ia or general formula (1S,2R)-Ib.

[0025] [ka] In the present invention, the halogen is F, Cl, Br or I.

[0026] In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, the term "C1-C6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, including a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, and the like, and preferably an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group, but is not limited to these.

[0027] In the present invention, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group.

[0028] In the present invention, the term "C2-C6 alkenyl group" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including, but not limited to, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, and a hexenyl group.

[0029] In the present invention, the term "C2-C6 alkynyl group" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including, but not limited to, an ethynyl group, a propargyl group, a butynyl group, an isobutynyl group, a pentynyl group, and a hexynyl group.

[0030] In the present invention, the term "C3-C10 cycloalkyl group" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. The terms "C3-C8 cycloalkyl group", "C3-C7 cycloalkyl group", and "C3-C6 cycloalkyl group" have similar meanings.

[0031] In the present invention, the term "C3-C10 cycloalkenyl group" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecenyl groups. The term "C3-C7 cycloalkenyl group" has a similar meaning.

[0032] In the present invention, the terms "aromatic ring" or "aryl group" have the same meaning, and preferably the "aryl group" is a "C6-C12 aryl group" or a "C6-C10 aryl group". The term "C6-C12 aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as a phenyl group, a naphthyl group, etc. The term "C6-C10 aryl group" has a similar meaning.

[0033] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. The heteroatoms in this context include oxygen, sulfur and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0034] In the present invention, the term "3- to 12-membered heterocyclic group" refers to a saturated or unsaturated 3- to 12-membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as a dioxacyclopentyl group. The term "3- to 7-membered heterocyclic group" has a similar meaning.

[0035] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms in a particular group with a specified substituent. The specified substituents are the corresponding substituents described above or in the individual examples. Unless otherwise stated, a substituted group may have one substituent selected from a specified group at any substitutable position of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl group, may be combined with another ring, such as a cycloalkyl group, to form a spiro-bicyclic system, for example, the two rings share a common carbon atom. As will be appreciated by those skilled in the art, the combinations of substituents envisioned in the present invention are those that are stable or chemically feasible. The substituents may be, for example, deuterium, C 1-8 Alkyl group, C 2-8 Alkenyl group, C 2-8 Alkynyl group, C 3-8 Cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, halogens, hydroxyl groups, carboxyl groups (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group, alkoxy group, C 1-10 Such as, but not limited to, a sulfonyl group.

[0036] In a more preferred embodiment of the present invention, the compound of the present invention represented by general formula (I) is preferably the following specific compound.

[0037] [Table 1] TIFF0007605579000004.tif250157TIFF0007605579000005.tif242156TIFF0007605579000006.t if250158TIFF0007605579000007.tif252157TIFF0007605579000008.tif242157TIFF00076055790 00009.tif249156TIFF0007605579000010.tif249156TIFF0007605579000011.tif241156TIFF000 7605579000012.tif249157TIFF0007605579000013.tif250155TIFF0007605579000014.tif240156 TIFF0007605579000015.tif249155TIFF0007605579000016.tif249155TIFF0007605579000017.t if248157TIFF0007605579000018.tif251158TIFF0007605579000019.tif248156TIFF00076055790 The compounds of the present invention have asymmetric centers, chiral axes and chiral planes and may exist in the form of racemates, R-isomers or S-isomers. Those skilled in the art can separate the racemates to obtain the R-isomers and / or S-isomers by conventional techniques.

[0038] The present invention provides a medicament salt of the compound of general formula I, specifically, the compound of general formula I reacts with an inorganic acid or an organic acid to form a common medicament salt. For example, the common medicament salt can be obtained by reacting the compound of general formula I with an inorganic acid or an organic acid, the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc., and the organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, tert-butyl ether ... The general formula I compounds may be used in the preparation of carboxylic acids, such as fluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid, and hydroxyethanesulfonic acid, or may be used in the preparation of sodium, potassium, calcium, aluminum, or ammonium salts formed with the compounds of general formula I and inorganic bases, or may be used in the preparation of methylamine, ethylamine, or ethanolamine salts formed with the compounds of general formula I and organic bases.

[0039] Another aspect of the present invention provides a method for producing a compound represented by general formula I, which is carried out according to the following scheme 1, scheme 2 or scheme 3. Compounds of formula (I) may be prepared by the method depicted in Scheme 1 below.

[0040] The structural formulas and R group symbols used in the following schemes are used in this section only. Compounds of formula (II) and (III) can be obtained commercially or synthesized by ordinary techniques in the art. Those skilled in the art will understand that the compounds exemplified below may exist in the form of hydrochloride salts when HCl is used in the final step of preparation.

[0041] Compounds of formula (II) and (III) can be reacted under conventional reductive amination conditions to give compounds of formula (I). The addition reaction is usually carried out in the presence of a polar solvent (e.g., methanol) and an acid (e.g., acetic acid). The acid is usually present in an amount of 100 mol % relative to compound (I). The reducing agent is usually a borohydride (e.g., sodium cyanoborohydride).

[0042] Scheme 1 [ka] Here, A, W, X, Y, Z, R1, R2, and R3 are each as defined above, R4 is selected from the group consisting of H, m, or a methyl group, and V is -CH2-W- or -W-CH2-.

[0043] Compounds of formula (I) can be conveniently prepared from the synthesized cyclopropylamine (IV) and a suitably protected aldehyde (V) by the method shown in Scheme 2. Amine (IV) and aldehyde (V) undergo reductive amination to give intermediate formula (VI). The amino group is then protected. The protecting group on the X or Y group is then removed to give compound formula (VII) and the appropriate R1 substituent is functionalized to give compound formula (VIII). The amine is then deprotected and functionalized with the R3 group.

[0044] Scheme 2 [ka] Here, A, W, X, Y, Z, R1, R2, and R3 are each as defined above, R4 is selected from the group consisting of H, m, or a methyl group, and V is -CH2-W- or -W-CH2-.

[0045] Compounds of formula (II) and (IV) can be synthesized as shown in Scheme 3. Cinnamic acid (IX) is condensed with dimethylhydroxyamine in the presence of a condensing agent (e.g. HATU) and a base (e.g. DIPEA) to give amide (X). This is then cyclopropylated and reacted under standard conditions (e.g. trimethylsulfoxonium iodide and sodium hydride) to give compound of formula (XI). The amide is then hydrolyzed to give acid of formula (XII). This is then reacted under standard Curtius rearrangement conditions to give the required compound of formula (IV). Compound of formula (IV) is converted to compound of formula (II) under standard conditions.

[0046] Scheme 3 [ka] The compounds of formula (1R,2S)-I and (1S,2R)-I can be obtained by the preparation methods described in Scheme 4 and Scheme 5, respectively, and the specific scanning steps are the same as those in Scheme 2.

[0047] [ka] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds of general formula (I) or their medicament salts, enantiomers, diastereomers or racemates, and optionally one or more medicament carriers, excipients, adjuvants, auxiliary agents and / or diluents, such as odorants, fragrances, sweeteners, etc.

[0048] The pharmaceutical composition provided by the present invention preferably contains 1-99% by weight of active ingredient, and the suitable ratio is that the compound of general formula I as the active ingredient accounts for 65wt%-99wt% of the total weight, and the rest is pharma- ceutically acceptable carrier, diluent or solution or salt solution.

[0049] The compounds and pharmaceutical compositions provided by the present invention may be in a variety of forms, for example, tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and may be present in suitable solid or liquid carriers or diluents, and in suitable sterile equipment for injection or infusion.

[0050] Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional manufacturing methods in the pharmaceutical field. The compound of formula I is contained in a unit dose of the preparation in an amount of 0.05-200 mg, preferably in an amount of 0.1 mg-100 mg.

[0051] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via oral, nasal, cutaneous, pulmonary or gastrointestinal routes. Oral administration is the most preferred. The most preferred daily dosage is 0.01 mg to 200 mg / kg body weight, administered in one dose, or 0.01 mg to 100 mg / kg body weight, administered in several doses. Regardless of which administration method is used, the optimal dosage for an individual is determined by the specific treatment. Usually, a small dosage is administered first, and then gradually increased until the optimal dosage is found.

[0052] In yet another aspect of the present invention, there is provided a lysine-specific demethylase 1 (LSD1) inhibitor comprising one or more selected from the group consisting of a fluorine-substituted cyclic amine compound represented by the above general formula I, a medicament salt, racemate, R-isomer, S-isomer, or a mixture thereof, and optionally one or more medicament carriers, excipients, adjuvants, auxiliary agents and / or diluents.

[0053] The compounds and compositions of the present invention are used for the treatment and prevention of malignant tumor diseases associated with lysine-specific demethylase 1 (LSD1) inhibitors, including, but not limited to, cancer, leukemia, and the like.

[0054] Thus, in yet another aspect of the present invention, there is provided the use of a compound represented by the above general formula I, its pharmaceutical salt, racemate, R-isomer, S-isomer or a mixture thereof in the manufacture of a medicament for treating malignant tumor diseases associated with lysine-specific demethylase 1 (LSD1) inhibitors, such as cancer, leukemia and the like.

[0055] In yet another aspect of the present invention, there is provided a method for treating malignant tumor diseases associated with lysine-specific demethylase 1 (LSD1) inhibitors, such as cancer, leukemia, etc., comprising administering to a patient in need of such treatment one or more compounds selected from the group consisting of a compound represented by the above general formula I, its pharmaceutical salt, racemate, R-isomer, S-isomer, or mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Specific embodiments active ingredient The present invention provides a fluorine-substituted cyclopropylamine compound having the structure represented by the following general formula I, or a racemate, R-isomer, S-isomer, pharma- ceutically acceptable salt, or a mixture thereof:

[0057] [ka] General formula I however, A is selected from a substituted or unsubstituted aromatic ring (preferably a benzene ring) or a substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the substituted benzene ring or substituted aromatic heterocycle contains 1-3 substituents in each ring; Here, the substituents in the substituted aromatic ring or substituted aromatic heterocycle are independently selected from hydrogen, a hydrogen isotope, a halogen, an unsubstituted or substituted C1 to C12 linear or branched alkyl group, an unsubstituted or substituted C1 to C12 linear or branched alkoxy group, an unsubstituted or substituted C2 to C12 linear or branched unsaturated hydrocarbon group, an unsubstituted or substituted C3 to C6 cycloalkyl group, a C1 to C6 linear or branched alkyl group substituted with a C1 to C6 alkoxy group, a C1 to C6 substituted with a C3 to C6 cycloalkyl group, A linear or branched alkyl group, a hydroxy group, a cyano group, a nitro group, a C1-C6 linear or branched hydroxyalkyl group or a mercapto group, oxygen (=O), an unsubstituted or substituted C6-C12 aryl group (e.g., a phenyl group, a naphthyl group), an unsubstituted or substituted C6-C12 aryloxy group (e.g., a phenyl group, a naphthyl group), an unsubstituted or substituted phenoxy group, a carboxy group, an acyl group (e.g., an acetyl group), and a sulfonyl group (including a benzenesulfonyl group and an alkylsulfonyl group). Preferably, the substituents are selected from the group consisting of halogen, a C1-C4 linear or branched alkyl group, a halogen-substituted C1-C4 linear or branched alkyl group, a C1-C4 alkyloxy group, and a phenyl group substituted with a cyano group; alternatively, any two substituents in the substituted aromatic ring or substituted aromatic heterocycle may be linked together with adjacent carbon atoms or heteroatoms to form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S; and the 5- to 7-membered heterocycle may be selected from the group consisting of a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from N, O, and S. The ring may be optionally substituted with a substituent selected from the group consisting of hydrogen, a hydrogen isotope, a halogen, a C1-C6 linear or branched alkyl group substituted with 1 to 3 halogens or an unsubstituted group, a C1-C6 linear or branched alkoxy group substituted with 1 to 3 halogens or an unsubstituted group, and a hydroxy group; each R1 is independently a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, hydrogen, a substituted or unsubstituted C1-C6 alkyl group, -SO2Ra, -NC(O)Ra, -(CH2) m C(O)ORa, -C(O)O(CH2) m Ra, -C(O)ORa, -C(O)Ra, -(CH2) mORa, -C(O)NRaRb, -C(S)NRaRb, -CORa, -NRcRd, a substituted or unsubstituted amino group, a substituted or unsubstituted urea, a substituted or unsubstituted amide, a substituted or unsubstituted sulfoamide, a substituted or unsubstituted aralkyl group, and a substituted or unsubstituted heteroaralkyl group, where m is an integer of 1 to 3, and preferably the substituent is a halogen, a hydroxy group, a carboxy group, a cyano group, an amino group, a C1 to C4 alkyl group, a halogen-substituted C1 to C4 alkyl group, a C1 to C4 alkyl ester group, a C1 to C4 alkylsulfonyl group, an aminophenylamide group ( [ka] ), an arylalkyl group, and an aryl group; Each Ra is independently a hydrogen atom, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenylmethyl group, a 3,5-dimethylisoxazol-4-yl group, a 1,2-dimethyl-1H-imidazol-4-yl group, a substituted or unsubstituted C3-C7 cycloalkyl group, a substituted or unsubstituted C3-C7 heterocyclic group, a substituted or unsubstituted C3-C7 heterocyclic alkyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C3 alkylamino group, -NHPh, or a substituted or unsubstituted 5-10 membered alkyl group. heteroaryl group, substituted or unsubstituted arylalkyl group, and substituted or unsubstituted heteroarylalkyl group, wherein the substituent is preferably selected from the group consisting of a C1-C4 alkyl group, a halogen-substituted C1-C4 alkyl group, a C1-C4 alkyl group substituted with a phenyl group, a C1-C4 alkyl ester group, a C3-C7 cyclic group, a C3-C7 cyclic alkyl group, a C3-C7 heterocyclic group, a C3-C7 heterocycloalkyl group substituted with a benzyl group, an aryl group, a halogen, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a carboxy group, and a benzyl group substituted with a carboxy group; Rb is hydrogen or a C1-C3 alkyl group, or, if attached to the same atom, Ra together with Rb forms a 5- or 6-membered heterocycloalkyl ring; Rc and Rd are each independently selected from hydrogen, a substituted or unsubstituted C1-C3 linear or branched alkyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkoxy group, a substituted or unsubstituted 4-6 membered heterocyclic group, a substituted or unsubstituted C1-C3 alkyl acyl group, a substituted or unsubstituted aryl acyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted benzyl group, and a substituted or unsubstituted aryl group, the C1-C3 linear or branched alkyl group may be substituted with one or more groups selected from a methylsulfonyl group, a C1-C3 alkoxy group, a C1-C3 alkoxycarbonyl group, and an aryl group, and the heterocyclic group contains one heteroatom selected from oxygen, sulfur, and nitrogen, R2 is hydrogen or COOH; R3 is a C1-C4 alkyl group, an acyl group, -C(O)CF3 or hydrogen; W is -(CH2) 1-4 or -CH(Re)(CH2) 0-3 where Re is CN or a C1-C4 alkyl group; Y is N, C or none, X is N or C, Z is 0 or (CH2)q, where q is 0 to 2, and when q is 0, Z represents a bond; n is 0 to 3, The condition is that if Z is 0, then Y is N and X is C.

[0058] In one preferred embodiment of the present invention, A is selected from a substituted or unsubstituted benzene ring or a 5-12 membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the substituted benzene ring or the substituted aromatic heterocycle contains 1-3 substituents in each ring; Here, the substituents in the substituted aromatic ring or the substituted aromatic heterocycle are independently selected from the group consisting of hydrogen, a hydrogen isotope, a halogen, a carboxy group, a nitro group, a C1-C4 alkyl group, a C1-C4 alkanoyl group, a C1-C4 alkoxy group, a cyano group, oxygen (=O), and a sulfonyl group.

[0059] In one preferred embodiment of the present invention, each R1 is independently a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, hydrogen, a substituted or unsubstituted C1-C4 alkyl group, -SO2Ra, -NC(O)Ra, -(CH2) m C(O)ORa, -C(O)ORa, -C(O)Ra, -(CH2) m -ORa, -C(O)NRaRb, -NRcRd, a substituted or unsubstituted aralkyl group, and a substituted or unsubstituted heteroaralkyl group, where m is an integer of 1 to 3; each Ra is independently hydrogen, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenylmethyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C4 alkenyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C3 alkylamino group, -NHPh, or a substituted or unsubstituted 5-10 membered heteroaryl group; Rb is hydrogen or a C1-C3 alkyl group; Rc and Rd are each independently selected from hydrogen, a C1-C3 linear or branched alkyl group, a substituted or unsubstituted C3-C5 cycloalkyl group, a substituted or unsubstituted C1-C3 alkoxy group, a substituted or unsubstituted 4-6 membered heterocyclic group, a substituted or unsubstituted C1-C3 alkyl acyl group, a substituted or unsubstituted aryl acyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted benzyl group, and a substituted or unsubstituted aryl group, the heterocyclic group containing one heteroatom selected from oxygen, sulfur, and nitrogen; The substituent is selected from the group consisting of a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C8 cycloalkyl group, a 3-12 membered heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxy group, a carboxy group (-COOH), a C1-C8 aldehyde group, a C2-10 acyl group, a C2-10 ester group, an amino group, and an alkoxy group.

[0060] In another preferred embodiment of the present invention, X is N, and R1 linked to X is selected from a substituted or unsubstituted aryl group, a heteroaryl group, an aralkyl group, and a heteroaralkyl group, wherein the substituent is selected from the group consisting of a C1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C8 cycloalkyl group, a 3-12 membered heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxy group, a carboxy group (-COOH), a C1-C8 aldehyde group, a C2-10 acyl group, a C2-10 ester group, an amino group, and an alkoxy group.

[0061] In one preferred embodiment of the present invention, X is N, and R1 linked to X is selected from substituted or unsubstituted aryl C1-C4 alkyl groups and heteroaryl C1-C4 alkyl groups, wherein the substituents are selected from the group consisting of C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, C3-C8 cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, halogens, hydroxy groups, carboxy groups (-COOH), C1-C8 aldehyde groups, C2-10 acyl groups, C2-10 ester groups, amino groups, and alkoxy groups.

[0062] In one preferred embodiment of the present invention, W is -(CH2) 1-2 It is. In one preferred embodiment of the present invention, the structure of the compound is represented by the general formula (1R,2S)-Ia or the general formula (1S,2R)-Ib.

[0063] [ka] Manufacturing method The method for producing a fluorine-substituted cyclic amine compound as an active ingredient according to the present invention can be selected from the following scheme 1 or scheme 2.

[0064] Scheme 1 Compounds of formula (II) and (III) can be reacted under reductive amination conditions to give compounds of formula (I).

[0065] [ka] Scheme 2 After the reaction of the compound of formula (IV) with the compound of formula (V) to obtain the compound of formula (VI), the amino group is protected and then the protecting groups of the X and / or Y groups are removed to obtain the compound of formula (VII), the compound of formula (VII) is functionalized with the R1 substituent to obtain the compound of formula (VIII), and the protecting group of the amino group is removed and the compound of formula (VIII) is functionalized with the R3 group to obtain the compound of formula (I).

[0066] [ka] wherein A, W, X, Y, Z, R1, R2, and R3 are as defined above, R4 is selected from the group consisting of H or a methyl group, and V is -CH2-W- or -W-CH2-. In one preferred embodiment of the present invention, the method for preparing the compound of formula (II) comprises the following steps: The cinnamic acid compound of formula (IX) is condensed with dimethylhydroxyamine in the presence of a condensing agent and a base to obtain the amide compound of formula (X); then cyclopropylated and reacted to obtain the compound of formula (XI); then the compound of formula (XI) is hydrolyzed to obtain the compound of formula (XII); then reacted under Curtius rearrangement conditions to obtain the compound of formula (IV), and the R group of the compound of formula (IV) is functionalized to obtain the compound of formula (II);

[0067] [ka] The compounds of formula (1R,2S)-I and (1S,2R)-I can be obtained by the preparation methods described in Scheme 4 and Scheme 5, respectively, and the specific scanning steps are the same as those in Scheme 2.

[0068] [ka] The present invention is further described by way of example in the following examples, which are intended to illustrate the invention only and are not intended to limit the invention in any way.

[0069] Example 1 Benzyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A1) [ka] 20mL of anhydrous methanol was placed in a 100mL eggplant flask, 167mg of trans-2-phenylcyclopropylamine and 300mg of 4-fluoro-4-formylpiperidine-1-carboxylate were weighed and added to the methanol solution, 72μl of acetic acid was added to the reaction system, heated under nitrogen gas protection and refluxed for 10 minutes, cooled to room temperature, 142mg of sodium cyanoborohydride was added to the solution, stirred at room temperature for 5 hours, and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, methanol was removed by rotary drying, 50mL of water was added, and the mixture was washed three times with 50mL of dichloromethane, the organic layer was rotary dried, and the desired product A1 was obtained by column chromatography with dichloromethane:methanol = 50:1 (310mg, yield 72%). 1H NMR(600MHz,MeOD)δ 7.41-7.34(m,4H),7.36-7.30(m,3H),7.27-7.24(m,1H),7.22-7.19(m,2H),5.15(s,2 H),4.14-4.08(m,2H),3.54(d,J=20.1Hz,2H),3.27-3.14(m,2H),3.07(dt,J=8.0,4.1 Hz,1H),2.60(ddd,J=10.3,6.6,3.6Hz,1H),2.02-1.95(m,2H),1.87-1.72(m,2H),1.6 0(ddd,J=10.4,6.8,4.4Hz,1H),1.41(dt,J=7.8,6.7Hz,1H);LRMS(ESI):383.21[M+H] + .

[0070] Example 2 N-((4-fluoropiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A2) [ka]

[0071] 2.1 Synthesis of tert-butyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to 4-fluoro-4-formylpiperidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and production method were the same as in Example 1, and 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl was obtained (yield 75%).

[0072] 2.2 Synthesis of final product A2 3.5g of 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl was dissolved in 30mL of 2M hydrochloric acid in 1,4-dioxane and stirred at room temperature for 10 hours. After the reaction was completed, the solvent was removed by rotary drying to obtain a white solid. The solid was dissolved in a small amount of methanol, a large amount of ethyl acetate was added, and ultrasonic waves were applied to precipitate a white solid. After suction filtration, the cake was dried to obtain 4.4g of the dihydrochloride salt of the target product A2 (yield 97%). 1 H NMR(400MHz,D2O)δ 7.30(t,J=7.4Hz,2H),7.22(t,J=7.3Hz,1H),7.14(d,J=7.5Hz,2H),3.55(d,J=20.3Hz,2 H),3.38(dd,J=13.4,4.7Hz,2H),3.21(td,J=13.2,3.1Hz,2H),2.97(dt,J=8.0,4.1Hz,1H ),2.52(ddd,J=10.4,6.7,3.6Hz,1H),2.25-2.10(m,2H),1.96(dtd,J=37.8,14.7,4.9Hz ,2H),1.50(ddd,J=10.9,7.1,4.4Hz,1H),1.36(q,J=7.2Hz,1H);LRMS(ESI):249.17[M+H] + .

[0073] Example 3 Methyl 4-((4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (A3) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to 4-((4-fluoro-4-formylpiperidin-1-yl)methyl)benzoate methyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A3 (yield 63%). 1H NMR(400MHz,D2O)δ 7.95(d,J=8.3Hz,2H),7.48(d,J=8.2Hz,2H),7.27-7.18(m,2H),7.18-7.12(m,1H),7.08-7.04(m ,2H),4.31(s,2H),3.79(s,3H),3.48(d,J=20.2Hz,2H),3.39(d,J=12.5Hz,2H),3.23(t,J=12.2H z,2H),2.90(dt,J=7.9,4.0Hz,1H),2.44(ddd,J=10.4,6.7,3.6Hz,1H),2.21-2.07(m,2H),2.04- 1.81(m,2H),1.43(ddd,J=10.9,7.2,4.4Hz,1H),1.29(q,J=7.3Hz,1H);LRMS(ESI):397.22[M+H] + .

[0074] Example 4 (1s,4s)-4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexylamine (A4) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate-t-butyl to ((1s,4s)-4-fluoro-4-formylcyclohexyl)carbamate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 2, and product A4 was obtained (yield 70%). 1 H NMR(400MHz,DMSO-d6)δ 7.33-7.27(m,2H),7.25-7.16(m,3H),3.51(d,J=19.8Hz,2H),3.28-3.18 (m,1H),3.05(dt,J=7.9,4.1Hz,1H),2.61(ddd,J=10.3,6.6,3.6Hz,1H), 2.21-2.10(m,2H),2.08-1.97(m,2H),1.87-1.66(m,4H),1.60(ddd,J=10 .5,6.8,4.4Hz,1H),1.38(dt,J=7.9,6.7Hz,1H);LRMS(ESI):263.18[M+H] + .

[0075] Example 5 4-((4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (A5) [ka]

[0076] 5.1 Synthesis of tert-butyl 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamido)methyl)piperidine-1-carboxylate [ka] 210mg of the product obtained in Example 2.1, 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl ester, was dissolved in 15ml of chloroform, and 1.2ml of triethylamine was added. Then, 0.44ml of anhydrous trifluoroacetic acid was slowly added dropwise to the solution. After stirring at room temperature for 30 minutes, 6ml of 1M sodium carbonate solution was added to quench the reaction, and the organic layer was separated. The aqueous layer was extracted twice with 5ml of dichloromethane, and the organic layer was combined and then the solvent was removed by rotary drying. The product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1.09g of yellow oily product, which was 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamido)methyl)piperidine-1-carboxylate-t-butyl ester (yield 85%).

[0077] 5.2 Synthesis of 2,2,2-trifluoro-N-((4-fluoropiperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride [ka] 1.09 g of 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamido)methyl)piperidine-1-carboxylate-t-butyl was dissolved in 15 ml of 2 M hydrochloric acid in 1,4-dioxane and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by rotary drying to obtain a yellow solid, which was 2,2,2-trifluoro-N-((4-fluoropiperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride (yield 99%).

[0078] 5.3 Synthesis of 4-((4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamino)methyl)piperidin-1-yl)benzoate-t-butyl [ka] 1.1 g of 2,2,2-trifluoro-N-((4-fluoropiperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride was dissolved in 20 ml of acetonitrile, and 784 mg of 4-bromomethylbenzoate-t-butyl and 1.2 g of potassium carbonate were added to the reaction system in order, and the mixture was heated to reflux for 2 hours, and the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the acetonitrile was removed by rotary drying, and 30 mL of water was added, and the mixture was extracted three times with 20 mL of dichloromethane. The organic layer was rotary dried and separated by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain 720 mg of 4-((4-fluoro-4-((2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetylamino)methyl)piperidin-1-ylmethyl)benzoate-t-butyl (yield 47%).

[0079] 5.4 Synthesis of final product A5 720 mg of 4-((4-fluoro-4-((2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetylamino)methyl)piperidin-1-ylmethyl)benzoate-t-butyl was dissolved in 20 ml of ethanol, 10 ml of 1M sodium hydroxide solution was added, and the mixture was heated and refluxed for 2 hours, after which the heating was stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary drying. 30 mL of water was added, and the mixture was extracted three times with 20 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then rotary dried. The resulting pale yellow oil was dissolved in 1M hydrochloric acid solution, heated at 90 ° C for 1 hour, and then the reaction was stopped. The reaction solution was stirred in an ice bath for 1 hour, and a solid precipitated. The mixture was filtered by suction, and the cake was dried to obtain a white solid. The product was the dihydrochloride salt of the target product A5, 540 mg (yield 88%). 1 H NMR(400MHz,DMSO-d6)δ 8.00-7.93(m,2H),7.44(dt,J=7.4,1.2Hz,2H),7.26-7.11(m,5H),3.54(d ,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76-2.64(m,2H),2.62-2.4 9(m,3H),2.05-1.85(m,3H),1.45(ddt,J=25.1,13.2,7.2Hz,2H),0.95(td ,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H] + .

[0080] Example 6 N-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A6) [ka]

[0081] 6.1 Synthesis of N-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide [ka] Except for replacing 4-bromomethylbenzoate-t-butyl with bromomethylbenzene, the other necessary raw materials, reagents and preparation methods were the same as in Example 5.3, and 210 mg of the product N-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide was obtained (yield 70%).

[0082] 6.2 Synthesis of final product A6 210mg of N-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide was dissolved in 10ml of ethanol, 5ml of 1M sodium hydroxide solution was added, and the mixture was heated and refluxed for 2 hours. Then, the heating was stopped, the mixture was cooled to room temperature, and the solvent was removed by rotary drying. 30mL of water was added, and the mixture was extracted three times with 20mL of dichloromethane. The organic layer was rotary dried, and the mixture was separated by column chromatography (dichloromethane:methanol=40:1) to obtain 149mg of the desired product A6 (yield 91%). 1 H NMR(500MHz,D2O)δ 7.50-7.41(m,5H),7.35-7.28(m,2H),7.27-7.22(m,1H),7.18-7.12(m,2H),4.32(s,2H) ,3.54(d,J=20.3Hz,2H),3.47(d,J=8.3Hz,2H),3.28(t,J=12.7Hz,2H),2.97(dt,J=8.0,4 .1Hz,1H),2.52(ddd,J=10.4,6.7,3.6Hz,1H),2.22(dd,J=15.3,8.4Hz,2H),2.11-1.86(m ,2H),1.50(ddd,J=10.9,7.2,4.4Hz,1H),1.37(q,J=7.2Hz,1H);LRMS(ESI):339.22[M+H] + .

[0083] Example 7 Methyl 3-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propionate (A7) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to methyl 3-(4-fluoro-4-formylpiperidin-1-yl)propionate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A7 (yield 57%). 1 H NMR(500MHz,D2O)δ 7.32(t,J=7.5Hz,2H),7.25(t,J=7.4Hz,1H),7.16(d,J=7.5Hz,2H),3.68(s,3H),3.61 -3.54(m,4H),3.46(t,J=7.0Hz,2H),3.32-3.23(m,2H),3.00(dt,J=8.0,4.1Hz,1H),2. 93-2.85(m,2H),2.55(ddd,J=10.4,6.7,3.6Hz,1H),2.30-2.20(m,2H),2.16-1.94(m,2 H),1.52(ddd,J=11.1,7.2,4.4Hz,1H),1.38(q,J=7.3Hz,1H);LRMS(ESI):335.21[M+H] + .

[0084] Example 8 1-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)-3-phenyl-1-acetone (A8) [ka]

[0085] 8.1 Synthesis of 2,2,2-trifluoro-N-((4-fluoro-1-(3-phenylpropionyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide [ka] 200 mg of 2,2,2-trifluoro-N-((4-fluoropiperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride, the product of Example 5.2, was dissolved in 10 ml of dry dichloromethane, and 0.22 ml of triethylamine was added. 106 mg of 3-phenylpropionyl chloride dissolved in dichloromethane was added dropwise in an ice bath. After the addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with 15 ml of water and 15 ml of dichloromethane. The organic layer was collected and dried by rotary drying to obtain a colorless oily product, which was the crude product of 2,2,2-trifluoro-N-((4-fluoro-1-(3-phenylpropionyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide.

[0086] 8.2 Synthesis of the final product A8 Except for changing N-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetamide to 2,2,2-trifluoro-N-((4-fluoro-1-(3-phenylpropionyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide, the other required raw materials, reagents and preparation methods were the same as those in Example 6.2, and product A8 was obtained (yield 72%). 1 H NMR(400MHz,DO)δ 7.28-7.12(m,5H),7.14-7.04(m,5H),4.14(d,J=13.5Hz,1H),3.61(d,J=14.1 Hz,1H),3.21(d,J=20.3Hz,2H),3.06(t,J=13.2Hz,1H),2.90-2.62(m,5H),2.5 7-2.47(m,1H),2.46-2.37(m,1H),1.78(t,J=12.4Hz,1H),1.62(t,J=12.5Hz,1 H),1.48-1.21(m,3H),0.81(dt,J=39.9,13.9Hz,1H);LRMS(ESI):381.23[M+H] + .

[0087] Example 9 Phenyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A9) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to 4-fluoro-4-formylpiperidine-1-carboxylate phenyl, other necessary raw materials, reagents and preparation methods were the same as in Example 1 to obtain product A9 (yield 79%). 1 H NMR(400MHz,D2O)δ 7.30(t,J=7.4Hz,2H),7.24(t,J=7.2Hz,2H),7.16(t,J=7.1Hz,2H),7.08(d,J=7.4Hz,2H),6.98( d,J=7.6Hz,2H),4.11(d,J=13.8Hz,1H),3.87(d,J=13.6Hz,1H),3.41(d,J=20.4Hz,2H),3.23(t,J =12.7Hz,1H),3.10(t,J=12.9Hz,1H),2.94-2.85(m,1H),2.49-2.40(m,1H),1.94-1.83(m,2H),1. 83-1.58(m,2H),1.43(ddd,J=10.8,7.1,4.0Hz,1H),1.35-1.22(m,1H).;LRMS(ESI):369.19[M+H] + .

[0088] Example 10 3-Cyclohexyl-1-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)-1-acetone (A10) [ka] Except for changing 3-phenylpropionyl chloride to 3-cyclohexylpropionyl chloride, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A10 was obtained (yield 54%). 1H NMR(400MHz,DMSO)δ 7.34-7.27(m,2H),7.25-7.16(m,3H),4.48-4.41(m,1H),3.95-3.88(m,1H),3.53(d,J=20.1Hz ,2H),3.40(ddd,J=14.2,12.4,2.9Hz,1H),3.05(dt,J=7.9,4.1Hz,1H),2.96(td,J=12.8,3.0Hz ,1H),2.58(ddd,J=10.3,6.5,3.5Hz,1H),2.42(td,J=7.5,3.6Hz,2H),2.11-1.93(m,2H),1.93- 1.54(m,8H),1.53-1.34(m,3H),1.33-1.09(m,4H),1.01-0.82(m,2H);LRMS(ESI):387.27[M+H] + .

[0089] Example 11 4-Fluoro-N-methyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexan-1-amine (A11) [ka]

[0090] 11.1 Synthesis of N-((4-amino-1-fluorocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to (4-fluoro-4-formylcyclohexyl)carbamate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Examples 1, 5.1 and 5.2, and the product N-((4-amino-1-fluorocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide hydrochloride was obtained (yield 39%).

[0091] 11.2 Synthesis of the final product A11 Except for changing benzyl 4-fluoro-4-formylpiperidine-1-carboxylate to formaldehyde (containing 8% to 14% methanol) and trans-2-phenylcyclopropyl-1-amine to N-((4-amino-1-fluorocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide, the other necessary raw materials, reagents and preparation methods were the same as those in Examples 1 and 6.2, and product A11 was obtained (yield 64%). 1 H NMR(400MHz,D2O)δ 7.24-7.17(m,2H),7.16-7.10(m,1H),7.07-7.02(m,2H),3.34(d,J=20.4Hz,2H),3.06-2.9 D2O 5(m,1H),2.85(dt,J=8.0,4.1Hz,1H),2.54(s,3H),2.41(ddd,J=10.4,6.7,3.6Hz,1H),2.01-1.89(m,4 H),1.64-1.43(m,4H),1.39(ddd,J=10.5,7.2,4.4Hz,1H),1.30-1.19(m,1H);LRMS(ESI):277.20[M+H] + .

[0092] Example 12 N-((4-fluoro-1-(3-phenylpropyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A12) [ka] Except for changing bromomethylbenzene to bromopropylbenzene, the other necessary raw materials, reagents and preparation methods were the same as those in Example 6, and product A12 was obtained (yield 75%). 1H NMR(400MHz,DO)δ 7.45-7.39(m,4H),7.38-7.31(m,4H),7.28-7.23(m,2H),3.71-3.58(m,4H) ,3.33-3.16(m,4H),3.09(dt,J=8.0,4.1Hz,1H),2.77(t,J=7.4Hz,2H),2.64 (ddd,J=10.4,6.7,3.6Hz,1H),2.38-2.26(m,2H),2.22-2.01(m,4H),1.62(d dd,J=10.5,7.2,4.4Hz,1H),1.48(q,J=7.2Hz,1H);LRMS(ESI):367.25[M+H] + .

[0093] Example 13 N-((1-([1,1'-biphenyl]-4-methyl)-4-fluoropiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A13) [ka] Except for changing bromomethylbenzene to 4-bromomethyl-1,1'-biphenyl, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A13 was obtained (yield 80%). 1 H NMR (400MHz, MeOD) δ 7.78(d,J=8.1Hz,2H),7.74-7.64(m,4H),7.49(t,J=7.6Hz,2H),7.44-7.38(m ,1H),7.33(t,J=7.4Hz,2H),7.29-7.14(m,3H),4.48(s,2H),3.72-3.54(m,4H) ,3.38(d,J=13.2Hz,2H),3.09(t,J=4.6Hz,1H),2.64(t,J=9.6Hz,1H),2.40-2 .13(m,4H),1.67-1.59(m,1H),1.42(q,J=7.0Hz,1H);LRMS(ESI):415.27[M+H] + .

[0094] Example 14 N-((1-(3-cyclohexylpropyl)-4-fluoropiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A14) [ka] Except for changing bromomethylbenzene to bromopropylcyclohexane, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A14 was obtained (yield 74%). 1 H NMR(400MHz,D2O)δ 7.45-7.39(m,2H),7.38-7.32(m,1H),7.28-7.23(m,2H),3.73-3.58(m,4H),3.29( td,J=13.2,2.9Hz,2H),3.22-3.15(m,2H),3.10(dt,J=8.0,4.0Hz,1H),2.64(ddd,J =10.5,6.9,3.7Hz,1H),2.41-2.30(m,2H),2.25-2.02(m,2H),1.86-1.55(m,8H),1. 49(q,J=7.3Hz,1H),1.35-1.04(m,6H),0.99-0.82(m,2H);LRMS(ESI):373.29[M+H] + .

[0095] Example 15 N-((4-fluoro-1-methylpiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A15) [ka] Except for changing (4-fluoro-4-formylcyclohexyl)carbamate-t-butyl to 4-fluoro-4-formylpiperidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 11 to obtain product A15 (yield 34%). 1H NMR(400MHz,D2O)δ 7.30-7.24(m,2H),7.22-7.17(m,1H),7.11(dd,J=7.1,1.8Hz,2H),3.52(d,J=20.3Hz,2H),3.43(dd,J =12.7,4.5Hz,2H),3.20(td,J=13.2,3.1Hz,2H),2.94(dt,J=8.0,4.1Hz,1H),2.81(s,3H),2.49(ddd, J=10.4,6.7,3.6Hz,1H),2.19(dd,J=15.1,8.6Hz,2H),2.03(td,J=15.1,14.7,4.9Hz,1H),1.93(td,J =14.5,4.8Hz,1H),1.47(ddd,J=10.5,7.2,4.4Hz,1H),1.33(q,J=7.2Hz,1H);LRMS(ESI):263.18[M+H] + .

[0096] Example 16 N-((4-fluoro-1-(methylsulfonyl)benzyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A16) [ka] Except for changing bromomethylbenzene to 1-bromomethyl-4-methylsulfonylbenzene, the other necessary raw materials, reagents and preparation methods were the same as those in Example 6, and product A16 was obtained (yield 72%). 1 H NMR (400MHz, MeOD) δ 8.10-8.06(m,2H),7.92-7.87(m,2H),7.33-7.28(m,2H),7.25-7.16(m,3H) ,4.53(s,2H),3.65(d,J=20.1Hz,2H),3.53(d,J=12.5Hz,2H),3.42-3.30(m, 2H),3.16(s,3H),3.10-3.05(m,1H),2.66-2.56(m,1H),2.37-2.16(m,4H),1 .61(dt,J=11.0,6.2Hz,1H),1.40(q,J=7.1Hz,1H);LRMS(ESI):417.19[M+H] + .

[0097] Example 17 N-((4-fluoro-1-(naphthyl-2-methyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A17) [ka] Except for changing bromomethylbenzene to 2-bromomethylnaphthalene, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A17 was obtained (yield 60%). 1 H NMR(400MHz,DMSO-d6)δ 7.95-7.77(m,3H),7.69(d,J=1.5Hz,1H),7.61-7.47(m,3H),7.26-7.11(m,5H),3.6 6(s,2H),3.00(dt,J=12.6,7.2Hz,2H),2.66(s,1H),2.60(s,1H),2.46(dt,J=12.6, 7.2Hz,2H),1.93(ddt,J=25.1,14.2,7.2Hz,3H),1.53(ddt,J=25.1,13.1,7.0Hz,2H ),0.95(td,J=7.0,5.1Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):389.23[M+H] + .

[0098] Example 18 N-((1-fluorocyclohexyl)methyl)-trans-2-phenylcyclopropylamine (A18) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to 1-fluorocyclohexane-1-carbaldehyde, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A18 (yield 82%). 1H NMR(400MHz,MeOD)δ 7.36-7.30(m,2H),7.28-7.24(m,1H),7.22(tt,J=5.9,1.2Hz,2H),3.47(d,J=20.0Hz,2H),3.06(dt,J=8.0,4.1Hz,1H),2.59(ddd,J=10.3,6. 6,3.6Hz,1H),1.99-1.88(m,2H),1.74-1.62(m,6H),1.59(ddd,J=10.3,6.8,4.4Hz,2H),1.40(dt,J=7.9,6.7Hz,2H);LRMS(ESI):248.17[M+H] + .

[0099] Example 19 (4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)carbamate benzyl (A19) [ka] Except for changing benzyl 4-fluoro-4-formylpiperidine-1-carboxylate to benzyl (4-fluoro-4-formylcyclohexyl)carbamate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A19 (yield 64%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.02(s,2H),4.11(p,J=7.0Hz,1H),2.73-2.64(m,2H),1.94-1.72(m,5H),1.6 5-1.50(m,2H),1.54-1.43(m,2H),0.99(td,J=6.9,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H] + .

[0100] Example 20 N-((4-fluoro-1-phenylpiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A20) [ka] Except for changing bromomethylbenzene to bromobenzene, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A20 was obtained (yield 41%). 1 H NMR(400MHz,DMSO-d6)δ 7.30-7.11(m,7H),7.07-6.99(m,2H),6.80(tt,J=7.4,2.0Hz,1H),4.00(d t,J=12.6,7.2Hz,2H),3.33(dt,J=12.4,7.0Hz,2H),2.77-2.64(m,2H),2. 60(s,1H),2.06-1.84(m,3H),1.50(ddt,J=25.2,13.2,7.1Hz,2H),0.97(t d,J=7.0,5.1Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):325.20[M+H] + .

[0101] Example 21 Cyclohexylmethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A21) [ka] Except for changing 3-phenylpropionyl chloride to cyclohexylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A21 was obtained (yield 63%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),4.02(dt,J=12.4,7.1Hz,2H),3.91-3.85(m,2H),3.27 (dt,J=12.4,7.1Hz,2H),2.76-2.64(m,2H),2.04-1.85(m,3H),1.77-1.65 (m,2H),1.70-1.56(m,4H),1.60-1.42(m,2H),1.34-1.12(m,6H),0.95(td ,J=7.0,5.0Hz,1H),0.71(td,J=6.9,5.0Hz,1H);LRMS(ESI):389.25[M+H] + .

[0102] Example 22 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate pyridin-4-ylmethyl (A22) [ka] Except for changing 3-phenylpropionyl chloride to pyridin-4-ylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A22 was obtained (yield 53%). 1 H NMR(400MHz,DMSO-d6)δ 8.58(d,J=5.1Hz,2H),7.70(d,J=5.1Hz,2H),7.26-7.11(m,5H),5.80(s, 2H),4.17(dt,J=12.6,7.2Hz,2H),3.10(dt,J=12.5,7.0Hz,2H),2.75-2.6 4(m,2H),2.04-1.83(m,3H),1.63(ddt,J=25.2,13.2,7.1Hz,2H),0.92(td ,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):384.20[M+H] + .

[0103] Example 23 Phenethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A23) [ka] Except for changing 3-phenylpropionyl chloride to phenethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A23 was obtained (yield 60%). 1H NMR(400MHz,DMSO-d6)δ 7.27-7.11(m,10H),4.41(t,J=7.5Hz,2H),4.05(dt,J=12.4,7.0Hz,2H),3.30(dt,J=12.6,7.2Hz,2H),2.86(t,J=7.5Hz,2H),2.78-2.64(m,2 H),2.05-1.86(m,3H),1.65(ddt,J=25.2,13.2,7.1Hz,2H),0.96(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H] + .

[0104] Example 24 Ethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A24) [ka] Except for changing 3-phenylpropionyl chloride to ethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A24 was obtained (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),4.10-3.98(m,4H),3.25(dt,J=12.5,7.1Hz,2H),2.77-2.64(m,2H),2.60(s,1H),2.00-1.82(m,3H),1.64(ddt, LRMS(ESI):321.19[M+H] + .

[0105] Example 25 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (1H-indol-5-yl)methyl (A25) [ka] Except for changing 3-phenylpropionyl chloride to (1H-indol-5-yl)methyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A25 was obtained (yield 36%). 1 H NMR(400MHz,DMSO-d6)δ 11.53(s,1H),8.06(t,J=1.5Hz,1H),7.61(d,J=7.5Hz,1H),7.50-7.40(m,2H),7.26-7.11(m ,5H),6.65(dd,J=7.6,1.5Hz,1H),5.02(s,2H),4.04(dt,J=12.4,7.1Hz,2H),3.30(dt,J=12. 6,7.2Hz,2H),2.76-2.64(m,2H),2.60(s,1H),2.05-1.86(m,3H),1.64(ddt,J=25.2,13.2,7 .1Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):422.22[M+H] + .

[0106] Example 26 1-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)pyridin-1-yl)-1-ethanone (A26) [ka] Except for changing 3-phenylpropionyl chloride to acetyl chloride, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A26 was obtained (yield 76%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),3.96(dt,J=12.5,7.1Hz,2H),2.93(dt,J=12.5,7.1Hz,2H),2.71-2.61(m,2H),2.60(s,1H),2.10(s,3H),2.00-1 .82(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.66(td,J=7.0,5.1Hz,1H);LRMS(ESI):291.18[M+H] + .

[0107] Example 27 Thiophen-2-ylmethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A27) [ka] Except for changing 3-phenylpropionyl chloride to thiophen-2-ylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A27 was obtained (yield 70%). 1 H NMR(400MHz,DMSO-d6)δ 7.30(dd,J=6.4,2.5Hz,1H),7.26-7.11(m,5H),7.05-6.96(m,2H),5.61(s,2H),4.19(dt,J=12.5,7.1Hz,2H),3.11(dt,J=12.5,7.1Hz,2H), 2.75-2.64(m,2H),2.08-1.82(m,3H),1.73-1.55(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):389.16[M+H] + .

[0108] Example 28 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate furan-2-ylmethyl (A28) [ka] Except for the fact that 3-phenylpropionyl chloride was replaced with furan-2-ylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A28 was obtained (yield 76%). 1H NMR(400MHz,DMSO-d6)δ 7.45(dd,J=7.0,1.9Hz,1H),7.26-7.11(m,5H),6.44-6.32(m,2H),5.09(s,2H),4.06 (dt,J=12.5,7.1Hz,2H),3.31(dt,J=12.5,7.2Hz,2H),2.76-2.64(m,2H),2.60(s,1H) ),1.99(dt,J=10.9,6.0Hz,1H),1.98-1.86(m,2H),1.65(ddt,J=25.3,13.3,7.1Hz,2 H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):373.18[M+H] + .

[0109] Example 29 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-fluorobenzyl (A29) [ka] Except for changing 3-phenylpropionyl chloride to 4-fluorobenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A29 was obtained (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.35(dd,J=7.2,5.7Hz,2H),7.26-7.11(m,7H),5.21-5.15(m,2H),4.03(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75-2.64(m,2 H),2.00-1.82(m,3H),1.64(ddt,J=25.1,13.2,7.0Hz,2H),0.94(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):401.20[M+H] + .

[0110] Example 30 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-chlorobenzyl (A30) [ka] Except for changing 3-phenylpropionyl chloride to 4-chlorobenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A30 was obtained (yield 75%). 1 H NMR (400MHz, DMSO-d6) δ 7.39(d,J=7.5Hz,2H),7.34-7.26(m,2H),7.26-7.11(m,5H),5.18(s,1H),4 .04(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75-2.64(m,2H) ,2.60(s,1H),2.00-1.82(m,3H),1.64(ddt,J=25.3,13.2,7.2Hz,2H),0.94( td,J=6.9,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):417.17[M+H] + .

[0111] Example 31 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-bromobenzyl (A31) [ka] Except for changing 3-phenylpropionyl chloride to 4-bromobenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A31 was obtained (yield 70%). 1 H NMR (400MHz, DMSO-d6) δ 7.58(d,J=7.6Hz,2H),7.29-7.22(m,2H),7.27-7.11(m,5H),5.18(s,1H),4 .02(dt,J=12.5,7.1Hz,2H),3.28(dt,J=12.5,7.1Hz,2H),2.75-2.64(m,2H) ,2.60(s,1H),2.04-1.86(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.95( td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):461.12[M+H]+ .

[0112] Example 32 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-methoxybenzyl (A32) [ka] Except for changing 3-phenylpropionyl chloride to 4-methoxybenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A32 was obtained (yield 76%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),7.03-6.96(m,2H),6.94-6.87(m,2H),5.18(s,1H),4.0 3(dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.28(dt,J=12.5,7.1Hz,2H),2.76 -2.64(m,2H),2.60(s,1H),2.04-1.85(m,3H),1.72-1.54(m,2H),0.95(td ,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):413.22[M+H] + .

[0113] Example 33 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-trifluoromethylbenzyl (A33) [ka] Except for changing 3-phenylpropionyl chloride to 4-trifluoromethylbenzyl chloroformate, the other necessary raw materials, reagents and preparation method were the same as in Example 8, and product A33 was obtained (yield 68%). 1H NMR (400MHz, DMSO-d6) δ 7.69(d,J=7.2Hz,2H),7.58-7.52(m,2H),7.26-7.11(m,5H),5.18(s,1H),4 .03(dt,J=12.5,7.2Hz,2H),3.27(dt,J=12.5,7.1Hz,2H),2.74-2.64(m,2H) ,2.60(s,1H),1.94(ddt,J=25.0,14.1,7.1Hz,3H),1.73-1.54(m,2H),0.96( td,J=7.0,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):451.19[M+H] + .

[0114] Example 34 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-3,5-dimethoxybenzyl (A34) [ka] Except for changing 3-phenylpropionyl chloride to 3,5-dimethoxybenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A34 was obtained (yield 77%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),6.59(dt,J=2.2,1.0Hz,2h),6.33(t,J=2.0Hz,1H),5.02(d,J=1. 2Hz,2H),4.16(dt,J=12.6,7.2Hz,2H),3.66(s,6H),3.09(dt,J=12.5,7.1Hz,2H),2. 77-2.64(m,2H),2.60(s,1H),2.05-1.81(m,3H),1.61(ddt,J=25.1,13.2,7.2Hz,2H ),0.94(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):443.23[M+H] + .

[0115] Example 35 4-((4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carbonyloxy)methyl)benzoic acid (A35) [ka]

[0116] 35.1 Synthesis of 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamino)methyl)piperidine-1-carboxylate-4-(t-butoxycarbonyl)benzyl [ka] Except for changing 3-phenylpropionyl chloride to 4-((chloroformyloxy)methyl)benzoate-t-butyl, the other necessary raw materials, reagents and preparation method were the same as in Example 8.1, and 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamino)methyl)piperidine-1-carboxylate-4-(t-butoxycarbonyl)benzyl was obtained (yield 77%).

[0117] 35.2 Synthesis of the final product A35 Except for changing 4-((4-fluoro-4-((2,2,2-trifluoro-N-(2-phenylcyclopropyl)acetylamino)methyl)piperidin-1-ylmethyl)benzoate-t-butyl to 4-fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamino)methyl)piperidine-1-carboxylate-4-(t-butoxycarbonyl)benzyl, the other necessary raw materials, reagents and preparation methods were the same as in Example 5.4, and the hydrochloride salt of product A35 was obtained (yield 85%). 1H NMR (400MHz, DMSO-d6) δ 12.91(s,1H),7.93-7.86(m,2H),7.46-7.39(m,2H),7.26-7.11(m,5H),5.18(s ,1H),4.03(dt,J=12.6,7.2Hz,2H),3.29(dt,J=12.5,7.2Hz,2H),2.76-2.64(m ,2H),2.60(s,1H),2.05-1.86(m,3H),1.63(ddt,J=25.3,13.2,7.2Hz,2H),0.9 5(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):427.20[M+H] + .

[0118] Example 36 (E)-1-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)-3-phenyl-2-propylene-1-one (A36) [ka] Except for changing 3-phenylpropionyl chloride to cinnamoyl chloride, the other necessary raw materials, reagents and preparation method were the same as in Example 8, and product A36 was obtained (yield 88%). 1 H NMR(400MHz,CD3OD)δ 7.66-7.54(m,3H),7.43-7.34(m,3H),7.31(tt,J=6.9,1.0Hz,2H),7.25-7.16(m,4H),4.56(d,J= 12.8Hz,1H),4.27(d,J=13.3Hz,1H),3.61-3.45(m,3H),3.17-3.09(m,1H),3.06(dt,J=7.9,4.0H z,1H),2.58(ddd,J=10.3,6.6,3.6Hz,1H),2.07(q,J=12.6,11.4Hz,2H),1.85(tt,J=25.7,13.1H z,2H),1.58(ddd,J=10.6,6.8,4.4Hz,1H),1.40(dt,J=7.9,6.7Hz,1H);LRMS(ESI):379.21[M+H] + .

[0119] Example 37 N-Benzyl-4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-thiocarbamide (A37) [ka] Except for changing 3-phenylpropionyl chloride to benzyl isothiocyanate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A37 was obtained (yield 58%). 1 H NMR(400MHz,DMSO-d6)δ 7.36-7.13(m,10H),7.13(s,1H),4.75(s,2H),3.97(dt,J=12.5,7.1Hz,2H),2.82(q ,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.47(dt,J=12.5,7.0Hz,2H),1.89(q,J=7 .0Hz,1H),1.77(ddt,J=25.3,13.2,7.2Hz,2H),1.47(ddt,J=25.3,13.2,7.2Hz,2H) ,0.97(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):398.20[M+H] + .

[0120] Example 38 N-benzyl-4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carbamide (A38) [ka] Except for changing 3-phenylpropionyl chloride to benzyl isocyanate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A38 was obtained (yield 52%). 1H NMR(400MHz,DMSO-d6)δ 7.30(s,3H),7.34-7.23(m,2H),7.27-7.11(m,5H),4.27(s,2H),4.11( dt,J=12.5,7.1Hz,2H),3.09(dt,J=12.5,7.1Hz,2H),2.72-2.57(m,3H ),2.04-1.85(m,3H),1.59(ddt,J=25.1,13.2,7.1Hz,2H),0.94(td,J=7.0,5.0Hz,1H),0.68(td,J=7.0,4.9Hz,1H);LRMS(ESI):382.22[M+H] + .

[0121] Example 39 N-((1-((benzyloxy)methyl)-4-fluoropiperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A39) [ka] Except for changing bromomethylbenzene to benzyl chloromethyl ether, the other necessary raw materials, reagents and preparation methods were the same as those in Example 6, and product A39 was obtained (yield 64%). 1 H NMR(400MHz,DMSO-d6)δ 7.37-7.25(m,5H),7.29-7.11(m,5H),4.68(s,1H),4.44(s,2H),3.06(dt,J=12.5,7.2Hz,2H),2.75-2.64(m,2H),2.63-2.51(m,3H),1. 96-1.78(m,3H),1.47(ddt,J=25.3,13.3,7.1Hz,2H),0.94(td,J=7.0,4.9Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):369.23[M+H] + .

[0122] Example 40 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexane-1-carboxylate benzyl (A40) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-fluoro-4-formylcyclohexane-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A40 (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.38-7.26(m,5H),7.26-7.11(m,5H),5.11(s,2H),2.74-2.64(m,2H),2.27(p,J=6.9Hz,1H),2.18-2.05(m,2H),1.9 8-1.74(m,6H),1.61-1.42(m,2H),0.95(td,J=7.0,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):382.21[M+H] + .

[0123] Example 41 Cyclopentylmethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A41) [ka] Except for changing 3-phenylpropionyl chloride to cyclopentylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A41 was obtained (yield 69%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),4.04(dt,J=12.5,7.1Hz,2H),3.88(s,2H),3.28(dt, J=12.6,7.2Hz,2H),2.72(s,1H),2.66(s,1H),2.60(s,1H),1.96(ddt,J LRMS(ESI):375.24[M+H] + .

[0124] Example 42 Cyclobutylmethyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A42) [ka] Except for changing 3-phenylpropionyl chloride to cyclobutylmethyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A42 was obtained (yield 71%). 1 H NMR (400MHz, DMSO-d6) δ 7.26-7.11(m,5H),4.13(dt,J=12.5,7.1Hz,2H),3.88(d,J=7.0Hz,2H),3.1 1(dt,J=12.5,7.0Hz,2H),2.90(q,J=6.9Hz,1H),2.62-2.47(m,2H),2.14-1 .96(m,4H),1.90-1.77(m,2H),1.80-1.68(m,2H),1.71-1.58(m,4H),0.93( td,J=6.9,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):361.22[M+H] + .

[0125] Example 43 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A43) [ka] Except for changing 3-phenylpropionyl chloride to 4-((chloroformyloxy)methyl)piperidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Examples 8.1 and 5.4, and the dihydrochloride salt of product A43 was obtained (yield 61%). 1H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),4.03(dt,J=12.5,7.1Hz,2H),3.88(s,2H),3.27(dt,J=12.6,7.2Hz ,2H),3.04(dt,J=12.5,7.2Hz,2H),2.75-2.57(m,5H),2.44(s,1H),2.04-1.86(m,2H), 1.91(s,1H),1.66(s,1H),1.64(ddt,J=25.3,13.7,7.1Hz,2H),1.45(dt,J=13.1,7.1Hz ,2H),1.18(dt,J=13.3,7.2Hz,2H),0.95(s,1H),0.71(s,1H);LRMS(ESI):390.25[M+H] + .

[0126] Example 44 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-3-chlorobenzyl (A44) [ka] Except for changing 3-phenylpropionyl chloride to 3-chlorobenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A44 was obtained (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.51-7.45(m,1H),7.39-7.26(m,3H),7.26-7.11(m,5H),5.02(s,2H),4 .04(dt,J=12.5,7.1Hz,2H),3.26(dt,J=12.5,7.0Hz,2H),2.76-2.64(m ,2H),2.01-1.83(m,3H),1.64(ddt,J=25.1,13.2,7.0Hz,2H),0.93(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):417.17[M+H] + .

[0127] Example 45 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-2-chlorobenzyl (A45) [ka] Except for changing 3-phenylpropionyl chloride to 2-chlorobenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A45 was obtained (yield 70%). 1 H NMR(400MHz,DMSO-d6)δ 7.45-7.31(m,2H),7.26-7.05(m,7H),5.09(d,J=0.9Hz,2H),4.03(dt,J=12.5,7.1Hz,2H),3.26(dt,J=12.5,7.0Hz,2H),2.75-2.6 4(m,2H),2.00-1.82(m,3H),1.73-1.55(m,2H),0.94(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):417.17[M+H] + .

[0128] Example 46 (4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)(phenyl)ketone (A46) [ka] Except for changing 3-phenylpropionyl chloride to benzoyl chloride, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A46 was obtained (yield 66%). 1 H NMR (400MHz, DMSO-d6) δ 7.59(tt,J=7.2,2.2Hz,1H),7.50-7.36(m,4H),7.26-7.11(m,5H),3.75(dt,J= 12.5,7.1Hz,2H),3.13(dt,J=12.6,7.2Hz,2H),2.76-2.64(m,2H),2.60(s,1H) ,1.98-1.86(m,2H),1.90-1.80(m,1H),1.63(ddt,J=25.1,13.2,7.0Hz,2H),0. 96(td,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):353.20[M+H] + .

[0129] Example 47 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-4-t-butylbenzyl (A47) [ka] Except for changing 3-phenylpropionyl chloride to 4-t-butylbenzyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as in Example 8, and product A47 was obtained (yield 69%). 1 H NMR(400MHz,DMSO-d6)δ 7.39(t,J=6.3Hz,4H),7.26-7.11(m,5H),5.18(d,J=1.2Hz,2H),4.04(dt ,J=12.6,7.2Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.77-2.64(m,2H),2.0 0-1.82(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),1.31(s,9H),0.94(td ,J=7.0,5.1Hz,1H),0.70(td,J=7.0,5.1Hz,1H);LRMS(ESI):439.27[M+H] + .

[0130] Example 48 4-Fluoro-2-methyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A48) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-fluoro-2-methyl-4-formylpiperidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A48 (yield 68%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.50(d,J=12.3Hz,1H),5.31(d,J=12.4Hz,1H),4.16(dt ,J=12.4,7.1Hz,1H),3.79(h,J=6.8Hz,1H),3.21(dt,J=12.4,7.1Hz,1H),3.04(dd,J=25.2,12. 4Hz,1H),2.90-2.66(m,2H),2.12-1.60(m,4H),1.46(ddd,J=25.3,13.1,7.0Hz,1H),1.25(d,J =6.8Hz,3H),0.94(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,4.9Hz,1H).LRMS(ESI):397.22[M+H] + .

[0131] Example 49 4-Fluoro-2,6-dimethyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A49) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-fluoro-2,6-dimethyl-4-formylpiperidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A49 (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.35(d,J=12.4Hz,1H),3.88(q,J=6.9Hz,2H),2.74-2.64(m,2H),2.60(s,1H),1.94-1.78(m,3H),1. 51(ddd,J=25.3,13.2,7.0Hz,2H),1.25(d,J=6.8Hz,6H),0.95(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):411.24[M+H] + .

[0132] Example 50 4-fluoro-4-(((trans-2-(naphthalen-2-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A50) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(naphthalen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A50 was obtained (yield 60%). 1 H NMR (400MHz, DMSO-d6) δ 7.94-7.81(m,3H),7.57-7.39(m,4H),7.39-7.26(m,5H),5.22(s,2H),4.04(dt ,J=12.4,7.2Hz,2H),3.30(dt,J=12.5,7.1Hz,2H),2.76(q,J=7.0Hz,1H),2.66( s,1H),2.60(s,1H),2.05-1.87(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),0. 99(td,J=7.0,5.0Hz,1H),0.75(td,J=7.0,5.0Hz,1H);LRMS(ESI):433.22[M+H] + .

[0133] Example 51 Benzyl 4-fluoro-4-(((trans-2-(benzothiophen-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A51) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(benzothiophen-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A51 was obtained (yield 55%). 1H NMR(400MHz,DMSO-d6)δ 7.96(d,J=7.5Hz,1H),7.68(s,1H),7.55-7.44(m,2H),7.32(dtd,J=8.9,7.4,2.3H z,6H),5.22(s,2H),4.03(dt,J=12.6,7.2Hz,2H),3.30(dt,J=12.5,7.0Hz,2H),2.7 7(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.05-1.87(m,3H),1.73-1.55(m,2H) ,0.99(td,J=7.0,4.9Hz,1H),0.77(td,J=7.0,4.9Hz,1H);LRMS(ESI):439.18[M+H] + .

[0134] Example 52 Benzyl 4-fluoro-4-(((trans-2-(pyridin-4-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A52) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(pyridin-4-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A52 was obtained (yield 65%). 1 H NMR(400MHz,DMSO-d6)δ 8.50(d,J=5.1Hz,2H),7.39-7.26(m,5H),7.22(d,J=5.2Hz,2H),5.22(s, 2H),4.02(dt,J=12.5,7.0Hz,2H),3.34-3.13(m,3H),2.66(s,1H),2.60( s,1H),1.94(ddt,J=25.3,13.9,7.1Hz,2H),1.79-1.54(m,3H),0.86(td,J=7.0,4.9Hz,1H),0.61(td,J=7.0,5.0Hz,1H);LRMS(ESI):384.20[M+H] + .

[0135] Example 53 4-Fluoro-4-(((trans-2-(1H-indol-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A53) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(1H-indol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A53 was obtained (yield 57%). 1 H NMR(400MHz,DMSO-d6)δ 11.53(s,1H),7.82(s,1H),7.56(d,J=7.5Hz,1H),7.43(d,J=7.5Hz,1H),7.39-7.24(m,6H),6. 64(dd,J=7.4,1.4Hz,1H),5.22(s,2H),4.03(dt,J=12.5,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2 H),2.76(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),2.05-1.87(m,3H),1.64(ddt,J=25.1,13.2 ,7.2Hz,2H),0.99(td,J=7.0,4.9Hz,1H),0.76(td,J=6.9,5.0Hz,1H);LRMS(ESI):422.22[M+H] + .

[0136] Example 54 4-Fluoro-4-(((trans-2-(1-methyl-1H-indol-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A54) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(1-methyl-1H-indol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A54 was obtained (yield 67%). 1H NMR(400MHz,DMSO-d6)δ 7.66(t,J=1.5Hz,1H),7.52(d,J=7.5Hz,1H),7.39-7.26(m,5H),7.17(d,J=7.5Hz,1H),7.02(dd,J=7.5, 1.5Hz,1H),6.53(dd,J=7.5,1.6Hz,1H),5.22(s,2H),4.12(dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.12(dt ,J=12.5,7.1Hz,2H),2.75(q,J=6.9Hz,1H),2.66(s,1H),2.60(s,1H),2.02-1.84(m,3H),1.65(ddt,J=2 5.1,13.2,7.2Hz,2H),0.96(td,J=7.0,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):436.23[M+H] + .

[0137] Example 55 Benzyl 4-fluoro-4-(((trans-2-(indolin-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A55) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(indolin-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A55 (yield 55%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),6.95(d,J=2.0Hz,1H),6.69(dd,J=7.4,2.0Hz,1H),6.47(d,J=7.5Hz,1H),5.83 (s,1H),5.22(s,2H),4.02(dt,J=12.5,7.2Hz,2H),3.65-3.43(m,2H),3.28(dt,J=12.5,7.1Hz,2H ),2.88(ddd,J=18.5,10.3,8.0Hz,1H),2.77-2.57(m,4H),2.04-1.82(m,3H),1.63(ddt,J=25.1,1 3.2,7.1Hz,2H),0.95(td,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):424.23[M+H] + .

[0138] Example 56 4-Fluoro-4-(((trans-2-(1-(benzenesulfonyl)indolin-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A56) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(1-(benzenesulfonyl)indolin-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A56 was obtained (yield 70%). 1H NMR(400MHz,DMSO-d6)δ 7.68-7.51(m,5H),7.39-7.26(m,5H),7.17(d,J=2.0Hz,1H),6.75(dd,J=7.5,1.9Hz,1H),6.63(d,J=7.5Hz,1H),5. 22(s,2H),4.43-4.22(m,2H),4.19-4.09(m,1H),3.99(dt,J=12.5,7.1Hz,1H),3.32(dt,J=12.5,7.1Hz,1H),3.08( dt,J=12.5,7.1Hz,1H),2.97(q,J=6.9Hz,1H),2.92-2.83(m,2H),2.66(s,1H),2.60(s,1H),2.09-1.72(m,4H),1.6 3(ddt,J=25.1,13.2,7.1Hz,1H),0.90(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):564.23[M+H] + .

[0139] Example 57 4-Fluoro-4-(((trans-2-(1H-indol-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A57) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(1H-indol-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A57 (yield 61%). 1H NMR(400MHz,DMSO-d6)δ 10.75(s,1H),7.58(dd,J=7.4,1.5Hz,1H),7.39-7.26(m,3H),7.32(s,3H),7.17(s,1H) ,7.02(dtd,J=32.8,7.4,1.5Hz,2H),5.22(s,2H),3.89-3.71(m,3H),2.89(dt,J=12.5,7 .2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.72-1.46(m ,3H),0.71(td,J=6.9,5.0Hz,1H),0.46(td,J=7.0,5.1Hz,1H);LRMS(ESI):422.22[M+H] + .

[0140] Example 58 4-Fluoro-4-(((trans-2-(imidazo[1,2-α]pyridin-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A58) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-((imidazo[1,2-α]pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A58 was obtained (yield 51%). 1H NMR(400MHz,DMSO-d6)δ 8.47(dd,J=7.4,1.5Hz,1H),7.89(s,1H),7.47(dd,J=7.5,1.6Hz,1H),7.39-7.26(m,5H),7.21(td,J= 7.5,1.5Hz,1H),6.85(td,J=7.4,1.4Hz,1H),5.22(s,2H),3.83(dt,J=12.4,7.2Hz,2H),3.76(q,J=7. 0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H) ,1.72-1.46(m,3H),0.82(td,J=7.0,4.9Hz,1H),0.57(td,J=7.0,5.0Hz,1H);LRMS(ESI):422.21[M+H] + .

[0141] Example 59 Benzyl 4-fluoro-4-(((trans-2-(2,3-dihydrobenzofuran-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A59) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(2,3-dihydrobenzofuran-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A59 was obtained (yield 65%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.05(d,J=2.0Hz,1H),6.96(dd,J=7.5,2.1Hz,1H),6.78(d,J=7.5Hz,1H),5 .22(s,2H),4.47-4.37(m,2H),4.03(dt,J=12.5,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.9 9(ddd,J=18.6,6.2,2.5Hz,1H),2.77-2.57(m,4H),2.04-1.84(m,3H),1.63(ddt,J=25.1,13.2 ,7.1Hz,2H),0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):425.22[M+H] + .

[0142] Example 60 4-fluoro-4-(((trans-2-(chroman-6-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A60) [ka] Except for the fact that trans-2-phenylcyclopropylamine was changed to trans-2-(chroman-6-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A60 was obtained (yield 66%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.04-6.98(m,1H),6.96-6.89(m,1H),6.77(d,J=7.4Hz,1H),5. 22(s,2H),4.08-3.91(m,3H),3.94-3.84(m,1H),3.28(dt,J=12.5,7.1Hz,2H),2.77 -2.64(m,3H),2.60(s,1H),2.50-2.36(m,1H),2.04-1.74(m,5H),1.73-1.54(m,2H) ,0.95(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,4.9Hz,1H);LRMS(ESI):439.23[M+H] + .

[0143] Example 61 4-fluoro-4-(((trans-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A61) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A61 was obtained (yield 69%). 1 H NMR(400MHz,DMSO-d6)δ 10.01(s,1H),7.39-7.26(m,5H),7.20(d,J=2.1Hz,1H),7.11(dd,J=7.5,1.9Hz,1H),6.98(d,J=7.5Hz,1H), 5.22(s,2H),4.14(dt,J=12.5,7.1Hz,2H),3.31-3.07(m,4H),2.89-2.70(m,2H),2.66(s,1H),2.60(s,1H), 2.48(ddd,J=15.2,4.4,1.7Hz,1H),2.11(ddt,J=25.1,13.2,7.2Hz,2H),1.89(q,J=7.0Hz,1H),1.67(ddt,J =25.3,13.2,7.2Hz,2H),0.96(td,J=6.9,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):452.23[M+H] + .

[0144] Example 62 Benzyl 4-fluoro-4-(((trans-2-(thiophen-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A62) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(thiophen-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A62 was obtained (yield 75%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.22(d,J=7.5Hz,1H),6.95-6.86(m,2H),5.22(s,2H),3.83(dt,J=12. 4,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1H ),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7.0 Hz,1H),0.69(td,J=6.9,5.0Hz,1H),0.44(td,J=7.0,5.0Hz,1H);LRMS(ESI):389.16[M+H] + .

[0145] Example 63 4-fluoro-4-(((trans-2-(furan-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A63) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(furan-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A63 was obtained (yield 75%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,6H),7.11(d,J=1.5Hz,1H),6.13(dd,J=7.5,1.5Hz,1H),5.22(s,2H),3.83(dt ,J=12.5,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.4,7.2Hz,2H),2.66(s,1H),2.60( s,1H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7 .0Hz,1H),0.78(td,J=7.0,5.0Hz,1H),0.53(td,J=6.9,5.0Hz,1H);LRMS(ESI):373.18[M+H] + .

[0146] Example 64 4-Fluoro-4-(((trans-2-(thiazol-2-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A64) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(thiazol-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A64 was obtained (yield 70%). 1 H NMR(400MHz,DMSO-d6)δ 7.69(d,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.39-7.26(m,5H),5.22(s,2H),3.83(dt,J=1 2.4,7.2Hz,2H),3.76(q,J=7.0Hz,1H),2.89(dt,J=12.5,7.2Hz,2H),2.66(s,1H),2.60(s,1 H),1.88(ddt,J=25.1,12.3,7.1Hz,2H),1.63(ddt,J=25.3,12.5,7.1Hz,2H),1.51(q,J=7. 0Hz,1H),0.78(td,J=7.0,4.9Hz,1H),0.53(td,J=6.9,5.0Hz,1H);LRMS(ESI):390.16[M+H] + .

[0147] Example 65 Benzyl 4-fluoro-4-(((trans-2-(4-fluorophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A65) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(4-fluorophenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A65 was obtained (yield 78%). 1H NMR (400MHz, DMSO-d6) δ 7.39-7.26(m,5H),7.16(ddd,J=7.0,5.8,1.1Hz,2H),7.12-7.03(m,2H),5. 22(s,2H),4.04(dt,J=12.5,7.1Hz,2H),3.25(dt,J=12.5,7.1Hz,2H),2.75- 2.64(m,2H),2.00-1.82(m,3H),1.64(ddt,J=25.1,13.2,7.2Hz,2H),0.95( td,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):401.20[M+H] + .

[0148] Example 66 4-Fluoro-4-(((trans-2-(4-cyanophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A66) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(4-cyanophenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A66 was obtained (yield 72%). 1 H NMR(400MHz,DMSO-d6)δ 7.73-7.66(m,2H),7.33(tdd,J=8.7,4.2,2.8Hz,7H),5.22(s,2H),4.09(dt,J=12.4,7.1Hz,2H),3.23(dt,J=12.4,7.1Hz,2H),2.73-2.64(m,2 H),2.01-1.83(m,3H),1.67(ddt,J=25.3,13.2,7.2Hz,2H),0.95(td,J=7.0,4.9Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):408.20[M+H] + .

[0149] Example 67 4-fluoro-4-(((trans-2-(4-methoxyphenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A67) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(4-methoxyphenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A67 was obtained (yield 70%). 1 H NMR (400MHz, DMSO-d6) δ 7.39-7.26(m,5H),7.10-7.03(m,2H),6.95-6.88(m,2H),5.22(s,2H),4.03 (dt,J=12.5,7.1Hz,2H),3.79(s,3H),3.28(dt,J=12.5,7.2Hz,2H),2.77-2 .64(m,2H),2.04-1.82(m,3H),1.63(ddt,J=25.1,13.2,7.1Hz,2H),0.95(t d,J=7.0,5.1Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):413.22[M+H] + .

[0150] Example 68 4-fluoro-4-(((trans-2-(2-acetylphenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A68) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(2-acetylphenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A68 was obtained (yield 70%). 1H NMR(400MHz,DMSO-d6)δ 7.66(dd,J=7.5,2.0Hz,1H),7.46(td,J=7.5,2.1Hz,1H),7.39-7.26(m,5H),7.27-7 .12(m,2H),5.22(s,2H),4.04(dt,J=12.6,7.2Hz,2H),3.24(dt,J=12.5,7.0Hz,2H) ,2.73-2.64(m,2H),2.60(s,1H),2.50(s,3H),2.08-1.82(m,3H),1.72-1.54(m,2H) ,0.85(td,J=7.0,5.0Hz,1H),0.53(td,J=7.0,5.0Hz,1H).LRMS(ESI):425.22[M+H] + .

[0151] Example 69 4-fluoro-4-(((trans-2-([1,1'-biphenyl]-4-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A69) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-([1,1'-biphenyl]-4-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A69 was obtained (yield 68%). 1 H NMR (400MHz, DMSO-d6) δ 7.70(dd,J=7.6,2.0Hz,2H),7.54-7.37(m,5H),7.37-7.26(m,7H),5.22(s,2 H),4.04(dt,J=12.4,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.75(q,J=6.9 Hz,1H),2.66(s,1H),2.60(s,1H),2.04-1.85(m,3H),1.73-1.55(m,2H),0.96 (td,J=7.0,4.9Hz,1H),0.72(td,J=7.0,5.1Hz,1H);LRMS(ESI):459.24[M+H] + .

[0152] Example 70 4-fluoro-4-(((trans-2-(4-methylphenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A70) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(4-methylphenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A70 was obtained (yield 75%). 1 H NMR (400MHz, DMSO-d6) δ 7.39-7.26(m,5H),7.12-7.04(m,2H),7.06-6.98(m,2H),5.22(s,2H),4.03 (dt,J=12.6,7.2Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.77-2.64(m,2H),2 .21(s,3H),2.04-1.84(m,3H),1.63(ddt,J=25.1,13.2,7.0Hz,2H),0.95(t d,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):397.22[M+H] + .

[0153] Example 71 4-fluoro-4-(((trans-2-(4-nitrophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A71) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(4-nitrophenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A71 was obtained (yield 72%). 1H NMR(400MHz,DMSO-d6)δ 8.22-8.13(m,2H),7.39-7.26(m,7H),5.22(s,2H),3.95(dt,J=12.6,7.2H z,2H),3.19(dt,J=12.4,7.1Hz,2H),2.81(q,J=7.0Hz,1H),2.66(s,1H),2. 60(s,1H),1.96-1.72(m,3H),1.56(ddt,J=25.3,13.7,7.1Hz,2H),0.95(t d,J=7.0,4.9Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):428.19[M+H] + .

[0154] Example 72 4-(trans-2-(((1-((benzyloxy)carbonyl)-4-fluoropiperazin-4-yl)methyl)amino)cyclopropyl)benzoic acid (A72) [ka] Except for changing trans-2-phenylcyclopropylamine to 4-(trans-2-aminocyclopropyl)benzoic acid, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A72 was obtained (yield 60%). 1 H NMR(400MHz,DMSO-d6)δ 12.91(s,1H),7.87-7.81(m,2H),7.39-7.26(m,5H),7.22(dd,J=7.4,1.1Hz,2H), 5.22(s,2H),4.03(dt,J=12.4,7.1Hz,2H),3.29(dt,J=12.5,7.1Hz,2H),2.77-2. 64(m,2H),2.60(s,1H),2.04-1.86(m,3H),1.64(ddt,J=25.1,13.2,7.1Hz,2H),0 .97(td,J=7.0,4.9Hz,1H),0.72(td,J=7.0,5.1Hz,1H);LRMS(ESI):427.20[M+H] + .

[0155] Example 73 Benzyl 4-fluoro-4-(((trans-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)piperidine-1-carboxylate (A73) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(3,4-difluorophenyl)cyclopropylamine, the other necessary raw materials, reagents and preparation method were the same as in Example 1, and product A73 was obtained (yield 75%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.22(m,6H),7.01-6.88(m,2H),5.22(s,2H),4.03(dt,J=12.4,7.0Hz,2H),3.29(dt,J=12.6,7.2Hz,2H),2.77-2.64(m,2H),2.0 3-1.85(m,3H),1.64(ddt,J=25.3,13.7,7.1Hz,2H),0.98(td,J=6.9,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):419.19[M+H] + .

[0156] Example 74 4-Fluoro-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetylamido)methyl)piperidine-1-carboxylate benzyl (A74) [ka] Except for changing 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl to product A1 obtained in Example 1, the other necessary raw materials, reagents and preparation methods were the same as those in Example 5.1 to obtain product A74 (yield 80%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),3.99(dt,J=12.4,7.1Hz,2H),3.31(s,1H),3.25(s,1H),3.16(dt,J=12.5,7.1Hz,2H),2. 85(q,J=7.0Hz,1H),2.10-1.86(m,3H),1.67-1.48(m,2H),1.04(td,J=7.0,4.9Hz,1H),0.76(td,J=7.0,5.0Hz,1H);LRMS(ESI):479.19[M+H] + .

[0157] Example 75 4-fluoro-4-((methyl(trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A75) [ka] Except for changing trans-2-phenylcyclopropylamine to N-methyl-trans-2-phenylcyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as in Example 1, and product A75 was obtained (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),4.02(dt,J=12.5,7.1 Hz,2H),3.24(dt,J=12.5,7.1Hz,2H),2.67(q,J=7.0Hz,1H),2.40(d,J=6. 3Hz,4H),1.99-1.80(m,3H),1.62(ddt,J=25.1,13.2,7.0Hz,2H),0.94(td ,J=6.9,5.0Hz,1H),0.70(td,J=7.0,5.0Hz,1H);LRMS(ESI):397.22[M+H] + .

[0158] Example 76 4-Fluoro-4-(1-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate benzyl (A76) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-acetyl-4-fluoropiperidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A76 (yield 48%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),4.02(dt,J=12.5,7.1Hz,2H),3. 30(dt,J=12.5,7.1Hz,2H),3.02(dq,J=25.1,6.8Hz,1H),2.80(q,J=7.0Hz,1H),2.11 (s,1H),2.07-1.86(m,3H),1.65(ddt,J=25.1,13.2,7.0Hz,2H),1.10(d,J=6.7Hz,3H ),0.96(td,J=7.0,5.0Hz,1H),0.71(td,J=7.0,5.1Hz,1H);LRMS(ESI):397.22[M+H] + .

[0159] Example 77 4-Fluoro-4-((N-(trans-2-phenylcyclopropyl)acetylamino)methyl)piperidine-1-carboxylate benzyl (A77) [ka] Except for changing 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl to product A1 obtained in Example 1 and changing trifluoroacetic anhydride to acetic anhydride, the other necessary raw materials, reagents and preparation methods were the same as in Example 5.1 to obtain product A77 (yield 84%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),4.09(dt,J=12.6,7. 2Hz,2H),3.42-3.29(m,3H),3.25(s,1H),2.78(q,J=7.0Hz,1H),2.08(s ,3H),1.96-1.70(m,3H),1.55(ddt,J=25.1,13.2,7.1Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,5.0Hz,1H);LRMS(ESI):425.22[M+H] + .

[0160] Example 78 3-Fluoro-3-(((trans-2-phenylcyclopropyl)amino)methyl)azetidine-1-carboxylate benzyl (A78) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 3-fluoro-3-formylazetidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A78 (yield 68%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),4.16(d,J=11.3Hz,1H), 4.09(d,J=11.1Hz,1H),3.85(d,J=11.1Hz,1H),3.79(d,J=11.2Hz,1H),2.9 0(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),1.91(q,J=6.9Hz,1H),0.95(t d,J=7.0,5.0Hz,1H),0.72(td,J=7.0,5.0Hz,1H);LRMS(ESI):355.17[M+H] + .

[0161] Example 79 2-Fluoro-2-(((trans-2-phenylcyclopropyl)amino)methyl)morpholine-4-carboxylate benzyl (A79) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 2-fluoro-2-formylmorpholine-4-carboxylate, the other required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A79 (yield 60%). 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.41(d,J=1.2Hz,2H),4.10(dd,J=25.2,12.6Hz, 1H),3.86-3.72(m,1H),3.74-3.61(m,2H),3.51-3.36(m,2H),3.15(dd,J=25.2,12.4Hz, 1H),2.88(dd,J=25.1,12.5Hz,1H),2.78(q,J=7.0Hz,1H),1.88(q,J=7.0Hz,1H),1.55(s ,1H),0.95(td,J=7.0,5.0Hz,1H),0.69(td,J=7.0,4.9Hz,1H);LRMS(ESI):385.18[M+H] + .

[0162] Example 80 4-fluoro-4-(2-((trans-2-phenylcyclopropyl)amino)ethyl)piperidine-1-carboxylate benzyl (A80) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-fluoro-4-(2-oxoethyl)piperidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A80 (yield 78%). 1H NMR(400MHz,DMSO-d6)δ 7.39-7.26(m,5H),7.26-7.11(m,5H),5.22(s,2H),4.11(dt,J=12.4,7 .0Hz,2H),3.11(tt,J=12.0,7.4Hz,3H),2.97(dt,J=12.3,7.8Hz,1H),2 .71(q,J=7.0Hz,1H),1.96-1.77(m,3H),1.72-1.41(m,4H),0.89(td,J=7.0,4.9Hz,1H),0.64(td,J=7.0,4.9Hz,1H);LRMS(ESI):397.22[M+H] + .

[0163] Example 81 3-Fluoro-3-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate benzyl (A81) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 3-fluoro-3-formylpiperidine-1-carboxylate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A81 (yield 77%). 1 H NMR(400MHz,DMSO-d6)δ 7.32(dq,J=6.0,3.2Hz,5H),7.26-7.11(m,5H),6.44(d,J=12.3Hz,1H),4.63(d,J=12.5Hz,1 H),4.11(dd,J=25.1,12.5Hz,1H),3.76(d,J=12.5Hz,1H),3.38-3.18(m,2H),3.02(dd,J=25. 2,12.4Hz,1H),2.75(dd,J=25.3,12.5Hz,1H),2.74(s,1H),1.98-1.80(m,3H),1.70(d,J=13 .2Hz,1H),1.57(dd,J=25.1,13.2Hz,1H),0.94(s,1H),0.70(s,1H);LRMS(ESI):383.21[M+H] + .

[0164] Example 82 N-((4-fluoro-1-(benzenesulfonyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A82) [ka] Except for changing 3-phenylpropionyl chloride to benzenesulfonyl chloride, the other necessary raw materials, reagents and preparation methods were the same as those in Example 8, and product A82 was obtained (yield 74%). 1 H NMR(400MHz,DMSO-d6)δ 7.92-7.84(m,2H),7.63(hept,J=2.5Hz,3H),7.26-7.11(m,5H),3.79(dt,J=12.4,7.1Hz,2H),3.35(dt,J=12.4,7.2Hz,2H),2.72-2.64(m,2H) ),1.75(ddt,J=25.1,13.1,7.0Hz,2H),1.67-1.49(m,3H),0.89(td,J=7.0,5.0Hz,1H),0.63(td,J=6.9,5.0Hz,1H);LRMS(ESI):389.16[M+H] + .

[0165] Example 83 2-(4-fluoro-4-(((trans-2-phenylcyclohexyl)amino)methyl)piperidin-1-yl)ethanol (A83) [ka] Except for changing bromomethylbenzene to 2-bromoethanol, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A83 was obtained (yield 55%). 1H NMR (400MHz, DMSO-d6) δ 7.26-7.11(m,5H),4.25(t,J=5.0Hz,1H),3.53(td,J=7.2,5.0Hz,2H),3.08(dt, J=12.5,7.2Hz,2H),2.74-2.64(m,2H),2.60(s,1H),2.49(dt,J=12.2,7.2Hz,4H ),2.00-1.89(m,1H),1.94-1.82(m,2H),1.42(ddt,J=25.1,13.2,7.0Hz,2H),0. 95(td,J=6.9,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):293.20[M+H] + .

[0166] Example 84 N-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)acetamide (A84) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to N-(4-fluoro-4-formylcyclohexyl)acetamide, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A84 (yield 65%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),5.49(s,1H),3.44(p,J=7.0Hz,1H),2.72-2.61(m,2H), 2.60(s,1H),2.33-2.18(m,2H),1.99(s,3H),1.95-1.75(m,3H),1.77-1.66 (m,2H),1.67(dd,J=5.8,4.3Hz,1H),1.61(dt,J=12.3,6.8Hz,1H),0.99(t d,J=7.0,5.0Hz,1H),0.66(td,J=7.0,5.0Hz,1H);LRMS(ESI):305.21[M+H] + .

[0167] Example 85 N-benzyl-4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexylamine (A85) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate to 4-(benzylamino)-1-fluorocyclohexane-1-carbaldehyde, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A85 (yield 72%). 1 H NMR(400MHz,DMSO-d6)δ 7.37-7.11(m,10H),4.09(s,2H),2.72-2.57(m,3H),2.09-1.98(m,2H),1.98-1.83(m,5H),1.67 -1.49(m,4H),0.99(td,J=7.0,4.9Hz,1H),0.66(td,J=6.9,5.0Hz,1H);LRMS(ESI):353.23[M+H] + .

[0168] Example 86 N-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)aniline (A86) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to 1-fluoro-4-(phenylamino)cyclohexane-1-carbaldehyde, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A86 (yield 64%). 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.12(m,5H),7.17-7.03(m,2H),6.74-6.60(m,3H),6.26(s,1H),3. 06(p,J=7.0Hz,1H),2.76-2.64(m,2H),2.60(s,1H),1.97-1.71(m,5H),1. 53(ddt,J=25.3,11.6,6.4Hz,2H),1.42(dq,J=12.7,6.9Hz,2H),0.95(td,J=6.9,5.0Hz,1H),0.68(td,J=7.0,5.0Hz,1H);LRMS(ESI):339.22[M+H] + .

[0169] Example 87 N-(4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexyl)benzenesulfonylamide (A87) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate benzyl to N-(4-fluoro-4-formylcyclohexyl)benzenesulfonylamide, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1 to obtain product A87 (yield 68%). 1 H NMR(400MHz,DMSO-d6)δ 7.86-7.77(m,2H),7.68-7.55(m,4H),7.26-7.11(m,5H),3.05(p,J=7.0Hz,1H),2.75(q,J=7.0Hz,1H),2.66(s,1H),2.60(s,1H),1.93 -1.74(m,5H),1.68-1.57(m,1H),1.62-1.44(m,3H),0.94(td,J=7.0,5.1Hz,1H),0.67(td,J=6.9,5.0Hz,1H);LRMS(ESI):403.18[M+H] + .

[0170] Example 88 (1r,4r)-4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexylamine (A88) [ka] Except for changing 4-fluoro-4-formylpiperidine-1-carboxylate-t-butyl to ((1r,4r)-4-fluoro-4-formylcyclohexyl)carbamate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 2, and product A88 was obtained (yield 72%). 1H NMR(400MHz,DMSO-d6)δ 7.26-7.11(m,5H),2.83(p,J=7.0Hz,1H),2.76-2.64(m,2H),2.60(s,1H),1.91-1.69(m,5H),1.62-1.44(m,2H),1 .47-1.32(m,2H),1.30(s,2H),0.90(td,J=6.9,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):263.18[M+H] + .

[0171] Example 89 (1-methylpiperidin-4-yl)methyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A89) [ka] Except for changing 3-phenylpropionyl chloride to (1-methylpiperidin-4-yl)methyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Examples 8.1 and 5.4, and the dihydrochloride salt of product A89 was obtained (yield 66%). 1 H NMR(400MHz,MeOD)δ 7.33(tt,J=7.9,1.5Hz,2H),7.30-7.22(m,1H),7.26-7.19(m,2H),4.08(d,J=15.2Hz ,4H),3.62-3.51(m,4H),3.29-3.14(m,2H),3.08(p,J=4.2Hz,2H),3.03(dd,J=13.0,2 .5Hz,1H),2.88(s,3H),2.64(ddd,J=10.3,6.6,3.6Hz,1H),2.09-1.95(m,5H),1.94- 1.76(m,2H),1.76-1.58(m,3H),1.41(dt,J=7.9,6.7Hz,1H);LRMS(ESI):404.26[M+H] + .

[0172] Example 90 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (1-benzylpiperidin-4-yl)methyl (A90) [ka] Except for the fact that 3-phenylpropionyl chloride was replaced with (1-benzylpiperidin-4-yl)methyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Examples 8.1 and 5.4, and the dihydrochloride salt of product A90 was obtained (yield 57%). 1 H NMR(400MHz,MeOD)δ 7.57(dd,J=6.7,2.9Hz,2H),7.52-7.46(m,3H),7.31(tt,J=8.3,1.6Hz,2H),7.26-7.22(m,1H), 7.22-7.17(m,2H),4.32(s,2H),4.06(d,J=16.2Hz,4H),3.56(s,1H),3.54-3.45(m,3H),3.28-2. 95(m,5H),2.61(ddd,J=10.3,6.6,3.6Hz,1H),2.04-1.92(m,5H),1.91-1.75(m,2H),1.74-1.64( m,2H),1.60(ddd,J=10.4,6.8,4.4Hz,1H),1.39(dt,J=7.8,6.7Hz,1H);LRMS(ESI):478.29[M+H] + .

[0173] Example 91 4-((4-(((4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carbonyl)oxo)methyl)piperidin-1-yl)methyl)benzoic acid (A91) [ka] Except for changing 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate-t-butyl to 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (1-(t-butoxycarbonyl)piperidin-4-yl)methyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 5, and the dihydrochloride salt of product A91 was obtained (yield 35%). 1H NMR(500MHz,D2O)δ 7.98(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.28(t,J=7.5Hz,2H),7.24-7.19(m,1H),7.12(d,J=7.2Hz ,2H),4.27(s,2H),3.91-3.88(m,4H),3.48-3.39(m,4H),3.15-3.03(m,2H),3.00-2.90(m,3H),2.50(dd d,J=10.4,6.7,3.6Hz,1H),1.99-1.81(m,5H),1.69(td,J=13.3,5.0Hz,1H),1.62(td,J=13.3,5.1Hz,1H ),1.48(ddd,J=11.0,7.0,4.4Hz,1H),1.45-1.37(m,2H),1.34(q,J=7.2Hz,1H);LRMS(ESI):524.28[M+H] + .

[0174] Example 92 N-((4-fluoro-1-(piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A92) [ka] Except for changing 3-phenylpropionyl chloride to 4-((chlorosulfonyl)methyl)piperidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Examples 8.1 and 5.4, and the dihydrochloride salt of product A92 was obtained (yield 68%). 1H NMR(500MHz,MeOD)δ 7.31(t,J=7.5Hz,2H),7.24(d,J=7.5Hz,1H),7.20(d,J=7.3Hz,2H),3.79-3.71(m,2H) ,3.58(d,J=20.1Hz,2H),3.51(dt,J=12.6,3.4Hz,3H),3.36-3.23(m,4H),3.16-2.99(m ,3H),2.62(ddd,J=10.3,6.6,3.6Hz,1H),2.30(dd,J=14.7,3.7Hz,2H),2.10-1.86(m,6 H),1.61(ddd,J=10.8,6.8,4.4Hz,1H),1.39(q,J=7.0Hz,1H);LRMS(ESI):410.22[M+H] + .

[0175] Example 93 N-((4-fluoro-1-(methylsulfonyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A93) [ka] Except for changing 3-phenylpropionyl chloride to methanesulfonyl chloride, the other necessary raw materials, reagents and preparation methods were the same as those in Examples 8.1 and 5.4, to obtain the dihydrochloride salt of product A93 (yield 80%). 1 H NMR (400MHz, DMSO-d6) δ 9.71(s,2H),7.33-7.28(m,2H),7.25-7.21(m,1H),7.21-7.17(m,2H),3.54 -3.42(m,4H),2.99-2.93(m,3H),2.92(s,3H),2.64(ddd,J=10.1,6.4,3.5Hz ,1H),2.14-2.04(m,2H),1.97-1.87(m,1H),1.87-1.77(m,1H),1.66(ddd,J= 10.4,6.1,4.4Hz,1H),1.27(dt,J=7.7,6.3Hz,1H);LRMS(ESI):327.15[M+H] + .

[0176] Example 94 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate azetidin-3-ylmethyl (A94) [ka] Except for changing 3-phenylpropionyl chloride to 3-((chloroformyl)oxo)methyl)azetidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Examples 8.1 and 5.4, and the dihydrochloride salt of product A94 was obtained (yield 70%). 1 H NMR(400MHz,DMSO-d6)δ 7.27-7.10(m,5H),4.13(dt,J=12.5,7.1Hz,2H),3.88(d,J=7.0Hz,2H),3.43(dd,J=11.1,7.0Hz,2H),3.15-3.02(m,4H),2.71-2.5 6(m,4H),2.01-1.86(m,3H),1.75-1.58(m,2H),0.99(td,J=7.0,5.1Hz,1H),0.67(td,J=7.0,5.0Hz,1H).;LRMS(ESI):362.22[M+H] + .

[0177] Example 95 4-Fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-yl (A95) [ka] Except for changing 3-phenylpropionyl chloride to 4-((chloroformyl)oxo)piperidine-1-carboxylate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Examples 8.1 and 5.4, and the dihydrochloride salt of product A95 was obtained (yield 65%). 1H NMR (400MHz, DMSO-d6) δ 7.26-7.11(m,5H),4.82(p,J=7.0Hz,1H),4.13(dt,J=12.5,7.1Hz,2H),3.1 1(dt,J=12.5,7.1Hz,2H),2.90(dt,J=12.4,7.1Hz,2H),2.72-2.56(m,5H), 2.02-1.84(m,3H),1.77-1.53(m,4H),1.29(dq,J=13.9,7.1Hz,2H),0.99(t d,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):376.23[M+H] + .

[0178] Example 96 4-((4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzonitrile (A96) [ka] Except for changing bromomethylbenzene to 4-(bromomethyl)benzonitrile, the other necessary raw materials, reagents and preparation methods were the same as those in Example 6, and product A96 was obtained (yield 62%). 1 H NMR (400MHz, MeOD) δ 7.91-7.83(m,4H),7.35-7.30(m,2H),7.28-7.24(m,1H),7.24-7.19(m,2H), 4.52(s,2H),3.67(d,J=20.1Hz,2H),3.54(d,J=12.4Hz,2H),3.44-3.34(m,2 H),3.10(dt,J=7.8,4.0Hz,1H),2.70-2.60(m,1H),2.40-2.20(m,4H),1.64( dt,J=11.0,6.0Hz,1H),1.42(dt,J=7.8,6.8Hz,1H);LRMS(ESI):364.21[M+H] + .

[0179] Example 97 N-((4-fluoro-1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A97) [ka] Except for changing bromomethylbenzene to 4-(bromomethyl)piperidine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 6, and product A97 was obtained (yield 73%). 1 H NMR(400MHz,DMSO-d6)δ 8.46(d,J=5.1Hz,2H),7.40(d,J=5.1Hz,2H),7.26-7.11(m,5H),4.33(s, 2H),2.97(dt,J=12.5,7.1Hz,2H),2.72-2.57(m,3H),2.33(dt,J=12.5,7. 1Hz,2H),1.95-1.73(m,3H),1.56(ddt,J=25.1,13.2,7.2Hz,2H),0.99(td ,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):340.21[M+H] + .

[0180] Example 98 N-((4-fluoro-1-(thiophen-3-ylmethyl)piperidin-4-yl)methyl)-trans-2-phenylcyclopropylamine (A98) [ka] Except for changing bromomethylbenzene to 3-(bromomethyl)thiophene, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A98 was obtained (yield 75%). 1 H NMR(400MHz,DMSO-d6)δ 7.31-7.11(m,6H),6.96-6.87(m,2H),3.69(s,2H),3.04(dt,J=12.5,7.1Hz,2H),2.72-2.57(m,3H),2.34(dt,J=12.5,7.2Hz,2H),1.9 5-1.74(m,3H),1.56(ddt,J=25.1,13.2,7.0Hz,2H),0.99(td,J=7.0,5.0Hz,1H),0.67(td,J=7.0,5.0Hz,1H);LRMS(ESI):345.17[M+H] + .

[0181] Example 99 (1-(cyclopropylmethyl)piperidin-4-yl)methyl 4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (A99) [ka] Except for changing 3-phenylpropionyl chloride to (1-(cyclopropylmethyl)piperidin-4-yl)methyl chloroformate, the other necessary raw materials, reagents and preparation methods were the same as those in Examples 8.1 and 5.4, and the dihydrochloride salt of product A99 was obtained (yield 60%). 1 H NMR(400MHz,MeOD)δ 7.34-7.28(m,2H),7.26-7.22(m,1H),7.22-7.17(m,2H),4.15-3.98(m,4H),3.78-3.66(m,2H),3.55(d ,J=20.2Hz,2H),3.25-3.10(m,2H),3.10-2.96(m,5H),2.61(ddd,J=10.3,6.6,3.6Hz,1H),2.09-1.94( m,5H),1.92-1.65(m,4H),1.61(ddd,J=10.5,6.8,4.4Hz,1H),1.39(dt,J=7.9,6.7Hz,1H),1.16(ddtd, J=12.4,9.7,7.3,4.5Hz,1H),0.80-0.74(m,2H),0.46(dt,J=6.3,4.7Hz,2H);LRMS(ESI):404.26[M+H] + .

[0182] Example 100 N-(2-aminophenyl)-4-((4-fluoro-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide (A100) [ka] Except for changing bromomethylbenzene to (2-(4-(bromomethyl)benzoylamido)phenyl)carbamate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as in Example 6, and product A100 was obtained (yield 45%). 1H NMR(400MHz,MeOD)δ 8.21(d,J=7.9Hz,2H),7.86(d,J=8.0Hz,2H),7.60-7.46(m,4H),7.33(t,J=7.4Hz ,2H),7.24(dd,J=14.2,7.2Hz,3H),4.55(s,2H),3.68(d,J=20.0Hz,2H),3.57(d,J =10.4Hz,2H),3.47-3.36(m,2H),3.14-3.06(m,1H),2.71-2.64(m,1H),2.45-2.21 (m,4H),1.70-1.62(m,1H),1.43(dd,J=13.9,7.0Hz,1H);LRMS(ESI):473.26[M+H] + .

[0183] Example 101 4-((4-(((2-(5-bromothiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidin-1-yl)methyl)benzoate-t-butyl (A101) [ka] Except for changing trans-2-phenylcyclopropylamine to trans-2-(5-bromothiophen-2-yl)cyclopropylamine and 4-fluoro-4-formylpiperidine-1-carboxylate to benzyl 4-((4-fluoro-4-formylpiperidin-1-yl)methyl)benzoate-t-butyl, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A101 was obtained (yield 61%). 1H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.34(dt,J=8.4,1.1Hz,2H),7.00(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),3.57 (t,J=1.0Hz,2H),3.18(ddd,J=25.1,14.5,4.9Hz,1H),3.04(dt,J=7.5,4.9Hz,1H),2.96(ddd,J=25 .1,14.6,4.9Hz,1H),2.87(ddd,J=12.1,6.2,4.3Hz,2H),2.81(dtd,J=7.5,6.4,5.7Hz,1H),2.59- 2.49(m,3H),2.11-1.93(m,4H),1.89(td,J=6.4,1.3Hz,2H),1.55(s,6H).LRMS(ESI):523.14[M+H] + .

[0184] Example 102 4-((4-(((2-(5-bromothiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidin-1-yl)methyl)benzoic acid (A102) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(5-bromothiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 5, and product A102 was obtained (yield 73%). 1 H NMR(400MHz,DMSO-d6)δ 7.99-7.93(m,2H),7.37(dt,J=8.4,1.1Hz,2H),7.02(d,J=8.4Hz,1H),6.71(d,J=8.4H z,1H),3.55(t,J=1.0Hz,2H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.08(dt,J=7.3,4.9 Hz,1H),3.01(ddd,J=25.1,14.4,4.9Hz,1H),2.91-2.78(m,3H),2.61(ddd,J=12.3,6. 4,4.1Hz,2H),2.48(td,J=6.4,5.6Hz,1H),2.11-1.85(m,6H).LRMS(ESI):467.07[M+H]+ .

[0185] Example 103 Methyl 4-((4-(((2-(5-bromothiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidin-1-yl)methyl)benzoate (A103) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(5-bromothiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 3, and product A103 was obtained (yield 67%). 1 H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.34(dt,J=8.4,1.1Hz,2H),7.03(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1 H),3.89(s,2H),3.55(t,J=1.0Hz,2H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.08(dt,J=7 .3,4.9Hz,1H),3.01(ddd,J=25.1,14.4,5.0Hz,1H),2.91-2.78(m,3H),2.61(ddd,J=12.1 ,6.4,4.2Hz,2H),2.48(td,J=6.4,5.6Hz,1H),2.11-1.85(m,6H).LRMS(ESI):481.09[M+H] + .

[0186] Example 104 Ethyl 4-((4-(((2-(5-bromothiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidin-1-yl)methyl)benzoate (A104) [ka] Except for changing trans-2-phenylcyclopropylamine to trans-2-(5-bromothiophen-2-yl)cyclopropylamine and 4-fluoro-4-formylpiperidine-1-carboxylate to benzyl 4-((4-fluoro-4-formylpiperidin-1-yl)methyl)benzoate, the other necessary raw materials, reagents and preparation methods were the same as those in Example 1, and product A104 was obtained (yield 75%). 1 H NMR(400MHz,DMSO-d6)δ 7.96-7.89(m,2H),7.35(dt,J=8.4,1.1Hz,2H),7.03(d,J=8.4Hz,1H),6.68(d,J=8.4Hz,1H),4.44-4.27(m,2 H),3.58(dt,J=12.8,1.1Hz,1H),3.52(dt,J=12.8,1.1Hz,1H),3.22(ddd,J=25.3,14.6,4.9Hz,1H),3.07(dt, J=7.3,4.8Hz,1H),3.02-2.88(m,1H),2.91-2.82(m,3H),2.59(ddd,J=12.3,6.1,4.5Hz,2H),2.53(td,J=6.4 ,5.6Hz,1H),2.11-1.93(m,4H),1.89(td,J=6.4,1.3Hz,2H),1.39(t,J=7.0Hz,3H)..LRMS(ESI):495.10[M+H] + .

[0187] Example 105 4-((4-fluoro-4-(((2-(5-(4-fluorophenyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate-t-butyl (A105) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(5-(4-fluorophenyl)thiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 101, and product A105 was obtained (yield 71%). 1H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.63-7.55(m,2H),7.31(dt,J=8.5,1.0Hz,2H),7.21-7.13(m,3H),6.73(d,J=8.4Hz,1H),3 .57(t,J=1.0Hz,2H),3.20(ddd,J=25.1,14.6,4.8Hz,1H),3.01(dt,J=7.3,4.9Hz,1H),2.97-2.78(m,4H),2.58 (ddd,J=12.3,6.3,4.2Hz,2H),2.28(td,J=6.4,5.6Hz,1H),2.07(ddd,J=13.6,6.4,4.2Hz,1H),2.02(dd,J=13 .5,4.2Hz,1H),2.02-1.94(m,1H),1.98-1.89(m,2H),1.92-1.85(m,1H),1.55(s,7H).LRMS(ESI):539.25[M+H] + .

[0188] Example 106 4-((4-(((2-(5-(4-chlorophenyl)thiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidin-1-yl)methyl)benzoate-t-butyl (A106) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(5-(4-chlorophenyl)thiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 106, and product A106 was obtained (yield 77%). 1H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.54-7.47(m,2H),7.42-7.36(m,2H),7.31(dt,J=8.4,1.0Hz,2H),7.1 9(d,J=8.4Hz,1H),6.74(d,J=8.4Hz,1H),3.57(t,J=1.0Hz,2H),3.20(ddd,J=25.1,14.7,4 .9Hz,1H),3.01(dt,J=7.3,4.8Hz,1H),2.97-2.78(m,4H),2.58(ddd,J=12.1,6.4,4.2Hz, 2H),2.28(td,J=6.4,5.6Hz,1H),2.11-1.86(m,6H),1.55(s,7H).LRMS(ESI):555.22[M+H] + .

[0189] Example 107 4-((4-fluoro-4-(((2-(5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate-t-butyl (A107) [ka] Except for the fact that trans-2-phenylcyclopropylamine was changed to trans-2-(5-(4-trifluoromethylphenyl)thiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 101, and product A107 was obtained (yield 66%). 1 H NMR(400MHz,DMSO-d6)δ 7.97-7.90(m,2H),7.77-7.70(m,2H),7.64-7.58(m,2H),7.37-7.28(m,3H),6.91(d, J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.23-3.10( m,1H),3.08-2.82(m,5H),2.49(ddd,J=12.3,6.3,4.4Hz,2H),2.29(td,J=6.5,5.6Hz ,1H),2.11-1.93(m,5H),1.89(t,J=6.4Hz,2H),1.55(s,7H).LRMS(ESI):589.24[M+H]+ .

[0190] Example 108 4-((4-fluoro-4-(((2-(5-phenylthiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate-t-butyl (A108) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(5-phenylthiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 108, and product A108 was obtained (yield 73%). 1 H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.78-7.70(m,2H),7.49-7.40(m,3H),7.32(dd,J=8.4,1.5Hz,3H),6.8 8(d,J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.18(ddd,J =25.3,14.5,5.1Hz,1H),3.07-2.95(m,1H),2.99-2.92(m,1H),2.91-2.79(m,3H),2.53-2. 42(m,3H),2.11-1.90(m,4H),1.89(t,J=6.4Hz,2H),1.55(s,7H).LRMS(ESI):521.26[M+H] + .

[0191] Example 109 4-((4-fluoro-4-(((2-(5-(naphthalen-1-yl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate-t-butyl (A109) [ka] Except for the fact that trans-2-phenylcyclopropylamine was changed to trans-2-(5-(naphthalen-1-yl)thiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 101, and product A109 was obtained (yield 77%).1 H NMR(400MHz,DMSO-d6)δ 8.06-7.99(m,1H),7.98-7.89(m,4H),7.69(dd,J=7.9,0.8Hz,1H),7.61(t,J=7.8Hz.1H),7.52(pd,J=7.4,1.5Hz,2H),7.3 7-7.28(m,3H),6.88(d,J=8.4Hz,1H),3.59(dt,J=12.6,0.9Hz,1H),3.53(dt,J=12.6,1.0Hz,1H),3.17(ddd,J=25.1,14.3 ,5.1Hz,1H),3.10-2.95(m,2H),2.94(ddd,J=12.1,6.2,4.3Hz,2H),2.85(dtd,J=7.3,6.3,5.6Hz,1H),2.59(ddd,J=12.1, 6.1,4.4Hz,2H),2.29(td,J=6.4,5.6Hz,1H),2.11-1.96(m,4H),1.99-1.87(m,2H),1.55(s,7H).LRMS(ESI):571.27[M+H] + .

[0192] Example 110 4-fluoro-4-(((2-(5-(4-(trifluoromethyl)phenyl)thiophen-2-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A110) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(5-(4-trifluoromethylphenyl)thiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A110 was obtained (yield 55%). 1H NMR(400MHz,DMSO-d6)δ 7.68-7.62(m,2H),7.57-7.51(m,2H),7.30(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),4.23(dd,J=10.6,6.2Hz,1H),4.02(ddd,J=12.1,6.5,4.1 Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.70(ddd,J=11.9,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.20(ddd,J=25.3,14.6,4.9Hz,1H),3.08(dt ,J=7.5,4.9Hz,1H),3.04-2.95(m,1H),2.99-2.91(m,2H),2.84(dtd,J=7.5,6.3,5.6Hz,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.46(td,J= 6.4,5.6Hz,1H),2.06(dddd,J=25.1,13.6,6.4,4.1Hz,2H),2.00-1.81(m,5H),1.63-1.53(m,2H),1.51-1.41(m,2H).LRMS(ESI):540.22[M+H] + .

[0193] Example 111 4-(((2-(5-bromothiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A111) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(5-bromothiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as in Example 43 to obtain product A111 (yield 65%). 1H NMR(400MHz,DMSO-d6)δ 7.02(d,J=8.4Hz,1H),6.72(d,J=8.4Hz,1H),4.25(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.5,4.1Hz,2H), 3.83(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.3,14.5 ,5.0Hz,1H),3.09-2.97(m,1H),3.01-2.92(m,3H),2.85-2.71(m,3H),2.48(td,J=6.4,5.6Hz,1H),2.06(dddd,J =25.3,13.6,6.4,4.1Hz,2H),1.99-1.80(m,5H),1.64-1.54(m,2H),1.50-1.40(m,2H).LRMS(ESI):474.11[M+H] + .

[0194] Example 110 4-fluoro-4-(((2-(6-(4-methoxyphenyl)pyridin-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A112) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(4-methoxyphenyl)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A112 was obtained (yield 63%). 1H NMR(400MHz,DMSO-d6)δ 8.40(d,J=1.8Hz,1H),7.83-7.76(m,2H),7.66(d,J=8.5Hz,1H),7.41(dd,J=8.4,1.8Hz,1H),7.03-6.97(m,2H),4.08(dd,J= 10.6,6.2Hz,1H),4.06-3.96(m,3H),3.83(s,2H),3.68(ddd,J=12.1,6.4,4.0Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J=25 .1,14.7,4.8Hz,1H),3.11-2.97(m,2H),3.00-2.92(m,2H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H), 2.09(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.01-1.78(m,6H),1.65-1.55(m,2H),1.52-1.42(m,2H).LRMS(ESI):497.28[M+H] + .

[0195] Example 113 4-(((2-(5-cyclopropylthiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A113) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(5-cyclopropylthiophen-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as in Example 43 to obtain product A113 (yield 67%). 1H NMR(400MHz,DMSO-d6)δ 6.75(q,J=8.4Hz,2H),4.25(dd,J=10.5,6.3Hz,1H),4.02(ddd,J=12.1,6.4,4.0Hz,2H),3.83(dd,J=10.6, 6.2Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.22-3.11(m,1H),3.14-3.08(m,1H),3.09-2.92(m,4H),2 .85-2.71(m,3H),2.38(td,J=6.4,5.5Hz,1H),2.32(p,J=5.8Hz,1H),2.06(dddd,J=25.3,13.6,6.4,4.1Hz ,2H),1.99-1.87(m,2H),1.91-1.80(m,3H),1.63-1.53(m,6H),1.49-1.39(m,2H).LRMS(ESI):436.24[M+H] + .

[0196] Example 114 4-(((2-(5-((4-cyanophenyl)ethynyl)thiophen-2-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A114) [ka] Except for the use of trans-4-((5-(2-aminocyclopropyl)thiophen-2-yl)ethynyl)benzonitrile instead of trans-2-phenylcyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as in Example 43, and product A114 was obtained (yield 51%). 1H NMR(400MHz,DMSO-d6)δ 7.65-7.59(m,2H),7.59-7.53(m,2H),7.24(d,J=8.4Hz,1H),6.85(d,J=8.4Hz,1H),4.08(dd,J=10.5,6.3Hz,1H),4.07-3. 97(m,3H),3.68(ddd,J=12.1,6.5,4.1Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J=25.1,14.1,5.2Hz,1H),3.11-2.98(m,2H) ),3.01-2.88(m,3H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.39(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.3,13.6,6.6,4.2H z,2H),2.01-1.80(m,5H),1.60(dtd,J=13.4,6.4,4.2Hz,2H),1.47(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):521.23[M+H] + .

[0197] Example 115 4-Fluoro-4-(((2-(6-phenylpyridin-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A115) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(6-phenylpyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43 to obtain product A115 (yield 68%). 1H NMR (400MHz, DMSO-d6) δ 8.45(d,J=1.9Hz,1H),8.02-7.94(m,2H),7.69(d,J=8.4Hz,1H),7.45(dd,J=8. 4,2.0Hz,1H),7.44-7.34(m,3H),4.15(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12 .0,6.5,4.1Hz,2H),3.93(dd,J=10.5,6.3Hz,1H),3.69(ddd,J=12.1,6.4,4.2H z,2H),3.36(p,J=4.1Hz,1H),3.27-3.19(m,1H),3.23-3.10(m,1H),3.05(ddd, J=25.3,14.7,4.9Hz,1H),2.98(dt,J=6.3,4.1Hz,1H),2.98-2.92(m,1H),2.77 (ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.09(dddd,J=25.1 ,13.4,6.4,4.1Hz,2H),2.03-1.92(m,2H),1.95-1.79(m,4H),1.59(dtd,J=12. 8,6.3,4.1Hz,2H),1.46(dtd,J=13.2,6.2,4.0Hz,2H).LRMS(ESI):467.27[M+H] + .

[0198] Example 116 4-(((2-(6-(4-ethylphenoxy)pyridin-3-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A116) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(4-ethylphenoxy)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A116 was obtained (yield 64%). 1H NMR(400MHz,DMSO-d6)δ 7.97(d,J=1.9Hz,1H),7.61-7.55(m,2H),7.36(dd,J=8.4,1.8Hz,1H),7.1 2(dt,J=8.4,1.1Hz,2H),7.01(d,J=8.4Hz,1H),4.23(dd,J=10.4,6.2Hz,1H ),4.03(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.5,6.3Hz,1H),3.69(d dd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.28-3.12(m,2H),3.06 (ddd,J=25.3,14.7,4.8Hz,1H),2.96(ddt,J=14.6,6.4,4.1Hz,2H),2.80- 2.63(m,3H),2.59-2.48(m,1H),2.40(td,J=6.4,5.6Hz,1H),2.09(dddd,J= 25.3,13.6,6.4,4.1Hz,2H),2.03-1.81(m,6H),1.64-1.54(m,2H),1.46(dt d,J=13.4,6.3,4.2Hz,2H),1.24(t,J=7.2Hz,3H).LRMS(ESI):511.30[M+H] + .

[0199] Example 117 4-Fluoro-4-(((2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A117) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A117 was obtained (yield 71%). 1H NMR(400MHz,DMSO-d6)δ 8.46(d,J=1.9Hz,1H),8.34(t,J=2.2Hz,1H),7.86(ddd,J=7.7,2.2,1.2Hz,1H),7.77(ddd,J=7.9,2.2,1.3Hz,1H),7.72-7.63(m,2H),7.47(d d,J=8.4,2.0Hz,1H),4.08(dd,J=10.4,6.2Hz,1H),4.08-3.97(m,3H),3.68(ddd,J=12.1,6.5,4.2Hz,2H),3.37(p,J=4.1Hz,1H),3.18(ddd,J= 25.1,14.7,4.8Hz,1H),3.06(dtd,J=7.5,6.4,5.6Hz,1H),3.04-2.91(m,3H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.20(td,J=6.5,5.7Hz,1H), 2.08(dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.00-1.78(m,6H),1.65-1.55(m,2H),1.47(dtd,J=13.2,6.2,4.0Hz,2H).LRMS(ESI):535.26[M+H] + .

[0200] Example 118 4-fluoro-4-(((2-(6-(4-fluorophenyl)pyridin-3-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A118) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(4-fluorophenyl)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43 to obtain product A118 (yield 75%). 1H NMR(400MHz,DMSO-d6)δ 8.41(d,J=1.8Hz,1H),8.18-8.11(m,2H),7.66(d,J=8.5Hz,1H),7.42(dd,J =8.4,1.8Hz,1H),7.20-7.12(m,2H),4.14(dd,J=10.6,6.2Hz,1H),4.03(dd d,J=12.1,6.4,4.0Hz,2H),3.83(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1 ,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.3,14.7,4.9Hz,1H ),3.09-2.96(m,1H),3.00-2.90(m,3H),2.75(ddt,J=14.5,6.4,4.1Hz,2H) ,2.40(td,J=6.4,5.6Hz,1H),2.07(dddd,J=25.1,13.5,6.4,4.0Hz,2H),1. 97(ddd,J=13.4,6.4,4.0Hz,1H),1.96-1.86(m,3H),1.89-1.81(m,2H),1.6 4-1.54(m,2H),1.45(dtd,J=13.2,6.3,4.0Hz,2H).LRMS(ESI):485.26[M+H] + .

[0201] Example 119 4-(((2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A119) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(4-chlorophenyl)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A119 was obtained (yield 71%). 1H NMR(400MHz,DMSO-d6)δ 8.41(d,J=1.9Hz,1H),7.85-7.79(m,2H),7.68(d,J=8.4Hz,1H),7.46-7.35(m,3H),4.14(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4 .2Hz,2H),3.82(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.3,14.7,4.9Hz,1H),3. 09-2.90(m,4H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.40(td,J=6.4,5.6Hz,1H),2.07(dddd,J=25.1,13.5,6.4,4.1Hz,2H),2.01-1.88(m, 2H),1.92-1.85(m,2H),1.89-1.81(m,2H),1.58(dtd,J=12.8,6.3,4.0Hz,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):501.24[M+H] + .

[0202] Example 120 4-(((2-(6-(3,5-dimethoxyphenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A120) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(6-(3,5-dimethoxyphenyl)pyridin-3-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A120 was obtained (yield 61%). 1H NMR (400MHz, DMSO-d6) δ 8.40(d,J=1.9Hz,1H),7.68(d,J=8.4Hz,1H),7.34(dd,J=8.4,2.0Hz,1H),7 .19(d,J=2.0Hz,2H),6.58(t,J=2.2Hz,1H),4.23(dd,J=10.4,6.2Hz,1H),4. 04(ddd,J=12.1,6.4,4.0Hz,2H),3.86-3.80(m,1H),3.81(s,5H),3.68(ddd, J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.18(ddd,J=25.3,14.7,4.9 Hz,1H),3.06(dtd,J=7.3,6.2,5.4Hz,1H),3.04-2.95(m,1H),2.99-2.91(m ,2H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.21(td,J=6.5,5.7Hz,1H),2.09( dddd,J=25.3,13.6,6.4,4.1Hz,2H),2.00-1.78(m,6H),1.59(dtd,J=13.4,6 .3,4.0Hz,2H),1.45(dtd,J=13.4,6.3,4.1Hz,2H).LRMS(ESI):527.30[M+H] + .

[0203] Example 121 4-(((2-(6-bromopyridin-3-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A121) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(6-bromopyridin-2-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43 to obtain product A121 (yield 62%). 1H NMR(400MHz,DMSO-d6)δ 8.18(d,J=1.8Hz,1H),7.49(d,J=8.4Hz,1H),7.34(dd,J=8.4,1.8Hz,1H),4.25(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4.2Hz,2H),3. 82(dd,J=10.6,6.2Hz,1H),3.68(ddd,J=12.1,6.4,4.2Hz,2H),3.35(p,J=4.1Hz,1H),3.15(ddd,J=25.1,14.7,4.9Hz,1H),3.08-2.94(m,2H),2 .98-2.89(m,2H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.23(td,J=6.4,5.6Hz,1H),2.06(dddd,J=25.1,13.4,6.4,4.1Hz,2H),2.01-1.89(m,2H) ),1.90(dd,J=6.4,4.1Hz,0H),1.90(s,1H),1.91-1.80(m,3H),1.64-1.54(m,2H),1.45(dtd,J=13.4,6.3,4.1Hz,2H).LRMS(ESI):469.15[M+H] + .

[0204] Example 122 4-(((2-(2-chlorothiazol-5-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A122) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(2-chlorothiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43 to obtain product A122 (yield 65%). 1H NMR (400MHz, DMSO-d6) δ 7.35(s,1H),4.16(dd,J=10.6,6.2Hz,1H),4.04(ddd,J=12.1,6.4,4.2Hz,2H) ,3.94(dd,J=10.4,6.2Hz,1H),3.69(ddd,J=12.1,6.4,4.2Hz,2H),3.20-3.07 (m,2H),3.10-2.87(m,5H),2.82-2.72(m,3H),2.16-1.88(m,6H),1.84(hept, J=6.2Hz,1H),1.64-1.54(m,2H),1.50-1.40(m,2H).LRMS(ESI):431.16[M+H] + .

[0205] Example 123 4-fluoro-4-(((2-(2-(4-fluorophenyl)thiazol-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A123) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(2-(4-fluorophenyl)thiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A123 was obtained (yield 70%). 1H NMR(400MHz,DMSO-d6)δ 7.70-7.62(m,2H),7.58(s,1H),7.26-7.18(m,2H),4.13(dd,J=10.5,6.3Hz,1H),4.03(ddd,J=12.1,6.4,4.0Hz,2H),3.82 (dd,J=10.5,6.3Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.6,4.9Hz,1H),3. 09-2.97(m,1H),3.00-2.90(m,4H),2.93-2.85(m,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.4,6.4,4.0Hz, 1H),2.08-1.97(m,3H),2.00-1.81(m,3H),1.64-1.54(m,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):491.22[M+H] + .

[0206] Example 124 4-(((2-(2-(4-chlorophenyl)thiazol-5-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A124) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(2-(4-chlorophenyl)thiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A124 was obtained (yield 71%). 1H NMR(400MHz,DMSO-d6)δ 8.05-7.99(m,2H),7.60-7.50(m,3H),4.13(dd,J=10.4,6.2Hz,1H),4.02(ddd,J=12.1,6.4,4.2Hz,2H),3.82(dd,J=10.6,6 .2Hz,1H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.5,5.1Hz,1H),3.09-2.97(m,1H) ,3.01-2.94(m,2H),2.97-2.90(m,2H),2.93-2.85(m,1H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.4,6.4,4.0Hz ,1H),2.08-1.99(m,3H),2.02-1.81(m,3H),1.64-1.54(m,2H),1.45(dtd,J=13.4,6.3,4.2Hz,2H).LRMS(ESI):507.19[M+H] + .

[0207] Example 125 4-Fluoro-4-(((2-(2-phenylthiazol-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A125) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(2-phenylthiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43 to obtain product A125 (yield 69%). 1H NMR(400MHz,DMSO-d6)δ 7.96-7.90(m,2H),7.58(s.1H),7.53-7.41(m,3H),4.14(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.1,6.5,4.1Hz,2H),3.83(dd, J=10.4,6.2Hz,1H),3.70(ddd,J=11.9,6.4,4.0Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.4,5.0Hz,1H),3.09-2.97( m,1H),3.01-2.94(m,2H),2.97-2.90(m,2H),2.93-2.85(m,1H),2.76(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.5,6.5,4. 1Hz,1H),2.08-1.99(m,3H),2.01-1.81(m,3H),1.64-1.54(m,2H),1.45(dtd,J=13.2,6.3,4.0Hz,2H).LRMS(ESI):473.23[M+H] + .

[0208] Example 126 4-Fluoro-4-(((2-(2-(4-methoxyphenyl)thiazol-5-yl)cyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl (A126) [ka] Except for the fact that trans-2-phenylcyclopropylamine was replaced with trans-2-(2-(4-methoxyphenyl)thiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A126 was obtained (yield 67%). 1H NMR(400MHz,DMSO-d6)δ 8.11-8.05(m,2H),7.57(s,1H),7.25-7.19(m,2H),4.15(dd,J=10.5,6.3Hz,1H),4.02(ddd,J=12.1,6.5,4.1Hz,2 H),3.86-3.80(m,1H),3.81(s,3H),3.69(ddd,J=12.1,6.4,4.0Hz,2H),3.36(p,J=4.1Hz,1H),3.16(ddd,J=25.1,1 4.6,4.9Hz,1H),3.09-2.85(m,6H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.6,6.5,4.2Hz,1H),2.08- 2.00(m,2H),2.03-1.92(m,2H),1.96-1.80(m,2H),1.63-1.53(m,2H),1.50-1.40(m,2H).LRMS(ESI):503.24[M+H] + .

[0209] Example 127 4-(((2-(2-(3,5-dimethoxyphenyl)thiazol-5-yl)cyclopropyl)amino)methyl)-4-fluoropiperidine-1-carboxylate piperidin-4-ylmethyl (A127) [ka] Except for the use of trans-2-phenylcyclopropylamine instead of trans-2-(2-(3,5-dimethoxyphenyl)thiazol-5-yl)cyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as those in Example 43, and product A127 was obtained (yield 59%). 1H NMR(400MHz,DMSO-d6)δ 7.56(s,1H),7.10(d,J=2.2Hz,2H),6.59(t,J=2.2Hz,1H),4.13(dd,J=10.4,6.2Hz,1H),4.03(ddd,J=12.1,6.4,4.2Hz, 2H),3.86-3.80(m,1H),3.81(s,4H),3.69(ddd,J=12.1,6.5,4.1Hz,2H),3.35(p,J=4.1Hz,1H),3.16(ddd,J=25.1,14.2, 5.2Hz,1H),3.09-2.85(m,6H),2.75(ddt,J=14.5,6.4,4.1Hz,2H),2.09(ddd,J=13.6,6.4,4.0Hz,1H),2.08-1.96(m,3H) ),1.95(ddd,J=13.6,6.5,4.2Hz,1H),1.95-1.81(m,2H),1.64-1.54(m,2H),1.50-1.40(m,2H).LRMS(ESI):533.25[M+H] + .

[0210] Example 128 4-Fluoro-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl ((1R,2S)-A43) [ka] Except for changing trans-2-phenylcyclopropylamine to (1R,2S)-2-phenylcyclopropylamine, the other necessary raw materials, reagents and production method were the same as in Example 43, and the product (1R,2S)-A43 was obtained (yield 49%). 1H NMR(400MHz,D2O)δ 7.32(t,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.16(d,J=7.3Hz,2H),3.95(d,J=6.0 Hz,4H),3.47(d,J=20.5Hz,2H),3.38(d,J=13.0Hz,2H),3.12(t,J=12.0Hz,2H),3. 01-2.87(m,3H),2.53(ddd,J=10.3,6.6,3.5Hz,1H),2.04-1.85(m,5H),1.79-1.70 (m,1H),1.65(td,J=13.7,5.1Hz,1H),1.55-1.33(m,4H);LRMS(ESI):390.25[M+H] + .

[0211] Example 129 4-Fluoro-4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate piperidin-4-ylmethyl ((1S,2R)-A43) [ka] Except for changing trans-2-phenylcyclopropylamine to (1S,2R)-2-phenylcyclopropylamine, the other necessary raw materials, reagents and production method were the same as in Example 43, and the product (1S,2R)-A43 was obtained (yield 52%). 1 H NMR(400MHz,D2O)δ 7.31(t,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.15(d,J=7.2Hz,2H),3.94(d,J=5.9Hz,4H) ,3.47(d,J=20.5Hz,2H),3.38(d,J=12.8Hz,2H),3.12(t,J=12.4Hz,2H),2.95(ddd,J=19. 8,10.5,7.1Hz,3H),2.52(ddd,J=10.3,6.7,3.6Hz,1H),2.04-1.86(m,5H),1.74(td,J=13 .3,5.0Hz,1H),1.64(td,J=13.7,5.2Hz,1H),1.55-1.33(m,4H);LRMS(ESI):390.25[M+H] + .

[0212] Example 130 4-fluoro-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (1-benzylpiperidin-4-yl)methyl ((1R,2S)-A90) [ka] Except for changing trans-2-phenylcyclopropylamine to (1R,2S)-2-phenylcyclopropylamine, the other necessary raw materials, reagents and preparation methods were the same as in Example 90, and the product (1R,2S)-A90 was obtained (yield 44%). 1 H NMR(500MHz,MeOD)δ 7.58(dd,J=6.6,2.8Hz,2H),7.51-7.45(m,3H),7.31(t,J=7.4Hz,2H),7.25-7.21(m,1H), 7.21-7.18(m,2H),4.31(s,2H),4.05(d,J=13.7Hz,4H),3.58-3.46(m,4H),3.24-3.13(m,2 H),3.09-2.99(m,3H),2.62(ddd,J=10.3,6.6,3.6Hz,1H),2.08-1.77(m,7H),1.69(td,J=1 5.0,3.5Hz,2H),1.64-1.58(m,1H),1.39(dd,J=14.5,6.8Hz,1H);LRMS(ESI):478.29[M+H] + .

[0213] Example 131 4-((4-fluoro-4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid ((1R,2S)-A5) [ka] Except for changing trans-2-phenylcyclopropylamine to (1R,2S)-2-phenylcyclopropylamine, the other necessary raw materials, reagents and production method were the same as in Example 5, and the product (1R,2S)-A5 was obtained (yield 22%). 1H NMR(400MHz,DMSO-d6)δ 8.02-7.93(m,2H),7.50(dt,J=7.4,1.2Hz,2H),7.26-7.10(m,5H),3.54(d ,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76-2.62(m,2H),2.62-2.4 9(m,3H),2.05-1.82(m,3H),1.45(ddt,J=25.1,13.2,7.1Hz,2H),0.95(td ,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H] + .

[0214] Example 132 4-((4-fluoro-4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid ((1S,2R)-A5) [ka] Except for changing trans-2-phenylcyclopropylamine to (1S,2R)-2-phenylcyclopropylamine, the other necessary raw materials, reagents and production method were the same as in Example 90, and the product (1S,2R)-A5 was obtained (yield 24%). 1 H NMR(400MHz,DMSO-d6)δ 8.00-7.93(m,2H),7.44(dt,J=7.4,1.2Hz,2H),7.26-7.11(m,5H),3.54(d ,J=1.5Hz,2H),3.11(dt,J=12.6,7.2Hz,2H),2.76-2.64(m,2H),2.62-2.4 9(m,3H),2.05-1.85(m,3H),1.45(ddt,J=25.1,13.2,7.2Hz,2H),0.95(td ,J=7.0,4.9Hz,1H),0.71(td,J=7.0,5.0Hz,1H);LRMS(ESI):383.21[M+H] + .

[0215] Examples of pharmacological activity tests Example 1. Molecular level activity test: 1. LSD1 in vitro activity experiment Selection method: Selection based on lysine-specific demethylase 1 (LSD1) activity Equipment: Microplate reader Envision TM (PerkinElmer, USA).

[0216] Materials: Human recombinant LSD1, LSD1 protein fragment (aa158-end) of fusion GST expressed in an E. coli expression system and purified in this laboratory; LSD1 activity detection kit LANCE Ultra LSD1 Histone H3-Lysine 4 Demethylase Assay, purchased from Perkin Elmer; H3 polypeptide substrate ARTK(me1)QTARKSTGGKAPRKQLA-GG-K(Biotin)-NH2, synthesized by GL Biochem Ltd.

[0217] Principle: LSD1 can specifically remove the methylation modification of the lysine at K4 position in the H3 polypeptide substrate, thereby making the substrate unmethylated. This method uses histone H3 methylated polypeptide (1-24) as the substrate, and introduces a biotin label at the C position of the substrate. LSD1 can initiate a reaction with the participation of FAD to remove the methylation modification at the substrate H3K4. The Eu-labeled H3K4-based antibody binds to the substrate through an antigen-antibody reaction, and at the same time, the streptavidin-labeled receptor interacts with the specificity of biotin through streptavidin and binds. Thus, the Eu-labeled donor interacts with the streptavidin-labeled receptor. In fluorescence resonance energy transfer, when two fluorescent groups approach each other due to the interaction of biological molecules, a part of the energy captured by the hole compound upon excitation is released, with an emission wavelength of 620 nm, and the other part of the energy is transferred to the acceptor, with an emission wavelength of 665 nm. The emission at 665 nm is generated only by FRET with the donor. Therefore, when the biological molecules interact, there are two emissions at 620 nm and 665 nm, and when there is no interaction, there is only one emission at 620 nm. The ratio of the fluorescence signals at the two emission wavelengths of 620 nm and 665 nm can be detected to reflect the LSD1 demethylation activity. At the same time, a blank control was set up to determine the strength of the enzyme activity. The experiment used ORY-1001 and GSK-2879552 as positive inhibitors.

[0218] Sample treatment: Samples were dissolved in DMSO and stored at low temperature, and the final concentration of DMSO in the system was adjusted to a range that would not affect activity measurement. In the first screening, the activity of the sample was measured under a single concentration condition, e.g., 20 μM. For samples that showed activity under a certain condition, e.g., when the inhibition rate (% Inhibition) was greater than 50, the activity-dose dependency, i.e., IC50 value, was measured and obtained by performing a nonlinear fit of the activity of the sample to the concentration of the sample. The calculation software was Graphpad Prism5, and the fitting model was sigmoidal dose-response (variable slope). In most inhibitor screening models, the bottom and top of the fitting curve were set to 0 and 100, respectively. Test Results:

[0219] [Table 2] TIFF0007605579000177.tif1621662. MAOA and MAOB in vitro activity experiments Screening method: Screening based on monoamine oxidase (MAOA) and MAOB activity Equipment: Microplate reader Envision TM (PerkinElmer, USA).

[0220] Materials: Human recombinant MAOA, purchased from Promega; Human recombinant MAOB, purchased from Sigma; The MAOA and MAOB activity detection kit MAO-Glo was purchased from Promega.

[0221] Principle: This method uses a specific luciferin derivative as a substrate, and MAOA or MAOB catalyzes the substrate to produce luciferin methyl ester, which is then fluoresced by the action of luciferase, and the intensity of the fluorescent signal can reflect the activity of MAOA or MAOB. At the same time, a blank control was set up to determine the intensity of the enzyme activity. Tranylcypromine (TCP) was used as a positive inhibitor in the experiment.

[0222] Sample treatment: Samples were dissolved in DMSO and stored at low temperature, and the final concentration of DMSO in the system was adjusted to a range that would not affect activity measurement. In the initial screening, the activity of the samples was measured at a single concentration condition, e.g., 100 μM. For samples that showed activity at a certain condition, e.g., % Inhibition > 50, the activity-dose dependency, i.e., IC 50 The activity of the sample was measured and a nonlinear fit was performed to the sample concentration. The software used for calculations was Graphpad Prism5, and the fitting model was sigmoidal dose-response (variable slope). For most inhibitor screening models, the bottom and top of the fitted curve were set to 0 and 100. Test Results:

[0223] [Table 3] TIFF0007605579000179.tif134128

[0224] Example 2. Activity test at the cellular level: 1.CD86 gene expression activation test: Experimental principle: Quantitative Real-time PCR is a method of DNA amplification reaction using fluorescent chemicals to measure the total amount of product after each cycle of polymerase chain reaction (PCR). It is a method of quantitative analysis of specific DNA sequences in test samples by internal or external reference method. During the exponential phase of PCR amplification, the Ct value of the template is linearly related to the initial copy number of the template, which is the basis for quantification.

[0225] Materials: Leukemia cell line MV4-11: childhood acute lymphoblastic leukemia, immunobiphenotype, AF4-MLL fusion t(4,11), sensitive to LSD1 inhibitors that activate CD86 expression (Analytical Biochemistry 442(2013)104-106).

[0226] Testing Method: 1. MV4-11 cells were accurately counted at 350w / mL and placed in a 12-well plate at 900μL / well. 2. 3 μL of the test compound or positive compound was added to 147 μL of medium and mixed evenly, and 100 μL was taken and added to the 12-well plate on which the cells were spread, mixed evenly, and incubated in a thermostatic chamber at 37°C and 5% CO2 for 24 hours. 3. The sample was collected in a 1.5 mL Eppendorf tube and centrifuged at 2000 rpm for 3 minutes. The supernatant was discarded and 500 mL of TRIzol was added to dissolve the sample, followed by allowing it to stand for 3 minutes. 4. 100 μL of trichloromethane was added, the Eppendorf tube was vigorously shaken for 15 s, allowed to stand for 3 min, and centrifuged at 12,000 rpm for 15 min. 5. The supernatant was aspirated and placed into a new Eppendorf tube, 200 μL of isopropanol was added, and the tube was placed in a -20°C refrigerator for 15 minutes and centrifuged at 12,000 rpm for 10 minutes. 6. The supernatant was discarded, and 500 μL of 4°C 75% ethanol was added, mixed uniformly, and centrifuged at 7,500 rpm for 10 minutes. 7. The supernatant was discarded, the Eppendorf tube was dried in a draft chamber, 20-30 μL of RNA enzyme-inactivated deionized water was added, and the mixture was mixed uniformly to detect the RNA concentration. 8. All samples were adjusted to 750ng / 8μL, and RT-kit enzyme and substrate were added, followed by reverse transcription at 42℃ for 15min, and the enzyme was inactivated at 85℃ for 2min. 9. 100 μL of deionized water was added to the Eppendorf tube and mixed evenly. 10. The QPCR sample was mixed in a ratio of 7.6 μL sample + 0.65 μL forward primer + 0.65 μL reverse primer + 11.1 μL SYBR, placed in an 8-tube tube, centrifuged at 1500 rpm for 1 minute, and QPCR was started. 11. The data was compiled and activation folds were calculated using the 2^(-ΔΔct) method (BLOOD, 8 AUGUST 2013 VOLUME 122, NUMBER 6). Test Results:

[0227] [Table 4]

[0228] 2. Testing the inhibitory activity of compounds against cell growth by MTS method Experimental principle: The MTS method is used to detect the growth inhibitory effect of the test compound on leukemia cell MV (4:11), and the principle is that succinate dehydrogenase in the mitochondria of living cells reduces exogenous thiazolyl blue to formazan, a poorly soluble blue crystal.

[0229] Materials: Leukemia cell line MV4-11: childhood acute lymphoblastic leukemia, immune biphenotype, AF4-MLL fusion t(4,11), sensitive to LSD1 inhibitors that suppress cell growth (Cancer cell.°2012,17;21(4):473-487).

[0230] Testing Method: 1. MV4-11 cells in the logarithmic growth phase were harvested and counted accurately to 16,000 cells / mL, and the diluted cell solution was placed into a 96-well plate at 90 μL / well. 2. Fresh medium was taken and added to the 96-well plate on which the cell suspension was placed at 90 μL / well. 3. On a compound plate, the test compound and the positive compounds ORY-1001 and GSK2879552 at a concentration of 10 mM were taken and diluted in DMSO in a 3-fold gradient to provide 8 points each. 4. Take 2 μL of each diluted compound and place it in a 96-well plate containing 98 μL of blank medium. For the DMSO group, add 2 μL of DMSO to 98 μL of blank medium, mix evenly, and prepare for use. 5. Compounds were mixed homogeneously in the medium and added to the 96-well plate with cells at 20μL / well, and three duplicate wells were prepared and mixed homogeneously. In the blank group, 200μL of IMDM medium was added, and in the DMSO group, DMSO diluted in medium was added to 180μL of cell-containing medium. 6. The plates were incubated in a constant temperature bath at 37°C and 5% CO2 for 10 days. 7. After 10 days, MTS was added, incubated for 2.5 hours, and the values ​​were read. Test Results:

[0231] [Table 5] TIFF0007605579000182.tif250118TIFF0007605579000183.tif147135

[0232] Example 3. Effect of chronic drugs on animals: Inhibitory effect of LSD1 inhibitors on the growth of human acute myeloid leukemia MV4-11 tumors subcutaneously transplanted in nude mice Method of formulation: Accurately measure the drug and add saline to make it 0.3mg / ml, and the administration volume is 10ml / kg.

[0233] Animals: Balb / c male nude mice, weighing 17-20g, were purchased from Beijing VITAL RIVER Laboratory Animal Co., Ltd. Each group had 5 animals. Cell line: MV4-11 cell line was inoculated subcutaneously in the right armpit of nude mice, and the cell inoculation volume was 5 × 10 6 After the formation of transplanted tumors, the experiment was started.

[0234] Testing Method: Female nude mice weighing 20±3 g were inoculated with the MV4-11 cell line subcutaneously in the right armpit of the nude mice, with a cell inoculation dose of 5 × 10 6 After tumor formation, the diameter of the transplanted tumor was measured with a caliper and the tumor was determined to be between 100 and 300 mm. 3 The animals were then divided into a model control group and a treatment group based on body weight and tumor volume, with 5 animals per group. The model control group was administered an equal amount of blank solvent. After grouping, the animals were orally administered intragastrically every day for 21 days.

[0235] Tumor weight suppression rate %=(Wc-W T ) / Wc×100% Note: Wc: tumor weight in the control group, W T : Tumor weight of treatment group. Data processing: Data are shown as mean ± standard error, and statistical methods used included significance testing using two-tailed T-TEST tests. Test Results:

[0236] [Table 6] TIFF0007605579000185.tif74158

[0237] Example 4: Pharmacokinetic studies in mice Testing Method: For GSK2879552, 15μL of plasma sample was taken into a centrifuge tube, 60μL of methanol:acetonitrile (1:1, v / v) was added, vortexed for 1 min, centrifuged (11000 rpm) for 5 min, 20μL of the supernatant was taken, 80μL of water was added, and the mixture was mixed uniformly by vortexing before analysis. The linear range of GSK2879552 was 0.3-12500ng / mL.

[0238] For A1, 15μL of plasma sample was taken in a centrifuge tube, 60μL of methanol:acetonitrile (1:1, v / v) was added, vortexed for 1 min, centrifuged (11000 rpm) for 5 min, 20μL of the supernatant was taken, 80μL of water was added, and the mixture was mixed uniformly with a vortex before analysis. The linear range of A1 was 3.0-25000ng / mL.

[0239] For A2, 15μL of plasma sample was taken in a centrifuge tube, 60μL of methanol:acetonitrile (1:1, v / v) was added, vortexed for 1min, centrifuged (11000rpm) for 5min, 20μL of the supernatant was taken, 40μL of water was added, and the mixture was mixed uniformly by vortexing before analysis. The linear range of A2 was 0.3-5000ng / mL.

[0240] For A4, 15 μL of plasma sample was taken in a centrifuge tube, 60 μL of methanol:acetonitrile (1:1, v / v) was added, vortexed for 1 min, centrifuged (11000 rpm) for 5 min, 20 μL of the supernatant was taken, 40 μL of water was added, and the mixture was mixed uniformly with a vortex before analysis. The linear range of A4 was 1.0-5000 ng / mL.

[0241] The experimental procedures for A43, A90, (1R,2S)-A43 and (1R,2S)-A90 were the same as those for A1. Test Results: Summary table of pharmacokinetic parameters of GSK2879552, A1, A2, A4, A43, A90, (1R,2S)-A43 and (1R,2S)-A90

[0242] [Table 7] TIFF0007605579000187.tif33170

[0243] All documents related to the present invention are incorporated herein by reference as if each document were incorporated individually. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. A fluorine-substituted cyclopropylamine compound having a structure represented by general formula I, or its semi-isomer, R-isomer, S-isomer, pharma- ceutically acceptable salt, or a mixture thereof. 【Chemistry 1】 (A is selected from a substituted or unsubstituted phenyl group or a 5-12 membered aromatic heterocycle containing 1-4 heteroatoms selected from substituted or unsubstituted oxygen, sulfur and nitrogen, said aromatic heterocycle being selected from a thienyl group and a pyridinyl group, wherein said substituted phenyl group or substituted aromatic heterocycle is substituted with 1-3 substituents on each ring, said substituents being selected from the group consisting of isotopes of hydrogen, halogens and unsubstituted or substituted C1-C12 straight or branched alkyl groups. R 2 is hydrogen or COOH. R 3 is hydrogen. W is -(CH 2 ). Y is CH 2 It is. Z is (CH 2 )q, where q is 1. n is 0. X is NR 1 or C(R 1 ) 2 . Each R 1 is independently selected from a substituted or unsubstituted C6 to C12 aryl group, hydrogen, a substituted or unsubstituted C1 to C6 alkyl group, -SO 2 Ra, -NHC(O)Ra, -C(O)O(CH 2 ) m Ra, -C(O)ORa, -C(O)Ra, -NRcRd, a substituted or unsubstituted aralkyl group, and a substituted or unsubstituted heteroaralkyl group, where m is an integer from 1 to 3, and the substituent is selected from the group consisting of a carboxy group, a cyano group, a substituted or unsubstituted C1 to C4 alkyl ester group, a C1 to C4 alkylsulfonyl group, an aralkyl group, and a C6 to C12 aryl group. Each Ra is independently selected from the group consisting of hydrogen, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, a substituted or unsubstituted C3-C7 heterocyclic group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, and a substituted or unsubstituted 5-10 membered heteroaryl group, wherein the substituent is selected from the group consisting of a C1-C4 alkyl group, a C1-C4 alkyl group substituted with a halogen, a C1-C4 alkyl group substituted with a phenyl group, a C1-C4 alkyl ester group, a halogen, a C1-C4 alkoxy group, and a carboxyl group. Rc is selected from hydrogen, unsubstituted or halogen-substituted C1-C3 straight or branched chain alkyl groups. Rd is hydrogen. The aryl group in the aralkyl group and the substituted or unsubstituted aralkyl group is a C6 to C12 aryl group, the alkyl group in the aralkyl group, the substituted or unsubstituted aralkyl group, and the substituted or unsubstituted heteroaralkyl group is methyl, ethyl, propyl, or butyl, and the heteroaryl group in the substituted or unsubstituted heteroaralkyl group is pyridinyl.

2. A is an unsubstituted phenyl group; 2. The fluorine-substituted cyclopropylamine compound according to claim 1, or its racemate, R-isomer, S-isomer, pharma- ceutically acceptable salt, or a mixture thereof.

3. Each R 1 are independently a substituted or unsubstituted C6 to C12 aryl group, a substituted or unsubstituted C1 to C4 alkyl group, -SO 2 selected from Ra, -NHC(O)Ra, -C(O)ORa, -C(O)Ra, -NRcRd, and substituted or unsubstituted aralkyl groups, the aryl group in the substituted or unsubstituted aralkyl group is a C6 to C12 aryl group, and the alkyl group in the substituted or unsubstituted aralkyl group is methyl, ethyl, propyl, or butyl; each Ra is independently hydrogen, a substituted or unsubstituted phenyl group, an unsubstituted C3-C7 cycloalkyl group, or a substituted or unsubstituted C1-C4 alkyl group; Rc is selected from hydrogen, C1-C3 straight or branched chain alkyl groups; 2. The fluorine-substituted cyclopropylamine compound according to claim 1, or its racemate, R-isomer, S-isomer, pharma- ceutically acceptable salt, or a mixture thereof.

4. X is NR 1 And R connected to X 1 is a substituted or unsubstituted C6-C12 aryl group, wherein the substituent is selected from the group consisting of a C6-C12 aryl group and a carboxy group (-COOH), and the fluorine-substituted cyclopropylamine compound according to claim 1, and its racemic form, R-isomer, S-isomer, pharma- ceutically acceptable salt or mixture thereof.

5. X is NR 1 And R connected to X 1 is a substituted or unsubstituted C6-C12 aryl C1-C4 alkyl group, wherein the substituent is a carboxy group (-COOH), and the fluorine-substituted cyclopropylamine compound according to claim 1, and its racemic form, R-isomer, S-isomer, pharma- ceutically acceptable salt or mixture thereof.

6. The fluorine-substituted cyclopropylamine compound according to claim 1, wherein the compound has a structure represented by the general formula (1R, 2S)-Ia or the general formula (1S, 2R)-Ib, or a racemic mixture, an R-isomer, an S-isomer, a pharma- ceutically acceptable salt, or a mixture thereof. 【Chemistry 2】

7. A fluorine-substituted cyclopropylamine compound selected from the following compounds, or a racemic modification, an R-isomer, an S-isomer, a pharma- ceutically acceptable salt, or a mixture thereof: 【Table 1】

8. The pharma- ceutically acceptable salts can be obtained by reacting the fluorine-substituted cyclopropylamine compound with an inorganic or organic acid, and the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, or phosphoric acid, and the organic acid is citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propanoic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenyl The fluorine-substituted cyclopropylamine compound according to claim 1, which is a sodium, potassium, calcium, aluminum or ammonium salt formed with acetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid or hydroxyethanesulfonic acid, or a compound of formula I and an inorganic base, or a methylamine, ethylamine or ethanolamine salt formed with a compound of formula I and an organic base, or a racemic, R-isomer, S-isomer, pharma- ceutically acceptable salt or a mixture thereof.

9. A pharmaceutical composition for treating or preventing a tumor disease, comprising a therapeutically effective amount of one or more selected from the group consisting of the fluorine-substituted cyclopropylamine compound according to claim 1, its pharma- ceutically acceptable salt, racemate, R-isomer and S-isomer.

10. The pharmaceutical composition of claim 9, wherein the tumor disease is a malignant tumor disease associated with lysine-specific demethylase 1 (LSD1), selected from the group consisting of brain cancer (glioma), glioblastoma, leukemia, Banayan-Zonana syndrome, Cowden disease, cerebellar dysgenetic gangliocytoma, breast cancer, inflammatory breast cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, renal cancer, ovarian cancer, pancreatic adenocarcinoma, prostate cancer, sarcoma, osteosarcoma, and giant cell tumor of bone and thyroid.

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