A phenylcyclopropylamine compound, its preparation method and application

Abstract

The present invention discloses a phenylcyclopropylamine compound, a preparation method and an application thereof. The phenylcyclopropylamine compound includes a structural general formula I and its corresponding salts. Biological activity experiments show that the phenylcyclopropylamine compound has excellent inhibitory effects on LSD1, thus opening up a new way for finding a new class of innovative drugs based on the LSD1 target.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and particularly relates to a phenylcyclopropylamine compound, a preparation method thereof and an application thereof. Background Art

[0002] Histone lysine-specific demethylase 1 (LSD1) is the first histone demethylase discovered, which specifically removes methyl groups at monomethylated and dimethylated H3K4 and H3K9 sites through a flavin adenine dinucleotide (FAD)-dependent mechanism, thereby regulating gene expression and transcriptional activity. Current studies have confirmed that LSD1 is overexpressed in a variety of tumor cells. LSD1 can regulate gene expression by activating or inhibiting chromatin domains through histone demethylation, and regulate the occurrence and development of various tumors by affecting the expression of essential factors in cell proliferation and differentiation. In addition, LSD1 is also closely related to the occurrence and development of other diseases such as viral infections, central nervous system diseases, cardiovascular and cerebrovascular diseases, etc. In addition, LSD1 plays an important role in maintaining brown fat metabolism, and targeting LSD1 also provides a new strategy for the treatment of metabolic-related diseases. Therefore, as a promising drug target, LSD1 has attracted more and more attention from medicinal chemists. And it is of great significance to develop novel small molecule inhibitors of LSD1. Summary of the Invention

[0003] In order to solve the above-mentioned deficiencies existing in the prior art, the purpose of the present invention is to provide a phenylcyclopropylamine compound, a preparation method thereof and an application thereof, and this phenylcyclopropylamine compound has good inhibitory effect on LSD1.

[0004] The technical solution of the present invention to solve the above technical problems is as follows:

[0005] The first object of the present invention is to provide a phenylcyclopropylamine compound, including structural general formula I and its corresponding salts:

[0006]

[0007] Wherein, R1 is hydrogen, halogen;

[0008] R2 is hydrogen, halogen;

[0009] R4 is hydrogen, alkyl or substituted alkyl, benzyl or substituted benzyl;

[0010] R7 is

[0011] Ring A is an aromatic ring, a substituted aromatic ring or a heteroaromatic ring, C 3-7 alicyclic ring or substituted alicyclic ring;

[0012] X is methylene, carbonyl, sulfonyl;

[0013] R5 is an alkyl or a substituted alkyl, C 3-8 a cycloaliphatic or a substituted cycloaliphatic, benzyl or a substituted benzyl, C 1-6 an amide group or a substituted amide group;

[0014] R6 is an alkyl or a substituted alkyl, an alkenyl or a substituted alkenyl, an alkynyl or a substituted alkynyl, a nitrile group;

[0015] R3 is an alkyl or a substituted alkyl, an aryl or a substituted aryl, C 3-8 a cycloaliphatic or a substituted cycloaliphatic;

[0016] R8 is hydrogen, a halogen;

[0017] R9 is hydrogen, a halogen.

[0018] Furthermore, R1 is hydrogen, a halogen;

[0019] R2 is hydrogen, a halogen;

[0020] R4 is hydrogen, C 1-10 an alkyl or a substituted alkyl, benzyl or a substituted benzyl (substituents such as heteroaryl substitution);

[0021] R7 is

[0022] Ring A is C 5-6 an aromatic ring or a substituted aromatic ring or a heteroaromatic ring, C 3-7 a cycloaliphatic or a substituted cycloaliphatic;

[0023] X is a methylene group, a carbonyl group, a sulfonyl group;

[0024] R5 is C 1-10 a straight-chain or branched-chain alkyl or a substituted straight-chain or branched-chain alkyl, benzyl or a substituted benzyl (substituents such as heteroaryl substitution), C 3-8 an oxacycloaliphatic system, C 3-8 a azacycloaliphatic system, C 3-8 an azacycloalkylmethylene group, an amino-substituted C 3-8 a cycloaliphatic system, C 1-6 an amide group or a substituted amide group;

[0025] R6 is C 1-10 an alkyl or a substituted alkyl, C 2-10 an alkenyl or a substituted alkenyl, C 2-10 an alkynyl or a substituted alkynyl, a nitrile group;

[0026] R3 is C 1-10 an alkyl or a substituted alkyl (such as an aryl-substituted alkylethyl), an aryl or a substituted aryl, C 3-8 an oxacycloaliphatic system, C3-8 Azaalicyclic ring system, amino-substituted C 3-8 Alicyclic ring system, C 3-8 Azaalkylidene methylene;

[0027] R8 is hydrogen, halogen;

[0028] R9 is hydrogen, halogen.

[0029] Furthermore, R1 is hydrogen, halogen;

[0030] R2 is hydrogen, halogen;

[0031] R4 is hydrogen, R7 is Ring A is X is methylene, carbonyl, sulfonyl;

[0032] R5 is

[0033] R6 is R3 is R8 is hydrogen, halogen;

[0034] R9 is hydrogen, halogen.

[0035] Furthermore, the specific structure of the above phenylcyclopropylamine compounds is as follows:

[0036]

[0037]

[0038]

[0039] For the phenylcyclopropylamine compounds described by the above general formula I, their corresponding salts can be salts formed by the reaction of the compounds with inorganic acids or organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and the organic acids include citric acid, formic 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, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, mandelic acid, salicylic acid, glutamic acid, and isethionic acid, etc.

[0040] When R7 is and X is methylene, the general formula of the structure is as follows:

[0041]

[0042] It is prepared by the following method:

[0043] (1) Preparation of Compound 1-1

[0044] The amino protection reaction of Compound 3-1 was carried out to obtain Intermediate 3-2. Intermediate 3-2 was subjected to a substitution reaction with Compound 3-3 under the condition of a strong base (such as NaH) to obtain Compound 1-1 (substitution reaction conditions: 0-4 °C, stirring reaction for 3-6 h); or

[0045] Compound 3-1 and Compound 3-4 were subjected to reductive amination reaction to obtain Compound 3-5. The amino protection reaction of Compound 3-5 was carried out to obtain Compound 1-1;

[0046] The specific reaction formulas are as follows:

[0047]

[0048] (2) Preparation of Compound 1-2

[0049] Compound 3-1 and Compound 4-1 were subjected to reductive amination reaction to obtain Compound 4-2. The amino protection reaction of Compound 4-2 was carried out to obtain Compound 4-3, and then the product 1-2 was obtained through an oxidation reaction; the specific reaction formulas are as follows:

[0050]

[0051] (3) Preparation of Compound 1-3

[0052] Compound 2-1 and Compound 2-2 were subjected to a substitution reaction to obtain Compound 1-3; or

[0053] Compound 2-3 and Compound 2-2 were subjected to reductive amination reaction to obtain 1-3; or

[0054] Compound 2-4 and Compound 2-5 were subjected to a substitution reaction to obtain 1-3; the specific reaction formulas are as follows:

[0055]

[0056] (4) Preparation of the compound represented by General Formula I-2

[0057] Compound 1-1 and Compound 1-3 were subjected to a substitution reaction, and then the tert-butoxycarbonyl protection was removed under acidic conditions to obtain the compound represented by General Formula I-1. The compound represented by General Formula I-1 and an aldehyde were subjected to reductive amination reaction to obtain the compound represented by General Formula I-2; or

[0058] Compound 1-2 and Compound 1-3 were subjected to reductive amination reaction to obtain the compound represented by General Formula I-1. The compound represented by General Formula I-1 and an aldehyde were subjected to reductive amination reaction to obtain the compound represented by General Formula I-2; the specific reaction formulas are as follows:

[0059]

[0060] When R7 is and X is a carbonyl group, the general structural formula is as follows:

[0061]

[0062] It is prepared by the following method:

[0063] React compound 5-1, compound 1-3, a condensing agent (such as HATU) and a base (such as DIPEA) to obtain compound 5-2, and react compound 5-2 with compound 3-1 through reductive amination to obtain the compound shown in general formula I-3. The specific reaction formula is as follows:

[0064]

[0065] When R7 is and X is a sulfonyl group, the general structural formula is as follows:

[0066]

[0067] It is prepared by the following method:

[0068] React compound 6-1, compound 1-3 and a base (such as triethylamine) to obtain the sulfonamide compound shown in general formula 6-2, and react the sulfonamide compound shown in general formula 6-2 with compound 3-1 through a substitution reaction to obtain the compound shown in general formula I-4. The specific reaction formula is as follows:

[0069]

[0070] When R7 is , R8 is the same as R1, and R9 is the same as R2. The general structural formula is as follows:

[0071]

[0072] It is prepared by the following method:

[0073] Compound 3-2 (amine-protected substituted phenylcyclopropylamine), 1,4-bis(bromomethyl)benzene and a strong base (such as NaH) undergo a substitution reaction to obtain the compound shown in general formula 7-1. The compound shown in general formula 7-1 undergoes a substitution reaction with a primary amine under basic conditions to obtain the compound shown in general formula 7-2. The compound shown in general formula 7-1 is deprotected under acidic conditions to obtain the compound shown in general formula II. The specific reaction formula is as follows:

[0074]

[0075] The second object of the present invention is to use the above-mentioned phenylcyclopropylamine compounds for preparing LSD1 inhibitors or directly as LSD1 inhibitors.

[0076] The third object of the present invention is to provide a pharmaceutical composition, which comprises the above-mentioned phenylcyclopropylamine compounds and a pharmaceutically acceptable carrier.

[0077] The present invention has the following beneficial effects:

[0078] The present invention has successfully synthesized a series of phenylcyclopropylamine compounds, and through bioactivity experiments, it is shown that the phenylcyclopropylamine compounds have excellent inhibitory effects on LSD1, thereby opening up a new way for finding a new class of innovative drugs based on the LSD1 target. Detailed implementation manners

[0079] The following examples are only used to explain the present invention and are not intended to limit the scope of the present invention. For those not specified in the examples, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0080] Example 1: (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (1)

[0081]

[0082] The preparation method comprises the following steps:

[0083] (1) Synthesis of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate

[0084]

[0085] 5 g of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine, 10.18 ml of di-tert-butyl dicarbonate, and 4.49 ml of triethylamine were added to 20 ml of dichloromethane solution, stirred at room temperature, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, it was concentrated under reduced pressure and separated by column chromatography to obtain tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (yield 90%).

[0086] (2) Synthesis of tert-butyl (4-(bromomethyl)benzyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate

[0087]

[0088] 4 g of tert-butyl (1R,2S)-(2-(3,4-difluorophenyl)cyclopropyl)carbamate, 3.92 g of 1,4-bis(bromomethyl)benzene, and 1.78 g of sodium hydride (60% paraffin oil) were added to 50 ml of N,N-dimethylformamide solution. The mixture was stirred at 0 °C for 4 h. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, it was concentrated under reduced pressure and separated by column chromatography to obtain tert-butyl (4-(bromomethyl)benzyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate (yield 20.8%). 1 H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.05 - 6.97 (m, 1H), 6.90 - 6.75 (m, 2H), 4.60 (d, J = 16.2 Hz, 1H), 4.49 (s, 2H), 4.32 (d, J = 15.5 Hz, 1H), 2.62 - 2.56 (m, 1H), 2.14 - 2.08 (m, 1H), 1.43 (s, 9H), 1.31 - 1.23 (m, 4H), 1.08 (q, J = 6.6 Hz, 1H).

[0089] (3) Synthesis of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)carbamate

[0090]

[0091] 200 mg of tert-butyl (4-(bromomethyl)benzyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate, 36 mg of N-methylprop-2-yn-1-amine, 92 mg of potassium carbonate, and 7 mg of potassium iodide were added to 5 ml of acetonitrile solution. The mixture was reacted at 80 °C for 4 h. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was completed, it was concentrated under reduced pressure and separated by column chromatography to obtain tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)carbamate (145 mg, yield 74%). 11H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.00 (dt, J = 10.4, 8.3 Hz, 1H), 6.80 (br, 1H), 4.59 (d, J = 15.4 Hz, 1H), 4.32 (d, J = 15.3 Hz, 1H), 3.87 (s, 2H), 3.42 (d, J = 2.4 Hz, 2H), 2.62 - 2.55 (m, 1H), 2.26 (t, J = 2.4 Hz, 1H), 2.15 - 2.07 (m, 1H), 1.43 (s, 9H), 1.31 - 1.23 (m, 4H), 1.07 (q, J = 6.7 Hz, 1H).

[0092] (4) Synthesis of (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride

[0093] After deprotecting ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)carbamate, (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine was obtained. 100 mg of (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine was added to 5 ml of ethyl acetate solution to obtain system S1. 660 μl of hydrochloric acid ethyl acetate solution (4 M) was dissolved in 2 ml of ethyl acetate and slowly added dropwise to the above S1 system. Stir at room temperature for 30 min, a large amount of white solid was produced, and filtered by suction to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (67 mg, yield 57%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.38 (s, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.37 - 7.27 (m, 1H), 7.25 - 7.17 (m, 1H), 7.01 - 6.94 (m, 1H), 4.43 - 4.23 (m, 4H), 4.09 - 3.85 (m, 3H), 2.92 - 2.81 (m, 1H), 2.71 (s, 3H), 2.62 - 2.55 (m, 1H), 1.71 - 1.58 (m, 1H), 1.33 - 1.22 (m, 1H).

[0094] Example 2:

[0095] (1R,2S)-N-(4-((Methyl(prop-2-yn-1-yl)amino)methyl)benzyl)-2-phenylcyclopropan-1-amine dihydrochloride (2)

[0096]

[0097] Replace tert-butyl (4-(bromomethyl)benzyl)(2-(3,4-difluorophenyl)cyclopropyl)carbamate with tert-butyl (4-(bromomethyl)benzyl)(2-phenylcyclopropyl)carbamate, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain (1R,2S)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)-2-phenylcyclopropan-1-amine hydrochloride (yield 48%). 1 H NMR(400MHz,Methanol-d4)δ7.71(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),7.31(t,J=7.4Hz,2H),7.26-7.21(m,1H),7.15(d,J=7.2Hz,2H),4.48(s,4H),4.08(br,2H),3.50(t,J=2.5Hz,1H),3.33(p,J=1.6Hz,1H),3.04(dt,J=7.9,4.0Hz,1H),2.94(s,3H),2.56(ddd,J=10.3,6.6,3.6Hz,1H),1.61(ddd,J=10.8,6.8,4.4Hz,1H),1.39(dt,J=7.7,6.7Hz,1H).

[0098] Example 3: (1R,2S)-N-(3-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)-2-phenylcyclopropan-1-amine dihydrochloride (3)

[0099]

[0100] Replace tert-butyl (4-(bromomethyl)benzyl)(2-(3,4-difluorophenyl)cyclopropyl)carbamate with tert-butyl (3-(bromomethyl)benzyl)(2-phenylcyclopropyl)carbamate, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain (1R,2S)-N-(3-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)-2-phenylcyclopropan-1-amine (yield 37%). 11H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 1H), 7.73 - 7.55 (m, 3H), 7.37 - 7.28 (m, 2H), 7.28 - 7.22 (m, 1H), 7.13 (d, J = 7.5 Hz, 2H), 4.45 (d, J = 19.5 Hz, 4H), 4.08 (s, 2H), 3.49 (s, 1H), 3.08 - 3.00 (m, 1H), 2.93 (s, 3H), 2.61 - 2.49 (m, 1H), 1.68 - 1.56 (m, 1H), 1.42 - 1.35 (m, 1H).

[0101] Example 4: (1R,2S)-2-(3,4-Difluorophenyl)-N-(4-((methyl(propyl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (4)

[0102]

[0103] Replace N-methylpropargylamine with N-methylpropan-1-amine, and use the same other required raw materials, reagents and preparation methods as in Example 1 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((methyl(propyl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (yield 49%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.17 (s, 2H), 7.72 - 7.57 (m, 4H), 7.40 - 7.29 (m, 1H), 7.26 - 7.15 (m, 1H), 7.05 - 6.93 (m, 1H), 4.44 - 4.13 (m, 4H), 3.02 - 2.92 (m, 1H), 2.92 - 2.80 (m, 2H), 2.60 (s, 3H), 2.58 - 2.53 (m, 1H), 1.83 - 1.68 (m, 2H), 1.66 -

[0104] 1.55 (m, 1H), 1.35 - 1.23 (m, 1H), 0.94 - 0.77 (m, 3H).

[0105] Example 5: (1R,2S)-N-(4-((allyl(methyl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (5)

[0106]

[0107] Replace N-methylpropargylamine with N-methylprop-2-en-1-amine, and use the same required raw materials, reagents and preparation method as in Example 1 to obtain (1R,2S)-N-(4-((allyl(methyl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (yield 33%). 1 H NMR(400MHz,DMSO-d6)δ7.66-7.60(m,4H),7.34(dt,J=10.9,8.6Hz,1H),7.24-7.17(m,1H),7.02-6.96(m,1H),6.05(ddt,J=17.1,10.4,7.0Hz,1H),5.55(d,J=6.2Hz,1H),5.51(s,1H),4.29(d,J=14.6Hz,4H),3.71-3.67(m,2H),2.90(dt,J=8.0,4.1Hz,1H),2.58-2.55(m,4H),1.58(dt,J=10.5,5.6Hz,1H),1.31(q,J=6.9Hz,1H).

[0108] Example 6: (1R,2S)-2-(3,4-Difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (6)

[0109]

[0110] Its preparation method includes the following steps:

[0111] (1) Synthesis of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine

[0112]

[0113] Add 500 mg of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine and 340 mg of furan-2-carbaldehyde to 20 ml of methanol solution. After monitoring the formation of intermediates by thin-layer chromatography (TLC), slowly add 168 mg of sodium borohydride. After the reaction is complete, evaporate the solvent, and obtain 470 mg of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine by column chromatography (yield 64%).

[0114] (2) Synthesis of (1R,2S)-N-(4-(bromomethyl)benzyl)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine

[0115]

[0116] 200 mg of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine, 254 mg of 1,4-bis(bromomethyl)benzene, and 166 mg of potassium carbonate were added to 8 ml of acetonitrile solution, and stirred at room temperature. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, it was concentrated under reduced pressure, and separated by column chromatography to obtain (1R,2S)-N-(4-(bromomethyl)benzyl)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine (280 mg, yield 81%).

[0117] (3) Synthesis of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine

[0118]

[0119] 100 mg of (1R,2S)-N-(4-(bromomethyl)benzyl)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)cyclopropan-1-amine, 48 mg of N-methylprop-2-yn-1-amine, 96 mg of potassium carbonate, and 7.7 mg of potassium iodide were added to an acetonitrile solution, and reacted at 80 °C for 4 h. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, it was concentrated under reduced pressure, and separated by column chromatography to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine (120 mg, yield 62%).

[0120] (4) Synthesis of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride

[0121] 100 mg of (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine was added to 5 ml of ethyl acetate solution to obtain system S2. 130 μl of hydrochloric acid ethyl acetate solution (4 M) was dissolved in 2 ml of ethyl acetate, and slowly added dropwise to the above S2 system, and stirred at room temperature for 30 min. A large amount of white solid was produced, and filtered by suction to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(furan-2-ylmethyl)-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (67 mg, yield 57%). 11H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 2H), 7.92 - 7.56 (m, 6H), 7.37 - 7.24 (m, 1H), 7.14 - 6.77 (m, 2H), 6.54 (s, 1H), 4.45 - 4.28 (m, 4H), 4.03 (s, 1H), 3.93 (s, 2H), 3.83 - 3.48 (m, 4H), 2.98 - 2.77 (m, 1H), 2.46 - 2.25 (m, 1H), 1.43 (s, 1H), 1.25 - 1.11 (m, 1H).

[0122] Example 7: (1R,2S)-2-(3,4-Difluorophenyl)-N-isobutyl-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (7)

[0123]

[0124] Replace furan-2-carbaldehyde with isobutyraldehyde, and use the same required raw materials, reagents and preparation method as in Example 6 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-isobutyl-N-(4-((methyl(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (yield 45%). 1 1H NMR (400 MHz, Chloroform-d) δ 7.24 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.02 - 6.91 (m, 1H), 6.64 - 6.54 (m, 2H), 3.77 (d, J = 13.5 Hz, 1H), 3.61 - 3.53 (m, 3H), 3.31 (d, J = 2.3 Hz, 1H), 2.34 (s, 3H), 2.32 - 2.23 (m, 3H), 1.90 - 1.81 (m, 2H), 1.80 - 1.75 (m, 1H), 1.08 - 1.00 (m, 1H), 0.90 - 0.82 (m, 7H).

[0125] Example 8: (1R,2S)-2-(3,4-Difluorophenyl)-N-(4-(((furan-2-ylmethyl)(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (8)

[0126]

[0127] Replace N-methyl propargylamine with N-(furan-2-ylmethyl) propargylamine, and use the same required raw materials, reagents and preparation method as in Example 1 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-(((furan-2-ylmethyl)(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropane-1-amine dihydrochloride (yield 51%). 1 H NMR(400MHz,DMSO-d6)δ10.42-10.06(m,2H),7.80(s,1H),7.73-7.51(m,4H),7.38-7.28(m,1H),7.27-7.16(m,1H),7.06-6.94(m,1H),6.71(s,1H),6.59-6.50(m,1H),4.41-4.08(m,6H),3.79(s,1H),3.66(s,1H),2.94-2.82(m,1H),2.61-2.53(m,1H),1.68-1.54(m,1H),1.36-1.24(m,1H).

[0128] Example 9: N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)tetrahydro-2H-pyran-4-amine dihydrochloride (9)

[0129]

[0130] Replace N-methyl propargylamine with N-(furan-2-ylmethyl) propargylamine, and use the same required raw materials, reagents and preparation method as in Example 1 to obtain N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)tetrahydro-2H-pyran-4-amine dihydrochloride (yield 33%). 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),10.51-10.15(m,2H),7.69(s,4H),7.38-7.29(m,1H),7.28-7.19(m,1H),7.04-6.94(m,1H),4.67(br,1H),4.30(s,2H),4.15(br,1H),4.08-3.84(m,4H),3.55-3.43(m,2H),3.38-3.23(m,2H),2.87(s,1H),2.60(s,1H),2.20(s,1H),2.03(br,3H),1.71-1.59(m,1H),1.36-1.21(m,1H).

[0131] Example 10: 2-((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(prop-2-yn-1-yl)amino)acetamide dihydrochloride (10)

[0132]

[0133] Replace N-methylpropargylamine with 2-(prop-2-yn-1-ylamino)acetamide, and use the rest of the required raw materials, reagents and preparation methods the same as in Example 1 to obtain 2-((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(prop-2-yn-1-yl)amino)acetamide dihydrochloride (yield 36%). 1 H NMR(400MHz,DMSO-d6)δ10.17(dd,J=14.2,5.7Hz,1H),7.88(br,1H),7.64(d,J=8.1Hz,2H),7.57(br,2H),7.52(d,J=8.1Hz,2H),7.33(dt,J=10.8,8.6Hz,2H),7.26-7.19(m,2H),7.02-6.96(m,2H),4.29(t,J=4.5Hz,2H),4.24(br,2H),3.86(br,2H),3.79(br,1H),3.70(br,2H),2.88(dt,J=8.9,4.6Hz,1H),2.56(ddd,J=10.1,6.4,3.6Hz,1H),1.61(ddd,J=10.5,6.3,4.5Hz,1H),1.30(dt,J=7.8,6.3Hz,1H).

[0134] Example 11: N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (11)

[0135]

[0136] Replace N-methylpropargylamine with tert-butyl 3-(prop-2-yn-1-ylamino)pyrrolidine-1-carboxylate, and use the rest of the required raw materials, reagents and preparation methods the same as in Example 1 to obtain N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (yield 36%). 11H NMR (400 MHz, DMSO-d6) δ 10.32 - 10.10 (m, 2H), 9.85 (br, 1H), 9.71 (br, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.34 (dt, J = 10.8, 8.6 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.02 - 6.96 (m, 1H), 4.30 - 4.26 (m, 1H), 4.13 (brs, 2H), 3.84 (brs, 1H), 3.70 (brs, 1H), 3.64 - 3.49 (m, 3H), 3.41 - 3.33 (m, 1H), 3.26 - 3.14 (m, 1H), 2.87 (dt, J = 8.7, 4.6 Hz, 1H), 2.57 (ddd, J = 10.1, 6.5, 3.6 Hz, 1H), 2.39 - 2.13 (m, 2H), 1.62 (ddd, J = 10.4, 6.2, 4.4 Hz, 1H), 1.30 (dt, J = 7.9, 6.3 Hz, 1H).

[0137] Example 12: N-((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)cyclohexyl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (12)

[0138]

[0139] Replace N-methylpropargylamine with tert-butyl 3-(prop-2-yn-1-ylamino)pyrrolidine-1-carboxylate, and 1,4-bis(bromomethyl)benzene with 1,4-bis(bromomethyl)cyclohexane. The rest of the required raw materials, reagents and preparation methods are the same as in Example 1, to obtain N-((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)cyclohexyl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (yield 45%). 11H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.26 (s, 2H), 7.39 - 7.32 (m, 1H), 7.31 - 7.22 (m, 1H), 7.11 - 7.02 (m, 1H), 3.95 (s, 2H), 3.88 - 3.83 (m, 2H), 3.37 (br, 2H), 3.17 (br, 1H), 2.96 - 2.87 (m, 3H), 2.80 (dd, J = 12.8, 6.6 Hz, 2H), 2.57 (ddd, J = 10.0, 6.3, 3.3 Hz, 1H), 2.35 - 2.23 (m, 1H), 2.17 - 2.04 (m, 1H), 1.89 - 1.78 (m, 4H), 1.73 - 1.53 (m, 3H), 1.29 (q, J = 6.8 Hz, 1H), 0.96 (q, J = 10.5 Hz, 4H).

[0140] Example 13: N-((5-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (13)

[0141]

[0142] Its preparation method comprises the following steps:

[0143] (1) Synthesis of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-(hydroxymethyl)furan-2-yl)methyl)carbamate

[0144]

[0145] Add 200 mg of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine and 164 mg of 5-(hydroxymethyl)furan-2-carbaldehyde to 10 ml of methanol solution. Monitor the reaction by thin-layer chromatography (TLC). After the intermediate is formed, slowly add 67 mg of sodium borohydride to the system and stir at room temperature for 3 h. Monitor by TLC until the intermediate completely reacts, then add 149 mg of sodium bicarbonate and 310 mg of tert-butoxycarbonyl, stir at room temperature. After the reaction is complete, concentrate under reduced pressure, evaporate the solvent, extract, and separate by column chromatography to obtain the target product tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-(hydroxymethyl)furan-2-yl)methyl)carbamate (340 mg, yield 76%).

[0146] (2) Synthesis of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-formylfuran-2-yl)methyl)carbamate

[0147]

[0148] 200 mg of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-(hydroxymethyl)furan-2-yl)methyl)carbamate and 337 mg of Dess-Martin periodinane were added to 10 ml of dichloromethane solvent, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC and was found to be complete, yielding the target product tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-formylfuran-2-yl)methyl)carbamate (136 mg, yield 68.36%).

[0149] (3) Synthesis of tert-butyl 3-(((5-(((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)(prop-2-yn-1-yl)amino)pyrrolidine-1-carboxylate

[0150]

[0151] 200 mg of tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)((5-formylfuran-2-yl)methyl)carbamate and 118 mg of tert-butyl 3-aminopyrrolidine-1-carboxylate were added to 20 ml of methanol solution. After the formation of an intermediate was monitored by thin-layer chromatography (TLC), 30 mg of sodium borohydride was slowly added until the reaction was complete. 67 mg of sodium bicarbonate and 95 mg of propargyl bromide were added to the above system, and the mixture was stirred at room temperature until a new product was detected by TLC. The mixture was concentrated under pressure and purified by column chromatography to obtain tert-butyl 3-(((5-(((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)(prop-2-yn-1-yl)amino)pyrrolidine-1-carboxylate (146 mg, yield 47%).

[0152] (4) Synthesis of N-((5-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride

[0153] 200 mg of tert-butyl 3-(((5-(((tert-butoxycarbonyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)(prop-2-yn-1-yl)amino)pyrrolidine-1-carboxylate was added to 10 ml of ethyl acetate solution to form system S3. 1.71 ml of hydrochloric acid ethyl acetate solution (4 M) was dissolved in 5 ml of ethyl acetate and slowly added dropwise to the above system. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure to obtain N-((5-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)furan-2-yl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (74 mg, yield 47%). 1 H NMR(400MHz,Deuterium Oxide)δ7.22-7.09(m,1H),6.99-6.91(m,1H),6.85-6.80(m,1H),6.67(d,J=3.4Hz,1H),6.62(d,J=3.4Hz,1H),4.49-4.38(m,2H),4.34-4.22(m,1H),4.14-3.97(m,2H),3.81-3.72(m,3H),3.61-3.53(m,1H),3.41-3.29(m,2H),3.05-2.99(m,1H),2.99-2.90(m,1H),2.58-2.46(m,1H),2.35-2.25(m,1H),2.18-2.04(m,1H),1.50-1.40(m,1H),1.34-1.27(m,1H).

[0154] Example 14: N-((6-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)pyridin-2-yl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (A14)

[0155]

[0156] 1,4-Bis(bromomethyl)benzene was replaced with 2,6-bis(bromomethyl)pyridine, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain N-((6-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)pyridin-2-yl)methyl)-N-(prop-2-yn-1-yl)pyrrolidin-3-amine trihydrochloride (yield 35%). 11H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 2H), 9.99 (s, 1H), 9.93 (s, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.09 (dt, J = 9.8, 2.9 Hz, 1H), 4.64 (s, 2H), 4.54 (s, 2H), 4.30 (t, J = 8.0 Hz, 2H), 3.81 - 3.77 (m, 1H), 3.70 - 3.59 (m, 2H), 3.48 - 3.33 (m, 2H), 3.29 - 3.14 (m, 1H), 3.05 (dt, J = 8.2, 4.1 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.44 - 2.30 (m, 2H), 1.81 - 1.72 (m, 1H), 1.34 (q, J = 6.8 Hz, 1H).

[0157] Example 15: N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(pyrrolidin-3-yl)cyanamide hydrochloride (15)

[0158]

[0159] Replace N-methylpropargylamine with tert-butyl 3-cyanopyrrolidine-1-carboxylate, and use the same required raw materials, reagents and preparation methods as in Example 1 to obtain N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(pyrrolidin-3-yl)cyanamide hydrochloride (yield 27%). 1 1H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.22 (dt, J = 10.4, 8.5 Hz, 1H), 7.09 (ddd, J = 11.3, 7.7, 2.2 Hz, 1H), 6.98 (br, J = 7.7 Hz, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 4.14 - 4.03 (m, 1H), 3.64 - 3.56 (m, 1H), 3.53 - 3.38 (m, 3H), 3.07 - 2.98 (m, 1H), 2.50 (br, 0H), 2.46 - 2.34 (m, 1H), 2.31 - 2.22 (m, 1H), 1.62 - 1.53 (m, 1H), 1.44 - 1.37 (m, 1H).

[0160] Example 16: N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)piperidin-4-amine trihydrochloride (16)

[0161]

[0162] Replace N-methyl propargylamine with tert-butyl 4-((prop-2-yn-1-ylamino)piperidine-1-carboxylate, and use the same required raw materials, reagents and preparation methods as in Example 1 to obtain N-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N-(prop-2-yn-1-yl)piperidin-4-amine trihydrochloride (yield 42%). 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J = 22.3 Hz, 2H), 9.43 (s, 1H), 9.07 (d, J = 11.1 Hz, 1H), 7.66 (s, 4H), 7.34 (dt, J = 10.8, 8.6 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.04 - 6.95 (m, 1H), 4.29 (t, J = 5.5 Hz, 2H), 4.14 (brs, 1H), 3.74 (br, 4H), 3.40 (d, J = 12.5 Hz, 1H), 3.04 - 2.91 (m, 2H), 2.90 - 2.85 (m, 1H), 2.62 - 2.54 (m, 1H), 2.34 (br, 2H), 2.17 (br, 2H), 1.63 (ddd, J = 10.4, 6.2, 4.4 Hz, 1H), 1.30 (dt, J = 7.9, 6.3 Hz, 1H).

[0163] Example 17: (1R,2S)-2-(3,4-difluorophenyl)-N-(4-(((piperidin-4-ylmethyl)(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine trihydrochloride (17)

[0164]

[0165] Replace N-methyl propargylamine with tert-butyl 4-((prop-2-yn-1-yl-12-azaalkyl)methyl)piperidine-1-carboxylate, and use the same required raw materials, reagents and preparation methods as in Example 1 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-(((piperidin-4-ylmethyl)(prop-2-yn-1-yl)amino)methyl)benzyl)cyclopropan-1-amine trihydrochloride (yield 29%). 1HNMR(400MHz, DMSO-d6) δ 11.78(br, 1H), 10.38 - 10.00(m, 2H), 9.05(s, 2H), 7.85 - 7.57(m, 4H), 7.35(dt, J = 10.8, 8.6Hz, 1H), 7.24(ddd, J = 12.1, 7.7, 2.2Hz, 1H), 7.04 - 6.97(m, 1H), 4.32 - 4.26(m, 2H), 3.89(br, 2H), 3.64 - 3.57(m, 4H), 3.21(d, J = 12.5Hz, 2H), 2.93 - 2.85(m, 2H), 2.84 - 2.75(m, 2H), 2.58(ddd, J = 10.1, 6.4, 3.5Hz, 1H), 2.12(d, J = 25.1Hz, 2H), 1.93(d, J = 16.7Hz, 1H), 1.63(ddd, J = 10.4, 6.2, 4.4Hz, 1H), 1.31(dt, J = 7.8, 6.3Hz, 2H).

[0166] Example 18: N 1 -(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N 1 -(prop-2-yn-1-yl)cyclohexane-1,4-diamine trihydrochloride (18)

[0167]

[0168] Replace N-methylpropargylamine with tert-butyl (4-(prop-2-yn-1-ylamino)cyclohexyl)carbamate, and use the same required raw materials, reagents and preparation methods as in Example 1 to obtain N 1 -(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)-N 1 -(prop-2-yn-1-yl)cyclohexane-1,4-diamine trihydrochloride (yield 18%). 11H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.24 (d, J = 16.4 Hz, 2H), 8.46 - 8.19 (m, 3H), 7.88 - 7.54 (m, 4H), 7.35 (dt, J = 10.8, 8.6 Hz, 1H), 7.25 (ddd, J = 12.1, 7.8, 2.2 Hz, 1H), 7.00 (dt, J = 7.5, 3.1 Hz, 1H), 4.60 (br, 1H), 4.31 (d, J = 5.0 Hz, 2H), 4.25 (br, 1H), 4.09 - 3.95 (m, 1H), 3.90 (br, 1H), 3.78 - 3.64 (m, 1H), 3.34 - 3.20 (m, 1H), 2.97 (br, 1H), 2.88 (br, 1H), 2.59 (t, J = 8.0 Hz, 1H), 2.31 (d, J = 29.1 Hz, 2H), 2.12 (d, J = 12.3 Hz, 2H), 1.86 (br, J = 41.4 Hz, 2H), 1.64 (dt, J = 10.3, 5.5 Hz, 1H), 1.43 (br, 2H), 1.31 (q, J = 6.9 Hz, 1H).

[0169] Example 19: (1R,2S)-N-(4-((((1H-Indol-3-yl)methyl)(prop-2-yn-1-yl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (19)

[0170]

[0171] Replace N-methyl propargylamine with N-((1H-indol-3-yl)methyl)prop-2-yn-1-amine, and use the same other required raw materials, reagents and preparation methods as in Example 1 to obtain (1R,2S)-N-(4-((((1H-indol-3-yl)methyl)(prop-2-yn-1-yl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (yield 26%). 11H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 10.23 (s, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.72 - 7.61 (m, 5H), 7.46 (d, J = 8.1 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.26 - 7.19 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.02 - 6.96 (m, 1H), 4.55 (s, 2H), 4.30 (s, 3H), 3.99 (s, 1H), 3.67 (s, 1H), 2.88 (s, 1H), 2.63 - 2.54 (m, 1H), 1.68 - 1.58 (m, 1H), 1.35 - 1.26 (m, 1H).

[0172] Example 20: (1R,2S)-N-(4-((((1H-Pyrrol-3-yl)methyl)(prop-2-yn-1-yl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (20)

[0173]

[0174] Replace N-methylpropargylamine with N-((1H-pyrrol-3-yl)methyl)prop-2-yn-1-amine, and use the rest of the required raw materials, reagents and preparation methods the same as in Example 1 to obtain (1R,2S)-N-(4-((((1H-pyrrol-3-yl)methyl)(prop-2-yn-1-yl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine dihydrochloride (yield 31%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 11.14 (s, 1H), 10.16 (s, 2H), 7.69 - 7.61 (m, 4H), 7.32 (dt, J = 10.8, 8.6 Hz, 1H), 7.22 (ddd, J = 12.1, 7.7, 2.2 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.82 (q, J = 2.4 Hz, 1H), 6.28 (brs, 1H), 4.30 (br, 4H), 4.21 - 4.09 (m, 2H), 3.90 (brs, 1H), 3.71 - 3.56 (m, 2H), 2.88 (s, 1H), 2.60 - 2.53 (m, 1H), 1.62 (ddd, J = 10.4, 6.3, 4.5 Hz, 1H), 1.30 (dt, J = 7.8, 6.3 Hz, 1H).

[0175] Example 21: (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((prop-2-yn-1-yl(pyridin-3-ylmethyl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (21)

[0176]

[0177] Replace N-methylpropargylamine with N-(pyridin-3-ylmethyl)prop-2-yn-1-amine, and use the same other required raw materials, reagents and preparation methods as in Example 1 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-((prop-2-yn-1-yl(pyridin-3-ylmethyl)amino)methyl)benzyl)cyclopropan-1-amine dihydrochloride (21) (yield 46%). 1 H NMR(400MHz,DeuteriumOxide)δ7.22-7.09(m,1H),6.99-6.91(m,1H),6.85-6.80(m,1H),6.67(d,J=3.4Hz,1H),6.62(d,J=3.4Hz,1H),4.49-4.38(m,2H),4.34-4.22(m,1H),4.14-3.97(m,2H),3.81-3.72(m,3H),3.61-3.53(m,1H),3.41-3.29(m,2H),3.05-2.99(m,1H),2.99-2.90(m,1H),2.58-2.46(m,1H),2.35-2.25(m,1H),2.18-2.04(m,1H),1.50-1.40(m,1H),1.34-1.27(m,1H).

[0178] Example 22: 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide monohydrochloride (22)

[0179]

[0180] Its preparation method includes the following steps:

[0181] (1) Synthesis of 4-formyl-N-methyl-N-(prop-2-yn-1-yl)benzamide

[0182]

[0183] 300 mg of 4-formylbenzoic acid, 165 mg of N-methylpropargylamine, 920 mg of HATU (N,N,N’,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate), and 870 μl of DIPEA (N,N-diisopropylethylamine) were added to 10 ml of DMF solution (N,N-dimethylformamide), and the mixture was stirred at room temperature for 6 h. The reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, extraction was carried out, and column chromatography was used for separation to obtain 310 mg of 4-formyl-N-methyl-N-(prop-2-yn-1-yl)benzamide (yield 77%).

[0184] (2) Synthesis of 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide

[0185]

[0186] 200 mg of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine and 238 mg of 4-formyl-N-methyl-N-(prop-2-yn-1-yl)benzamide were added to 10 ml of methanol solution. The reaction was monitored by thin layer chromatography (TLC). After the intermediate was formed in the reaction, sodium borohydride was slowly added to the system, and the mixture was stirred at room temperature for 3 h until the reaction was completely finished. The solvent was concentrated under reduced pressure and evaporated to dryness, followed by extraction and column chromatography separation. The resulting product was 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide (370 mg, yield 88%).

[0187] (3) Synthesis of 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide monohydrochloride

[0188] 100 mg of 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide was added to 5 ml of ethyl acetate solution. 85 μl of hydrochloric acid ethyl acetate solution (4 M) dissolved in 2 ml of ethyl acetate was slowly added dropwise to the above system, and the mixture was stirred at room temperature for 30 min, during which a large amount of white solid was produced. Filtration by suction was carried out to obtain 4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzamide monohydrochloride (54 mg, yield 49%). 11H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.38 - 7.30 (m, 1H), 7.28 - 7.20 (m, 1H), 7.04 - 6.96 (m, 1H), 4.39 - 3.93 (m, 4H), 3.33 - 3.22 (m, 1H), 3.07 - 2.99 (m, 1H), 2.98 - 2.86 (m, 3H), 2.56 - 2.52 (m, 1H), 1.63 - 1.51 (m, 1H), 1.36 - 1.27 (m, 1H).

[0189] Example 23: 4 - ((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (23)

[0190]

[0191] Its preparation method comprises the following steps:

[0192] (1) 4-(Bromomethyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide

[0193]

[0194] 200 mg of 4-(bromomethyl)benzenesulfonyl chloride, 52 mg of N-methylpropargylamine, and 155 μl of triethylamine were added to 10 ml of dichloromethane solution, stirred at room temperature for 6 h, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was completely finished, extraction was carried out, and column chromatography separation was performed to obtain 4-(bromomethyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (194 mg, yield 88%).

[0195] (2) Synthesis of 4 - ((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide

[0196] 200 mg of 4-(bromomethyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide, 223 mg of 2-(3,4-difluorophenyl)cyclopropan-1-amine, and 137 mg of potassium carbonate were added to 10 ml of acetonitrile solution, stirred at room temperature for 6 h, and the reaction was monitored by thin-layer chromatography (TLC). After the reaction was completely finished, extraction was carried out, and column chromatography separation was performed to obtain 4 - ((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-N-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (120 mg, yield 46%). 11H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.04 - 6.97 (m, 1H), 6.76 - 6.70 (m, 1H), 6.70 - 6.65 (m, 1H), 4.03 (d, J = 2.3 Hz, 2H), 4.00 - 3.90 (m, 2H), 2.83 (s, 3H), 2.34 - 2.26 (m, 1H), 2.05 (t, J = 2.4 Hz, 1H), 1.89 - 1.82 (m, 1H), 1.15 - 1.08 (m, 1H), 0.96 - 0.88 (m, 1H).

[0197] Example 24: 4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)-N - methyl - N - (prop - 2 - yn - 1 - yl)benzenesulfonamide monohydrochloride (24)

[0198]

[0199] 100 mg of 4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)-N - methyl - N - (prop - 2 - yn - 1 - yl)benzenesulfonamide was added to 5 ml of ethyl acetate solution. 85 μl of ethyl acetate solution of hydrochloric acid (4 M) was dissolved in 2 ml of ethyl acetate and slowly added dropwise to the above system. The mixture was stirred at room temperature for 30 min, and a large amount of white solid was produced. It was filtered by suction to obtain 4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)-N - methyl - N - (prop - 2 - yn - 1 - yl)benzenesulfonamide monohydrochloride (79 mg, yield 72%). 1 1H NMR (400 MHz, DMSO - d6) δ 10.26 (s, 2H), 7.86 - 7.79 (m, 4H), 7.37 - 7.28 (m, 1H), 7.27 - 7.20 (m, 1H), 7.05 - 6.98 (m, 1H), 4.39 (s, 2H), 4.02 (d, J = 2.2 Hz, 2H), 3.15 (t, J = 2.2 Hz, 1H), 2.96 - 2.88 (m, 1H), 2.74 (s, 3H), 2.63 - 2.55 (m, 1H), 1.67 - 1.59 (m, 1H), 1.35 - 1.27 (m, 1H).

[0200] Example 25: (1S,2R)-2-(3,4 - difluorophenyl)-N - (4 - ((((4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)benzyl)(methyl)amino)methyl)benzyl)cyclopropan - 1 - amine trihydrochloride (25)

[0201]

[0202] Its preparation method comprises the following steps:

[0203] (1) Synthesis of di-tert-butyl ((((methylaza)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate)

[0204]

[0205] Add 200 mg of tert-butyl ((4-(bromomethyl)benzyl)((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate), 63 μl of methylamine (40% aqueous solution), 92 mg of potassium carbonate, and 7 mg of potassium iodide to 5 ml of acetonitrile solution, stir at room temperature, monitor the reaction by thin-layer chromatography (TLC), after the reaction is complete, concentrate under reduced pressure, and separate by column chromatography to obtain di-tert-butyl ((((methylaza)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate) (yield 83%).

[0206] (2) Synthesis of (1S,2R)-2-(3,4-difluorophenyl)-N-(4-(((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(methyl)amino)methyl)benzyl)cyclopropan-1-amine trihydrochloride

[0207] Add 100 mg of di-tert-butyl ((((methylaza)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate) to 5 ml of dichloromethane, add 1 ml of trifluoroacetic acid, stir at room temperature for 4 h, monitor the reaction by thin-layer chromatography (TLC), after the reaction is complete, evaporate the solvent to obtain the product (1S,2R)-2-(3,4-difluorophenyl)-N-(4-(((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(methyl)amino)methyl)benzyl)cyclopropan-1-amine trihydrochloride (yield 63%). 11H NMR (400 MHz, Deuterium Oxide) δ 7.50 (d, J = 7.9 Hz, 4H), 7.39 (d, J = 7.9 Hz, 4H), 7.09 - 6.99 (m, 2H), 6.81 - 6.73 (m, 2H), 6.73 - 6.67 (m, 2H), 4.45 (d, J = 13.3 Hz, 2H), 4.35 (d, J = 13.3 Hz, 2H), 4.24 (s, 4H), 2.85 - 2.78 (m, 2H), 2.64 (s, 3H), 2.25 - 2.15 (m, 2H), 1.46 - 1.38 (m, 2H), 1.31 - 1.23 (m, 2H).

[0208] Example 26: N,N - Bis(4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)benzyl)pyrrolidin - 3 - amine tetrahydrochloride (26)

[0209]

[0210] Replace methylamine with tert - butyl 3 - aminopyrrolidine - 1 - carboxylate, and use the same required raw materials, reagents and preparation method as in Example 25 to obtain N,N - bis(4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)benzyl)pyrrolidin - 3 - amine tetrahydrochloride (yield 51%). 1 1H NMR (400 MHz, Deuterium Oxide) δ 7.45 (d, J = 7.8 Hz, 4H), 7.33 (d, J = 7.8 Hz, 4H), 7.06 - 6.94 (m, 2H), 6.75 - 6.62 (m, 4H), 4.44 (dd, J = 13.3, 2.1 Hz, 2H), 4.32 (d, J = 13.3 Hz, 2H), 4.27 - 4.07 (m, 5H), 3.73 - 3.49 (m, 3H), 3.38 - 3.25 (m, 1H), 2.82 - 2.70 (m, 2H), 2.59 - 2.43 (m, 1H), 2.43 - 2.28 (m, 1H), 2.22 - 2.11 (m, 2H), 1.46 - 1.36 (m, 2H), 1.31 - 1.21 (m, 2H).

[0211] Example 27: N 1 ,N 1 -Bis(4 - ((((1R,2S)-2-(3,4 - difluorophenyl)cyclopropyl)amino)methyl)benzyl)cyclohexane - 1,4 - diamine tetrahydrochloride (27)

[0212]

[0213] Replace methylamine with tert-butyl (4-aminocyclohexyl)carbamate, and use the same required raw materials, reagents and preparation method as in Example 25 to obtain N 1 ,N 1 -bis(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)cyclohexane-1,4-diamine tetrahydrochloride (yield 47%). 1 H NMR (400 MHz, Deuterium Oxide) δ 7.49 - 7.40 (m, 4H), 7.38 - 7.25 (m, 4H), 7.05 - 6.94 (m, 2H), 6.79 - 6.61 (m, 4H), 4.51 - 3.99 (m, 8H), 3.58 - 3.21 (m, 1H), 3.26 - 3.14 (m, 1H), 2.82 - 2.68 (m, 2H), 2.27 - 2.10 (m, 4H), 2.11 - 1.99 (m, 2H), 1.99 - 1.79 (m, 2H), 1.78 - 1.65 (m, 1H), 1.44 - 1.33 (m, 3H), 1.30 - 1.20 (m, 2H).

[0214] Example 28: N,N-bis(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)tetrahydro-2H-pyran-4-amine trihydrochloride (28)

[0215]

[0216] Replace methylamine with tetrahydro-2H-pyran-4-amine, and use the same required raw materials, reagents and preparation method as in Example 25 to obtain N,N-bis(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)tetrahydro-2H-pyran-4-amine trihydrochloride (yield 63%). 11H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.11 (s, 4H), 7.76 - 7.65 (m, 4H), 7.60 (d, J = 7.8 Hz, 4H), 7.36 - 7.28 (m, 2H), 7.28 - 7.20 (m, 2H), 7.05 - 6.96 (m, 2H), 4.55 - 4.41 (m, 2H), 4.29 (s, 4H), 4.19 - 4.06 (m, 2H), 3.99 - 3.89 (m, 2H), 3.34 - 3.29 (m, 1H), 3.15 (t, J = 11.8 Hz, 2H), 2.87 (s, 2H), 2.63 - 2.55 (m, 2H), 2.25 - 2.10 (m, 2H), 2.01 - 1.88 (m, 2H), 1.66 - 1.56 (m, 2H), 1.31 (q, J = 6.8 Hz, 2H).

[0217] Example 29: (1R,2S)-N-(4-(((2-(1H-indol-3-yl)ethyl))(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine trihydrochloride (29)

[0218]

[0219] Replace methylamine with tryptamine, and use the remaining required raw materials, reagents and preparation methods as in Example 25 to obtain (1R,2S)-N-(4-(((2-(1H-indol-3-yl)ethyl))(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)amino)methyl)benzyl)-2-(3,4-difluorophenyl)cyclopropan-1-amine trihydrochloride (yield 54%). 1 1H NMR (400 MHz, Deuterium Oxide) δ 7.47 - 7.30 (m, 9H), 7.11 (t, J = 7.6 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.96 - 6.84 (m, 3H), 6.69 - 6.59 (m, 2H), 6.56 - 6.48 (m, 2H), 4.47 - 4.21 (m, 8H), 3.22 - 3.14 (m, 2H), 2.99 - 2.91 (m, 2H), 2.71 - 2.64 (m, 2H), 2.12 (br, 2H), 1.41 - 1.32 (m, 2H), 1.23 - 1.13 (m, 2H).

[0220] Example 30: N,N-Bis(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)aniline dihydrochloride (30)

[0221]

[0222] Replace methylamine with aniline, and use the remaining required raw materials, reagents and preparation methods the same as in Example 25 to obtain N,N-bis(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)aniline dihydrochloride (yield 72%). 1 HNMR(400MHz,DMSO-d6)δ10.19-9.89(m,4H),7.53(d,J=7.9Hz,4H),7.38-7.25(m,6H),7.25-7.15(m,2H),7.08(t,J=7.8Hz,2H),7.03-6.93(m,2H),6.75-6.55(m,3H),4.71(s,4H),4.31-4.17(m,4H),2.91-2.80(m,2H),2.57-2.53(m,2H),1.66-1.54(m,2H),1.35-1.25(m,2H).

[0223] Example 31: (1R,2S)-2-(3,4-Difluorophenyl)-N-(4-(((4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(piperidin-4-ylmethyl)amino)methyl)benzyl)cyclopropan-1-amine tetrahydrochloride (31)

[0224]

[0225] Replace methylamine with tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, and use the remaining required raw materials, reagents and preparation methods the same as in Example 25 to obtain (1R,2S)-2-(3,4-difluorophenyl)-N-(4-(((4-((((2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)(piperidin-4-ylmethyl)amino)methyl)benzyl)cyclopropan-1-amine tetrahydrochloride (yield 63%). 1HNMR(400MHz,Deuterium Oxide)δ7.50(d,J=7.8Hz,4H),7.42(d,J=7.9Hz,4H),7.08-6.96(m,2H),6.84-6.64(m,4H),4.49-4.42(m,2H),4.38-4.32(m,2H),4.27(s,4H),3.32(d,J=13.0Hz,2H),2.99(d,J=6.4Hz,2H),2.93-2.85(m,2H),2.84-2.76(m,2H),2.26-2.15(m,2H),2.07(br,1H),1.85(d,J=14.0Hz,2H),1.47-1.38(m,2H),1.35-1.15(m,4H).

[0226] Example 32: (4 - ((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)piperidin-4-amine tetrahydrochloride (32)

[0227]

[0228] Methylamine was replaced with tert-butyl 4-aminopiperidine-1-carboxylate, and the remaining required raw materials, reagents and preparation methods were the same as in Example 25 to obtain (4 - ((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)benzyl)piperidin-4-amine tetrahydrochloride (yield 59%). 1 H NMR(400MHz,Deuterium Oxide)δ7.53-7.42(m,4H),7.41-7.23(m,4H),7.08-6.95(m,2H),6.80-6.62(m,4H),4.58-4.12(m,8H),4.06(d,J=11.5Hz,2H),3.51(d,J=5.1Hz,1H),3.40-3.27(m,2H),2.77(d,J=6.1Hz,2H),2.18(br,2H),2.10-1.94(m,4H),1.48-1.36(m,2H),1.34-1.21(m,2H).

[0229] Example 32: LSD1 Inhibitory Activity Assay

[0230] Experimental method: The samples were the above-mentioned synthetic compounds 1-22 and 24-32. Sample stock solution: Weigh 1-2 mg of each sample and dissolve it in DMSO (dimethyl sulfoxide) to form a mother liquor with a concentration of 10 mM. Dilute it to the required concentration with DMSO during the experiment. Incubate each sample with the human complex protein LSD1 / CoREST purified from the Escherichia coli expression system, and then add the H3K4me2 polypeptide synthesized by GL Biochem (Shanghai) Ltd. to incubate for 30 min. After the incubation, add the fluorescent dye Amplex Red and horseradish peroxidase HRP to react for 5 min, and then use an EnVision microplate reader (PerkinElmer, Waltham, MA, USA) to measure the fluorescence signal (E X = 535 nm, E m = 595 nm), and calculate its inhibition rate. Specifically, the inhibition rate calculation formula is as follows:

[0231]

[0232] Among them, the "fluorescence intensity of the sample group", "fluorescence intensity of the standard group", and "fluorescence intensity of the blank group" in the above inhibition rate calculation formula are all fluorescence intensity values measured by referring to the above experimental method. The differences are as follows: Under the same conditions, the measurement object of the "fluorescence intensity of the sample group" is the sample solution containing the above-mentioned compound to be tested, the measurement object of the "fluorescence intensity of the standard group" is the standard solution, and this standard solution does not contain the sample compared with the sample solution. The measurement object of the "fluorescence intensity of the blank group" is the blank sample without the LSD1 / CoREST complex protein and the H3K4me2 polypeptide. Use Graphpad Prism 8.0 to process the IC 50 data of the above sample compounds, and the results are shown in Table 1.

[0233] Table 1 Inhibition activity data table of the compounds provided in the examples of the present invention against LSD1 / CoREST

[0234]

[0235]

[0236] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A phenylcyclopropylamine compound, characterized in that, Comprising the structural general formula I and its corresponding salts: Wherein, R1 is hydrogen, halogen; R2 is hydrogen, halogen; R4 is hydrogen, , ; R7 is ; Ring A is , , , , ; X is methylene, carbonyl, sulfonyl; R5 is , , , , , , , , , , , ; R6 is , , , .

2. The phenylcyclopropylamine compound according to claim 1, wherein The specific structure is as follows: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 3. The phenylcyclopropylamine compound according to any one of claims 1-2, characterized in that When R7 is , and X is methylene, the structural general formula is as follows: It is prepared by the following method: (1) Preparation of compound 1-1 Performing an amino protection reaction on compound 3-1 to obtain intermediate 3-2, and subjecting intermediate 3-2 to a substitution reaction with compound 3-3 under strong base conditions to obtain compound 1-1; or Performing reductive amination on compound 3-1 and compound 3-4 to obtain compound 3-5, and performing an amino protection reaction on compound 3-5 to obtain compound 1-1; The specific reaction formula is as follows: (2) Preparation of compound 1-2 Performing reductive amination on compound 3-1 and compound 4-1 to obtain compound 4-2, performing an amino protection reaction on compound 4-2 to obtain compound 4-3, and then obtaining the product 1-2 through an oxidation reaction; the specific reaction formula is as follows: (3) Preparation of compound 1-3 Performing a substitution reaction on compound 2-1 and compound 2-2 to obtain compound 1-3; or Performing reductive amination on compound 2-3 and compound 2-2 to obtain 1-3; or Performing a substitution reaction on compound 2-4 and compound 2-5 to obtain 1-3; the specific reaction formula is as follows: (4) Preparation of the compound represented by general formula I-2 Performing a substitution reaction on compound 1-1 and compound 1-3, and then removing the tert-butoxycarbonyl protection under acidic conditions to obtain the compound represented by general formula I-1. The compound represented by general formula I-1 undergoes reductive amination with an aldehyde to obtain the compound represented by general formula I-2; or Performing reductive amination on compound 1-2 and compound 1-3 to obtain the compound represented by general formula I-1. The compound represented by general formula I-1 undergoes reductive amination with an aldehyde to obtain the compound represented by general formula I-2; the specific reaction formula is as follows: 。 4. The phenylcyclopropylamine compound according to any one of claims 1-2, characterized in that, When R7 is , and X is a carbonyl group, the general structural formula is as follows: It is prepared by the following method: Reacting compound 5-1, compound 1-3, a condensing agent and a base to obtain compound 5-2, and performing reductive amination on compound 5-2 and compound 3-1 to obtain the compound represented by general formula I-3, the specific reaction formula is as follows: 。 5. The phenylcyclopropylamine compound according to any one of claims 1-2, characterized in that, When R7 is , and X is a sulfonyl group, the structural general formula is as follows: It is prepared by the following method: Reacting compound 6-1, compound 1-3 and a base to obtain the sulfonamide compound represented by general formula 6-2, and performing a substitution reaction on the sulfonamide compound represented by general formula 6-2 and compound 3-1 to obtain the compound represented by general formula I-4, the specific reaction formula is as follows: 。 6. Use of the phenylcyclopropylamine compound according to any one of claims 1-5 in the preparation of an LSD1 inhibitor.

7. A pharmaceutical composition, characterized in that, Comprising the phenylcyclopropylamine compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier.

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