Preparation and application of novel MAO-B inhibitor containing tetrahydronaphthalene-1-amine structure

Abstract

The invention provides preparation and application of a novel MAO-B inhibitor containing a tetrahydronaphthalene-1-amine structure, and belongs to the field of medicine. The derivative is a compound as shown in a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The compound disclosed by the invention can be used for inhibiting MAO (monoamine oxidase), and particularly can be used for selectively inhibiting MAO-B; the compound can be used for treating Parkinson's disease, Alzheimer's disease, emotional disorder and other diseases, and has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and mainly relates to the preparation of a tetralin-1-amine-containing structural compound and its pharmaceutical use as a selective monoamine oxidase B (MAO-B) inhibitor. Background Art

[0002] Parkinson's disease (PD) is a common neurodegenerative disease in clinical practice. With the aging of the population and the extension of human life expectancy, the burden of Parkinson's disease is gradually increasing. According to statistics in 2016, the number of Parkinson's disease patients in the world has reached 6 million, and it is doubling. Its prevalence, disability rate and mortality rate are the fastest growing among neurological diseases. In fact, my country is the most populous country in the world, and there are more than 3 million Parkinson's disease patients. It is estimated that by 2030, the number of patients in my country will reach 5 million, and the incidence rate of middle-aged and elderly people over 65 years old will be 1.7%.

[0003] The pathological feature of Parkinson's disease is the degeneration of dopaminergic neurons in the substantia nigra of the midbrain, leading to pathophysiological changes in the downstream basal circuits. The loss of dopaminergic neurons and the resulting defects in dopamine transmission ultimately lead to motor and mental dysfunction. Dopamine degradation requires two enzymes, monoamine oxidase (MAO) and catechol-2-O-2-methyltransferase (COMT). Dopamine is oxidatively degraded in the brain by MAO-B, and a large number of oxygen free radicals are produced during its metabolism, which damage neurons.

[0004] Monoamine oxidase (MAO) is a flavin adenine dinucleotide enzyme that is mainly located on the outer membrane of mitochondria in tissue cells such as the brain, liver and intestinal mucosa. MAO catalyzes the oxidation of endogenous or exogenous monoamines to produce deamination reactions, producing hydrogen peroxide, ammonia and aldehydes, which cause the monoamines in the body to lose their physiological activity. Unnecessary MAO enzyme activity can cause neurodegenerative traumatic disorders and mitochondrial damage. There are two subtypes of this enzyme: MAO-A and MAO-B. MAO-B is a complex enzyme of the mitochondrial membrane and plays an important role in dopamine metabolism. MAO-B can decompose dopamine into homovanillic acid, accompanied by the free radical hydrogen peroxide (H 2 O 2 ) is produced, which has a toxic effect on nerve cells, leading to increased neuronal damage and death. Therefore, inhibiting MAO-B activity can prevent dopamine degradation, increase the concentration of dopamine in the brain, inhibit the production of peroxides in dopamine oxidation metabolism, reduce the production of oxygen free radicals, and improve the symptoms of Parkinson's disease. It can also block the conversion of MPTP into MPP + , delaying the process of substantia nigra cell death and changing the course of PD in patients.

[0005] The non-selectivity and irreversibility of some drugs on the market (such as phenylproline and selegiline) can lead to many serious adverse reactions, such as postural hypotension, hypertensive crisis, "caseous reaction", liver toxicity, etc. In order to overcome these adverse reactions, the design and screening of highly effective and low-toxic MAO-B inhibitors is still one of the current research hotspots for alleviating PD symptoms and improving the health and quality of life of PD patients. Summary of the invention

[0006] The purpose of the present invention is to provide an inhibitor having good inhibitory effect and high selectivity on MAO-B, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a synthesis method and use thereof.

[0007] The present invention solves the problem by adopting the following technical solution:

[0008] A compound containing a tetralin-1-amine structure, as shown in Formula I:

[0009]

[0010] in,

[0011] R 4 For H, R 1 -R 3 is selected from hydrogen, halogen, hydroxy, nitro, amino, formula II;

[0012]

[0013] n is an integer selected from 1-2, and the symbol "∧" in brackets represents CH 2 ;

[0014] Y is selected from O or S;

[0015] X 1 , X 2 is selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, and nitrile;

[0016] The acid for forming the salt is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and the like.

[0017] Specifically, the compound containing a tetrahydronaphthalene-1-amine structure shown in Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is specifically selected from the following compounds:

[0018]

[0019]

[0020] The present invention also provides a synthesis of a tetralin-1-amine structure, and the method is as follows:

[0021]

[0022] The method firstly adopts coupling reaction to synthesize a compound containing tetralin-1-amine structure, and then obtains the target compound through reduction reaction and amino substitution reaction;

[0023] The reduction reaction is to reduce the ketone to an amino group using sodium cyanoborohydride and ammonium acetate, and then to replace the hydrogen on the amino group with propyne bromide to further obtain a compound.

[0024] The compound of formula I containing a tetralin-1-amine structure, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof can be synthesized by general chemical methods.

[0025] Generally, the salt can be prepared by dissolving the synthesized compound in toluene, and passing dry hydrochloric acid gas therein, and obtaining a hydrochloride product after crystallization.

[0026] The present invention further provides the use of the tetralin-1-amine structure compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a selective MAO-B inhibitor. The MAO-B inhibitor can be used to treat MAO-B-mediated neurodegenerative diseases, and the MAO-B-mediated neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, schizophrenia, depression and the like.

[0027] The present invention also provides the use of the tetralin-1-amine compound described in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in preparing a drug, wherein the drug is used to treat diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia, depression, etc.

[0028] The present invention also provides a pharmaceutical composition, which is an injection, tablet, capsule, powder, granule, suspension or oral liquid prepared with the tetralin-1-amine compound described in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a schematic diagram of the general structure of the patent of the present invention. DETAILED DESCRIPTION

[0029] Unless otherwise specified, the raw materials and equipment used in the specific implementation of the present invention are all known products and can be obtained commercially. The present invention is now further described in detail in conjunction with the embodiments, but is not limited to these embodiments.

[0030] The structures of the compounds in the following examples were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a VNMRS600 nuclear magnetic spectrometer from Agilent Technologies, USA, with a displacement unit of parts per million (ppm). The measurement solvent was deuterated chloroform (CDCl 3 ), deuterated dimethyl sulfoxide (DMSO-d 6 ), with tetramethylsilane (TMS) as the internal standard. MS was determined using an ACQUITY UPLC LCT Premier XE (ESI) mass spectrometer.

[0031] Example 1: Preparation of 5-(benzyloxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-1)

[0032]

[0033] The specific preparation method is as follows:

[0034] Step 1: Preparation of 5-(Benzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1b)

[0035] Take 5-hydroxy-1-tetralone 1a (0.5 g, 30.82 mmol) and dissolve it in acetone, add potassium carbonate (0.51 g, 36.90 mmol), drop benzyl bromide (0.58 g, 33.91 mmol), stir and reflux at 85 ° C for 5 h. After the reaction is complete, the reaction solution is cooled to room temperature, poured into water, extracted with ethyl acetate (15 mL) three times, and the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 20:1) is used to separate and purify the intermediate product 1b (0.64 g, 25.36 mmol, white solid, yield 82.28%), which is directly used for the next step.

[0036] Step 2: Preparation of 5-(benzyloxy)-1,2,3,4-tetrahydronaphthalene-1-amine (1c)

[0037] Compound 1b (0.32 g, 12.68 mmol) was dissolved in a mixed solution of isopropanol and methanol (1:1), and sodium cyanoborohydride (0.398 g, 63.33 mmol) and ammonium acetate (0.98 g, 127.14 mmol) were added in batches under stirring in an ice bath at 0°C, and the mixture was evacuated and stirred at 25°C for 1.5 h under nitrogen protection, and then the reaction flask was moved to 90°C for reaction for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate (15 mL) three times, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and directly used for the next step.

[0038] Step 3: Preparation of 5-(benzyloxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-1)

[0039] Compound 1c (0.3 g, 11.84 mmol) was dissolved in a mixed solvent of water and tetrahydrofuran (2:1), and sodium hydroxide solution (1.5 mL) was slowly added under stirring. After stirring for 10 min, propargyl bromide (0.155 g, 13.03 mmol) was added, and the reaction bottle was moved to 60 ° C and refluxed for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate (15 mL) for 3 times, and the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 25:1) was used to separate and purify the target product 1d (0.12 g, 4.12 mmol, light yellow oil, yield 34.8%). The purified product was dissolved in toluene, and dry HCL gas was passed through to prepare hydrochloride, and 57 mg of white crystals (I-1) were obtained, with a yield of 15%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.48-7.43(m,2H),7.43-7.37(m,2H),7.36-7.29(m,1H),7.24(t,J=7.9 Hz,1H),7.15(d,J=7.8Hz,1H),7.09-7.06(m,1H),5.14(s,2H),4.47(t,J= 4.9Hz,1H),3.97-3.82(m,2H),3.77(t,J=2.5Hz,1H),2.80-2.73(m,1H),2 .63-2.54(m,1H),2.22-2.16(m,1H),2.02-1.89(m,2H),1.83-1.74(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.42,137.64,131.73,128.95,128.25,127.76,127.63,126.95,122.40,112. 35,80.21,75.58,69.68,53.90,33.97,24.24,22.76,17.11.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 21 NONa:314.1523; Found:314.1521.

[0040] Example 2: Preparation of 5-((3-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-2)

[0041]

[0042] The operation was the same as in Example 1, except that benzyl bromide was replaced by 3-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 87 mg of white crystals (I-2) were obtained. The yield was 12%. 1 H NMR(600MHz,Chloroform-d)δ7.36-7.31(m,1H),7.25(d,J=7.3Hz,1H),7.22-7.16(m, 2H),7.16-7.12(m,1H),7.03-6.97(m,1H),6.84(d,J=8.0Hz,1H),5.04(s,2H),4.62(t ,J=4.9Hz,1H),3.70-3.58(m,2H),3.01-2.94(m,1H),2.70-2.62(m,1H),2.57(d,J=2. 2Hz,1H),2.39-2.30(m,1H),2.27-2.17(m,1H),2.07-1.99(m,1H),1.90-1.82(m,1H). 13 C NMR(151MHz,Chloroform-d)δ156.44,130.28,130.10,128.22,126.78,122.54,122.40,114.81,114.66, 113.95,113.81,111.70,78.17,73.61,69.06,53.68,33.37,24.68,22.34,17.38.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 FNONa:334.1423; Found:334.1427.

[0043] Example 3: Preparation of 5-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-3)

[0044]

[0045] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-bromobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 80 mg of white crystals (I-3) were obtained. The yield was 15%. 1H NMR(600MHz,Chloroform-d)δ7.53-7.48(m,2H),7.34-7.28(m,2H),7.16-7. 09(m,1H),6.97(d,J=7.7Hz,1H),6.75-6.72(m,1H),5.06-4.97(m,2H),4.00( t,J=4.1Hz,1H),3.57-3.45(m,2H),2.90-2.83(m,1H),2.64-2.58(m,1H),2. 28(t,J=2.4Hz,1H),2.02-1.92(m,1H),1.92-1.85(m,1H),1.83-1.73(m,2H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.22,137.12,131.88,131.78,129.89,127.64,126.96,122.54,121.34,112. 37,80.21,75.58,68.91,53.87,33.96,24.22,22.73,17.11.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 NOBr:370.0809; Found:370.0807.

[0046] Example 4: Preparation of 5-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-4)

[0047]

[0048] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 75 mg of a light yellow solid (I-4) was obtained. The yield was 13%. 1 H NMR (600 MHz, DMSO-d 6)δ7.54-7.48(m,2H),7.26-7.20(m,3H),7.16(d,J=7.7Hz,1H),7.09-7.06(m,1H),5.12(s,2H),4.47(d,J=4.7Hz,1H),3.96-3.89(m,1H), 3.87-3.82(m,1H),3.76(t,J=2.5Hz,1H),2.78-2.71(m,1H),2.62-2.53(m,1H),2.23-2.15(m,1H),2.02-1.89(m,2H),1.81-1.74(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.33,133.86,131.77,130.00,129.94,127.65,126.95,122.47,115.84,115.70,1 12.37,80.19,75.59,69.01,53.90,33.97,24.25,22.74,17.12.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaF:332.1432; Found:332.1427.

[0049] Example 5: Preparation of N-(prop-2-yn-1-yl)-5-((3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydronaphthalene-1-amine (I-5)

[0050]

[0051] The operation was the same as in Example 1, except that benzyl bromide was replaced by 3-trifluoromethylbenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.5 g of a white solid (I-5) was obtained. The yield was 35%. 1 H NMR (600 MHz, DMSO-d 6)δ7.82(s,1H),7.78(d,J=7.6Hz,1H),7.70(d,J=7.8Hz,1H),7.65(t,J=7.7Hz,1 H),7.26(t,J=7.9Hz,1H),7.18(d,J=7.7Hz,1H),7.10-7.07(m,1H),5.25(s,2H) ,4.48(t,J=4.8Hz,1H),3.98-3.81(m,2H),3.76(t,J=2.5Hz,1H),2.80-2.74(m, 1H),2.64-2.56(m,1H),2.24-2.14(m,1H),2.04-1.89(m,2H),1.84-1.72(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.20,139.20,131.84,131.75,130.13,127.65,127.01,125.00,124.16,124.13,122.68, 112.36,80.21,75.57,68.87,66.83,53.87,33.96,24.22,22.69,17.12.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 21 NOF 3 :360.1582;Found:360.1575.

[0052] Example 6: Preparation of 5-((4-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-6)

[0053]

[0054] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-chlorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.24 g of a white solid (I-6) was obtained. The yield was 22%. 1H NMR(600MHz,Chloroform-d)δ6.50-6.42(m,4H),6.24-6.19(m,1H),6.15(d,J=7.8Hz,1H),6.04(d,J=8.1Hz,1H),4.12(d,J=1.8Hz,2H),3.50-3.4 2(m,1H),2.96-2.79(m,2H),2.74(q,J=2.3Hz,1H),1.78-1.70(m,1H),1. 60-1.52(m,1H),1.23-1.13(m,1H),1.01-0.86(m,2H),0.83-0.71(m,1H). 13 C NMR(151MHz,Chloroform-d)δ160.99,141.46,137.56,136.54,134.33,133.71,1 32.41,131.70,127.30,117.11,84.95,73.64,58.61,38.70,28.99,27.48,21.89.

[0055] HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 NOCl:326.1313; Found:326.1312.

[0056] Example 7: Preparation of 5-((4-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-7)

[0057]

[0058] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-methylbenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.26 g of a white solid (I-7) was obtained. The yield was 25%. 1 H NMR (600 MHz, DMSO-d 6)δ7.36-7.32(m,2H),7.26-7.18(m,3H),7.14(d,J=7.7Hz,1H),7.08-7.05(m,1H),5.08(s,2H),4.46(s,1H),3.96-3.88(m,1H),3.87-3.82 (m,1H),3.76(t,J=2.5Hz,1H),2.78-2.70(m,1H),2.62-2.51(m,1H),2.30(s,3H),2.24-2.14(m,1H),2.01-1.88(m,2H),1.81-1.73(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.45,137.50,134.58,131.69,129.49,127.90,127.61,126.92,122.33,112.35, 80.20,75.58,69.63,53.88,33.95,24.24,22.76,21.25,17.12.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 23 NONa:328.1682; Found:326.1677.

[0059] Example 8: Preparation of 5-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-8)

[0060]

[0061] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-nitrobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.14 g of a white solid (I-8) was obtained. The yield was 14%. 1 H NMR (600 MHz, DMSO-d 6)δ8.29-8.24(m,2H),7.76-7.71(m,2H),7.25(t,J=7.9Hz,1H),7.19(d,J= 7.8Hz,1H),7.08-7.04(m,1H),5.32(s,2H),4.48(t,J=4.4Hz,1H),3.97-3 .89(m,1H),3.88-3.81(m,1H),3.76(t,J=2.5Hz,1H),2.85-3.78(m,1H),2 .67-2.60(m,1H),2.24-2.18(m,1H),2.06-1.90(m,2H),1.84-1.76(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.01,147.47,145.57,131.94,128.41,127.70,126.99,124.13,122.78,112.35, 80.19,75.61,68.57,53.85,53.83,33.97,24.24,22.72,17.14.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 N 2 O 3 :337.1560;Found:337.1552.

[0062] Example 9: Preparation of 5-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-9)

[0063]

[0064] The operation was the same as in Example 1, except that benzyl bromide was replaced with 3,4-difluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.28 g of a white solid (I-9) was obtained with a yield of 32%. 1 H NMR (600 MHz, DMSO-d 6)δ7.55-7.50(m,1H),7.49-7.44(m,1H),7.35-7.30(m,1H),7.24(t,J=7.9H z,1H),7.19-7.16(m,1H),7.07-7.04(m,1H),5.13(s,2H),4.47(s,1H),3.97 -3.89(m,1H),3.88-3.82(m,1H),3.76(t,J=2.5Hz,1H),2.80-2.73(m,1H), 2.63-2.55(m,1H),2.22-2.15(m,1H),2.02-1.90(m,2H),1.82-1.73(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.11,131.83,127.69,126.96,122.64,118.13,118.01,116.91,116.79,112.33,80. 20,75.58,68.40,53.89,53.87,33.97,33.96,24.23,22.70,17.12.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 20 NOF 2 :328.1516;Found:328.1513.

[0065] Example 10: Preparation of N-(prop-2-yn-1-yl)-5-((4-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydronaphthalene-1-amine (I-10)

[0066]

[0067] The operation was the same as in Example 1, except that benzyl bromide was replaced by 4-trifluoromethylbenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.1 g of a white solid (I-10) was obtained. The yield was 10%. 1 H NMR (600 MHz, DMSO-d 6)δ7.78(d,J=8.1Hz,2H),7.69(d,J=8.0Hz,2H),7.25(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),7.07(d,J=8.1Hz,1H),5.26(s,2H),4.47(t,J=4.2H z,1H),3.97-3.83(m,2H),3.76(t,J=2.5Hz,1H),2.83-2.77(m,1H),2.6 5-2.58(m,1H),2.22-2.16(m,1H),2.03-1.90(m,2H),1.83-1.77(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.13,142.55,128.15,127.64,127.00,125.90,125.87,125.84,125.82,122.64, 112.33,80.18,75.63,68.82,53.89,34.00,24.24,22.72,17.09.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 21 NOF 3 :360.1578;Found:360.1575.

[0068] Example 11: Preparation of 5-((3-iodobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-11)

[0069]

[0070] The operation was the same as in Example 1, except that benzyl bromide was replaced by 3-iodobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 45 mg of a white solid (I-11) was obtained. The yield was 15%. 1 H NMR (600 MHz, DMSO-d 6)δ7.83(t,J=1.7Hz,1H),7.70(dt,J=7.9,1.3Hz,1H),7.48(dt,J=7.9,1.4Hz,1H),7 .23(dt,J=15.8,7.8Hz,2H),7.19-7.11(m,1H),7.05(d,J=8.2Hz,1H),5.12(s,2H),4 .47(s,1H),3.96-3.90(m,1H),3.89-3.82(m,1H),3.77(t,J=2.5Hz,1H),2.78-2.72 (m,1H),2.62-2.54(m,1H),2.21-2.16(m,1H),2.02-1.88(m,2H),1.82-1.76(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.21,140.33,136.94,136.20,131.80,131.20,127.61,127.08,126.98,122.58,112 .34,95.38,80.22,75.58,68.67,53.87,33.96,24.21,22.72,17.10.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 INO:416.0671; Found:416.0668.

[0071] Example 12: Preparation of 6-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-12)

[0072]

[0073] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 4-bromobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 0.14 g of a white solid (I-12) is obtained, with a yield of 9%. 1 HNMR (600 MHz, DMSO-d 6)δ7.61-7.56(m,2H),7.45(d,J=8.6Hz,1H),7.42-7.37(m,2H),6.90(dd,J=8 .6,2.7Hz,1H),6.84(d,J=2.7Hz,1H),5.10(s,2H),4.42(t,J=5.1Hz,1H),3. 93-3.88(m,1H),3.87-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.82-2.75(m,1H) ,2.73-2.65(m,1H),2.23-2.14(m,1H),2.01-1.89(m,2H),1.75-1.65(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.72,140.58,136.93,131.85,130.18,123.08,121.40,115.37,113.44,80.13, 75.63,68.74,53.64,40.54,33.84,28.83,24.85,17.83.HO-11HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaBr:392.0626; Found:392.0630.

[0074] Example 13: Preparation of 6-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-13)

[0075]

[0076] The operation was the same as in Example 1, except that 5-hydroxy-tetralone was replaced by 6-hydroxy-tetralone, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 54 mg of a white solid (I-13) was obtained, with a yield of 11%. 1 H NMR (600 MHz, DMSO-d 6)δ7.48-7.41(m,3H),7.39(t,J=7.6Hz,2H),7.35-7.29(m,1H),6.90(dd,J=8 .6,2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.11(s,2H),4.42(t,J=4.3Hz,1H),3. 94-3.86(m,1H),3.86-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.82-2.76(m,1H) ,2.73-2.65(m,1H),2.22-2.15(m,1H),2.02-1.89(m,2H),1.75-1.67(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.92,140.54,137.43,131.82,128.93,128.32,128.08,122.98,115.33,113. 43,80.09,75.68,69.57,53.62,33.82,28.84,24.89,17.86.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 21 NONa:314.1521; Found:314.1524.

[0077] Example 14: Preparation of 4-(((5-(prop-2-yn-1-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl)benzonitrile (I-14)

[0078]

[0079] The operation was the same as in Example 1, except that 5-hydroxy-tetralone was replaced by 6-hydroxy-tetralone, benzyl bromide was replaced by 4-cyanobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 32 mg of a white solid (I-14) was obtained, with a yield of 6%. 1 H NMR (600 MHz, DMSO-d 6)δ7.89-7.85(m,2H),7.63(d,J=8.0Hz,2H),7.47(d,J=8.6Hz,1H),6.93-6 .90(m,1H),6.86(q,J=4.5,4.0Hz,1H),5.24(s,2H),4.42(t,J=5.3Hz,1H), 3.91(m,1H),3.88-3.79(m,1H),3.75(d,J=5.1Hz,1H),2.83-2.76(m,1H),2 .74-2.66(m,1H),2.21-2.14(m,1H),1.98-1.89(m,2H),1.74-1.68(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.54,143.31,140.66,132.92,131.92,128.44,123.28,119.22,115.37,113.39,1 10.94,80.13,75.62,68.59,53.61,33.83,28.83,24.83,17.82.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 20 N 2 ONa:339.1473; Found:339.1479.

[0080] Example 15: Preparation of 6-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-15)

[0081]

[0082] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 3-chlorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salification, 0.11 g of a white solid (I-15) is obtained, with a yield of 11%. 1 HNMR (600 MHz, DMSO-d 6)δ7.51(t,J=1.7Hz,1H),7.47(d,J=8.6Hz,1H),7.45-7.36(m,3H),6.93- 6.89(m,1H),6.86(d,J=2.7Hz,1H),5.14(s,2H),4.43(p,J=4.8Hz,1H),3. 95-3.87(m,1H),3.87-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.77(m,1 H),2.69(m,1H),2.22-2.15(m,1H),2.03-1.90(m,2H),1.74-1.68(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.66,140.61,140.06,133.58,131.88,130.88,128.24,127.68,126.57,123.15,115. 37,113.39,80.12,75.63,68.61,53.60,33.81,28.83,24.84,17.85.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaCl:348.1131; Found:348.1132.

[0083] Example 16: Preparation of 6-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-16)

[0084]

[0085] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 4-chlorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 0.12 g of a white solid (I-16) is obtained, with a yield of 17%. 1 HNMR (600 MHz, DMSO-d 6)δ7.49-7.43(m,5H),6.91-6.88(m,1H),6.85(d,J=2.7Hz,1H),5.12(s,2H),4.42(p,J=4.8Hz,1H),3.93-3.87(m,1H),3.87-3.8 0(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.76(m,1H),2.73-2.65(m,1H),2.21-2.14(m,1H),2.02-1.89(m,2H),1.74-1.68(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.73,140.58,136.51,132.87,131.85,129.88,128.93,123.07,115.36,113. 43,80.13,75.63,68.71,53.63,33.82,28.83,24.85,17.84.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaCl:348.1131; Found:348.1126.

[0086] Example 17: Preparation of 6-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-17)

[0087]

[0088] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 3,4-difluorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 0.36 g of a white solid (I-17) is obtained, with a yield of 36%. 1 HNMR (600 MHz, DMSO-d 6)δ7.54-7.50(m,1H),7.50-7.42(m,2H),7.33-7.27(m,1H),6.92-6.88(m,1 H), 6.85 (d, J = 2.7Hz, 1H), 5.10 (s, 2H), 4.43 (t, J = 4.7Hz, 1H), 3.91 (d, J = 17. 2Hz,1H),3.82(d,J=17.0Hz,1H),3.75(t,J=2.5Hz,1H),2.84-2.75(m,1H), 2.73-2.66(m,1H),2.22-2.15(m,1H),2.03-1.90(m,2H),1.75-1.67(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.61,140.61,131.87,124.96,124.94,123.18,118.10,117.99,117.23,117.11,115. 36,113.40,80.13,75.63,68.25,53.60,33.81,28.83,24.85,17.85.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 19 NONaF 2 :350.1332;Found:350.1324.

[0089] Example 18: Preparation of 6-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-18)

[0090]

[0091] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 4-nitrobenzyl bromide, and other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 60 mg of a white solid (I-18) is obtained, with a yield of 7%. 1 H NMR (600 MHz, DMSO-d 6)δ8.29-8.23(m,2H),7.73-7.68(m,2H),7.46(d,J=8.6Hz,1H),6.95-6.90 (m,1H),6.88(d,J=2.8Hz,1H),5.30(s,2H),4.42(t,J=4.1Hz,1H),3.94-3 .88(m,1H),3.87-3.82(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.76(m,1H),2 .74-2.66(m,1H),2.20-2.12(m,1H),1.99-1.90(m,2H),1.76-1.68(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.50,147.48,145.42,140.66,131.91,128.61,124.12,115.40,113.42,80.08,75. 71,68.38,53.67,40.34(d,J=20.9Hz),33.90,28.83,24.86,17.80.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 N 2 O 3 :337.1552;Found:337.1547.

[0092] Example 19: Preparation of 6-((3-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-19)

[0093]

[0094] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 3-fluorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 60 mg of a white solid (I-19) is obtained, with a yield of 7%. 1 H NMR (600 MHz, DMSO-d 6)δ7.50-7.40(m,2H),7.30-7.24(m,2H),7.19-7.12(m,1H),6.93-6.89(m,1H),6.86(d,J=2.7Hz,1H),5.14(s,2H),4.42(t,J=4.3Hz,1H),3.9 4-3.86(m,1H),3.86-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.80(m,1H), 2.69(m,1H),2.22-2.15(m,1H),2.03-1.89(m,2H),1.76-1.67(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.68,140.60,131.87,131.01,130.95,123.91,123.89,123.16,115.36,115.13,114. 67,113.40,80.10,75.65,68.69,53.58,33.80,28.84,24.86,17.86.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaF:332.1427; Found:332.1429.

[0095] Example 20: Preparation of 6-((3-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-20)

[0096]

[0097] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 3-methylbenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salification, 0.115 g of a white solid (I-20) is obtained, with a yield of 13%. 1 HNMR (600 MHz, DMSO-d 6)δ7.46(d,J=8.6Hz,1H),7.30-7.23(m,2H),7.24-7.19(m,1H),7.16–7.11(m,1H),6. 90(dd,J=8.6,2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.06(s,2H),4.42(t,J=5.0Hz,1H), 3.94-3.87(m,1H),3.87-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.82-2.76(m,1H),2.72 -2.66(m,1H),2.31(s,3H),2.22-2.15(m,1H),2.02-1.90(m,2H),1.75-1.67(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.98,140.53,138.08,137.33,131.82,128.96,128.82,128.66,125.20,122.90,115.32, 113.39,80.12,75.64,69.63,53.63,33.81,28.84,24.88,21.48,17.86.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 23 NONa:328.1677; Found:328.1678.

[0098] Example 21: Preparation of 6-((4-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-21)

[0099]

[0100] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 4-methylbenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 60 mg of a white solid (I-21) is obtained, with a yield of 8%. 1 H NMR (600 MHz, DMSO-d 6)δ7.46(d,J=8.6Hz,1H),7.34-7.29(m,2H),7.19(d,J=7.7Hz,2H),6.88(dd,J=8 .6,2.7Hz,1H),6.83(d,J=2.7Hz,1H),5.05(s,2H),4.42(p,J=4.6Hz,1H),3.93-3 .86(m,2H),3.84-3.87(m,1H),3.75(t,J=2.5Hz,1H),2.82-2.78(m,1H),2.74-2. 68(m,1H),2.30(s,3H),2.22-2.15(m,1H),2.04-1.89(m,2H),1.74-1.66(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.95,140.51,137.55,134.38,131.80,129.46,128.19,122.85,115.34,113.42, 80.11,75.63,69.48,53.59,33.78,28.84,24.88,21.25,17.88.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 23 NONa:328.1677; Found:328.1680.

[0101] Example 22: Preparation of 6-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-22)

[0102]

[0103] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 6-hydroxy-tetralone, benzyl bromide is replaced by 4-fluorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 53 mg of a white solid (I-22) is obtained, with a yield of 9%. 1 H NMR (600 MHz, DMSO-d 6)δ7.52-7.45(m,3H),7.26-7.18(m,2H),6.90(dd,J=8.5,2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.09(s,2H),4.42(t,J=4.3Hz,1H),3.93-3.87(m, 1H),3.85-3.78(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.76(m,1H),2.72 -2.65(m,1H),2.22-2.14(m,1H),2.06-1.89(m,2H),1.74-1.67(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ158.80,140.57,133.66,131.84,130.37,130.31,123.01,115.81,115.67,115.32,1 13.41,80.11,75.64,68.85,53.57,33.78,28.84,24.87,17.88.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaF:332.1427; Found:332.1424.

[0104] Example 23: Preparation of 7-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-23)

[0105]

[0106] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 3,4-difluorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 86 mg of a white solid (I-23) is obtained, with a yield of 9%. 1 HNMR (600 MHz, DMSO-d 6)δ7.55-7.51(m,1H),7.49-7.44(m,1H),7.32(dq,J=5.3,2.6,2.2Hz,2H),7 .13(d,J=8.5Hz,1H),6.98(dd,J=8.5,2.7Hz,1H),5.19-5.08(m,2H),4.50- 4.42(m,1H),3.94-3.86(m,2H),3.76(t,J=2.5Hz,1H),2.77-2.71(m,1H),2 .68-2.61(m,1H),2.21-2.07(m,1H),2.05-1.89(m,2H),1.74-1.66(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.39,131.58,131.16,131.05,129.37,128.68,118.09,117.98,117.25,117.14,116.74, 115.94,80.14,75.57,68.47,54.32,40.41,33.88,27.83,24.68,18.46.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 20 NOF 2 :328.1513;Found:328.1514.

[0107] Example 24: Preparation of 7-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-24)

[0108]

[0109] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 4-nitrobenzyl bromide, and other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 85 mg of a white solid (I-24) is obtained. The yield is 8%. 1 H NMR (600 MHz, DMSO-d 6)δ8.29-8.23(m,2H),7.76-7.70(m,2H),7.37(d,J=2.7Hz,1H),7.12(d,J=8.5Hz,1H),7.00(dd,J=8.5,2.7Hz,1H),5.41-5.15(m,2H),4.45(s, 1H),3.93-3.81(m,2H),3.75(t,J=2.5Hz,1H),2.77-2.69(m,1H),2.66 -2.60(m,1H),2.17-2.10(m,1H),2.02-1.90(m,2H),1.74-1.63(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.26,147.46,145.51,131.65,131.34,131.10,128.68,124.10,116.75,116. 00,80.13,75.56,68.62,54.25,33.81,27.84,24.66,18.47.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 N 2 O 3 :337.1552;Found:337.1556.

[0110] Example 25: Preparation of 7-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-25)

[0111]

[0112] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 3-chlorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 75 mg of a white solid (I-25) is obtained, with a yield of 7%. 1 H NMR (600 MHz, DMSO-d 6)δ7.53-7.49(m,1H),7.45-7.36(m,3H),7.34(d,J=2.7Hz,1H),7.12(d,J= 8.5Hz,1H),6.98(dd,J=8.4,2.7Hz,1H),5.21-5.00(m,2H),4.45(t,J=4.6H z,1H),3.89(q,J=16.8Hz,2H),3.75(t,J=2.5Hz,1H),2.77-2.70(m,1H),2 .67-2.61(m,1H),2.17-2.10(m,1H),2.02-1.91(m,2H),1.74-1.65(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.47,140.14,133.60,131.63,131.12,131.04,130.86,128.24,127.70,126.63,116.67, 115.95,80.13,75.60,68.85,54.27,33.86,27.84,24.68,18.49.HRMS(ESI):m / z[M+Na]+calcd forC 20 H 20 NOClNa:348.1131; Found:348.1132.

[0113] Example 26: Preparation of 7-benzyloxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-26)

[0114]

[0115] The operation was the same as in Example 1, except that 5-hydroxy-tetralone was replaced with 7-hydroxy-tetralone, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 78 mg of a white solid (I-26) was obtained, with a yield of 10%. 1 H NMR (600 MHz, DMSO-d 6)δ7.48-7.43(m,2H),7.39(t,J=7.6Hz,2H),7.36-7.29(m,2H),7.10(d,J= 8.5Hz, 1H), 6.97 (dd, J=8.5, 2.6Hz, 1H), 5.14 (q, J=12.0Hz, 2H), 4.45 (t, J= 4.9Hz,1H),3.95-3.82(m,2H),3.76(t,J=2.5Hz,1H),2.76-2.70(m,1H),2 .69-2.60(m,1H),2.19-2.09(m,1H),2.04-1.90(m,2H),1.74-1.64(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.73,137.49,131.56,130.98,130.89,128.91,128.33,128.17,116.75,115. 85,80.13,75.62,69.80,54.26,33.86,27.84,24.69,18.51.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 21 NONa:314.1521; Found:314.1525.

[0116] Example 27: Preparation of 7-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-27)

[0117]

[0118] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 4-fluorobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 0.155 g of a white solid (I-27) is obtained, with a yield of 15%. 1 HNMR (600 MHz, DMSO-d 6)δ7.54-7.47(m,2H),7.32(d,J=2.6Hz,1H),7.27-7.19(m,2H),7.11(d,J =8.5Hz,1H),6.97(dd,J=8.5,2.6Hz,1H),5.19-4.99(m,2H),4.45(q,J=5. 1Hz,1H),3.99-3.83(m,2H),3.76(t,J=2.5Hz,1H),2.76-2.70(m,1H),2. 67-2.60(m,1H),2.16-2.10(m,1H),2.03-1.97(m,2H),1.72-1.66(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.61,131.55,131.01,130.97,130.43,130.38,116.76,115.87,115.81,115. 67,80.15,75.60,69.07,54.30,33.88,27.83,24.69,18.49.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 20 NONaF:332.1427; Found:332.1431.

[0119] Example 28: Preparation of 7-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-28)

[0120]

[0121] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 4-bromobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 0.1 g of a white solid (I-28) is obtained, with a yield of 9%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.62-7.55(m,2H),7.46-7.39(m,2H),7.31(d,J=2.6Hz,1H),7.11(d,J=8.5Hz,1H),6.96(dd,J=8 .5,2.6Hz,1H),5.17-5.07(m,2H),4.47-4.42(m,1H),3.94-3.84(m,2H),3.76(t,J=2.5Hz,1H),2.75

[0122] -2.69(m,1H),2.67-2.60(m,1H),2.15-2.09(m,1H),2.03-1.91(m,2H),1.73-1.69(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.50,136.99,131.85,131.03,130.25,121.42,116.75,115.91,80.15,7 5.59,68.97,54.30,40.41,33.88,27.83,24.68,18.48.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 NOBr:370.0807; Found:370.0804.

[0123] Example 29: Preparation of 4-(((8-(prop-2-yn-1-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl)benzonitrile (I-29)

[0124]

[0125] The operation is the same as that in Example 1, except that 5-hydroxy-tetralone is replaced by 7-hydroxy-tetralone, benzyl bromide is replaced by 4-cyanobenzyl bromide, and the other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 60 mg of a white solid (I-29) is obtained, with a yield of 6%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.91-7.84(m,2H),7.65(d,J=8.2Hz,2H),7.36(d,J=2.7Hz,1H),7.12(d,J =8.5Hz,1H),6.98(dd,J=8.5,2.7Hz,1H),5.34-5.21(m,2H),4.45(d,J=6.6Hz ,1H),3.88(q,J=16.8,16.4Hz,2H),3.76(t,J=2.5Hz,1H),2.76-2.69(m,1H) ,2.68-2.60(m,1H),2.20-2.08(m,1H),2.03-1.91(m,2H),1.76-1.64(m,1H). 13 C NMR (151 MHz, DMSO-d 6)δ156.32,143.39,132.91,131.64,131.07,128.52,119.23,116.73,115.96,110. 95,80.14,75.57,68.84,54.24,33.82,27.84,24.65,18.49.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 20 N 2 ONa:339.1473; Found:339.1476.

[0126] Example 30: Preparation of 5-(Benzylthio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-30)

[0127]

[0128] The specific preparation method is as follows:

[0129] Step 1: Preparation of 5-mercapto-3,4-dihydronaphthalen-1(2H)-one (2b)

[0130] Take 5-bromo-3,4-dihydronaphthalene-1(2H)-one 2a (1 g, 44.43 mmol) and dissolve it in 1,4-dioxane. Add potassium thioacetate (1.52 g, 133.08 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethoxanthene (0.51 g, 8.81 mmol) respectively. Vacuum and add tris(dibenzylideneacetone)dipalladium) (0.53 g, 0.57 mmol) under nitrogen protection. Keep the reaction at 109°C for 16 h under anaerobic conditions. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract it with ethyl acetate (25 mL) three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Column chromatography (petroleum ether:ethyl acetate=30:1) was used to separate and purify 2b (0.48 g, 26.93 mmol, brown solid, yield 60.61%), which was directly used for the next step.

[0131] Step 2: Preparation of 5-(Benzylthio)-3,4-dihydronaphthalen-1(2H)-one (2c)

[0132] Take 5-mercapto-3,4-dihydronaphthalen-1(2H)-one 2b (94 mg, 5.27 mmol) and dissolve it in tetrahydrofuran. Add sodium hydrogen sulfide (147.65 mg, 61.5 mmol) in batches under stirring at 0°C in an ice bath. After stirring for 15 min, add benzyl bromide (90 mg, 5.26 mmol) dropwise, and transfer to 85°C for reflux reaction for 4 h. After the reaction is complete, the reaction solution is cooled to room temperature, poured into water, extracted with ethyl acetate (15 mL) three times, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 15:1) is used to separate and purify 2c (80 mg, 4.46 mmol, yellow solid, yield 84.62%), which is directly used for the next step.

[0133] Step 3: Preparation of 5-(Benzylthio)-1,2,3,4-tetrahydronaphthalene-1-amine (2d)

[0134] Take 2c (0.30 g, 16.73 mmol) and dissolve it in a mixed solution of isopropanol and methanol (1:1). Add sodium cyanoborohydride (0.52 g, 83.66 mmol) and ammonium acetate (2.58 g, 334.6 mmol) in batches under stirring in an ice bath at 0°C, evacuate, stir at 25°C for 1.5 h under nitrogen protection, and then move the reaction bottle to 90°C for 8 h. After the reaction, cool the reaction solution to room temperature, pour it into water, extract it with ethyl acetate (15 mL) three times, combine the organic phases, wash with saturated brine, dry it over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 2d, which is directly used in the next step.

[0135] Step 4: Preparation of 5-(benzylthio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-30)

[0136] Take 2d (0.25g, 13.86mmol) and dissolve it in a mixed solvent of water and tetrahydrofuran (2:1), slowly drip sodium hydroxide solution (2mL) under stirring, and drip propargyl bromide (0.18g, 15.24mmol) after stirring for 10min, and move the reaction bottle to 60℃ reflux and stir for 8h. After the reaction is complete, the reaction solution is cooled to room temperature, poured into water, extracted with ethyl acetate (15mL) 3 times, and the organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 25:1) is used to separate and purify the target product 2e (0.19g, 6.18mmol, light yellow oil, yield 44.62%). The purified product is dissolved in toluene, and dry HCL gas is passed through to prepare hydrochloride, and 96mg white crystals (I-30) are obtained, with a yield of 17%. 1 HNMR (600 MHz, DMSO-d 6)δ7.42-7.38(m,3H),7.36(d,J=7.7Hz,1H),7.32(t,J=7.6Hz,2H),7.27-7.22(m,2H),4.47(d,J=4.5Hz,1H),4.26(s,2H),3.95-3 .82(m,2H),3.76(d,J=2.6Hz,1H),2.75-2.67(m,1H),2.55-2.51(m,1H),2.23-2.16(m,1H),2.03-1.87(m,2H),1.83-1.75(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ137.47,137.37,136.22,131.22,129.38,128.93,127.67,127.51,127.30,126. 65,80.19,75.58,54.21,36.06,33.95,26.29,24.02,17.40.HRMS(ESI):m / z[M+Na] + Calculate for C 20 H 21 NNaS:330.1296; Found:330.1292.

[0137] Example 31: Preparation of N-(prop-2-yn-1-yl)-5-((3-(trifluoromethyl)benzyl)thio)-1,2,3,4-tetrahydronaphthalene-1-amine (I-31)

[0138]

[0139] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 3-trifluoromethylbenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 50 mg of light yellow solid (I-31) is obtained. The yield is 16%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.72(d,J=1.9Hz,1H),7.72-7.67(m,1H),7.63-7.58(m,1H),7.55(t,J=7.7Hz,1H),7.42-7.34(m,2H),7.24(t,J=7.7Hz,1 H),4.47(d,J=5.4Hz,1H),4.36(s,2H),3.96-3.82(m,2H),3.76(t,J=2.5Hz,1H),2.77-2.69(m,1H),2.56-2.51(m,1H),2.22 -2.14(m,1H),2.01-1.86(m,2H),1.81-1.73(m,1H).13 C NMR (151 MHz, DMSO-d 6 )δ139.32,136.82,136.58,133.48,131.36,130.00,128.11,127.99,126.68,125.89,125. 87,124.36,80.20,75.56,54.25,35.48,33.97,26.40,24.01,17.40.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 21 F 3 NS:412.1120;Found:412.1114.

[0140] Example 32: Preparation of 5-((4-methoxybenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-32)

[0141]

[0142] The specific preparation method is as follows:

[0143] Step 1: Preparation of 5-((4-methoxybenzyl)thio)-3,4-dihydronaphthalen-1(2H)-one

[0144] 5-Bromo-3,4-dihydronaphthalene-1(2H)-one 2a (40 mg, 1.77 mmol) was dissolved in 1,4-dioxane, (4-methoxyphenyl) methyl mercaptan (35.6 mg, 2.30 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethoxanthene (20.56 mg, 0.44 mmol) were added respectively, and the mixture was evacuated. Cesium carbonate (43.14 mg, 1.32 mmol) and tris(dibenzylideneacetone)dipalladium (20.2 mg, 0.22 mmol) were added under nitrogen protection, and the mixture was reacted at 109°C for 16 h under anaerobic conditions. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, extracted three times with ethyl acetate (25 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 40:1) was used for separation and purification to obtain 5-((4-methoxybenzyl)thio)-3,4-dihydronaphthalen-1(2H)-one (30 mg, 1.01 mmol, light yellow solid, yield 56.60%), which was directly used for the next step.

[0145] Step 2: The subsequent steps were consistent with Example 30, with the same conditions. After separation and purification by column chromatography and salification, 0.2 g of white solid (I-32) was obtained with a yield of 18%. 1H NMR(600MHz,Chloroform-d)δ7.45(d,J=7.4Hz,1H),7.24(t,J=8.7Hz,4H),7.17(t,J=7.6Hz,1H),6.85-6.80(m,2H),4.59(s,1H),4.04(s,2H ),3.78(s,3H),3.63(s,2H),2.94-2.86(m,1H),2.65-2.57(m,1H),2.56(s,1H),2.29(d,J=13.7Hz,1H),2.18(s,1H),2.01(d,J=13.3Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ158.92,138.11,137.49,130.04,129.52,128.55,128.49,127.63,12 6.51,114.03,78.27,73.53,55.31,54.14,37.24,33.39,26.18,24.55,17.94.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 24 NOS:338.1578; Found:338.1579.

[0146] Example 33: Preparation of 5-((4-methylbenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-33)

[0147]

[0148] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 4-methylbenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 66 mg of a gray solid (I-33) is obtained. The yield is 15%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.37(t,J=6.9Hz,2H),7.30-7.26(m,2H),7.23(t,J=7.7Hz,1H),7.12(d,J=7.8Hz,2H),4.47(p,J=4.8Hz,1H),4.21(s,2H),3.95-3.80( m,2H),3.76(t,J=2.5Hz,1H),2.73-2.67(m,1H),2.57-2.46(m,2H),2.26(s,3H),2.23-2.17(m,1H),2.05-1.85(m,2H),1.82-1.75(m,1H). 13C NMR (151 MHz, DMSO-d 6 )δ137.61,136.84,136.16,134.19,131.17,129.49,129.28,127.43,127.20,126.62, 80.20,75.55,54.17,35.82,33.90,26.27,24.02,21.16,17.43.HRMS(ESI):m / z[M+Na] + Calculate for C 21 H 23 NSNa:344.1450; Found:344.1449.

[0149] Example 34: Preparation of 5-((4-bromobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-34)

[0150]

[0151] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 4-bromobenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 40 mg of a white solid (I-34) is obtained. The yield is 16%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.53-7.48(m,2H),7.38-7.33(m,4H),7.23(t,J=7.7Hz,1H),4.47(p,J=4.9Hz,1H),4.24(s,2H),3.96-3.88(m,1H ),3.88-3.79(m,2H),2.75-2.67(m,1H),2.56-2.50(m,1H),2.22-2.15(m,1H),2.03-1.87(m,2H),1.83-1.75(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ137.11,136.91,136.50,131.79,131.53,131.28,127.74,127.65,126.66,120. 72,80.22,75.54,54.21,35.27,33.95,26.34,24.00,17.41.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 BrNS:386.0585; Found:386.0578.

[0152] Example 35: Preparation of 5-((4-chlorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-35)

[0153]

[0154] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 4-chlorobenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 53 mg of a white solid (I-35) is obtained. The yield is 19%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.44-7.39(m,2H),7.39-7.33(m,4H),7.24(t,J=7.7Hz,1H),4.47(s,1H),4.26(s,2H),3.96-3.89(m,1H),3.89-3.82(m, 1H), 3.76 (t, J = 2.5Hz, 1H), 2.75-2.68 (m, 1H), 2.56-2.52 (m, 1H), 2.22-2.15 (m, 1H), 2.03-1.87 (m, 2H), 1.83-1.76 (m, 1H). 13 C NMR (151 MHz, DMSO-d 6 )δ136.94,136.68,136.49,132.21,131.29,131.18,128.87,127.74,127.65,126. 67,80.21,75.55,54.22,35.22,33.96,26.34,24.00,17.41.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 ClNS:342.1088; Found:342.1083.

[0155] Example 36: Preparation of 5-((4-methylphenethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-36)

[0156]

[0157] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 1-(2-bromoethyl)-4-methylbenzene. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 90 mg of a white solid (I-36) is obtained. The yield is 17%. 1H NMR(600MHz,Chloroform-d)δ7.44(d,J=7.5Hz,1H),7.25 -7.23(m,J=7.4Hz,1H),7.21(d,J=7.6Hz,1H),7.11(s,4H),4.64-4.56(m,1H),3.69-3.58(m,3H),3.18-3.07(m,2H),2.96-2.87( m,3H),2.66-2.59(m,1H),2.56(q,J=2.9,2.2Hz,1H),2.32(s,4H),2.27-2.17(m,1H),2.07-1.97(m,1H),1.86(d,J=14.5Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ138.03,137.15,136.99,136.10,129.60,129.25,128.38,127.25,127.2 0,126.47,78.25,73.51,54.11,34.74,33.98,33.37,26.15,24.50,21.06,17.89.HRMS(ESI):m / z[M+H] + Calculate for C 22 H 26 NS:336.1789;Found:336.1786.

[0158] Example 37: Preparation of 5-((3-chlorophenethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-37)

[0159]

[0160] The operation is the same as that of Example 30, except that benzyl bromide is replaced by 1-(2-bromoethyl)-3-chlorobenzene. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 72 mg of a white solid (I-37) is obtained. The yield is 12%. 1 H NMR (600 MHz, DMSO-d 6)δ7.43-7.40(m,1H),7.40-7.35(m,2H),7.36-7.25(m,3H),7.26-7.23(m,1H),4.48(s,1H),3.97-3.83(m,2H),3.77(t,J=2.5Hz,1H) ,3.32-3.21(m,2H),2.91(t,J=7.6Hz,2H),2.71-2.65(m,1H),2.53(s,1H),2.24-2.17(m,1H),2.05-1.89(m,2H),1.85-1.77(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ142.94,137.16,136.41,133.42,131.28,130.62,128.92,127.88,127.39,127.02,126.82, 126.79,80.22,75.57,54.25,34.26,33.96,32.48,26.40,24.02,17.40.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 23 ClNS:356.1243; Found:356.1240.

[0161] Example 38: Preparation of 5-((3-fluorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-38)

[0162]

[0163] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 3-fluorobenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 40 mg of a white solid (I-38) is obtained. The yield is 9%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.39-7.32(m,3H),7.26-7.21(m,3H),7.11-7.04(m,1H),4.50-4.44(m,1H),4.28(s,2H),3.95-3.82(m,2H),3.7 6(t,J=2.5Hz,1H),2.77-2.69(m,1H),2.58-2.51(m,1H),2.23-2.15(m,1H),2.04-1.87(m,2H),1.83-1.73(m,1H). 13 C NMR (151 MHz, DMSO-d 6)δ136.89,136.49,131.29,130.86,127.76,127.57,126.66,125.47,116.11,115.97,114. 55,114.41,80.20,75.55,54.20,35.40,33.93,26.33,24.00,17.41.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 FNS:326.1378; Found:326.1379.

[0164] Example 39: Preparation of 5-((4-fluorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-39)

[0165]

[0166] The operation was the same as in Example 30, except that benzyl bromide was replaced by 4-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 60 mg of a white solid (I-39) was obtained. The yield was 19%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.46-7.39(m,2H),7.39-7.35(m,2H),7.26-7.22(m,1H),7.19-7.10(m,2H),4.47(t,J=4.9Hz,1H),4.25(s,2H),3.96-3.81 (m,2H),3.76(t,J=2.5Hz,1H),2.74-2.68(m,1H),2.55-2.52(m,1H),2.23-2.15(m,1H),2.03-1.87(m,2H),1.82-1.76(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ137.16,136.43,133.67,131.34,131.28,127.67,127.58,126.66,115.77,115. 63,80.21,75.55,54.21,35.22,33.95,26.32,24.01,17.41.HRMS(ESI):m / z[M+H] + Calculate for C 20 H 21 FNS:326.1381; Found:326.1379.

[0167] Example 40: Preparation of 5-((3-fluorophenethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalene-1-amine (I-40)

[0168]

[0169] The operation was the same as in Example 30, except that benzyl bromide was replaced with 1-(2-bromoethyl)-3-fluorobenzene. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 40 mg of a white solid (I-40) was obtained. The yield was 21%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.43-7.39(m,1H),7.39-7.32(m,2H),7.29(t,J=7.7Hz,1H),7.18-7.14(m,1H ),7.14-7.10(m,1H),7.07-7.02(m,1H),4.48(t,J=4.3Hz,1H),3.96-3.83(m,2H) ,3.77(t,J=2.5Hz,1H),3.31-3.23(m,2H),2.93(t,J=7.6Hz,2H),2.72-2.66(m, 1H),2.54-2.51(m,1H),2.23-2.17(m,1H),2.04-1.89(m,2H),1.83-1.76(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ137.19,136.40,131.30,130.67,127.38,126.96,126.80,125.24,125.23,115.84,115.71,113 .68,113.54,80.20,75.58,54.23,34.37,33.96,32.47,26.39,24.02,17.40.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 23 FNS:340.1540; Found:340.1535.

[0170] Example 41: Preparation of N-(prop-2-yn-1-yl)-5-((4-(trifluoromethyl)benzyl)thio)-1,2,3,4-tetrahydronaphthalen-1-amine (I-41)

[0171]

[0172] The operation is the same as that in Example 30, except that benzyl bromide is replaced by 4-trifluoromethylbenzyl bromide. The other conditions remain unchanged. After separation and purification by column chromatography and salt formation, 20 mg of a white solid (I-41) is obtained. The yield is 4%. 1 H NMR (600 MHz, DMSO-d 6 )δ7.78(d,J=8.1Hz,2H),7.69(d,J=8.0Hz,2H),7.25(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),7.07(d,J=8.1Hz,1H),5.26(s,2H),4.47(t,J=4.2H z,1H),3.97-3.83(m,2H),3.76(t,J=2.5Hz,1H),2.83-2.77(m,1H),2.6 5-2.58(m,1H),2.22-2.16(m,1H),2.03-1.90(m,2H),1.83-1.77(m,1H). 13 C NMR (151 MHz, DMSO-d 6 )δ156.13,142.55,128.15,127.64,127.00,125.90,125.87,125.84,125.82,122.64, 112.33,80.18,75.63,68.82,53.89,34.00,24.24,22.72,17.09.HRMS(ESI):m / z[M+H] + Calculate for C 21 H 21 F 3 NS:376.1351;Found:376.134.

[0173] The beneficial effects of the present invention are demonstrated by specific experimental examples below.

[0174] Experimental Example 1 MAO Inhibitory Activity Test: The inhibitory activity of the above-obtained compounds on MAO-A and MAO-B was determined as follows:

[0175] In a 96-well black plate, test compound solution (10 μL at different concentrations) and MAO-A or MAO-B solution (30 μL, 12.5 μg / mL in PBS) were added. The black plate was then incubated at 37°C for 30 min. After incubation, 10 μL of kynurenamine PBS solution (MAO-A: 224 μM; MAO-B: 50 μM) was added and incubated at 37°C for another 30 min. Then, 40 μL of sodium hydroxide aqueous solution (2 mol / L) and 100 μL of water were added to terminate the reaction, and fluorescence was measured at 310 nm and 400 nm excitation and emission wavelengths on the multifunctional enzyme label, and the fluorescence was measured by 100-(IF i -IF 0 ) / (IF c -IF 0 )*100 to calculate the inhibition rate. When the concentration was 10 μM and the inhibition rate was >50%, the half inhibition concentration was further determined. The experimental results are shown in Table 1.

[0176] Table 1 Inhibitory activity of the compounds of the present invention on MAO-A and MAO-B a

[0177]

[0178]

[0179] Note: “a” refers to the average of three independent experiments.

[0180] As shown in Table 1, the inhibition level of all compounds can reach the μM level, and some can reach the nM level. Among them, the compounds chemically modified at position 6 have the most significant effect on MAO-B, far exceeding the positive control rasagiline and comparable to safinamide. Therefore, this type of compound can be used as a selective inhibitor of MAO-B.

Claims

1. A compound as shown in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. in, R4 is H, R1-R3 are selected from hydrogen, halogen, hydroxyl, nitro, amino, formula II; n is an integer selected from 1 to 2, and the symbol in brackets Represents CH2; Y is selected from O or S; X1, X2 are selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, nitrile; The acid for forming the salt is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and the like.

2. A method for preparing a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: (1) firstly synthesizing a compound containing a tetralone structure by a coupling reaction, and then obtaining the target compound by a reduction reaction and an amino substitution reaction; (2) The reduction reaction is to reduce the ketone to an amino group using sodium cyanoborohydride and ammonium acetate, and then to replace the hydrogen on the amino group with propargyl bromide to further obtain a compound.

3. According to claim 2, the compound of formula I, the acceptable salt can be synthesized by general chemical methods.

4. According to claim 3, in general, for example, the preparation of the salt can be carried out by dissolving the synthesized compound in toluene, and passing dry hydrochloric acid gas therein, and crystallizing to obtain the hydrochloride product.

5. The compound containing a tetralin-1-amine structure according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound is selected from the following compounds:

6. Use of the tetralin-1-amine structure-containing compound according to claims 1-5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a selective monoamine oxidase B (MAO-B) inhibitor, wherein the MAO-B inhibitor can be used to treat MAO-B-mediated neurodegenerative diseases, wherein the MAO-B-mediated neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, schizophrenia, depression and the like.

7. Use of the compound containing tetralin-1-amine structure according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for treating diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia, depression, etc.

8. A pharmaceutical composition, characterized in that: The drug combination is an injection, tablet, capsule, powder, granule, suspension or oral solution prepared with the tetralin-1-amine compound, or a pharmaceutically acceptable salt or a stereoisomer thereof as claimed in any one of claims 1 to 5 as an active ingredient and a pharmaceutically acceptable carrier.

Images