Preparation and use of a novel MAO-B inhibitor containing tetrahydronaphthalen-1-amine structure

Abstract

This invention provides a novel MAO-B inhibitor containing a tetrahydronaphthalene-1-amine structure, its preparation and uses, belonging to the pharmaceutical field. The derivative is a compound represented by Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The compound of this invention can be used to inhibit monoamine oxidase (MAO), particularly selectively inhibiting MAO-B; it has promising applications in the treatment of Parkinson's disease, Alzheimer's disease, mood disorders, and other diseases.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and mainly relates to the preparation of compounds containing tetrahydronaphthalene-1-amine structures and their use as selective monoamine oxidase B (MAO-B) inhibitors. Background Technology

[0002] Parkinson's disease (PD) is a common neurodegenerative disease. With an aging population and increased life expectancy, the disease burden is gradually increasing. According to 2016 statistics, the number of Parkinson's patients worldwide reached 6 million, and this number is doubling. Its prevalence, disability rate, and mortality rate are the fastest growing among neurological diseases. In fact, my country, the world's most populous country, has more than 3 million Parkinson's patients. It is projected that by 2030, the number of patients in my country will reach 5 million, with an incidence rate of 1.7% among people aged 65 and above.

[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 circuit. This loss of dopaminergic neurons and the resulting defects in dopamine transmission ultimately result in 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 via MAO-B, generating a large number of oxygen free radicals that damage neurons during its metabolism.

[0004] Monoamine oxidase (MAO) is a flavin adenine dinucleotide enzyme primarily located on the outer membrane of mitochondria in cells of tissues such as the brain, liver, and intestinal mucosa. MAO catalyzes the deamination reaction of endogenous or exogenous monoamines, producing hydrogen peroxide, ammonia, and aldehydes, thereby rendering the monoamines physiologically inactive. Unnecessary MAO activity can cause neurodemethylation trauma and mitochondrial damage. This enzyme has two subtypes: MAO-A and MAO-B. MAO-B is a complex enzyme of the mitochondrial membrane that plays a crucial role in dopamine metabolism. MAO-B breaks down dopamine into homovanillic acid, simultaneously generating the free radical hydrogen peroxide (H₂O₂), which has a toxic effect on nerve cells, leading to accelerated neuronal damage and death. Therefore, inhibiting MAO-B activity can prevent dopamine degradation, increase the concentration of dopamine in the brain, inhibit the peroxides produced in dopamine oxidation metabolism, reduce the generation of oxygen free radicals, and improve the symptoms of Parkinson's disease. It can also block the conversion of MPTP to MPP. + It slows down the process of substantia nigra cell death and alters the progression of PD in patients.

[0005] The non-selectivity and irreversibility of some marketed drugs (such as phenylpropanidine and selegiline) can lead to many serious adverse reactions, such as orthostatic hypotension, hypertensive crisis, caseous reaction, and liver toxicity. To overcome these adverse reactions, designing and screening highly effective and low-toxicity MAO-B inhibitors remains a hot research topic for alleviating PD symptoms and improving the health and quality of life of PD patients. Summary of the Invention

[0006] The purpose of this invention is to provide an inhibitor with good inhibitory effect and high selectivity against MAO-B, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as well as its synthesis method and uses.

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

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

[0009]

[0010] in,

[0011] R4 is H, and R1-R3 are selected from hydrogen, halogen, hydroxyl, nitro, amino, and formula II;

[0012]

[0013] n is an integer selected from 1 to 2, and the symbol “∧” in the parentheses represents CH2;

[0014] Y is selected from O or S;

[0015] X1 and X2 are selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, and nitrile.

[0016] The acids that form salts are selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etc.

[0017] Specifically, compounds having a tetrahydronaphthalene-1-amine structure as shown in Formula I, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, are specifically selected from the following compounds:

[0018]

[0019]

[0020] This invention also provides a method for synthesizing tetrahydronaphthalene-1-amine structures, as shown below:

[0021]

[0022] The method first uses a coupling reaction to synthesize compounds containing tetrahydronaphthalene-1-amine structures, and then obtains the target compound through a reduction reaction and an amino substitution reaction.

[0023] The reduction reaction involves using sodium cyanoborohydride and ammonium acetate to reduce the ketone to an amino group, followed by replacing the hydrogen atom on the amino group with bromopropyne to further obtain the compound.

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

[0025] Generally, salts are prepared by dissolving the synthesized compound in toluene and passing dry hydrochloric acid gas into it, followed by crystallization to obtain the hydrochloride product.

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

[0027] The present invention also provides the use of the tetrahydronaphthyl-1-amine compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for the treatment of diseases such as Alzheimer's disease, Parkinson's disease, schizophrenia, and depression.

[0028] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises an injection, tablet, capsule, powder, granule, suspension or oral liquid prepared by using a tetrahydronaphthyl-1-amine compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as the active ingredient, and a pharmaceutically acceptable carrier. Attached Figure Description

[0029] Figure 1 is a schematic diagram of the general structure of this invention patent. Detailed Implementation

[0030] Unless otherwise stated, the raw materials and equipment used in the specific embodiments of this invention are all known products and are commercially available. The invention will now be further described in detail with reference to embodiments, but is not limited to these embodiments.

[0031] 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 an Agilent Technologies VNMRS600 NMR spectrometer, with shift units in parts per million (ppm). The solvents used were deuterated chloroform (CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an ACQUITY UPLC LCT Premier XE (ESI) mass spectrometer.

[0032] Example 1: Preparation of 5-(benzyloxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-1)

[0033]

[0034] The specific preparation method is as follows:

[0035] Step 1: Preparation of 5-(benzyloxy)-3,4-dihydronaphthyl-1(2H)-one (1b)

[0036] Dissolve 0.5 g (30.82 mmol) of 5-hydroxy-1-tetrahydronaphthone 1a in acetone, add potassium carbonate (0.51 g, 36.90 mmol), and dropwise add benzyl bromide (0.58 g, 33.91 mmol). Refrigerate at 85 °C for 5 h with stirring. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, and extract three times with ethyl acetate (15 mL). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. Separate and purify by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 1b (0.64 g, 25.36 mmol, white solid, yield 82.28%), which is directly added to the next step.

[0037] Step 2: Preparation of 5-(benzyloxy)-1,2,3,4-tetrahydronaphthyl-1-amine (1c)

[0038] Compound 1b (0.32 g, 12.68 mmol) was dissolved in a 1:1 mixture of isopropanol and methanol. Sodium cyanoborohydride (0.398 g, 63.33 mmol) and ammonium acetate (0.98 g, 127.14 mmol) were added in portions under stirring in an ice bath at 0 °C. The mixture was stirred at 25 °C for 1.5 h under vacuum and nitrogen protection. The reaction flask was then transferred to 90 °C and reacted for 8 h. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and extracted three times with ethyl acetate (15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and directly added to the next step.

[0039] Step 3: Preparation of 5-(benzyloxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-1)

[0040] Compound 1c (0.3 g, 11.84 mmol) was dissolved in a mixed solvent of water and tetrahydrofuran (2:1). Sodium hydroxide solution (1.5 mL) was slowly added dropwise with stirring. After stirring for 10 min, bromopropyne (0.155 g, 13.03 mmol) was added dropwise. The reaction flask was then refluxed at 60 °C for 8 h with stirring. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and extracted three times with ethyl acetate (15 mL). The combined organic phases were 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, pale yellow oil, yield 34.8%). The purified product was dissolved in toluene, and dry HCl gas was passed through to prepare hydrochloride, yielding 57 mg of white crystals (I-1), yield 15%. 1 H NMR(600MHz,DMSO-d6)δ7.48-7.43(m,2H),7.43-7.37(m,2H),7.36-7.29(m,1H ),7.24(t,J=7.9Hz,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,1 H),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(151MHz,DMSO-d6)δ156.42,137.64,131.73,128.95,128.25,127.76,127.63,126.95,12 2.40,112.35,80.21,75.58,69.68,53.90,33.97,24.24,22.76,17.11.HRMS(ESI):m / z[M+Na] + calcd forC 20 H 21 NONa:314.1523; Found:314.1521.

[0041] Example 2: Preparation of 5-((3-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-2)

[0042]

[0043] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 3-fluorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 87 mg of white crystals (I-2) were obtained, with a yield of 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] + calcd for C 20 H 20 FNONa:334.1423; Found:334.1427.

[0044] Example 3: Preparation of 5-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-3)

[0045]

[0046] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 4-bromobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 80 mg of white crystals (I-3) were obtained, with a yield of 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(151MHz,DMSO-d6)δ156.22,137.12,131.88,131.78,129.89,127.64,126.96,122.54,12 1.34,112.37,80.21,75.58,68.91,53.87,33.96,24.22,22.73,17.11.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 NOBr:370.0809; Found:370.0807.

[0047] Example 4: Preparation of 5-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-4)

[0048]

[0049] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 4-fluorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 75 mg of pale yellow solid (I-4) was obtained, with a yield of 13%. 1 H NMR(600MHz,DMSO-d6)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). 13C NMR(151MHz,DMSO-d6)δ156.33,133.86,131.77,130.00,129.94,127.65,126.95,122.47,115.84 ,115.70,112.37,80.19,75.59,69.01,53.90,33.97,24.25,22.74,17.12.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 20 NONaF:332.1432; Found:332.1427.

[0050] Example 5: Preparation of N-(prop-2-yn-1-yl)-5-((3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydronaphthyl-1-amine (I-5)

[0051]

[0052] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 3-trifluoromethylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.5 g of white solid (I-5) was obtained, with a yield of 35%. 1 H NMR (600MHz, DMSO-d6) δ7.82(s,1H),7.78(d,J=7.6Hz,1H),7.70(d,J=7.8Hz,1H),7. 65(t,J=7.7Hz,1H),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),2.80-2.7 4(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(151MHz,DMSO-d6)δ156.20,139.20,131.84,131.75,130.13,127.65,127.01,125.00,124.16,124.1 3,122.68,112.36,80.21,75.57,68.87,66.83,53.87,33.96,24.22,22.69,17.12.HRMS(ESI):m / z[M+H] + calcd forC 21 H21 NOF3:360.1582; ​​Found:360.1575.

[0053] Example 6: Preparation of 5-((4-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-6)

[0054]

[0055] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 4-chlorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.24 g of white solid (I-6) was obtained, with a yield of 22%. 1 H 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.

[0056] HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 NOCl:326.1313; Found:326.1312.

[0057] Example 7: Preparation of 5-((4-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-7)

[0058]

[0059] The procedure was the same as in Example 1, except that benzyl bromide was replaced with 4-methylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.26 g of white solid (I-7) was obtained, with a yield of 25%.1 H NMR(600MHz,DMSO-d6)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(151MHz,DMSO-d6)δ156.45,137.50,134.58,131.69,129.49,127.90,127.61,126.92,122.3 3,112.35,80.20,75.58,69.63,53.88,33.95,24.24,22.76,21.25,17.12.HRMS(ESI):m / z[M+Na] + calcd for C 21 H 23 NONa:328.1682; Found:326.1677.

[0060] Example 8: Preparation of 5-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-8)

[0061]

[0062] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 4-nitrobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.14 g of white solid (I-8) was obtained, with a yield of 14%. 1H NMR (600MHz, DMSO-d6) 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,1 H),3.97-3.89(m,1H),3.88-3.81(m,1H),3.76(t,J=2.5Hz,1H),2.85-3.78(m,1 H),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(151MHz,DMSO-d6)δ156.01,147.47,145.57,131.94,128.41,127.70,126.99,124.13,122.7 8,112.35,80.19,75.61,68.57,53.85,53.83,33.97,24.24,22.72,17.14.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 N2O3:337.1560; Found:337.1552.

[0063] Example 9: Preparation of 5-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-9)

[0064]

[0065] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 3,4-difluorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.28 g of white solid (I-9) was obtained, with a yield of 32%. 1H NMR(600MHz,DMSO-d6)δ7.55-7.50(m,1H),7.49-7.44(m,1H),7.35-7.30(m,1H), 7.24(t,J=7.9Hz,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(151MHz,DMSO-d6)δ156.11,131.83,127.69,126.96,122.64,118.13,118.01,116.91,116.79,1 12.33,80.20,75.58,68.40,53.89,53.87,33.97,33.96,24.23,22.70,17.12.HRMS(ESI):m / z[M+H] + calcd for C 20 H 20 NOF2:328.1516; Found:328.1513.

[0066] Example 10: Preparation of N-(prop-2-yn-1-yl)-5-((4-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydronaphthyl-1-amine (I-10)

[0067]

[0068] The procedure was the same as in Example 1, except that benzyl bromo was replaced with 4-trifluoromethylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.1 g of white solid (I-10) was obtained, with a yield of 10%. 1H NMR(600MHz,DMSO-d6)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=4.2Hz,1H),3.97-3.83(m,2H),3.76(t,J=2.5Hz,1H),2.83-2.77(m,1H) ,2.65-2.58(m,1H),2.22-2.16(m,1H),2.03-1.90(m,2H),1.83-1.77(m,1H). 13 C NMR(151MHz,DMSO-d6)δ156.13,142.55,128.15,127.64,127.00,125.90,125.87,125.84,125.8 2,122.64,112.33,80.18,75.63,68.82,53.89,34.00,24.24,22.72,17.09.HRMS(ESI):m / z[M+H] + calcd for C 21 H 21 NOF3:360.1578; Found:360.1575.

[0069] Example 11: Preparation of 5-((3-iodobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-11)

[0070]

[0071] The procedure was the same as in Example 1, except that benzyl bromo ... 1H NMR (600MHz, DMSO-d6) 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),5.1 2(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(151MHz,DMSO-d6)δ156.21,140.33,136.94,136.20,131.80,131.20,127.61,127.08,126.98,1 22.58,112.34,95.38,80.22,75.58,68.67,53.87,33.96,24.21,22.72,17.10.HRMS(ESI):m / z[M+H] + calcd forC 20 H 21 INO:416.0671; Found:416.0668.

[0072] Example 12: Preparation of 6-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-12)

[0073]

[0074] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-bromobenzyl bromide. All other conditions remained the same. After separation and purification by column chromatography and salt formation, 0.14 g of white solid (I-12) was obtained, with a yield of 9%. 1HNMR(600MHz,DMSO-d6)δ7.61-7.56(m,2H),7.45(d,J=8.6Hz,1H),7.42-7.37(m,2 H),6.90(dd,J=8.6,2.7Hz,1H),6.84(d,J=2.7Hz,1H),5.10(s,2H),4.42(t,J=5.1 Hz,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 (151MHz, DMSO-d6) 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] + calcd forC 20 H 20 NONaBr:392.0626; Found:392.0630.

[0075] Example 13: Preparation of 6-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-13)

[0076]

[0077] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 54 mg of white solid (I-13) was obtained, with a yield of 11%. 1H NMR(600MHz,DMSO-d6)δ7.48-7.41(m,3H),7.39(t,J=7.6Hz,2H),7.35-7.29(m,1 H),6.90(dd,J=8.6,2.7Hz,1H),6.85(d,J=2.7Hz,1H),5.11(s,2H),4.42(t,J=4.3 Hz,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(151MHz,DMSO-d6)δ158.92,140.54,137.43,131.82,128.93,128.32,128.08,122.98,11 5.33,113.43,80.09,75.68,69.57,53.62,33.82,28.84,24.89,17.86.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 21 NONa:314.1521; Found:314.1524.

[0078] Example 14: Preparation of 4-(((5-(prop-2-yn-1-ylamino)-5,6,7,8-tetrahydronaphth-2-yl)oxy)methyl)benzonitrile (I-14)

[0079]

[0080] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-cyanobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 32 mg of white solid (I-14) was obtained, with a yield of 6%. 1H NMR (600MHz, DMSO-d6) δ7.89-7.85(m,2H),7.63(d,J=8.0Hz,2H),7.47(d,J=8.6 Hz,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(151MHz,DMSO-d6)δ158.54,143.31,140.66,132.92,131.92,128.44,123.28,119.22,115.37 ,113.39,110.94,80.13,75.62,68.59,53.61,33.83,28.83,24.83,17.82.HRMS(ESI):m / z[M+Na] + calcd forC 21 H 20 N2ONa:339.1473; Found:339.1479.

[0081] Example 15: Preparation of 6-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-15)

[0082]

[0083] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3-chlorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.11 g of white solid (I-15) was obtained, with a yield of 11%. 1HNMR(600MHz,DMSO-d6)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=4.8 Hz,1H),3.95-3.87(m,1H),3.87-3.79(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.7 7(m,1H),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(151MHz,DMSO-d6)δ158.66,140.61,140.06,133.58,131.88,130.88,128.24,127.68,126.57,12 3.15,115.37,113.39,80.12,75.63,68.61,53.60,33.81,28.83,24.84,17.85.HRMS(ESI):m / z[M+Na] + calcd forC 20 H 20 NONaCl:348.1131; Found:348.1132.

[0084] Example 16: Preparation of 6-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-16)

[0085]

[0086] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-chlorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.12 g of white solid (I-16) was obtained, with a yield of 17%. 1HNMR(600MHz,DMSO-d6)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 ),3.87-3.80(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(151MHz,DMSO-d6)δ158.73,140.58,136.51,132.87,131.85,129.88,128.93,123.07,11 5.36,113.43,80.13,75.63,68.71,53.63,33.82,28.83,24.85,17.84.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 20 NONaCl:348.1131; Found:348.1126.

[0087] Example 17: Preparation of 6-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-17)

[0088]

[0089] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3,4-difluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.36 g of white solid (I-17) was obtained, with a yield of 36%. 1HNMR(600MHz,DMSO-d6)δ7.54-7.50(m,1H),7.50-7.42(m,2H),7.33-7.27(m,1H) ,6.92-6.88(m,1H),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(151MHz,DMSO-d6)δ158.61,140.61,131.87,124.96,124.94,123.18,118.10,117.99,117.23,11 7.11,115.36,113.40,80.13,75.63,68.25,53.60,33.81,28.83,24.85,17.85.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 19 NONaF2:350.1332; Found:350.1324.

[0090] Example 18: Preparation of 6-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-18)

[0091]

[0092] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-nitrobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 60 mg of white solid (I-18) was obtained, with a yield of 7%. 1H NMR(600MHz,DMSO-d6)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,1 H),3.94-3.88(m,1H),3.87-3.82(m,1H),3.75(t,J=2.5Hz,1H),2.83-2.76(m,1 H),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(151MHz,DMSO-d6)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] + calcd forC 20 H 21 N2O3:337.1552; Found:337.1547.

[0093] Example 19: Preparation of 6-((3-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-19)

[0094]

[0095] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 60 mg of white solid (I-19) was obtained, with a yield of 7%. 1H NMR(600MHz,DMSO-d6)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=4.3H z,1H),3.94-3.86(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(151MHz,DMSO-d6)δ158.68,140.60,131.87,131.01,130.95,123.91,123.89,123.16,115.36,11 5.13,114.67,113.40,80.10,75.65,68.69,53.58,33.80,28.84,24.86,17.86.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 20 NONaF:332.1427; Found:332.1429.

[0096] Example 20: Preparation of 6-((3-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-20)

[0097]

[0098] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3-methylbenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.115 g of white solid (I-20) was obtained, with a yield of 13%. 1HNMR(600MHz,DMSO-d6)δ7.46(d,J=8.6Hz,1H),7.30-7.23(m,2H),7.24-7.19(m,1H),7.1 6–7.11(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(151MHz,DMSO-d6)δ158.98,140.53,138.08,137.33,131.82,128.96,128.82,128.66,125.20,122.9 0,115.32,113.39,80.12,75.64,69.63,53.63,33.81,28.84,24.88,21.48,17.86.HRMS(ESI):m / z[M+Na] + calcd for C 21 H 23 NONa:328.1677; Found:328.1678.

[0099] Example 21: Preparation of 6-((4-methylbenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-21)

[0100]

[0101] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-methylbenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 60 mg of white solid (I-21) was obtained, with a yield of 8%. 1H NMR(600MHz,DMSO-d6)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,1 H),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(151MHz,DMSO-d6)δ158.95,140.51,137.55,134.38,131.80,129.46,128.19,122.85,115.3 4,113.42,80.11,75.63,69.48,53.59,33.78,28.84,24.88,21.25,17.88.HRMS(ESI):m / z[M+Na] + calcd for C 21 H 23 NONa:328.1677; Found:328.1680.

[0102] Example 22: Preparation of 6-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-22)

[0103]

[0104] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 6-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 53 mg of white solid (I-22) was obtained, with a yield of 9%. 1H NMR (600MHz, DMSO-d6) 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),3.9 3-3.87(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(151MHz,DMSO-d6)δ158.80,140.57,133.66,131.84,130.37,130.31,123.01,115.81,115.67 ,115.32,113.41,80.11,75.64,68.85,53.57,33.78,28.84,24.87,17.88.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 20 NONaF:332.1427; Found:332.1424.

[0105] Example 23: Preparation of 7-((3,4-difluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-23)

[0106]

[0107] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3,4-difluorobenzyl bromide. All other conditions remained the same. After separation and purification by column chromatography and salt formation, 86 mg of white solid (I-23) was obtained, with a yield of 9%. 1HNMR(600MHz,DMSO-d6)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(151MHz,DMSO-d6)δ156.39,131.58,131.16,131.05,129.37,128.68,118.09,117.98,117.25,117.1 4,116.74,115.94,80.14,75.57,68.47,54.32,40.41,33.88,27.83,24.68,18.46.HRMS(ESI):m / z[M+H] + calcd for C 20 H 20 NOF2:328.1513; Found:328.1514.

[0108] Example 24: Preparation of 7-((4-nitrobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-24)

[0109]

[0110] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-nitrobenzyl bromide. All other conditions remained the same. After separation and purification by column chromatography and salt formation, 85 mg of white solid (I-24) was obtained, with a yield of 8%. 1H NMR (600MHz, DMSO-d6) δ8.29-8.23(m,2H),7.76-7.70(m,2H),7.37(d,J=2.7 Hz,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(151MHz,DMSO-d6)δ156.26,147.46,145.51,131.65,131.34,131.10,128.68,124.10,11 6.75,116.00,80.13,75.56,68.62,54.25,33.81,27.84,24.66,18.47.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 N2O3:337.1552; Found:337.1556.

[0111] Example 25: Preparation of 7-((3-chlorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-25)

[0112]

[0113] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 3-chlorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 75 mg of white solid (I-25) was obtained, with a yield of 7%. 1H NMR (600MHz, DMSO-d6) 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=4.6Hz,1H),3.89(q,J=16.8Hz,2H),3.75(t,J=2.5Hz,1H),2.77-2.70(m,1 H),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(151MHz,DMSO-d6)δ156.47,140.14,133.60,131.63,131.12,131.04,130.86,128.24,127.70,126.6 3,116.67,115.95,80.13,75.60,68.85,54.27,33.86,27.84,24.68,18.49.HRMS(ESI):m / z[M+Na]+calcd forC 20 H 20 NOClNa:348.1131; Found:348.1132.

[0114] Example 26: Preparation of 7-benzyloxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-26)

[0115]

[0116] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 78 mg of white solid (I-26) was obtained, with a yield of 10%. 1H NMR(600MHz,DMSO-d6)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,1 H),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(151MHz,DMSO-d6)δ156.73,137.49,131.56,130.98,130.89,128.91,128.33,128.17,11 6.75,115.85,80.13,75.62,69.80,54.26,33.86,27.84,24.69,18.51.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 21 NONa:314.1521; Found:314.1525.

[0117] Example 27: Preparation of 7-((4-fluorobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-27)

[0118]

[0119] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-fluorobenzyl bromide. The other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 0.155 g of white solid (I-27) was obtained, with a yield of 15%. 1HNMR(600MHz,DMSO-d6)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,1 H),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(151MHz,DMSO-d6)δ156.61,131.55,131.01,130.97,130.43,130.38,116.76,115.87,11 5.81,115.67,80.15,75.60,69.07,54.30,33.88,27.83,24.69,18.49.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 20 NONaF:332.1427; Found:332.1431.

[0120] Example 28: Preparation of 7-((4-bromobenzyl)oxy)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-28)

[0121]

[0122] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-bromobenzyl bromide. All other conditions remained the same. After separation and purification by column chromatography and salt formation, 0.1 g of white solid (I-28) was obtained, with a yield of 9%. 1 H NMR (600MHz, DMSO-d6) 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

[0123] -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(151MHz,DMSO-d6)δ156.50,136.99,131.85,131.03,130.25,121.42,116.75,115.9 1,80.15,75.59,68.97,54.30,40.41,33.88,27.83,24.68,18.48.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 NOBr:370.0807; Found:370.0804.

[0124] Example 29: Preparation of 4-(((8-(prop-2-yn-1-ylamino)-5,6,7,8-tetrahydronaphth-2-yl)oxy)methyl)benzonitrile (I-29)

[0125]

[0126] The procedure was the same as in Example 1, except that 5-hydroxy-tetrahydronaphthone was replaced with 7-hydroxy-tetrahydronaphthone, and benzyl bromide was replaced with 4-cyanobenzyl bromide. All other conditions remained the same. After separation and purification by column chromatography and salt formation, 60 mg of white solid (I-29) was obtained, with a yield of 6%. 1 H NMR (600MHz, DMSO-d6) 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). 13C NMR(151MHz,DMSO-d6)δ156.32,143.39,132.91,131.64,131.07,128.52,119.23,116.73,11 5.96,110.95,80.14,75.57,68.84,54.24,33.82,27.84,24.65,18.49.HRMS(ESI):m / z[M+Na] + calcd forC 21 H 20 N2ONa:339.1473; Found:339.1476.

[0127] Example 30: Preparation of 5-(benzylthio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-30)

[0128]

[0129] The specific preparation method is as follows:

[0130] Step 1: Preparation of 5-mercapto-3,4-dihydronaphthyl-1(2H)-one (2b)

[0131] 5-Bromo-3,4-dihydronaphthyl-1(2H)-one 2a (1 g, 44.43 mmol) was dissolved in 1,4-dioxane, and potassium thioacetate (1.52 g, 133.08 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethoxyxanthracene (0.51 g, 8.81 mmol) were added separately. Under vacuum and nitrogen protection, tris(dibenzylacetone)dipalladium (0.53 g, 0.57 mmol) was added, and the reaction was carried out 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, and extracted three times with ethyl acetate (25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated 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 added to the next step.

[0132] Step 2: Preparation of 5-(benzylthio)-3,4-dihydronaphthyl-1(2H)-one (2c)

[0133] Dissolve 94 mg (5.27 mmol) of 5-mercapto-3,4-dihydronaphthyl-1(2H)-one 2b in tetrahydrofuran. Add sodium hydride (147.65 mg, 61.5 mmol) in portions with stirring in an ice bath at 0°C. After stirring for 15 min, add benzyl bromide (90 mg, 5.26 mmol) dropwise. Transfer to 85°C and reflux for 4 h. After the reaction is complete, cool the reaction solution to room temperature, pour into water, and extract three times with ethyl acetate (15 mL). Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, and concentrate under reduced pressure. Separate and purify by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 2c (80 mg, 4.46 mmol, yellow solid, yield 84.62%), which is directly used in the next step.

[0134] Step 3: Preparation of 5-(benzylthio)-1,2,3,4-tetrahydronaphthyl-1-amine (2d)

[0135] Dissolve 2c (0.30 g, 16.73 mmol) in a 1:1 mixture of isopropanol and methanol. Add sodium cyanoborohydride (0.52 g, 83.66 mmol) and ammonium acetate (2.58 g, 334.6 mmol) in portions under stirring in an ice bath at 0 °C. The mixture is then stirred at 25 °C for 1.5 h under vacuum and nitrogen protection. The reaction flask is then transferred to 90 °C and reacted for 8 h. After the reaction is complete, the reaction solution is cooled to room temperature, poured into water, and extracted three times with ethyl acetate (15 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2d, which is directly added to the next step.

[0136] Step 4: Preparation of 5-(benzylthio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-30)

[0137] Dissolve 2d (0.25 g, 13.86 mmol) in a mixed solvent of water and tetrahydrofuran (2:1). Slowly add 2 mL of sodium hydroxide solution while stirring. After stirring for 10 min, add bromopropyne (0.18 g, 15.24 mmol). Transfer the reaction flask to 60 °C and reflux for 8 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, and extract three times with ethyl acetate (15 mL). Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Separate and purify by column chromatography (petroleum ether:ethyl acetate = 25:1) to obtain the target product 2e (0.19 g, 6.18 mmol, pale yellow oil, yield 44.62%). Dissolve the purified product in toluene, pass dry HCl gas through, and prepare hydrochloride to give 96 mg of white crystals (I-30), yield 17%. 1HNMR(600MHz,DMSO-d6)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,2 H),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(151MHz,DMSO-d6)δ137.47,137.37,136.22,131.22,129.38,128.93,127.67,127.51,12 7.30,126.65,80.19,75.58,54.21,36.06,33.95,26.29,24.02,17.40.HRMS(ESI):m / z[M+Na] + calcd for C 20 H 21 NNaS:330.1296; Found:330.1292.

[0138] Example 31: Preparation of N-(prop-2-yn-1-yl)-5-((3-(trifluoromethyl)benzyl)thio)-1,2,3,4-tetrahydronaphthyl-1-amine (I-31)

[0139]

[0140] The procedure was the same as in Example 30, except that benzyl bromide was replaced with 3-trifluoromethylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 50 mg of pale yellow solid (I-31) was obtained, with a yield of 16%. 1 H NMR (600MHz, DMSO-d6) 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,1H),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(151MHz,DMSO-d6)δ139.32,136.82,136.58,133.48,131.36,130.00,128.11,127.99,126.68,12 5.89,125.87,124.36,80.20,75.56,54.25,35.48,33.97,26.40,24.01,17.40.HRMS(ESI):m / z[M+H] + calcd for C 21 H 21 F3NS:412.1120; Found:412.1114.

[0141] Example 32: Preparation of 5-((4-methoxybenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-32)

[0142]

[0143] The specific preparation method is as follows:

[0144] Step 1: Preparation of 5-((4-methoxybenzyl)thio)-3,4-dihydronaphthyl-1(2H)-one

[0145] 5-Bromo-3,4-dihydronaphthyl-1(2H)-one 2a (40 mg, 1.77 mmol) was dissolved in 1,4-dioxane, and (4-methoxyphenyl)methanethiol (35.6 mg, 2.30 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethoxyxanthracene (20.56 mg, 0.44 mmol) were added under vacuum and nitrogen protection. Cesium carbonate (43.14 mg, 1.32 mmol) and tris(dibenzylacetone)dipalladium (20.2 mg, 0.22 mmol) were added, and the reaction was carried out 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, and extracted three times with ethyl acetate (25 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain 5-((4-methoxybenzyl)thio)-3,4-dihydronaphthyl-1(2H)-one (30 mg, 1.01 mmol, pale yellow solid, yield 56.60%), which was directly added to the next step.

[0146] Step 2: The subsequent steps are the same as in Example 30, with the conditions unchanged. After separation and purification by column chromatography and salt formation, 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] + calcd forC 21 H 24 NOS:338.1578; Found:338.1579.

[0147] Example 33: Preparation of 5-((4-methylbenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-33)

[0148]

[0149] The procedure was the same as in Example 30, except that benzyl bromide was replaced with 4-methylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 66 mg of gray solid (I-33) was obtained, with a yield of 15%. 1 H NMR (600MHz, DMSO-d6) 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(151MHz,DMSO-d6)δ137.61,136.84,136.16,134.19,131.17,129.49,129.28,127.43,127.2 0,126.62,80.20,75.55,54.17,35.82,33.90,26.27,24.02,21.16,17.43.HRMS(ESI):m / z[M+Na] + calcd for C 21 H 23 NSNa:344.1450; Found:344.1449.

[0150] Example 34: Preparation of 5-((4-bromobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-34)

[0151]

[0152] The procedure was the same as in Example 30, except that benzyl bromo was replaced with 4-bromobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 40 mg of white solid (I-34) was obtained, with a yield of 16%. 1 H NMR (600MHz, DMSO-d6) 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(151MHz,DMSO-d6)δ137.11,136.91,136.50,131.79,131.53,131.28,127.74,127.65,12 6.66,120.72,80.22,75.54,54.21,35.27,33.95,26.34,24.00,17.41.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 BrNS:386.0585; Found:386.0578.

[0153] Example 35: Preparation of 5-((4-chlorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-35)

[0154]

[0155] The procedure was the same as in Example 30, except that benzyl bromo was replaced with 4-chlorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 53 mg of white solid (I-35) was obtained, with a yield of 19%. 1 H NMR (600MHz, DMSO-d6) 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),3.8 9-3.82(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(151MHz,DMSO-d6)δ136.94,136.68,136.49,132.21,131.29,131.18,128.87,127.74,12 7.65,126.67,80.21,75.55,54.22,35.22,33.96,26.34,24.00,17.41.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 ClNS:342.1088; Found:342.1083.

[0156] Example 36: Preparation of 5-((4-methylphenethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-36)

[0157]

[0158] The procedure was the same as in Example 30, except that benzyl bromo was replaced with 1-(2-bromoethyl)-4-methylbenzene, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 90 mg of white solid (I-36) was obtained, with a yield of 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] + calcd for C 22 H 26 NS:336.1789; Found:336.1786.

[0159] Example 37: Preparation of 5-((3-chlorophenylethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-37)

[0160]

[0161] The procedure was the same as in Example 30, except that benzyl bromo was replaced with 1-(2-bromoethyl)-3-chlorobenzene, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 72 mg of white solid (I-37) was obtained, with a yield of 12%. 1H NMR (600MHz, DMSO-d6) 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(151MHz,DMSO-d6)δ142.94,137.16,136.41,133.42,131.28,130.62,128.92,127.88,127.39,127.0 2,126.82,126.79,80.22,75.57,54.25,34.26,33.96,32.48,26.40,24.02,17.40.HRMS(ESI):m / z[M+H] + calcd for C 21 H 23 ClNS:356.1243; Found:356.1240.

[0162] Example 38: Preparation of 5-((3-fluorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-38)

[0163]

[0164] The procedure was the same as in Example 30, except that benzyl bromide was replaced with 3-fluorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 40 mg of white solid (I-38) was obtained, with a yield of 9%. 1 H NMR (600MHz, DMSO-d6) 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),3.76(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). 13C NMR(151MHz,DMSO-d6)δ136.89,136.49,131.29,130.86,127.76,127.57,126.66,125.47,116.11,11 5.97,114.55,114.41,80.20,75.55,54.20,35.40,33.93,26.33,24.00,17.41.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 FNS:326.1378; Found:326.1379.

[0165] Example 39: Preparation of 5-((4-fluorobenzyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-39)

[0166]

[0167] The procedure was the same as in Example 30, except that benzyl bromide was replaced with 4-fluorobenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 60 mg of white solid (I-39) was obtained, with a yield of 19%. 1 H NMR (600MHz, DMSO-d6) 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(151MHz,DMSO-d6)δ137.16,136.43,133.67,131.34,131.28,127.67,127.58,126.66,11 5.77,115.63,80.21,75.55,54.21,35.22,33.95,26.32,24.01,17.41.HRMS(ESI):m / z[M+H] + calcd for C 20 H 21 FNS:326.1381; Found:326.1379.

[0168] Example 40: Preparation of 5-((3-fluorophenylethyl)thio)-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthyl-1-amine (I-40)

[0169]

[0170] The procedure was the same as in Example 30, except that benzyl bromo was replaced with 1-(2-bromoethyl)-3-fluorobenzene, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 40 mg of white solid (I-40) was obtained, with a yield of 21%. 1 H NMR(600MHz,DMSO-d6)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),2.72-2.6 6(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(151MHz,DMSO-d6)δ137.19,136.40,131.30,130.67,127.38,126.96,126.80,125.24,125.23,115.84,1 15.71,113.68,113.54,80.20,75.58,54.23,34.37,33.96,32.47,26.39,24.02,17.40.HRMS(ESI):m / z[M+H] + calcd for C 21 H 23 FNS:340.1540; Found:340.1535.

[0171] Example 41: Preparation of N-(prop-2-yn-1-yl)-5-((4-(trifluoromethyl)benzyl)thio)-1,2,3,4-tetrahydronaphthyl-1-amine (I-41)

[0172]

[0173] The procedure was the same as in Example 30, except that benzyl bromide was replaced with 4-trifluoromethylbenzyl bromide, and the other conditions remained unchanged. After separation and purification by column chromatography and salt formation, 20 mg of white solid (I-41) was obtained, with a yield of 4%.1 H NMR(600MHz,DMSO-d6)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=4.2Hz,1H),3.97-3.83(m,2H),3.76(t,J=2.5Hz,1H),2.83-2.77(m,1H) ,2.65-2.58(m,1H),2.22-2.16(m,1H),2.03-1.90(m,2H),1.83-1.77(m,1H). 13 C NMR(151MHz,DMSO-d6)δ156.13,142.55,128.15,127.64,127.00,125.90,125.87,125.84,125.8 2,122.64,112.33,80.18,75.63,68.82,53.89,34.00,24.24,22.72,17.09.HRMS(ESI):m / z[M+H] + calcd for C 21 H 21 F3NS:376.1351; Found:376.134.

[0174] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0175] Experimental Example 1: MAO Inhibitory Activity Test: The inhibitory activity of the compounds obtained above against MAO-A and MAO-B was determined according to the following method:

[0176] In a 96-well black plate, add 10 μL of the test compound solution (at different concentrations) and 30 μL of MAO-A or MAO-B solution (12.5 μg / mL in PBS). Incubate the black plate at 37°C for 30 min. After incubation, add 10 μL of kynurenamine PBS solution (MAO-A: 224 μM; MAO-B: 50 μM) and incubate for another 30 min at 37°C. Then, terminate the reaction by adding 40 μL of sodium hydroxide aqueous solution (2 mol / L) and 100 μL of water. Measure fluorescence on the multifunctional enzyme label using excitation and emission wavelengths of 310 nm and 400 nm, and analyze the fluorescence using 100-(IF) i -IF0) / (IF c The inhibition rate was calculated by multiplying the result by 100 (-IF0) by 100. When the inhibition rate was >50% at a concentration of 10 μM, the half-inhibition concentration was further determined, and the experimental results are shown in Table 1.

[0177] Table 1. Inhibitory activity of the compounds of the present invention against MAO-A and MAO-B. a

[0178]

[0179]

[0180] Note: "a" refers to the average of three independent experiments.

[0181] As shown in Table 1, all compounds exhibited inhibition levels of μM, with some reaching nM. The compounds with chemical modification at the sixth position showed the most significant inhibition against MAO-B, far exceeding the positive control rasagiline and comparable to safenamide. Therefore, these compounds can be used as selective inhibitors of MAO-B.

Claims

1. A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, Formula I in, R4 is H; the substituents for R1-R3 are selected as follows: R1 is of formula II, and R2-R3 are selected from hydrogen, halogen, hydroxyl, nitro, and amino groups; or R2 is of formula II, and R1 and R3 are selected from hydrogen, halogen, hydroxyl, nitro, and amino groups; or R3 is of formula II, and R1-R2 are selected from hydrogen, halogen, hydroxyl, nitro, and amino. Formula II n is an integer selected from 1 to 2, and the symbol in parentheses is " "Represents CH2; Y is selected from O or S; X1 and X2 are selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, and nitrile. The acids that form salts are selected from hydrochloric acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

2. The method for preparing the compound of Formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: First, a compound containing a tetrahydronaphthone structure was synthesized by a coupling reaction, and then the target compound was obtained through a reduction reaction and an amino substitution reaction. The reduction reaction involved using sodium cyanoborohydride and ammonium acetate to reduce the ketone to an amino group, and then replacing the hydrogen on the amino group with bromopropyne to further obtain the compound.

3. The method according to claim 2, wherein the acceptable salt is synthesized by conventional chemical methods.

4. The method according to claim 3, wherein the salt is prepared by dissolving the synthesized compound in toluene and passing dry hydrochloric acid gas into it, followed by crystallization to obtain the hydrochloride product.

5. The compound according to claim 1, wherein the compound is selected from the following compounds:

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

7. The use of the compound containing a tetrahydronaphthyl-1-amine structure according to claim 1 or 5, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, and depression.

8. A pharmaceutical composition, characterized in that: The drug combination described herein is an injection, tablet, capsule, powder, granule, suspension or oral liquid prepared by using a tetrahydronaphthyl-1-amine compound or a pharmaceutically acceptable salt thereof as the active ingredient and a pharmaceutically acceptable carrier.

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