Tacrine-selegiline derivatives and preparation methods and applications thereof

Abstract

The present invention discloses a series of tacrine-selegiline derivatives, their preparation methods, and applications, belonging to the field of pharmaceutical technology. The applicant's experimental results demonstrate that the tacrine-selegiline derivatives provided by the present invention exhibit excellent inhibitory activity against cholinesterase and monoamine oxidase, are promising for the treatment of Alzheimer's disease, and possess excellent potential medicinal value.

Description

Technical Field

[0001] The present invention relates to a tacrine-selegiline derivative and a preparation method and application thereof, belonging to the technical field of medicine. Background Art

[0002] Alzheimer's disease (AD) is the leading cause of dementia and one of the major forms of mental decline in late life. Clinically, it manifests as progressive memory and cognitive impairment, as well as behavioral abnormalities, placing a significant burden on human health, the economy, families, and society. With the aging population, the number of AD cases worldwide increased by 117% between 1990 and 2016. In 2019, the number of people with dementia worldwide exceeded 50 million, and this number is projected to reach 152 million by 2050. Currently, AD treatment primarily relies on acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, and rivastigmine) and N-methyl-D-aspartate (NMDA) receptor antagonists (memantine). However, these available drugs only improve symptoms such as cognitive and memory impairment but cannot slow or prevent AD progression. The increasing prevalence of dementia and the limited efficacy of drug treatments highlight the need for developing drugs with the potential to modify disease progression for the effective management of AD.

[0003] The pathogenesis of AD is complex and remains incompletely understood. However, several factors play a significant role in its pathogenesis, including acetylcholine deficiency, amyloid beta (Aβ) deposition, tau hyperphosphorylation to form senile plaques (SPs) and neurofibrillary tangles (NFTs), oxidative stress and biometal imbalance, as well as inflammation and cell cycle failure. Acetylcholinesterase (AChE), primarily present in the blood and synapses, is the primary enzyme responsible for hydrolyzing acetylcholine (~90%) and has been shown to be the most viable therapeutic target for ameliorating AD symptoms. In addition to AChE, butyrylcholinesterase (BuChE or BChE) is also present in the liver. These two enzymes share nearly 65% ​​amino acid sequence homology. BChE plays a crucial role as a compensatory enzyme in the progression of AD. When neurons in AD patients are severely damaged, AChE levels in the brain drop to 90% of normal values, while BChE levels can rise to 120% of physiological levels. Furthermore, studies have shown that BChE deposition in senile plaques is closely associated with the progressive accumulation of Aβ. Therefore, BChE can also be used as a drug target for the treatment of AD. Tacrine is the first cholinesterase inhibitor approved by the FDA for the treatment of AD, but its clinical application is limited by liver toxicity. Nevertheless, due to its good blood-brain barrier permeability, synthesizability, low molecular weight and easy-to-modify structure, it has been widely used in medicinal chemistry as a scaffold for the development of new multifunctional drugs without toxic side effects. In recent years, the modification of the tacrine structure has mainly focused on the replacement of the benzene ring with a heterocycle and molecular hybridization based on tacrine.

[0004] Monoamine oxidase (MAO) is a flavoprotein that catalyzes the oxidative deamination of monoamines (endogenous or exogenous) and exists as a dimer on the mitochondrial membrane. MAOs are divided into two subtypes, MAO-A and MAO-B, based on their substrates and inhibitor selectivity. Clinically, MAO-A inhibitors are primarily used to treat neurasthenia, depression, and anxiety, while MAO-B inhibitors are considered to have potential for treating Alzheimer's disease and Parkinson's disease (PD). Brain MAO-B expression increases fourfold with age, leading to the massive production of free radicals. Oxidative stress is also a mechanism of AD pathogenesis. Furthermore, AD patients often exhibit depressive symptoms, which are even considered a risk factor for AD. Furthermore, MAO-A can also affect neurotransmitter regulation in the brain. Therefore, dual inhibition of MAO-A and MAO-B, by slowing the metabolism of monoamine neurotransmitters and exerting indirect antioxidant effects, may be valuable in the treatment of AD. MAO inhibitors have been considered candidates for AD treatment. For example, selegiline is an irreversible, selective MAO-B inhibitor that acts as a neuroprotective agent in in vitro and in vivo models of AD, in which propargylamine is the pharmacophore structure of selegiline.

[0005] The recent failure of some drug candidates in late-stage clinical trials has led to the hypothesis that the development of drugs that can delay or prevent the progression of AD should not target a single target alone, but rather combine action on a specific target with further action on other key targets. Therefore, the multi-target ligand (MTDL) strategy is an important direction of current research. Multi-target drugs can act on more than one pathological target simultaneously and may be more promising and more effective in regulating the progression of AD. Because ChEs and MAOs are two key targets for the treatment of AD, many multi-target drugs that simultaneously target ChEs and MAOs have been discovered and developed. Ladostigil is a new neuroprotective agent developed from the carbamate portion of rivastigmine and the indoleamine portion of rasagiline. It has inhibitory activity against AChE, BChE, MAO-A, and MAO-B in the brain and has currently entered Phase IIb clinical trials.

[0006] This application synthesizes a series of novel tacrine-selegiline derivatives based on tacrine and selegiline, and studies their inhibitory effects on AChE / BuChE and MAO-A / B in vitro. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a series of tacrine-selegiline derivatives with novel structures and significant inhibitory activity on cholinesterase and monoamine oxidase, as well as preparation methods and applications thereof.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] The tacrine-selegiline derivative of the present invention is a compound having a structure represented by the following formula 9 or 10 or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Here, R1 represents a hydrogen atom, a methyl group or a fluorine atom, and n=2 to 8.

[0012] Furthermore, in the compound of the structure represented by formula 9, R1 represents a hydrogen atom, a methyl group or a fluorine atom, and n=2-8; in the compound of the structure represented by formula 10, R1 represents a hydrogen atom or a methyl group, and n=3-8.

[0013] Furthermore, in the compound of the structure represented by the above formula 10, R1 is a hydrogen atom, and n=6.

[0014] The preparation method of the tacrine-selegiline derivative of the present invention comprises the steps of:

[0015] 1) placing a compound represented by the following formula 1 and a compound represented by the following formula 2 in an organic solvent and reacting them under heating conditions to obtain a compound represented by the following formula 5;

[0016] 2) placing the compound of Formula 5 in an organic solvent and performing a nitrogen methylation reaction to obtain a compound of Formula 6;

[0017] 3) placing the compound represented by Formula 6 and the compound represented by the following Formula 3 in an organic solvent, adding an alkaline reagent to react to obtain a compound represented by Formula 7 or Formula 8;

[0018] 4) placing the compound represented by Formula 7 or Formula 8 and the compound represented by the following Formula 4 in an organic solvent, adding an alkaline reagent to react to obtain a compound represented by Formula 9 or Formula 10;

[0019]

[0020] In the above formulae, R1 represents a hydrogen atom, a methyl group or a fluorine atom, R2 represents a 3-hydroxyl group or a 4-hydroxymethyl group, and n=2 to 8.

[0021] In step 1) of the above preparation method, the reaction is usually carried out at a temperature of ≥60°C, more preferably at a temperature of ≥75°C, and more preferably at a temperature of ≥90°C. In order to increase the reaction rate, a catalyst is preferably added before the reaction. The catalyst can be sodium iodide and / or potassium iodide, preferably potassium iodide. The amount of the catalyst used is usually 0.03 to 0.1 times the molar amount of the compound represented by Formula 1.

[0022] In step 2) of the above-mentioned preparation method, the nitrogen methylation of the secondary amine in the structural compound shown in Formula 5 can be achieved by an existing known method, such as a method of adding a methylating agent thereto to carry out a nitrogen methylation reaction. The selection of the methylating agent and its dosage are the same as those in the prior art. Specifically, the methylating agent can be one or a combination of two or more selected from formaldehyde, dimethyl sulfate and dimethyl carbonate; the dosage of the methylating agent is preferably 2 to 5 times the molar amount of the structural compound shown in Formula 5. When the methylating agent is formaldehyde or contains formaldehyde, the reaction is preferably carried out under acidic conditions and a reducing agent needs to be added in combination; at this time, the acidic condition preferably refers to the pH of the system = 4 to 6, and acetic acid is usually used to adjust the pH value of the system; the reducing agent is usually one or a combination of two or more selected from sodium borohydride, potassium borohydride and sodium cyanoborohydride; the dosage of the reducing agent is usually 2 to 5 times the molar amount of the structural compound shown in Formula 5. When the methylating agent is dimethyl sulfate and / or dimethyl carbonate, the reaction is preferably carried out under alkaline conditions, usually under alkaline conditions of pH ≥ 8, and an organic base (such as triethylamine) is preferably used to adjust the pH value of the system. In this step, the reaction can be carried out under heating or non-heating conditions, preferably at room temperature.

[0023] The nitrogen methylation reaction in the above step 2) has a key influence on whether the target product can be obtained. The applicant found in the experiment that if the nitrogen methylation reaction in step 2) is not carried out and the compound with the structure shown in Formula 5 is directly used to carry out the next reaction, due to the presence of the imino group and the hydroxyl group or the phenolic hydroxyl group on tacrine, N-alkylation reaction and O-alkylation reaction will inevitably occur simultaneously, and the designed compound cannot be generated selectively and efficiently. In addition, when the alkyl chain is extended, the amino group and the hydroxyl group or the phenolic hydroxyl group on tacrine may undergo intramolecular alkylation simultaneously, thereby blocking the reaction site and affecting the further progress of the reaction designed by the established route.

[0024] In the above preparation method, the organic solvent involved can be one or a combination of two or more selected from 1,2-dichloroethane (DCE), chloroform, chlorobenzene, N,N-dimethylformamide (DMF), acetonitrile, n-pentanol, n-butanol, tert-butanol, methanol, and ethanol; preferably, N,N-dimethylformamide, acetonitrile, or n-pentanol. The amount of the organic solvent used can be determined as needed, generally to a level sufficient to dissolve the raw materials involved in the reaction.

[0025] In the above preparation method, the alkaline reagent involved can be a conventional choice in the prior art, preferably selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium hydroxide and potassium hydroxide. As for the amount of the alkaline reagent, in step 3), it is preferably 1 to 1.1 times the molar amount of the compound of the structure shown in Formula 6, and in step 4), it is preferably 3 to 5 times the molar amount of the compound of the structure shown in Formula 7 or Formula 8. The applicant found in the experiment that using sodium hydride as the alkaline reagent in step 3) can increase the yield of the product, while using potassium carbonate or cesium carbonate as the alkaline reagent in step 4) can increase the yield of the product.

[0026] In steps 3) and 4) of the above preparation method, the reaction can be carried out with or without heating. When the alkaline reagent selected is sodium hydride or contains sodium hydride, the reaction is preferably carried out at room temperature or in an ice bath. For other alkaline reagents, the reaction is preferably carried out with heating.

[0027] The ratio of the raw materials in each step of the above preparation method is their stoichiometric ratio, and the reaction time of each step is tracked and monitored by thin layer chromatography until the reaction is complete.

[0028] The above method produces a crude product of the target compound having the structure represented by Formula 9 or Formula 10. Therefore, the method of the present invention further includes a step of purifying the crude target compound. Specifically, conventional purification methods can be used to improve the purity of the target compound, such as silica gel column chromatography. More preferably, the reaction product is extracted before silica gel column chromatography to reduce the burden on the silica gel column. The eluent used for column chromatography is preferably a mixed solvent of petroleum ether (PE) and ethyl acetate (EA), or dichloromethane and methanol. In the mixed solvent, the volume ratio of petroleum ether to ethyl acetate is preferably 1:1 to 1:3, and the volume ratio of dichloromethane to methanol is preferably 20:1 to 10:1. If extraction is involved, the extractant should be the same polar solvent used in the reaction, such as 1,2-dichloroethane; conventional extractants such as dichloromethane or ethyl acetate may also be used.

[0029] To increase the yield of the target compound, it is preferred to purify the intermediate product obtained in steps 1) to 3) before proceeding to the next step. Purification is typically performed using silica gel column chromatography, and more preferably, the reaction product is extracted before silica gel column chromatography. For the compound represented by Formula 5 obtained in step 1), the eluent used for column chromatography is preferably a mixed solvent consisting of dichloromethane and methanol in a volume ratio of 20:1 to 10:1. For the compound represented by Formula 6 obtained in step 2), the eluent used for column chromatography is preferably a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 1:1 to 1:3. For the compound represented by Formula 7 or Formula 8 obtained in step 3), the eluent used for column chromatography is preferably a mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 4:1 to 1:1. If extraction is involved, the extractant should be the same polar solvent used in the reaction, such as 1,2-dichloroethane; conventional extractants such as dichloromethane or ethyl acetate may also be used.

[0030] The present invention has discovered through experiments that the above-mentioned tacrine-selegiline derivatives have good inhibitory activity against cholinesterase (AChE / BuChE) and / or monoamine oxidase (MAO-A / B) and blood-brain barrier permeability. Therefore, the present invention also includes the use of the above-mentioned tacrine-selegiline derivatives or pharmaceutically acceptable salts thereof in the preparation of cholinesterase inhibitors, or in the preparation of monoamine oxidase inhibitors, or in the preparation of cholinesterase / monoamine oxidase dual inhibitors. More specifically, the present invention includes the use of the above-mentioned tacrine-selegiline derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating Alzheimer's disease.

[0031] Furthermore, the present invention also includes a cholinesterase inhibitor, or a monoamine oxidase inhibitor, or a cholinesterase / monoamine oxidase dual inhibitor, which contains the above-mentioned tacrine-selegiline derivative or a pharmaceutically acceptable salt thereof.

[0032] Compared to the prior art, the present invention provides a series of structurally novel tacrine-selegiline derivatives and methods for their preparation. The applicant's experimental results demonstrate that the tacrine-selegiline derivatives provided by the present invention exhibit excellent inhibitory activity against cholinesterase and monoamine oxidase, and are promising for the treatment of Alzheimer's disease, demonstrating their potential medicinal value. DETAILED DESCRIPTION

[0033] In order to better explain the technical solution of the present invention, the present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0034] Some abbreviations appearing in the following embodiments are explained as follows:

[0035] Compound 1 represents a compound having a structure shown in Formula 1, Compound 2 represents a compound having a structure shown in Formula 2, Compound 3 represents a compound having a structure shown in Formula 3, Compound 4 represents a compound having a structure shown in Formula 4, Compound 5 represents a compound having a structure shown in Formula 5, Compound 6 represents a compound having a structure shown in Formula 6, Compound 7 represents a compound having a structure shown in Formula 7, Compound 8 represents a compound having a structure shown in Formula 8, Compound 9 represents a compound having a structure shown in Formula 9, and Compound 10 represents a compound having a structure shown in Formula 10.

[0036] Example 1: General preparation method of compounds 5a-5e

[0037]

[0038] In compound 1, R1 = H, CH3 or F; in compound 2, R2 = 3-OH or 4-CH2OH.

[0039] 5a: R1=H,R2=3-OH

[0040] 5b: R1=CH3,R2=3-OH

[0041] 5c: R1=F,R2=3-OH

[0042] 5d: R1=H,R2=4-CH2OH

[0043] 5e: R1=CH3,R2=4-CH2OH

[0044] Compound 1 (6.89 mmol, 1.0 equiv.) and KI (0.34 mmol, 0.05 equiv.) were dissolved in n-pentanol (20 mL) and stirred. Compound 2 (3-aminomethylphenol or 4-aminomethylbenzyl alcohol) (13.78 mmol, 2.0 equiv.) was then added. The mixture was stirred and refluxed at 130°C for 8–10 h (TLC monitoring). After completion of the reaction, the reaction mixture was concentrated to dryness, diluted with water, and extracted with EA (30 mL × 1, 20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / MeOH: 20 / 1–10 / 1, v / v) to afford compounds 5a–5e, characterized as follows:

[0045] Compound 3-(((1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenol (5a): yield 51%; pale yellow solid; 1H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.6Hz,1H),7.70(d,J=8.5Hz,1H),7.51(q,J=6. 8Hz,1H),7.28(q,J=6.7Hz,1H),7.08(q,J=6.6,5.8Hz,1H),6.75(d,J=9.1Hz,2H), 6.61(d,J=8.1Hz,1H), 6.00(d,J=10.2Hz,1H), 4.56(t,J=5.5Hz,2H), 2.89(q,J=5. 8Hz, 2H), 2.72 (d, J=6.1Hz, 2H), 1.78 (dt, J=20.4, 6.5Hz, 4H); HRMS (ESI): m / zcalcd for C 20 H 21 N2O + [M+H] + :305.1648; found:305.1691.

[0046] Compound 3-(((7-methyl-1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenol (5b): yield 54%; yellow solid; 1 H NMR (600MHz, DMSO-d6) δ9.36 (s, 1H), 7.90 (s, 1H), 7.60 (d, J = 8.5Hz, 1H), 7. 39–7.32(m,1H),7.08(t,J=7.9Hz,1H),6.75(d,J=7.2Hz,2H),6.60(dd,J=8. 1,2.3Hz,1H),6.11(d,J=7.6Hz,1H),4.54(d,J=7.1Hz,2H),2.86(t,J=6.3Hz ,2H),2.69(t,J=6.2Hz,2H),2.38(s,3H),1.82–1.70(m,4H); HRMS(ESI):m / z calcd forC 21 H 23 N2O + [M+H] + :319.1805; found:319.1860.

[0047] Compound 3-(((7-fluoro-1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenol (5c): yield 72%; pale yellow solid; 1H NMR (600MHz, DMSO-d6) δ9.33 (s, 1H), 7.86 (dd, J=11.4, 2.8Hz, 1H), 7.75 (dd, J=9 .2,5.8Hz,1H),7.42(td,J=8.6,2.7Hz,1H),7.08(t,J=8.0Hz,1H),6.73(dd,J=4 .4,2.3Hz,2H),6.59(dd,J=8.1,2.3Hz,1H),6.15(s,1H),4.51(d,J=7.1Hz,2H), 2.88(t,J=6.4Hz,2H),2.72(t,J=6.3Hz,2H),1.82–1.70(m,4H); HRMS(ESI):m / z calcd for C 20 H 20 FN2O + [M+H] + :323.1554; found:323.1588.

[0048] Compound (4-(((1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenyl)methanol (5d): yield 77%; yellow solid; 1 H NMR(600MHz,Methylene Chloride-d2)δ7.99(dd,J=8.5,1.4Hz,1H),7.83(dd,J=8.5,1.3Hz,1H),7.54(ddd,J=8.3,6.8,1.4Hz,1H),7.37–7.30(m,5H) ,4.68(s,2H),4.64–4.57(m,2H),4.24(s,1H),3.00(t,J=6.2Hz,2H),2.66(t,J=6.2Hz,2H),1.90–1.83(m,4H); HRMS(ESI):m / z calcd for C 21 H 23 N2O + [M+H] + :319.1805; found:319.1858.

[0049] Compound (4-(((7-methyl-1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenyl)methanol (5e): yield 62%; yellow solid; 1H NMR (600MHz, DMSO-d6) δ8.25(s,1H),8.12(s,1H),7.84(d,J=8.6Hz,1H),7.60(d,J=8.6Hz,1H),7.33(d,J=7.9Hz,2H),7.29(d,J=7.9Hz, 2H), 5.02 (d, J = 6.7Hz, 2H), 4.46 (s, 2H), 2.98 (d, J = 5.2Hz, 2H), 2.72 (d, J = 5.1Hz, 2H), 2.34 (s, 3H), 1.79 (t, J = 3.6Hz, 4H); HRMS (ESI): m / z calcd for C 22 H 25 N2O + [M+H] + :333.1961; found:333.2015.

[0050] Example 2: Preparation of Compounds 5a and 5e

[0051] Compound 5a: Compound 1 (where R1 = CH3, 6.89 mmol, 1.0 equiv.) was dissolved in n-pentanol (10 mL) and stirred. Compound 2 (where R2 = 3-OH, i.e., 3-aminomethylphenol) (13.78 mmol, 2.0 equiv.) was then added and stirred at 80°C under reflux until the reaction was complete (TLC monitoring). The reaction mixture was concentrated to dryness, diluted with water, and extracted with EA (30 mL x 1, 20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH: 20 / 1 to 10 / 1, v / v) to afford a pale yellow solid in 33% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the product to be Compound 5a.

[0052] Compound 5e: Compound 1 (where R1 = H, 6.89 mmol, 1.0 equiv.) and NaI (0.34 mmol, 0.05 equiv.) were placed in DCE (10 mL) and stirred to dissolve. Compound 2 (where R2 = 4-CH2OH, i.e., 4-aminomethylbenzyl alcohol) (13.78 mmol, 2.0 equiv.) was then added. The mixture was stirred and refluxed at 80°C until the reaction was complete (TLC monitoring). The reaction mixture was concentrated to dryness, diluted with water, and extracted with EA (30 mL × 1, 20 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH: 20 / 1 to 10 / 1, v / v) to afford a pale yellow solid in 50% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the product to be compound 5e.

[0053] Example 3: General preparation method of compounds 6a-6e

[0054]

[0055] In compound 5, R1=H, CH3 or F; R2=3-OH or 4-CH2OH.

[0056] 6a: R1=H,R2=3-OH

[0057] 6b: R1=CH3,R2=3-OH

[0058] 6c: R1=F,R2=3-OH

[0059] 6d: R1=H,R2=4-CH2OH

[0060] 6e: R1=CH3,R2=4-CH2OH

[0061] Compounds 5a-5e (4.24 mmol, 1.0 equiv.) were dissolved in DMF (30 mL) and then added with 40% formaldehyde solution (14.84 mmol, 3.5 equiv.) and glacial acetic acid (4.24 mmol, 1.0 equiv.) (pH = 4). After stirring at room temperature for 60 min, sodium cyanoborohydride (12.72 mmol, 3.0 equiv.) was added and the reaction was continued with stirring at room temperature for 6-8 h (TLC monitoring). After completion of the reaction, the reaction mixture was poured into an appropriate amount of water and extracted with EA (20 mL × 3, 10 mL × 1). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE / EA: 1 / 1 to 1 / 3, v / v) to afford compounds 6a-6e, characterized as follows:

[0062] Compound 3-((methyl(1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenol (6a): yield 78%; yellow solid; 1H NMR(600MHz,DMSO-d6)δ9.31(s,1H),8.09(d,J=8.4Hz,1H),7.89(d,J=8.4H z,1H),7.67(s,1H),7.52(s,1H),7.13(t,J=8.0Hz,1H),6.75–6.70(m,2H),6 .67(dd,J=8.1,2.4Hz,1H),4.38(s,2H),3.04(t,J=6.7Hz,2H),2.92(s,3H), 2.83(t,J=6.3Hz,2H),1.90–1.85(m,2H),1.80–1.74(m,2H); HRMS(ESI):m / z calcd forC 21 H 23 N2O + [M+H] + :319.1805; found:319.1813.

[0063] Compound 3-((methyl(7-methyl-1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)ph enol (6b): yield 80%; yellow solid; 1 H NMR(600MHz,Chloroform-d)δ8.11(d,J=8.6Hz,1H),7.74(s,1H),7.45(dd,J=8. 6,1.8Hz,1H),7.12(t,J=7.8Hz,1H),6.83(dd,J=8.0,2.5Hz,1H),6.77(t,J=2.0H z,1H),6.69(d,J=7.5Hz,1H),4.44(s,2H),3.22(t,J=6.6Hz,2H),3.01(s,3H),2. 67(t,J=6.2Hz,2H),2.49(s,3H),1.84(m,2H),1.77–1.69(m,2H); HRMS(ESI):m / z calcd for C 22 H 25 N2O + [M+H] + :333.1961;fo und:333.1991.

[0064] Compound 3-(((7-fluoro-1,2,3,4-tetrahydroacridin-9-yl)(methyl)amino)methyl)ph enol (6c): yield 72%; pale yellow solid; 1H NMR (600MHz, DMSO-d6) δ9.37 (s, 1H), 7.91 (dd, J=9.2, 5.6Hz, 1H), 7.70 (dd, J=1 0.7,2.9Hz,1H),7.52(td,J=8.7,2.8Hz,1H),7.13(t,J=8.0Hz,1H),6.76–6.70( m,2H),6.68–6.63(m,1H),4.27(s,2H),2.99(t,J=6.7Hz,2H),2.83(s,3H),2.8 1(d,J=6.4Hz,2H),1.85(p,J=6.4Hz,2H),1.75(p,J=6.0Hz,2H); HRMS(ESI):m / z calcd for C 21 H 22 FN2O + [M+H] + :337.1711;fo und:337.1746.

[0065] Compound (4-((methyl(1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)phenyl)methanol (6d): yield 69%; yellow solid; 1 H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.5,1.4Hz,1H),7.89(dt,J=8.4,0.9Hz,1H),7.57(ddd,J=8.3,6.8,1.4Hz,1H),7.43(ddd,J=8.2,6.7,1.3Hz,1H),7.35–7 .30(m,4H),4.67(s,2H),4.40(s,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2 .86(t,J=6.4Hz,2H),1.96–1.90(m,2H),1.84–1.79(m,2H); HRMS(ESI):m / z calcd for C 22 H 25 N2O + [M+H] + :333.1961; found:333.2016.

[0066] Compound (4-((methyl(7-methyl-1,2,3,4-tetrahydroacridin-9-yl)amino)methyl)ph enyl)methanol (6e): yield 76%; yellow solid;1 H NMR(600MHz,Chloroform-d)δ8.36(d,J=8.6Hz,1H),7.73(s,1H),7.57–7.48(m,1H ),7.35(d,J=8.1Hz,2H),7.20(dd,J=8.1,2.8Hz,2H),4.72(d,J=1.9Hz,2H),4.52(s ,2H),3.37(t,J=6.6Hz,2H),3.00(d,J=2.0Hz,3H),2.77–2.67(m,2H),2.51(d,J=2. 2Hz, 3H), 1.91 (dp, J=10.3, 3.9Hz, 2H), 1.78 (qd, J=5.8, 2.4Hz, 2H); HRMS (ESI): m / z calcd for C 23 H 27 N2O + [M+H] + :347.2118; found:347.2170.

[0067] Example 4: Preparation of Compounds 6a and 6e

[0068] Compound 5a (4.24 mmol, 1.0 equiv.) was dissolved in DMF (30 mL), and dimethyl sulfate (14.84 mmol, 3.5 equiv.) and triethylamine (6.36 mmol, 1.5 equiv.) were added (pH = 9). The reaction was stirred at room temperature for 8 h (TLC monitoring). After completion, the reaction mixture was poured into an appropriate amount of water and extracted with EA (20 mL × 3, 10 mL × 1). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE / EA: 1 / 1 to 1 / 3, v / v) to afford a yellow solid in 25% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the product to be compound 6a.

[0069] Compound 5e (4.24 mmol, 1.0 equiv.) was dissolved in chloroform (20 mL), and dimethyl carbonate (14.84 mmol, 3.5 equiv.) and diethylamine (6.36 mmol, 1.5 equiv.) were added (pH = 8). The reaction was stirred at room temperature for 8 h (TLC monitoring). After completion, the reaction mixture was poured into an appropriate amount of water and extracted with EA (20 mL x 3, 10 mL x 1). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE / EA: 1 / 1 to 1 / 3, v / v) to afford a yellow solid in 30% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the product to be compound 6e.

[0070] Example 5: General Preparation Method for Key Intermediates 7a-7o and 8a-81

[0071]

[0072] Compounds 6a-6e (3.10 mmol, 1.0 equiv.) were dissolved in DMF (20 mL) dried over molecular sieves. Under nitrogen, NaH (6.20 mmol, 2.0 equiv., 60% mineral oil) was added and stirred in an ice bath for 30 min. The corresponding compound 3 (18.6 mmol, 6.0 equiv.) was then added and the reaction was stirred at room temperature for 12 h. Unreacted NaH was quenched by adding an appropriate amount of ice water. The reaction was extracted with EA (30 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE / EA: 4 / 1 to 1 / 1, v / v) to afford compounds 7a-7o and 8a-8l as pale yellow to yellow oils. Specific characterization is as follows:

[0073] Compound 7a: Yield 31%; pale yellow oil; HRMS (ESI): m / z calculated for C 23 H 26 BrN2O + [M+H] + :425.1223; found:425.1226.

[0074] Compound 7b: Yield 62%; light yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.86(d,J=8.4Hz,1H),7.62(t,J=7.6Hz,1H),7.49 (t,J=7.6Hz,1H),7.25(t,J=7.8Hz,1H),6.94–6.88(m,2H),6.84(dd,J=8.2,2.5Hz,1H),4.39(s, 2H),4.03(t,J=6.0Hz,2H),3.64(t,J=6.5Hz,2H),3.01(t,J=6.7Hz,2H),2.89(s,3H),2.84(t,J= 6.3Hz,2H),2.22(p,J=6.3Hz,2H),1.89–1.83(m,2H),1.77(q,J=6.0Hz,2H).HRMS(ESI):m / zcalcd for C 24 H 28 BrN2O + [M+H] + :439.1380; found:439.1374.

[0075] Compound 7c: Yield 75%; pale yellow oil; 1 H NMR (600MHz, DMSO-d6) δ8.08(dd,J=8.5,1.4Hz,1H),7.86(dd,J=8.4,1.2Hz,1H),7.60(ddd,J=8.3,6.7,1.4Hz,1H),7.48( ddd,J=8.3,6.7,1.3Hz,1H),7.23(t,J=7.8Hz,1H),6.92–6.88(m,1H),6.87(t,J=2.0Hz,1H),6.82(dd,J=8.0,2.6Hz,1H), 4.37(s,2H),3.94(t,J=6.3Hz,2H),3.58(t,J=6.7Hz,2H),3.00(t,J=6.7Hz,2H),2.89(s,3H),2.84(t,J=6.4Hz,2H),1.94 (dd,J=8.5,6.2Hz,2H),1.87(qd,J=6.6,3.5Hz,2H),1.81(dt,J=9.0,6.4Hz,2H),1.79–1.73(m,2H).HRMS(ESI):m / zcalcd for C 25 H 30 BrN2O + [M+H] + :453.1536; found:453.1537.

[0076] Compound 7d: Yield 86%; light yellow oil; 1 H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.86(d,J=8.4Hz,1H),7.62(t,J=7.5Hz,1H),7.49(t,J=7.6Hz ,1H),7.23(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.85(s,1H),6.81(dd,J=8.2,2.6Hz,1H),4.39(s,2H),3. 90(t,J=6.4Hz,2H),3.54(t,J=6.7Hz,2H),3.01(t,J=6.6Hz,2H),2.90(s,3H),2.84(t,J=6.3Hz,2H),1.89–1 .82(m,4H),1.76(p,J=6.3Hz,2H),1.70(p,J=6.7Hz,2H),1.51(ddd,J=15.0,8.6,6.3Hz,2H).HRMS(ESI):m / z calcd for C 26 H 32 BrN2O + [M+H] + :467.1693; found:467.2531.

[0077] Compound 7e: yield 80%; yellow oil; 1 H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.86(d,J=8.3Hz,1H),7.62(t,J=7.6Hz,1H),7.49(t,J=7.6Hz,1H ),7.23(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.85(s,1H),6.83–6.78(m,1H),4.39(s,2H),3.89(t,J=6.4Hz,2 H),3.52(t,J=6.7Hz,2H),3.01(t,J=6.6Hz,2H),2.90(s,3H),2.83(t,J=6.4Hz,2H),1.87(p,J=6.6Hz,2H),1.81 (q,J=6.9Hz,2H),1.76(p,J=6.2Hz,2H),1.67(h,J=6.5Hz,2H),1.41(tq,J=9.5,4.5,3.8Hz,4H).HRMS(ESI):m / z calcd for C 27 H 34 BrN2O +[M+H] + :481.1849; found:481.2672.

[0078] Compound 7f: Yield 71%; pale yellow oil; 1 H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.86(d,J=8.4Hz,1H),7.62(t,J=7.6Hz,1H),7.48(t,J=7.6Hz,1H),7 .22(t,J=7.8Hz,1H),6.88(d,J=7.5Hz,1H),6.84(s,1H),6.80(dd,J=8.1,2.6Hz,1H),4.39(s,2H),3.88(t,J=6.6Hz, 2H),3.51(t,J=6.8Hz,2H),3.01(t,J=6.7Hz,2H),2.90(s,3H),2.83(t,J=6.4Hz,2H),1.86(p,J=6.6Hz,2H),1.80(q, J=7.1Hz,2H),1.75(p,J=6.1Hz,2H),1.67(p,J=6.8Hz,2H),1.39(h,J=7.9Hz,4H),1.35–1.30(m,2H).HRMS(ESI):m / z calcdfor C 28 H 36 BrN2O + [M+H] + :495.2006;found:495.2949.

[0079] Compound 7g: Yield 63%; pale yellow oil; 11H NMR (600 MHz, DMSO-d6) δ 8.08 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.61 (ddd, J = 8.3, 6.6, 1.4 Hz, 1H), 7.51–7.44 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.85 (t, J = 1.9 Hz, 1H), 6.81 (dd, J = 8.1, 2.5 Hz, 1H), 4.38 (s, 2H), 3.88 (t, J = 6.5 Hz, 2H), 3.52 (t, J = 6.7 Hz, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.89 (s, 3H), 2.84 (t, J = 6.4 Hz, 2H), 1.87 (p, J = 6.6 Hz, 2H), 1.82–1.73 (m, 4H), 1.67 (p, J = 6.8 Hz, 2H), 1.38 (dq, J = 13.9, 9.4, 7.6 Hz, 4H), 1.33–1.28 (m, 4H). HRMS (ESI): m / z calcd for C 29 H 38 BrN2O + [M + H] + : 509.2162; found: 509.2940.

[0080] Compound 7h: Yield 55%; yellow oil; 1 1H NMR (600 MHz, Methylene Chloride-d2) δ 7.86 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 1.9 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.91 (t, J = 2.0 Hz, 1H), 6.82 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 4.37 (s, 2H), 4.04 (t, J = 5.8 Hz, 2H), 3.61 (t, J = 6.5 Hz, 2H), 3.06 (t, J = 6.7 Hz, 2H), 2.92 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H), 2.53 (s, 3H), 2.32–2.25 (m, 2H), 1.96–1.88 (m, 2H), 1.81 (p, J = 6.2 Hz, 2H). HRMS (ESI): m / z calcd for C 25 H 30 BrN2O + [M + H] + : 453.1536; found: 453.1582.

[0081] Compound 7i: yield 75%; yellow oil; 1 H NMR (600MHz, DMSO-d6) δ7.85(s,1H),7.76(d,J=8.5Hz,1H),7.46(dd,J=8.5,1.9Hz,1H),7.24(t,J= 7.8Hz,1H),6.91–6.86(m,2H),6.82(dd,J=8.2,2.5Hz,1H),4.37(s,2H),3.92(t,J=6.2Hz,2H),3.58 (t,J=6.7Hz,2H),2.98(t,J=6.6Hz,2H),2.87(d,J=3.0Hz,3H),2.80(t,J=6.3Hz,2H),2.49(s,3H), 1.97–1.89(m,2H),1.82(ddd,J=20.8,10.4,6.1Hz,4H),1.74(t,J=5.9Hz,2H).HRMS(ESI):m / zcalcd for C 26 H 32 BrN2O + [M+H] + :467.1693; found:467.1687.

[0082] Compound 7j: yield 63%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ7.86(s,1H),7.81(d,J=8.6Hz,1H),7.42(dd,J=8.5,1.9Hz,1H),7.23(t,J=7.8Hz,1 H),6.92(d,J=7.5Hz,1H),6.89(t,J=2.1Hz,1H),6.80(dd,J=8.1,2.6Hz,1H),4.37(s,2H),3.91(t,J =6.4Hz,2H),3.46(t,J=6.8Hz,2H),3.06(t,J=6.7Hz,2H),2.92(s,3H),2.84(t,J=6.4Hz,2H),2.53 (s,3H),1.92(q,J=7.4,6.8Hz,4H),1.83–1.75(m,4H),1.60(tt,J=10.0,6.4Hz,2H).HRMS(ESI):m / z calcd for C 27 H 34 BrN2O + [M+H] + :481.1849; found:481.1812.

[0083] Compound 7k: yield 58%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ7.86(s,1H),7.82(s,1H),7.43(dd,J=8.5,1.9Hz,1H),7.23(t,J=7.8Hz,1H) ,6.94–6.86(m,2H),6.83–6.76(m,1H),4.37(s,2H),3.90(t,J=6.4Hz,2H),3.44(t,J=6.8Hz, 2H),3.06(t,J=6.7Hz,2H),2.91(s,3H),2.84(t,J=6.3Hz,2H),2.52(s,3H),1.94–1.86(m,4 H),1.81(t,J=6.0Hz,2H),1.76(d,J=6.8Hz,2H),1.49(tt,J=7.3,3.3Hz,4H).HRMS(ESI):m / z calcd for C 28 H 36 BrN2O + [M+H] + :495.2006;found:495.2070.

[0084] Compound 71: Yield 84%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ7.87(d,J=2.0Hz,1H),7.79(d,J=8.5Hz,1H),7.41(dd,J=8.5,1.9Hz,1H),7.23(t,J=7.8Hz, 1H),6.95–6.86(m,2H),6.79(dt,J=8.3,1.7Hz,1H),4.36(s,2H),3.89(t,J=6.5Hz,2H),3.43(t,J=6.9Hz,2 H),3.04(t,J=6.7Hz,2H),2.91(s,3H),2.85(t,J=6.3Hz,2H),2.52(s,3H),1.92(p,J=6.5Hz,2H),1.87(p,J =7.0Hz,2H),1.81(t,J=6.0Hz,2H),1.78–1.73(m,2H),1.49–1.43(m,4H),1.41–1.36(m,2H).HRMS(ESI):m / z calcd for C 29 H 38 BrN2O + [M+H]+ :509.2162; found:509.2220.

[0085] Compound 7m: Yield 69%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ7.87(s,1H),7.78(d,J=8.5Hz,1H),7.41(dd,J=8.5,1.9Hz,1H),7.22(t,J=7.8Hz,1H),6.94– 6.88(m,2H),6.79(dd,J=8.1,2.4Hz,1H),4.36(s,2H),3.89(t,J=6.5Hz,2H),3.43(t,J=6.9Hz,2H),3.04(t,J =6.7Hz,2H),2.90(s,3H),2.85(t,J=6.3Hz,2H),2.52(s,3H),1.94–1.89(m,2H),1.88–1.83(m,2H),1.81(d,J =6.0Hz,2H),1.75(dd,J=8.3,6.5Hz,2H),1.47–1.41(m,4H),1.36(qd,J=6.5,6.0,2.5Hz,4H).HRMS(ESI):m / z calcd for C 30 H 40 BrN2O + [M+H] + :523.2319; found:523.2382.

[0086] Compound 7n: yield 55%; yellow oil; 1 H NMR(600MHz,Chloroform-d)δ7.96(dd,J=9.2,5.5Hz,1H),7.70(dd,J=10.5,2.8Hz,1H),7.40–7.32(m,1 H),7.24(d,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.86(d,J=2.2Hz,1H),6.83–6.79(m,1H),4.33(s,2H), 3.91(t,J=6.4Hz,2H),3.43(t,J=6.8Hz,2H),3.11(t,J=6.7Hz,2H),2.90(s,3H),2.85(t,J=6.4Hz,2H), 1.92(dt,J=29.9,6.1Hz,4H),1.80(dt,J=20.3,7.2Hz,4H),1.50(p,J=4.1Hz,4H).HRMS(ESI):m / zcalcd for C27 H 33 BrFN2O + [M+H] + :499.1755; found:499.1812.

[0087] Compound 7o: Yield 82%; yellow oil; 1 H NMR(600MHz,Chloroform-d)δ7.97(dd,J=9.2,5.5Hz,1H),7.70(dd,J=10.5,2.8Hz,1H),7.39–7.33(m,1H),7.24(t, J=8.1Hz,1H),6.89(d,J=7.5Hz,1H),6.86(d,J=2.7Hz,1H),6.82(dd,J=8.3,2.4Hz,1H),4.33(s,2H),3.90(t,J=6.5 Hz,2H),3.41(t,J=6.8Hz,2H),3.11(t,J=6.7Hz,2H),2.90(s,3H),2.85(t,J=6.4Hz,2H),1.94(p,J=6.6Hz,2H),1.8 5(dp,J=16.4,6.5,6.0Hz,4H),1.76(p,J=6.8Hz,2H),1.48–1.41(m,4H),1.36(q,J=4.1,3.3Hz,4H).HRMS(ESI):m / z calcd forC 33 H 43 FN3O + [M+H] + :516.3385; found:516.3446.

[0088] Compound 8a: yield 45%; yellow oil; HRMS (ESI): m / z calculated for C 25 H 30 BrN2O + [M+H] + :453.1536; found:453.1532.

[0089] Compound 8b: Yield 60%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.5,1.4Hz,1H),7.89(dd,J=8.4,1.3Hz,1H),7.57(ddd,J=8.4, 6.7,1.5Hz,1H),7.43(ddd,J=8.2,6.7,1.3Hz,1H),7.36–7.27(m,4H),4.47(s,2H),4.40(s ,2H),3.50(t,J=6.2Hz,2H),3.46(t,J=6.8Hz,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2.8 6(t,J=6.4Hz,2H),2.00–1.90(m,4H),1.84–1.79(m,2H),1.77–1.71(m,2H).HRMS(ESI):m / z calcdfor C 26 H 32 BrN2O + [M+H] + :467.1693; found:467.1749.

[0090] Compound 8c: yield 74%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.5,1.4Hz,1H),7.92–7.87(m,1H),7.57(ddd,J=8.3,6.7,1.4Hz,1H),7.4 3(ddd,J=8.2,6.7,1.3Hz,1H),7.31(q,J=8.1Hz,4H),4.47(s,2H),4.40(s,2H),3.48(t,J=6.4Hz,2H) ,3.43(t,J=6.8Hz,2H),3.07(t,J=6.7Hz,2H),2.91(s,3H),2.86(t,J=6.3Hz,2H),1.93(p,J=6.6Hz,2 H),1.88(p,J=7.0Hz,2H),1.82(p,J=6.2Hz,2H),1.65–1.60(m,2H),1.54–1.48(m,2H).HRMS(ESI):m / z calcd for C 27 H 34 BrN2O + [M+H] + :481.1849; found:481.1902.

[0091] Compound 8d: yield 65%; yellow oil;1 H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.4,1.4Hz,1H),7.89(dd,J=8.4,1.3Hz,1H),7.57(ddd,J=8.4,6.7,1. 5Hz,1H),7.43(ddd,J=8.2,6.7,1.3Hz,1H),7.31(q,J=8.1Hz,4H),4.46(s,2H),4.40(s,2H),3.47( t,J=6.5Hz,2H),3.42(t,J=6.9Hz,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H), 1.93(p,J=6.6Hz,2H),1.89–1.79(m,4H),1.61(p,J=6.7Hz,2H),1.48–1.38(m,4H).HRMS(ESI):m / z calcd for C 28 H 36 BrN2O + [M+H] + :495.2006;found:495.2059.

[0092] Compound 8e: yield 58%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.5,1.4Hz,1H),7.89(dd,J=8.4,1.3Hz,1H),7.57(ddd,J=8.3,6.8,1.5Hz,1H),7 .43(ddd,J=8.2,6.7,1.3Hz,1H),7.31(q,J=8.0Hz,4H),4.46(s,2H),4.39(s,2H),3.46(t,J=6.5Hz,2H),3.4 4–3.38(m,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),1.93(p,J=6.6Hz,2H),1.88–1.77( m,4H),1.60(dt,J=8.8,6.5Hz,2H),1.46–1.40(m,2H),1.40–1.36(m,2H),1.36–1.33(m,2H).HRMS(ESI):m / z calcd for C 29 H 38 BrN2O + [M+H] +:509.2162; found:509.2209.

[0093] Compound 8f: yield 78%; yellow oil; 1 H NMR(600MHz,Methylene Chloride-d2)δ8.09(dt,J=8.4,0.9Hz,1H),7.89(d,J=8.4Hz,1H),7.57(ddd,J=8.5,6.8,1.5Hz,1H),7.43( ddd,J=8.2,6.7,1.3Hz,1H),7.35–7.26(m,4H),4.46(s,2H),4.39(s,2H),3.46(t,J=6.6Hz,2H),3.42(td,J= 6.9,3.2Hz,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),1.93(p,J=6.6Hz,2H),1.88–1.7 8(m,4H),1.59(q,J=6.9Hz,2H),1.46–1.40(m,2H),1.38–1.35(m,2H),1.33(d,J=3.9Hz,2H).HRMS(ESI):m / z calcd for C 30 H 40 BrN2O + [M+H] + :523.2319; found:523.2367.

[0094] Compound 8g: Yield 85%; light yellow oil; HRMS (ESI): m / z calculated for C 26 H 32 BrN2O + [M+H] + :467.1693; found:467.1683.

[0095] Compound 8h: 1H NMR(600MHz,Chloroform-d)δ8.19(d,J=8.1Hz,1H),7.78(s,1H),7.50(d,J=8.5Hz ,1H),7.32(d,J=7.6Hz,2H),7.25(s,2H),4.50(s,2H),4.47(s,2H),3.53(dd,J=6.8 ,5.4Hz,2H),3.44(t,J=6.7Hz,2H),3.28(t,J=6.7Hz,2H),2.97(s,3H),2.78(t,J=6 .3Hz,2H),2.53(s,3H),2.00–1.90(m,4H),1.82–1.76(m,4H).HRMS(ESI):m / zcalcd for C 27 H 34 BrN2O + [M+H] + :481.1849; found:481.1853.

[0096] Compound 8i: Yield 51%; pale yellow oil; 1 H NMR(600MHz,Chloroform-d)δ8.44(s,1H),7.74(s,1H),7.55(dd,J=21.6,8.6Hz,1H),7.33(d ,J=7.7Hz,2H),7.21(d,J=7.7Hz,2H),4.55(s,2H),4.51(s,2H),3.51(t,J=6.4Hz,2H),3.42(t ,J=6.7Hz,2H),3.03(s,3H),2.73(t,J=6.3Hz,2H),2.53(s,3H),2.34(t,J=7.6Hz,2H),1.96–1 .86(m,4H),1.79(dd,J=7.8,4.3Hz,2H),1.69–1.64(m,2H),1.58–1.52(m,2H).HRMS(ESI):m / z calcd forC 28 H 36 BrN2O + [M+H] + :495.2006; found:495.2027.

[0097] Compound 8j: Yield 65%; light yellow oil; 1H NMR(600MHz,Chloroform-d)δ7.90(d,J=8.5Hz,1H),7.81(s,1H),7.43(dd,J=8.5,1.9Hz,1H),7 .34–7.28(m,4H),4.50(s,2H),4.38(s,2H),3.49(t,J=6.5Hz,2H),3.41(t,J=6.8Hz,2H),3.12( t,J=6.7Hz,2H),2.90(s,3H),2.81(t,J=6.3Hz,2H),2.52(s,3H),1.93(p,J=6.5Hz,2H),1.86(p ,J=6.9Hz,2H),1.80(p,J=6.1Hz,2H),1.64(p,J=6.7Hz,2H),1.49–1.39(m,4H).HRMS(ESI):m / z calcdfor C 29 H 38 BrN2O + [M+H] + :509.2162; found:509.2187.

[0098] Compound 8k: Yield 55%; light yellow oil; 1 H NMR (600MHz, Chloroform-d) δ7.97 (d, J=8.6Hz, 1H), 7.80 (s, 1H), 7.45 (dd, J=8.6, 1.9Hz, 1H), 7.31 (q, J=8. 1Hz,4H),4.50(s,2H),4.40(s,2H),3.49(t,J=6.6Hz,2H),3.40(t,J=6.9Hz,2H),3.16(t,J=6.6Hz,2H),2.92 (s,3H),2.81(t,J=6.3Hz,2H),2.53(s,3H),1.93(qd,J=6.6,3.4Hz,2H),1.87–1.83(m,2H),1.82–1.78(m,2H ),1.66–1.60(m,2H),1.44(dd,J=10.8,4.3Hz,2H),1.41–1.37(m,2H),1.34(q,J=6.9Hz,2H).HRMS(ESI):m / z calcd for C 30 H 40 BrN2O + [M+H] + :523.2319; found:523.2349.

[0099] Compound 81: Yield 67%; pale yellow oil; 1H NMR(600MHz,DMSO-d6)δ7.85(s,1H),7.78(d,J=8.5Hz,1H),7.43–7.38(m,1H),7.31(q,J=8.2Hz,4 H),4.46(s,2H),4.38(s,2H),3.49–3.45(m,2H),3.43–3.40(m,2H),3.04(t,J=6.7Hz,2H),2.89(s ,3H),2.83(t,J=6.4Hz,2H),2.52(s,3H),1.91(p,J=6.6Hz,2H),1.85(q,J=7.2Hz,2H),1.82–1.77 (m,2H),1.60(p,J=6.8Hz,4H),1.42(t,J=7.4Hz,2H),1.32(q,J=4.0Hz,4H).HRMS(ESI):m / zcalcd for C 31 H 42 BrN2O + [M+H] + :537.2475; found:537.2509.

[0100] Example 6: General Preparation Method of Target Compounds 9a-9o and 10a-101

[0101]

[0102] The corresponding compounds 7a-7o or 8a-8l (2.32 mmol, 1.0 equiv.) were dissolved in acetonitrile (23 mL), and compound 4 (4.64 mmol, 2.0 equiv.) was added, followed by potassium carbonate (11.60 mmol, 5.0 equiv.). The mixture was stirred at reflux at 70°C for 12 h (TLC monitoring). After the reaction, the acetonitrile was dried under vacuum, and an appropriate amount of water was added. The aqueous phase was extracted with DCM (30 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EA: 1 / 1 to 1 / 3, v / v) to obtain light yellow to yellow oily compounds 9a-9o and 10a-10l, which were characterized as follows:

[0103] Target compound 9a: Yield 62%; pale yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.08(dd,J=8.4,1.4Hz,1H),8.00(d,J=8.4Hz,1H),7.60(ddd,J=8.3,6.7,1.4Hz,1H),7.45(ddd, J=8.2,6.7,1.3Hz,1H),7.24(t,J=7.8Hz,1H),6.91(d,J=7.5Hz,1H),6.87(t,J=2.1Hz,1H),6.84–6.79(m,1H),4. 41(s,2H),3.99(t,J=5.7Hz,2H),3.41(d,J=2.4Hz,2H),3.13(t,J=6.7Hz,2H),2.95(s,3H),2.85(t,J=6.3Hz,2H) ,2.82(t,J=5.7Hz,2H),2.37(s,3H),2.28(t,J=2.4Hz,1H),1.96–1.91(m,2H),1.82(ddt,J=9.5,6.2,3.5Hz,2H). 13 CNMR(150MHz, CDCl3)δ160.59,159.08,154.51,148.09,141.12,129.48,128.98,128.41,127.96,126.04,125.01,124.47,1 21.19,114.73,113.65,78.46,73.53,66.03,60.43,54.47,46.10,42.35,40.50,34.11,27.03,23.13,23.03.HRMS(ESI):m / z calcd forC 27 H 32 N3O + [M+H] + :414.2540; found:414.2603.

[0104] Target compound 9b: Yield 57%; light yellow oil; 1H NMR(600MHz, DMSO-d6)δ8.07(d,J=8.4Hz,1H),7.85(d,J=8.3Hz,1H),7.62–7.57(m,1H),7.49–7.44(m,1H), 7.22(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.86(s,1H),6.80(dd,J=8.2,2.4Hz,1H),4.36(s,2H),3.92(t ,J=6.4Hz,2H),3.25(d,J=2.5Hz,2H),3.07–3.03(m,1H),3.00(t,J=6.7Hz,2H),2.88(s,3H),2.84(t,J=6.4 Hz,2H),2.46(t,J=7.1Hz,2H),2.20(s,3H),1.89-1.83(m,2H),1.81(q,J=6.8Hz,2H),1.76(q,J=6.2Hz,2H). 13 C NMR (150MHz, DMSO) δ159.83,158.63,153.33,147.42,140.81,129.19,128.57,127.95,127.64,125.37,124.73,123.99,120.3 9,114.09,113.40,78.93,75.40,65.57,59.28,51.65,44.95,41.14,40.20,33.34,26.69,25.92,22.36,22.22.HRMS(ESI):m / z calcd for C 28 H 34 N3O + [M+H] + :428.2696; found:428.2763.

[0105] Target compound 9c: Yield 80%; pale yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.85(d,J=8.3Hz,1H),7.60(ddd,J=8.3,6.7,1.4Hz,1H),7.50–7.44(m, 1H),7.23(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.86(t,J=2.0Hz,1H),6.81(dd,J=8.2,2.5Hz,1H),4.36(s,2H),3.9 1(t,J=6.5Hz,2H),3.27(s,2H),3.04(d,J=2.4Hz,1H),3.00(t,J=6.7Hz,2H),2.88(s,3H),2.84(t,J=6.3Hz,2H),2.37 (t,J=7.2Hz,2H),2.19(s,3H),1.87(p,J=6.6Hz,2H),1.76(p,J=6.3Hz,2H),1.71–1.65(m,2H),1.50(p,J=7.3Hz,2H). 13 CNMR(150MHz,DMSO)δ162.86,160.22,158.93,154.01,147.09,141.12,129.69,128.63,127.93,125.62,125.29,124.45,120.73,1 14.36,113.70,79.25,75.99,67.38,59.56,54.74,45.07,41.43,40.59,33.55,26.68,26.40,23.58,22.73,22.54.HRMS(ESI):m / z calcd for C 29 H 36 N3O + [M+H] + :442.2853; found:442.2919.

[0106] Target compound 9d: Yield 86%; light yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.07(d,J=8.4Hz,1H),7.85(d,J=8.3Hz,1H),7.63–7.55(m,1H),7.47(dd,J=8.4,6.7Hz,1H),7.22( t,J=8.0Hz,1H),6.89(d,J=7.5Hz,1H),6.85(d,J=2.4Hz,1H),6.80(dd,J=8.2,2.4Hz,1H),4.36(s,2H),3.88(t,J=6.6Hz,2H ),3.26(s,2H),3.03(t,J=2.1Hz,1H),3.00(t,J=6.7Hz,2H),2.88(d,J=1.5Hz,3H),2.84(t,J=6.4Hz,2H),2.33(t,J=6.9Hz ,2H),2.18(s,3H),1.86(p,J=6.8Hz,2H),1.76(p,J=6.2Hz,2H),1.67(dp,J=14.6,7.1Hz,2H),1.41(dp,J=22.3,8.0Hz,4H). 13 C NMR (150MHz, DMSO) δ159.84,158.66,153.33,147.43,140.78,129.20,128.58,127.96,127.67,125.38,124.72,123.99,120.34,114. 10,113.38,79.09,75.27,67.24,59.28,54.83,44.88,41.19,40.22,33.34,28.41,26.48,25.92,23.28,22.37,22.22.HRMS(ESI):m / z calcd for C 30 H 38 N3O + [M+H] + :456.3009; found:456.3077.

[0107] Target compound 9e: Yield 83%; yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.07(d,J=8.4Hz,1H),7.85(d,J=8.3Hz,1H),7.60(t,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.22(t,J=7.8 Hz,1H),6.89(d,J=7.5Hz,1H),6.85(d,J=2.6Hz,1H),6.80(dd,J=8.2,2.6Hz,1H),4.36(s,2H),3.88(t,J=6.5Hz,2H),3.26(d,J=2 .4Hz,2H),3.03(d,J=2.4Hz,1H),3.00(t,J=6.7Hz,2H),2.88(s,3H),2.84(t,J=6.4Hz,2H),2.32(t,J=7.2Hz,2H),2.17(s,3H),1 .86(p,J=6.5Hz,2H),1.76(p,J=6.3Hz,2H),1.66(q,J=6.9Hz,2H),1.38(tdd,J=14.7,9.4,5.1Hz,4H),1.30(q,J=7.7,7.1Hz,2H). 13 C NMR (151MHz, DMSO) δ159.83,158.66,153.33,147.42,140.78,129.19,128.58,127.95,127.66,125.38,124.71,123.99,120.33,114.06,113 .41,79.07,75.26,67.22,59.28,54.85,44.87,41.19,40.22,33.34,28.52,26.75,26.43,25.92,25.29,22.37,22.22.HRMS(ESI):m / zcalcd for C 31 H 40 N3O + [M+H] + :470.3166; found:470.3234.

[0108] Target compound 9f: Yield 75%; pale yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.07(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,1H),7.60(t,J=7.5Hz,1H),7.47(t,J=7.6Hz,1H),7.22(t,J= 7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.84(d,J=2.4Hz,1H),6.80(dd,J=8.2,2.6Hz,1H),4.36(s,2H),3.88(t,J=6.6Hz,2H),3.25 (d,J=2.5Hz,2H),3.02(d,J=2.4Hz,1H),3.00(t,J=6.7Hz,2H),2.88(s,3H),2.84(t,J=6.4Hz,2H),2.31(t,J=7.2Hz,2H),2.1 6(s,3H),1.86(p,J=6.6Hz,2H),1.76(q,J=6.2Hz,2H),1.66(q,J=7.0Hz,2H),1.37(dt,J=10.6,5.2Hz,4H),1.32–1.26(m,4H). 13 C NMR (150MHz, DMSO) δ159.84,158.67,153.33,147.43,140.78,129.19,128.58,127.95,127.66,125.38,124.72,124.00,120.33,114.07,113 .41,79.09,75.25,67.23,59.29,54.90,44.86,41.19,40.23,40.06,3 3.34,28.48,26.71,26.66,25.92,25.36,22.38,22.23.HRMS(ESI):m / z calcd for C 32 H 42 N3O + [M+H] + :484.3322; found:484.3390.

[0109] Target compound 9g: Yield 66%; light yellow oil; 1H NMR (600MHz, DMSO-d6) δ8.08(d,J=8.4Hz,1H),7.85(dd,J=8.4,1.2Hz,1H),7.60(dd,J=8.4,6.8Hz,1H),7.47(dd,J=8.4,6.9Hz,1 H),7.22(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),6.85(d,J=2.6Hz,1H),6.80(dd,J=8.2,2.6Hz,1H),4.36(s,2H),3.88(td,J=6.6 ,1.6Hz,2H),3.25(d,J=2.4Hz,2H),3.02(t,J=2.3Hz,1H),3.00(t,J=6.7Hz,2H),2.88(s,3H),2.84(t,J=6.4Hz,2H),2.31(t,J=7 .3Hz,2H),2.17(s,3H),1.86(p,J=6.6Hz,2H),1.76(p,J=6.3Hz,2H),1.66(q,J=7.1Hz,2H),1.41–1.35(m,4H),1.32–1.25(m,6H). 13 C NMR (150MHz, DMSO) δ162.84,160.19,158.96,153.98,147.52,141.09,129.66,128.57,127.90,125.61,125.25,124.43,120.70,114.23,113.74 ,79.18,75.98,67.49,59.57,55.16,45.06,41.50,40.58,33.56,29.13, 28.94,28.81,26.99,26.39,25.72,22.73,22.54,22.38.HRMS(ESI):m / z calcd forC 33 H 44 N3O + [M+H] + :498.3479; found:498.3546.

[0110] Target compound 9h: Yield 85%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.88–7.85(m,1H),7.80(d,J=8.5Hz,1H),7.42(dd,J=8.5,1.9Hz,1H),7.23(t,J= 7.8Hz,1H),6.94–6.88(m,2H),6.81(ddd,J=8.2,2.6,1.0Hz,1H),4.36(s,2H),3.95(t,J=6.4Hz,2 H),3.33(d,J=2.4Hz,2H),3.05(t,J=6.7Hz,2H),2.91(s,3H),2.84(t,J=6.3Hz,2H),2.56(t,J=7 .1Hz,2H),2.53(s,3H),2.29(s,3H),2.24(t,J=2.4Hz,1H),1.94–1.87(m,4H),1.83–1.78(m,2H). 13 C NMR (150MHz, CDCl3) δ159.28,158.90,154.83,145.46,140.85,134.91,131.03,129.41,127.80,127.63,125.69,123.37,120.87,1 14.41,113.73,78.48,73.28,65.97,60.47,52.39,45.72,41.75,40.49,33.27,27.48,26.93,22.99,22.73,22.12.HRMS(ESI):m / z calcd for C 29 H 36 N3O + [M+H] + :442.2853; found:442.2918.

[0111] Target compound 9i: Yield 86%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.85(d,J=9.6Hz,2H),7.43(dd,J=8.7,1.9Hz,1H),7.22(q,J=6.7,5.7Hz,1H),6 .93–6.85(m,2H),6.80(dt,J=9.4,4.7Hz,1H),4.38(s,2H),3.91(q,J=6.7Hz,2H),3.32(d,J=2.4 Hz,2H),3.07(q,J=6.6Hz,2H),2.92(s,3H),2.83(q,J=6.5Hz,2H),2.53(s,3H),2.47–2.38(m,2 H),2.27(s,3H),2.24(t,J=2.4Hz,1H),1.94–1.88(m,2H),1.83–1.74(m,4H),1.63–1.56(m,2H). 13 C NMR (150MHz, CDCl3) δ159.53,159.36,153.89,146.73,141.25,134.57,130.54,129.39,128.81,128.09,126.02,123.32,120.92,114. 44,113.72,78.74,73.14,67.68,60.44,55.39,45.66,41.83,40.39,34.04,27.26,26.98,24.29,23.16,23.08,22.18.HRMS(ESI):m / z calcd for C 30 H 38 N3O + [M+H] + :456.3009; found:456.3075.

[0112] Target compound 9j: yield 87%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.86(s,1H),7.80(d,J=8.5Hz,1H),7.42(dd,J=8.5,1.9Hz,1H),7.22(t,J=7.8Hz,1 H),6.94–6.87(m,2H),6.80(dd,J=8.2,2.6Hz,1H),4.36(s,2H),3.90(t,J=6.5Hz,2H),3.31(d,J=2. 4Hz,2H),3.05(t,J=6.7Hz,2H),2.91(s,3H),2.84(t,J=6.3Hz,2H),2.52(s,3H),2.40(t,J=7.0Hz,2 H),2.26(s,3H),2.24(t,J=2.4Hz,1H),1.91(d,J=6.3Hz,2H),1.82–1.75(m,4H),1.53–1.43(m,4H). 13 C NMR (150MHz, DMSO) δ158.78,158.26,154.09,144.87,140.83,134.45,130.85,130.30,129.40,127.36,125.12,123.21,120.51,113.94, 113.62,77.17,69.84,67.16,59.41,54.67,44.70,40.77,40.38,32.72,28.48,26.17,25.74,23.24,22.47,22.19,21.63.HRMS(ESI):m / z calcd for C 31 H 40 N3O + [M+H] + :470.3166; found:470.3232.

[0113] Target compound 9k: yield 78%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.86(dt,J=1.9,0.9Hz,1H),7.83(d,J=8.5Hz,1H),7.43(dd,J=8.5,2.0Hz,1H),7.22(d,J=0.8Hz,1 H),6.91–6.87(m,2H),6.80(ddd,J=8.2,2.6,1.0Hz,1H),4.37(s,2H),3.89(t,J=6.5Hz,2H),3.31(d,J=2.4Hz,2H) ,3.07(t,J=6.7Hz,2H),2.91(s,3H),2.84(t,J=6.3Hz,2H),2.52(s,3H),2.41–2.36(m,2H),2.26(s,3H),2.24(t,J =2.4Hz,1H),1.91(d,J=6.4Hz,2H),1.83–1.78(m,2H),1.78–1.72(m,2H),1.49–1.43(m,4H),1.36(d,J=5.4Hz,2H). 13 C NMR (150MHz, CDCl3) δ159.40,158.08,156.30,143.75,140.35,135.47,131.81,129.54,127.03,126.46,125.30,123.54,120.75,114.43,113 .79,78.27,73.46,67.78,60.64,55.53,45.50,41.73,40.74,32.32,2 9.76,29.22,27.25,26.96,23.99,22.85,22.32,22.13.HRMS(ESI):m / z calcd for C 32 H 42 N3O + [M+H] + :484.3322; found:484.3386.

[0114] Target compound 91: Yield 78%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.89–7.85(m,1H),7.78(d,J=8.5Hz,1H),7.41(dd,J=8.5,1.9Hz,1H),7.22(t,J=7.7Hz, 1H),6.93–6.88(m,2H),6.82–6.77(m,1H),4.35(s,2H),3.89(t,J=6.5Hz,2H),3.30(d,J=2.4Hz,2H),3.0 4(t,J=6.7Hz,2H),2.90(s,3H),2.85(t,J=6.4Hz,2H),2.52(s,3H),2.40–2.34(m,2H),2.25(s,3H),2.2 3(t,J=2.4Hz,1H),1.94–1.89(m,2H),1.84–1.71(m,6H),1.48–1.40(m,4H),1.35(dt,J=9.9,6.5Hz,2H). 13 C NMR(150MHz,CD2Cl2)δ159.83,159.77,153.90,147.00,141.73,134.78, 130.52,129.54,128.98,128.51,126.30,123.65,121.03,114.54,113.9 3,79.43,72.81,68.24,60.59,56.06,45.84,41.84,40.49,34.28,29.69 ,29.66,27.90,27.69,27.21,26.42,23.44,23.35,22.11.HRMS(ESI):m / z calcd forC 33 H 44 N3O + [M+H] + :498.3479; found:498.3545.

[0115] Target compound 9m: Yield 83%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ7.87(s,1H),7.78(d,J=8.5Hz,1H),7.41(dd,J=8.6,1.9Hz,1H),7.22(t,J=7.8Hz,1H),6.92– 6.89(m,2H),6.81–6.77(m,1H),4.35(s,2H),3.89(t,J=6.6Hz,2H),3.30(d,J=2.4Hz,2H),3.04(t,J=6.7Hz, 2H),2.90(s,3H),2.85(t,J=6.3Hz,2H),2.52(s,3H),2.40–2.33(m,2H),2.25(s,3H),2.23(t,J=2.4Hz,1H), 1.94–1.88(m,2H),1.81(t,J=6.1Hz,2H),1.77–1.72(m,2H),1.44(dt,J=10.9,7.2Hz,4H),1.37–1.30(m,6H). 13 C NMR(151MHz,CD2Cl2)δ159.83,159.78,153.89,147.01,141.74,134.78,1 30.51,129.54,129.00,128.51,126.30,123.65,121.03,114.54,113.93,7 9.45,72.78,68.26,60.59,56.09,45.85,41.84,40.49,34.30,29.89,29.7 6,29.68,27.96,27.70,27.21,26.41,23.45,23.36,22.11.HRMS(ESI):m / z calcd for C 34 H 46 N3O + [M+H] + :512.3635; found:512.3701.

[0116] Target compound 9n: Yield 77%; yellow oil; 1H NMR(600MHz,Chloroform-d)δ7.97(dd,J=9.2,5.5Hz,1H),7.70(dd,J=10.5,2.8Hz,1H),7.39–7.33(m,1H),7.25–7.22(m,1H ),6.89(d,J=7.5Hz,1H),6.85(t,J=2.0Hz,1H),6.82(dd,J=8.2,2.4Hz,1H),4.33(s,2H),3.90(t,J=6.5Hz,2H),3.36(d,J=2. 3Hz,2H),3.11(t,J=6.7Hz,2H),2.90(s,3H),2.85(t,J=6.4Hz,2H),2.43(t,J=7.5Hz,2H),2.32(s,3H),2.22(d,J=2.2Hz,1H ),1.96–1.92(m,2H),1.81(d,J=12.6Hz,2H),1.77(q,J=7.1Hz,2H),1.49(dt,J=14.5,7.2Hz,4H),1.38(q,J=7.8,7.4Hz,2H). 13 C NMR (150MHz, CDCl3) δ159.43,153.92,145.15,140.79,131.36,129.50,128.87,126.88,120.81,118.52,118.35,115.88,113.80,107.88, 107.73,78.74,73.12,67.93,60.20,55.74,45.62,41.88,40.18,33.95,29.36,27.65,27.30,27.01,26.13,22.98,22.94.HRMS(ESI):m / z calcd for C 31 H 39 FN3O + [M+H] + :488.3072; found:488.3133.

[0117] Target compound 9o: yield 77%; yellow oil; 1H NMR(600MHz,Chloroform-d)δ7.96(dd,J=9.2,5.4Hz,1H),7.70(dd,J=10.5,2.8Hz,1H),7.36(td,J=8.6,2.8Hz,1H),7 .24(t,J=7.9Hz,1H),6.88(d,J=7.5Hz,1H),6.86(d,J=2.5Hz,1H),6.82(dd,J=8.1,2.5Hz,1H),4.32(s,2H),3.90(t,J =6.6Hz,2H),3.34(d,J=2.5Hz,2H),3.11(t,J=6.7Hz,2H),2.90(s,3H),2.84(t,J=6.4Hz,2H),2.44–2.37(m,2H),2.30 (s,3H),2.21(t,J=2.4Hz,1H),1.94(p,J=6.5Hz,2H),1.83–1.73(m,4H),1.45(q,J=9.5Hz,4H),1.34(d,J=9.7Hz,6H). 13 C NMR (150MHz, CDCl3) δ159.46,153.93,145.16,140.78,131.30,129.50,1 28.88,126.89,120.79,118.52,118.35,114.46,113.80,107.89,107.73 ,78.78,73.08,68.02,60.22,55.86,45.61,41.89,40.19,33.96,29.61, 29.44,29.38,27.71,27.48,27.01,26.12,22.98,22.94.HRMS(ESI):m / z calcd for C 33 H 43 FN3O + [M+H] + :516.3385; found:516.3446.

[0118] Target compound 10a: yield 37%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.4,1.4Hz,1H),7.89(d,J=8.4Hz,1H),7.57(ddd,J=8.5,6.8,1.5Hz,1H ),7.43(ddd,J=8.2,6.7,1.3Hz,1H),7.34–7.28(m,4H),4.47(s,2H),4.40(s,2H),3.51(t,J=6.5Hz ,2H),3.31(d,J=2.4Hz,2H),3.10–3.04(m,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),2.50–2.46(m,2 H),2.27(s,3H),2.24(t,J=2.4Hz,1H),1.93(p,J=6.6Hz,2H),1.84–1.79(m,2H),1.77–1.73(m,2H). 13 C NMR (150MHz, CDCl3) δ158.20,154.44,150.89,138.41,137.20,130.08,129.52,128.68,128.17,127.25,126.47,125.92,1 25.04,79.07,72.72,70.70,68.60,60.77,52.69,45.46,41.47,41.33,32.06,29.84,27.38,27.16,22.67.HRMS(ESI):m / z calcd for C 29 H 36 N3O + [M+H] + :442.2853; found:442.2902.

[0119] Target compound 10b: Yield 89%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.3,1.4Hz,1H),7.89(d,J=8.4Hz,1H),7.57(ddd,J=8.3,6.7,1.4Hz,1H),7.4 3(ddd,J=8.1,6.7,1.3Hz,1H),7.34–7.27(m,4H),4.47(s,2H),4.40(s,2H),3.49(t,J=6.4Hz,2H),3.30( d,J=2.4Hz,2H),3.07(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),2.42–2.37(m,2H),2.26(s,3H ),2.23(t,J=2.4Hz,1H),1.93(p,J=6.6Hz,2H),1.84–1.79(m,2H),1.63–1.60(m,2H),1.54–1.49(m,2H). 13 C NMR (150MHz, CDCl3) δ159.44,157.88,142.44,138.46,137.19,131.09,129.34,128.66,128.14,126.41,125.87,125.03,124. 55,74.84,72.68,70.68,70.34,60.74,55.27,45.20,41.31,32.04,29.82,27.50,27.14,23.76,22.66,21.67.HRMS(ESI):m / z calcd for C 30 H 38 N3O + [M+H] + :456.3009; found:456.3069.

[0120] Target compound 10c: yield 80%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.11–8.08(m,1H),7.89(dd,J=8.4,1.3Hz,1H),7.57(ddd,J=8.4,6.8,1.5Hz,1H),7.43(ddd,J=8.2 ,6.7,1.3Hz,1H),7.34–7.28(m,4H),4.46(s,2H),4.40(s,2H),3.47(t,J=6.6Hz,2H),3.30(d,J=2.4Hz,2H),3.07(t ,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),2.40–2.34(m,2H),2.25(s,3H),2.23(t,J=2.4Hz,1H),1.93(p,J =6.6Hz,2H),1.82(ddt,J=12.1,9.1,4.4Hz,2H),1.63–1.61(m,2H),1.45(tt,J=7.4,5.9Hz,2H),1.41–1.36(m,2H). 13 C NMR (150MHz, CD2Cl2) δ160.95,154.52,148.41,139.15,138.33,129.18,128.96,128.47,128.36,128.06,126.38,125.05,124.81 ,79.40,72.96,72.83,70.86,60.37,55.98,45.85,41.84,40.47,34.40,30.08,27.77,27.22,24.40,23.40,23.30.HRMS(ESI):m / z calcd for C 31 H 40 N3O + [M+H] + :470.3166; found:470.3224.

[0121] Target compound 10d: Yield 64%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.4,1.4Hz,1H),7.92–7.86(m,1H),7.57(ddd,J=8.3,6.7,1.4Hz,1H),7.43(ddd,J=8. 2,6.7,1.3Hz,1H),7.35–7.26(m,4H),4.46(s,2H),4.39(s,2H),3.46(t,J=6.6Hz,2H),3.29(d,J=2.4Hz,2H),3.0 7(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),2.40–2.33(m,2H),2.25(s,3H),2.24–2.22(m,2H),1.93(p ,J=6.6Hz,2H),1.82(q,J=6.1Hz,2H),1.70–1.68(m,2H),1.61–1.59(m,2H),1.44–1.42(m,2H),1.41–1.37(m,2H). 13 CNMR(150MHz, CDCl3)δ158.82,157.25,144.62,138.10,137.64,129.82,128.55,127.88,126.60,126.15,125.68,125.02,124.68,74.04 ,72.56,70.57,60.37,55.44,45.19,41.42,40.76,32.70,32.06,29.64,27.14,26.92,26.05,25.65,22.69,22.07.HRMS(ESI):m / zcalcd for C 32 H 42 N3O + [M+H] + :484.3322; found:484.3378.

[0122] Target compound 10e: yield 37%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.11–8.07(m,1H),7.89(d,J=8.4Hz,1H),7.57(ddd,J=8.3,6.7,1.4Hz,1H),7.43(ddd,J=8.3, 6.8,1.3Hz,1H),7.33–7.27(m,4H),4.46(s,2H),4.39(s,2H),3.46(t,J=6.6Hz,2H),3.29(d,J=2.4Hz,2H),3.0 7(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.3Hz,2H),2.36(dd,J=8.2,6.7Hz,2H),2.24(s,3H),2.22(t,J=2.4 Hz,1H),1.93(p,J=6.5Hz,2H),1.82(q,J=6.1Hz,2H),1.62–1.58(m,6H),1.44–1.41(m,2H),1.32–1.30(m,2H). 13 C NMR (150MHz, DMSO) δ159.47,154.42,146.56,138.17,137.69,128.64,128.36,128.24,127.57,127.36,126.58,125.17,124.36,77.48,71. 66,69.62,62.74,59.22,54.70,44.60,40.62,40.31,32.99,29.20,28.65,26.55,26.17,25.69,22.46,22.19,22.18.HRMS(ESI):m / zcalcd for C 33 H 44 N3O + [M+H] + :498.3479; found:498.3526.

[0123] Target compound 10f: Yield 51%; yellow oil; 1H NMR(600MHz,Methylene Chloride-d2)δ8.09(dd,J=8.5,1.4Hz,1H),7.89(dd,J=8.5,1.3Hz,1H),7.57(ddd,J=8.4,6.7,1.5Hz,1H),7.43(dd d,J=8.2,6.7,1.3Hz,1H),7.34–7.27(m,4H),4.46(s,2H),4.39(s,2H),3.46(t,J=6.6Hz,2H),3.29(d,J=2.5Hz,2H) ,3.07(t,J=6.7Hz,2H),2.90(s,3H),2.86(t,J=6.4Hz,2H),2.39–2.32(m,2H),2.24(s,3H),2.22(t,J=2.4Hz,1H),1 .93(p,J=6.6Hz,2H),1.85–1.78(m,2H),1.73–1.65(m,4H),1.62–1.57(m,2H),1.45–1.39(m,2H),1.39–1.32(m,4H). 13 C NMR (150MHz, CDCl3) δ160.14,155.39,147.12,138.48,137.95,128.81,128.75,128.27,127.93,127.63,125.80,125.23,124.55,78.51,73. 31,72.78,70.80,60.31,55.82,45.54,41.82,40.48,29.88,29.83,29.61,29.55,27.60,27.48,27.02,26.29,23.04,22.81.HRMS(ESI):m / z calcd for C 34 H 46 N3O + [M+H] + :512.3635; found:512.3688.

[0124] Target compound 10g: Yield 29%; light yellow oil; 1H NMR(600MHz,Chloroform-d)δ8.01(d,J=8.6Hz,1H),7.79(s,1H),7.46(d,J=8.5Hz,1H),7.32(d ,J=7.8Hz,2H),7.28(d,J=7.9Hz,2H),4.51(s,2H),4.42(s,2H),3.55(t,J=6.5Hz,2H),3.36(d, J=2.9Hz,2H),3.19(t,J=6.7Hz,2H),2.92(s,3H),2.80(t,J=6.3Hz,2H),2.55(t,J=7.4Hz,2H), 2.53(s,3H),2.32(s,3H),2.22(q,J=2.0Hz,1H),1.92(q,J=6.7,6.2Hz,2H),1.84–1.77(m,4H). 13 CNMR(150MHz, CDCl3)δ158.72,157.73,145.05,138.46,137.82,135.21,131.37,128.77,127.95,127.92,127.51,125.60,123.43 ,78.54,73.34,72.84,68.80,60.36,52.74,45.71,41.80,40.52,29.84,27.94,26.99,23.00,22.66,22.21.HRMS(ESI):m / zcalcd forC 30 H 38 N3O + [M+H] + :456.3009; found:456.3047.

[0125] Target compound 10h: Yield 42%; light yellow oil; 1H NMR(600MHz,Chloroform-d)δ8.11(d,J=8.7Hz,1H),7.79(s,1H),7.49(dd,J=8.7,1.9Hz,1H),7.32(d,J=7 .8Hz,2H),7.27(d,J=5.1Hz,2H),4.51(s,2H),4.45(s,2H),3.52(t,J=6.4Hz,2H),3.36(d,J=2.4Hz,2H),3. 24(t,J=6.7Hz,2H),2.95(s,3H),2.79(t,J=6.3Hz,2H),2.53(s,3H),2.50–2.45(m,2H),2.33(s,3H),2.22( t,J=2.4Hz,1H),1.93(dt,J=13.1,6.7Hz,2H),1.80(p,J=6.2Hz,2H),1.69–1.64(m,2H),1.61–1.56(m,2H). 13 C NMR (150MHz, CDCl3) δ159.09,156.22,144.03,138.12,138.07,135.56,131.86,128.74,127.96,127.14,126.58,125.38,123.52, 78.40,73.42,72.75,70.48,60.48,55.53,45.56,41.75,40.69,29.83,27.65,27.00,24.32,22.91,22.40,22.20.HRMS(ESI):m / z calcd for C 31 H 40 N3O + [M+H] + :470.3166; found:470.3222.

[0126] Target compound 10i: Yield 61%; pale yellow oil; 1H NMR(600MHz,Chloroform-d)δ7.92(d,J=8.5Hz,1H),7.80(s,1H),7.42(dd,J=8.5,1.9Hz,1H),7.33–7.26 (m,4H),4.49(s,2H),4.38(s,2H),3.48(t,J=6.6Hz,2H),3.33(d,J=2.4Hz,2H),3.13(t,J=6.7Hz,2H),2. 89(s,3H),2.80(t,J=6.4Hz,2H),2.51(s,3H),2.44–2.38(m,2H),2.29(s,3H),2.20(t,J=2.4Hz,1H),1.9 2(p,J=6.5Hz,2H),1.79(p,J=6.2Hz,2H),1.65(p,J=6.8Hz,2H),1.48(p,J=7.2Hz,2H),1.44–1.36(m,2H). 13 C NMR (150MHz, CDCl3) δ159.14,154.42,146.00,138.64,137.73,134.77,130.80,128.74,128.21,127.85,127.83,125.81,123.29,78. 61,73.16,72.81,70.56,60.22,55.67,45.55,41.83,40.33,33.59,29.73,27.46,26.91,24.12,23.04,22.86,22.14.HRMS(ESI):m / z calcd for C 32 H 42 N3O + [M+H] + :484.3322; found:484.3375.

[0127] Target compound 10j: Yield 82%; light yellow oil; 1H NMR(600MHz,Chloroform-d)δ8.01(d,J=8.6Hz,1H),7.78(s,1H),7.45(dd,J=8.6,1.9Hz,1H),7.33–7.25(m,4H) ,4.49(s,2H),4.41(s,2H),3.48(t,J=6.7Hz,2H),3.34(d,J=2.4Hz,2H),3.18(t,J=6.7Hz,2H),2.92(s,3H),2.79 (t,J=6.4Hz,2H),2.52(s,3H),2.43–2.38(m,2H),2.30(s,3H),2.20(t,J=2.4Hz,1H),1.92(p,J=6.6Hz,2H),1.79 (p,J=6.0Hz,2H),1.63(p,J=6.8Hz,2H),1.46(p,J=7.5Hz,2H),1.39(p,J=7.0Hz,2H),1.33(q,J=8.4,7.8Hz,2H). 13 C NMR (150MHz, CDCl3) δ158.63,155.33,144.93,138.34,137.92,135.14,131.31,128.72,127.92,127.89,127.43,125.54,123.40,78.47, 73.28,72.74,70.67,60.33,55.71,45.52,41.80,40.49,33.02,29.80,27.56,27.35,26.94,26.24,22.96,22.61,22.16.HRMS(ESI):m / z calcd forC 33 H 44 N3O + [M+H] + :498.3479; found:498.3529.

[0128] Target compound 10k: Yield 61%; pale yellow oil; 1H NMR(600MHz,Chloroform-d)δ8.31(d,J=8.6Hz,1H),7.75(s,1H),7.53(d,J=8.6Hz,1H),7.32(d,J=7.7Hz,2H), 7.22(d,J=7.6Hz,2H),4.50(s,2H),4.49(s,2H),3.51–3.45(m,2H),3.42(d,J=2.5Hz,2H),3.35(t,J=6.7Hz,2H) ,2.99(s,3H),2.74(t,J=6.3Hz,2H),2.52(s,3H),2.49(t,J=7.7Hz,2H),2.37(s,3H),2.27(t,J=2.4Hz,1H),1. 92(p,J=6.6Hz,2H),1.79(p,J=6.0Hz,2H),1.62(p,J=6.7Hz,2H),1.50(q,J=7.0,6.5Hz,2H),1.38–1.31(m,6H). 13 C NMR (150MHz, CDCl3) δ157.93,156.65,143.34,138.22,137.91,135.73,132.12,128.72,127.98,126.95,126.10,125.25,123.57,77.80,73. 89,72.72,70.81,60.52,55.60,45.29,41.54,40.75,32.03,29.81,29.46,27.42,27.20,27.00,26.25,22.84,22.25,22.19.HRMS(ESI):m / z calcd forC 34 H 46 N3O + [M+H] + :512.3635; found:512.3678.

[0129] Target compound 101: Yield 65%; light yellow oil; 1H NMR(600MHz,Chloroform-d)δ8.03(s,1H),7.79(s,1H),7.51–7.41(m,1H),7.32(d,J=8.0Hz,2H),7.28(d,J= 7.9Hz,2H),4.50(s,2H),4.42(s,2H),3.48(t,J=6.7Hz,2H),3.35(d,J=2.4Hz,2H),3.20(s,2H),2.93(s,3H), 2.80(t,J=6.3Hz,2H),2.53(s,3H),2.45–2.38(m,2H),2.31(s,3H),2.22(t,J=2.4Hz,1H),1.93(p,J=6.6Hz,2 H),1.82–1.77(m,2H),1.62(p,J=6.8Hz,2H),1.46(q,J=7.5Hz,2H),1.37(t,J=7.3Hz,2H),1.34–1.30(m,6H). 13 C NMR (150MHz, CDCl3) δ158.05,156.59,143.62,138.19,137.97,135.64,131.99,128.72,127.97,127.03,126.32,125.31,123.55,77.89,73.81, 72.72,70.85,60.49,55.65,45.32,41.58,40.71,32.19,29.85,29.55, 29.51,27.42,27.28,26.99,26.26,22.86,22.31,22.19.HRMS(ESI):m / z calcd forC 35 H 48 N3O + [M+H] + :526.3792; found:526.3851.

[0130] Example 7: Preparation of Target Compound 9h and Target Compound 10d

[0131] Compound 7h (2.32 mmol, 1.0 equiv.) was dissolved in chlorobenzene (30 mL), and compound 4 (4.64 mmol, 2.0 equiv.) was added, followed by potassium hydroxide (11.60 mmol, 5.0 equiv.). The mixture was stirred at reflux at 100°C for 8 h (TLC monitoring). After the reaction, the chlorobenzene was dried under vacuum, and an appropriate amount of water was added. The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (DCM / MeOH: 20 / 1 to 10 / 1, v / v) to obtain a yellow oil in 66% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the target compound 9h.

[0132] Compound 8d (2.32 mmol, 1.0 equiv.) was dissolved in ethanol (30 mL), and compound 4 (4.64 mmol, 2.0 equiv.) was added, followed by sodium tert-butoxide (11.60 mmol, 5.0 equiv.). The mixture was stirred at reflux at 70°C for 10 h (TLC monitoring). After the reaction, the ethanol was dried under vacuum, and an appropriate amount of water was added. The aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product, free of excess solvent, was purified by column chromatography (PE / EA: 1 / 1 to 1 / 3, v / v) to afford a yellow oil in 43% yield. Characterization by H NMR, C NMR, and high-resolution mass spectrometry confirmed the target compound 10d.

[0133] Experimental Example 1: Study on the AChE / BuChE inhibitory activity of target compounds 9a-9o and 10a-10l

[0134] The inhibitory activity of the target compounds against AChE or BuChE was evaluated using Ellman spectrophotometry.

[0135] AChE (EC3.1.1.7, from electric eel and human), BuChE (EC3.1.1.8, from horse serum and human), 5,5′-dithiobis-(2-nitrobenzoic acid) (Ellman's reagent, DTNB), S-butylthiocholine iodide (BTCI), acetylthiocholine iodide (ATCI), and donepezil were purchased from Sigma-Aldrich. The specific steps were as follows: First, the test compound was dissolved in DMSO and diluted to the desired concentration (DMSO concentration less than 1%) with Tis-HCl buffer (pH = 8.0). 160 μL of DTNB (1.5 mM), 50 μL of AChE (0.22 U / mL), and 10 μL of the test drug were added sequentially to a 96-well plate and incubated at 37°C for 6 minutes. Then, 30 μL of ATCI (15 mM) was added as a substrate, and the absorbance change at 405 nm was measured (0, 60, 120, and 180 seconds) in a microplate reader (SpectraMax Plus 384, Molecular devices, CA, USA). Inhibition rate = [1-(absorbance change of experimental group / absorbance change of blank group)] * 100%. The determination of butyrylcholinesterase activity simply requires replacing AChE with BuChE and changing the substrate to thiobutyrylcholine (BTCI). Other procedures are the same. The molar concentration of the compound that provides 50% inhibition is calculated using Graph Pad Prism version 7.00 software (GraphPad Software, San Diego, CA), which is the compound's IC. 50 Each experiment was repeated three times, and the results are expressed as mean ± SD. The results are shown in Tables 1 and 2.

[0136] Table 1. Inhibitory activity of compounds 9a-9o and 10a-10l against electric eel cholinesterase and human monoamine oxidase

[0137]

[0138]

[0139] a The results are expressed as the mean (n=3) ± SD of three independent experiments.

[0140] b na means no activity. “No activity” for a compound means that the inhibition rate is less than 45% under the test conditions at a concentration of 100 μM.

[0141] cnt. means not determined.

[0142] d Selectivity index of eeAChE: IC 50 (eqBuChE) / IC 50 (eeAChE).

[0143] e Selectivity index of hMAO-B: IC 50 (hMAO-A) / IC 50 (hMAO-B).

[0144] Table 2. Human cholinesterase activity of some compounds

[0145]

[0146]

[0147] a The results are expressed as the mean (n=3) ± SD of three independent experiments.

[0148] b Selectivity index of hAChE: IC 50 (hBuChE) / IC 50 (hAChE).

[0149] As can be seen from Table 1, the vast majority of compounds are effective inhibitors of AChE and BuChE. The inhibitory activity of compounds 9a-g, 9h-m, 10a-f, and 10g-l against AChE generally decreases with increasing carbon chain length. In contrast, in general, compounds with short carbon chains have relatively poor BuChE inhibitory activity. Among compounds 9h-m, compound 9h with a 3-carbon spacer has the strongest inhibitory activity against AChE (IC 50 =5.36±0.13 μM), but at this carbon chain length, the inhibitory activity against BuChE (IC 50 =9.90±0.29%μM) compared with the reference drug donepezil (eeAChE:IC 50 =0.043±0.002μM, eqBuChE:IC 50 =3.50±0.18μM) was about 3-fold lower. Interestingly, compounds containing 4, 5, and 6 methylene spacers showed good and balanced inhibitory activity against both AChE and BuChE, especially 10d (eeAChE:IC 50=8.76±0.12μM, eqBuChE: 0.46±0.24%μM). Furthermore, the introduction of different substituents at the 7-position of tacrine affects the compound's inhibitory activity against ChEs. As shown in Table 1, the introduction of a methyl group at the 7-position of tacrine showed a less pronounced difference in AChE inhibitory potency, but resulted in a decrease in the compound's inhibitory activity against BuChE. However, the introduction of a fluorine atom as an electron-withdrawing group at the 7-position of tacrine significantly reduced the inhibitory activity of compounds (9n-o) against both AChE and BuChE. Furthermore, by comparing the target compounds (9b-g vs. 10a-f and 9h-m vs. 10g-l), we also explored the SARS of the phenyl ring linking the tacrine and selegiline moieties. The results showed that, overall, compounds with benzyloxy linkages (10a-l) exhibited higher AChE inhibitory activity than compounds with phenol ether linkages (9b-m), with a particularly pronounced trend for chain lengths of 4 to 6. However, the inhibitory activity against BuChE is divided into two situations. For compounds with unsubstituted tacrine at the 7-position, changes in the linked benzyl ring have little effect on the inhibitory activity of BuChE; but for compounds with methyl substitution at the 7-position of tacrine, compounds linked with benzyloxy have stronger BuChE inhibitory activity.

[0150] In order to more accurately determine the cholinesterase activity of the target compounds, we chose to further determine the activity of some compounds 9a-g, 10b-d and 10h-j on human cholinesterase. As shown in Table 2, most compounds showed stronger inhibitory activity against human cholinesterase than electric eel cholinesterase. Taking into account the results of the assays on human cholinesterase and electric eel cholinesterase, most hybrids showed a good balance of AChE / BuChE inhibitory activity, especially 10d, which had the most balanced inhibitory activity against diacetylcholinesterase (IC 50 =8.76±0.12μM for eeAChE,IC 50 =0.46±0.24%μMfor eqBuChE; IC 50 =1.57±0.13%μM for hAChE,IC 50 =0.43±0.12 μM for hBuChE), which may show greater therapeutic potential in AD.

[0151] Experimental Example 2: Study on the hMAO-A / hMAO-B Inhibitory Activity of Target Compounds 9a-9o and 10a-101

[0152] The inhibitory effects of target compounds on MAO activity were determined by Amplex Red fluorescence assay, using rasagiline and iproniazid as control drugs. Monoamine oxidase (EC1.4.3.4), Amplex Red reagent, horseradish peroxidase (HRP), as well as rasagiline and iproniazid, were purchased from Sigma-Aldrich. The specific experimental procedures are as follows: Test compounds dissolved in DMSO were diluted in PBS buffer (0.05 M, pH 7.4) to various final concentrations (DMSO concentration less than 1%). Test compounds (20 μL) of various concentrations were incubated with PBS buffer containing hMAO-A or hMAO-B (80 μL) in the dark at 37°C for 15 minutes. The reaction was then initiated by adding 200 μM 10-acetyl-3,7dihydroxyphenoxazine reagent (Amplex Red assay kit), 1 U / mL horseradish peroxidase, and 1 mM tyramine. After the reaction, fluorescence changes in each solution were recorded over 20 minutes using a microplate reader (SpectraMax Plus 384, Molecular Devices, CA, USA). The detection conditions were an excitation wavelength of 545 nm and an emission wavelength of 590 nm. Inhibition rate = [1 - (fluorescence change in experimental group / fluorescence change in blank group)] × 100%. Results are expressed as the mean ± SD of three independent experiments. See Table 1 for the results.

[0153] As shown in Table 1, most of the synthesized compounds have effective inhibitory effects on MAO-A and MAO-B. 50 =65.61±1.12μM,6o:hMAO-B IC 50 =71.39±1.34μM), the other compounds (IC 50 The inhibitory activity of the drug against MAO-B was weaker than that of rasagiline (IC 50 =0.23±0.003μM), but were stronger than iproniazid (IC 50 =7.54±0.23μM). The analysis of the monoamine oxidase inhibitory activity of all the hybrids showed that there was an 8-carbon spacer between tacrine and selegiline (IC 50 =0.22±0.67%μM for hMAO-A) and 9m (IC 50=1.12±3.12%μM for hMAO-B) showed the strongest inhibitory potency against MAO-A and MAO-B, respectively. However, in general, compounds with a linker length of 5 or 6 carbon atoms (9e, 9j~k, 10c~d and 10i~j) were strong MAO-A / B inhibitors, some of which showed submicromolar activity against MAO-A. In addition, the introduction of a methyl group at the 7-position of tacrine had little effect on the MAO-A and MAO-B inhibitory activities of the phenol ether-linked compounds (9b~g, 9h~m), while for the benzyloxy-linked compounds (10a~f, 10g~l), their IC values ​​for inhibiting MAO-B were significantly higher than those for the phenol ether-linked compounds (9b~g, 9h~m). 50 The values ​​did not change significantly, but the inhibitory effect on MAO-A was significantly enhanced. Notably, substitution of a fluorine atom at the 7-position of tacrine significantly reduced the inhibitory potency against MAO-A / B, following the same trend as ChEs. Furthermore, overall, compounds with benzyloxy linkages showed stronger inhibitory activity against MAO-A, while compounds with phenol ether linkages showed greater inhibitory activity against MAO-B.

Claims

1. A tacrine-selegiline derivative having a structure represented by the following formula 9 or 10, or a pharmaceutically acceptable salt thereof: 、 ； in, R1 represents a hydrogen atom, a methyl group or a fluorine atom, and n = 2 to 8.

2. The tacrine-selegiline derivative according to claim 1, characterized in that: In formula 9, R1 represents a hydrogen atom, a methyl group or a fluorine atom, and n = 2 to 8; In formula 10, R1 represents a hydrogen atom or a methyl group, and n = 3 to 8.

3. The tacrine-selegiline derivative according to claim 1, characterized in that: In formula 10, R1 is a hydrogen atom, and n = 6.

4. The method for preparing the tacrine-selegiline derivative according to claim 1, characterized in that: The following steps are involved: 1) placing a compound represented by the following formula 1 and a compound represented by the following formula 2 in an organic solvent and reacting them under heating conditions to obtain a compound represented by the following formula 5; 2) placing the compound of Formula 5 in an organic solvent and performing a nitrogen methylation reaction to obtain a compound of Formula 6; 3) placing the compound represented by Formula 6 and the compound represented by the following Formula 3 in an organic solvent, adding an alkaline reagent to react to obtain a compound represented by Formula 7 or Formula 8; 4) placing the compound represented by Formula 7 or Formula 8 and the compound represented by the following Formula 4 in an organic solvent, adding an alkaline reagent to react to obtain a compound represented by Formula 9 or Formula 10; ； In the above formulae, R1 represents a hydrogen atom, a methyl group or a fluorine atom, R2 represents a 3-hydroxyl group or a 4-hydroxymethyl group, and n = 2 to 8.

5. The preparation method according to claim 4, characterized in that: In step 1), a catalyst is added before the reaction.

6. The preparation method according to claim 4, characterized in that: In step 2), a nitrogen methylation reaction is carried out by adding a methylating agent.

7. The preparation method according to claim 6, characterized in that: In step 2), the methylating agent is one or a combination of two or more selected from formaldehyde, dimethyl sulfate and dimethyl carbonate; When the methylating agent is formaldehyde or contains formaldehyde, the reaction is carried out under acidic conditions and a reducing agent needs to be added; When the methylating agent is dimethyl sulfate and / or dimethyl carbonate, the reaction is carried out under alkaline conditions.

8. The preparation method according to claim 4, characterized in that: In the above steps, the organic solvent involved is one or a combination of two or more selected from dichloromethane (DCM), 1,2-dichloroethane (DCE), chloroform, chlorobenzene, N,N-dimethylformamide (DMF), acetonitrile, n-pentanol, n-butanol and tert-butanol; In the above steps, the alkaline reagent involved is one or a combination of two or more selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium hydroxide and potassium hydroxide.

9. The preparation method according to any one of claims 4 to 8, characterized in that: The method further includes the step of purifying the prepared compound having the structure shown in Formula 9 or Formula 10.

10. Use of the tacrine-selegiline derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a preparation for treating cholinesterase, or in the preparation of a preparation for treating monoamine oxidase, or in the preparation of a preparation for treating a disease related to cholinesterase and monoamine oxidase, wherein the disease is Alzheimer's disease.

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