Preparation method and application of tacrine derivative

Abstract

The invention discloses a preparation method and application of tacrine derivatives, and belongs to the field of medicinal chemistry. The invention discloses a general formula of a tacrine derivative and four preparation routes of the tacrine derivative, and the obtained tacrine derivative or pharmaceutically acceptable salt of the tacrine derivative is combined with a carrier and an excipient to obtain a pharmaceutical composition. An enzymatic activity test on AChE shows that the compound has remarkable AChE activity inhibition effect, cell experiments show that when the concentration of the compound is 25 mu M, the survival rate of PC12 cells is higher than 80%, the compound has low cytotoxicity, when the concentration of H2O2 is 200 mu M, the cell survival rate is higher than 60%, the compound has good antioxidant activity, and the compound can be used for preparing a medicine for inhibiting AChE activity. The compound shows satisfactory anti-inflammatory activity in an LPS (Lipopolysaccharide)-induced NO production experiment. Therefore, the research result of the project has important significance in AD treatment targets and drug research and development.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a preparation method and application of a tacrine derivative. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease with an insidious onset and progressive development. The disease is more common in people over 65 years old. The prevalence of AD in people over 65 years old in my country has reached 5.9%, accounting for about 25% of the world's total. At present, the pathogenic mechanism of AD is still unclear, but researchers have also proposed some hypotheses for the pathological and biochemical mechanism of AD, such as the Tau protein theory, the Aβ protein theory, the calcium ion imbalance theory, the central cholinergic damage theory, the inflammatory immune theory, the mitochondrial cascade theory, etc.

[0003] At present, the drugs approved by the United States Food and Drug Administration (FDA) for the treatment of AD are mainly divided into the following categories: Acetylcholinesterase (AChE) inhibitors - Donepezil, Galantamine, Rivastigmine; N-methyl-D-aspartate receptor (NMDA) antagonist - Memantine; Aduanumab, the first monoclonal antibody drug, was launched in 2021. In addition, Sodium Oligomannate, an AD treatment drug targeting the brain-gut axis, was launched in China in 2019. In recent years, the research direction of AD treatment drugs has mainly targeted Aβ and Tau. Direct targeting of soluble Aβ can be divided into the following categories: γ-secretase inhibitors - Semagacestat; β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors - Verubecestat; anti-Aβ antibodies - solanezumab, crenezumab, bapineuzumab, gantenerumab, aducanumab, etc. 15 potential therapeutic drugs designed to target the role of Aβ in AD in various ways, including inhibiting enzymes involved in Aβ production and using antibodies to clear Aβ from the brain, have been verified in Phase III trials. However, as of May 2022, 13 of them have clearly failed to demonstrate clinical efficacy, and Swiss pharmaceutical company Roche disclosed in November 2022 that its anti-amyloid drug gantenerumab failed in Phase III trials. Aducanumab, an Aβ-targeting monoclonal antibody developed by Biogen and Eisai, has been approved by the FDA, becoming the seventh FDA-approved drug for the treatment of Alzheimer's disease. Anti-AD drugs targeting Tau protein are currently in the initial stage of research, and clinical trials of multiple drugs are underway.

[0004] In the biomedical field, effective treatment of AD has always been a major problem that has plagued mankind. Clinically used drugs can only alleviate the symptoms of AD patients, and there is still a lack of specific drugs or related therapies to delay the progression of the disease. Summary of the invention

[0005] The present invention designs and synthesizes a series of tacrine derivatives, and the results of in vitro tests on AChE inhibitory activity, antioxidant activity and anti-inflammatory activity show that the series of compounds have good biological activity and can be used as candidate drugs for Alzheimer's disease.

[0006] The present invention provides a tacrine derivative, as shown in general formula I:

[0007]

[0008] wherein n1, n2, and n3 are integers arbitrarily selected from 1 to 4; X is a N or O atom; Y is a 5-10 membered saturated or partially saturated heterocyclic group, wherein the heterocyclic group is substituted by 1 to 3 heteroatoms selected from N, O, and S;

[0009] R 1 is one of C1-C5 alkyl, phenyl C1-C3 alkyl, 3-10-membered saturated or partially saturated cycloalkyl C1-C3 alkyl, 5-10-membered heterocyclic or heteroaryl C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 3-10-membered saturated or partially saturated cycloalkyl C0-C3 alkylformyl, 5-10-membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl; wherein phenyl, cycloalkyl, heterocyclic and heteroaryl are optionally substituted by 0-3 R 3 replace;

[0010] R 2 It is one of hydroxyl, thiol, amino or ester or amide formed by connecting with acid; wherein the acid is arbitrarily selected from C1-C5 straight chain or branched alkyl formic acid, C1-C5 straight chain or branched alkyl sulfinic acid, C1-C5 straight chain or branched alkyl sulfonic acid, 5-10 membered heterocyclyl C0-C3 alkyl formic acid, 5-10 membered heterocyclyl C0-C3 alkyl sulfinic acid, 5-10 membered heterocyclyl C0-C3 alkyl sulfonic acid, 5-10 membered heteroaryl C0-C3 alkyl formic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfinic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfonic acid.

[0011] The R 3 Selected from halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) acyl, nitro, cyano.

[0012] Preferably, in the general formula I, n1, n2, and n3 are integers arbitrarily selected from 1 to 2;

[0013] X is a N or O atom;

[0014] Y is selected from a 5-10 membered saturated or partially saturated heterocyclic group, wherein the heterocyclic group is substituted by 1-3 heteroatoms selected from N, O and S;

[0015] R 1 is C1-C5 alkyl, phenyl C1-C3 alkyl, 5-10 membered heterocyclic or aromatic heterocyclic C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl;

[0016] R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight or branched alkyl carboxylic acid, C1-C5 straight or branched alkyl sulfonic acid, 5-10 membered heterocyclyl C0-C3 alkyl carboxylic acid, 5-10 membered heterocyclyl C0-C3 alkyl sulfonic acid, 5-10 membered heteroaryl C0-C3 alkyl carboxylic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfonic acid.

[0017] Further preferably, in the general formula I, X is a N atom;

[0018] Y is a 5-10 membered saturated or partially saturated heterocyclic group, which is substituted by 1-2 heteroatoms selected from N, O and S;

[0019] R 1 is phenyl C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl;

[0020] R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight or branched chain alkylcarboxylic acid, 5-10 membered heterocyclic C0-C3 alkylcarboxylic acid.

[0021] More preferably, in the general formula I, R 1 is phenyl C1-C3 alkyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl;

[0022] R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight or branched chain alkyl carboxylic acid.

[0023] More preferably, in the general formula I, Y is a 5-10 membered saturated or partially saturated heterocyclic group, and the heterocyclic group contains 1-2 heteroatoms selected from N or O;

[0024] R 1 is phenyl C1-C3 alkyl, phenyl C0-C3 alkylformyl;

[0025] R 2 It is hydroxyl.

[0026] Finally, preferably, the compound in the general formula I is any one of the following compounds:

[0027] 1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol;

[0028] 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)propan-2-ol;

[0029] 1-(4-(3,5-bis(trifluoromethyl)benzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol;

[0030] 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)propan-2-ol;

[0031] 1-(4-Benzylpiperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol;

[0032] 1-(4-(2,5-difluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol;

[0033] (2-Fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0034] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(2,4,5-trifluorophenyl)methanone;

[0035] (2,4-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone;

[0036] (2,6-dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone;

[0037] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3,4,5-trifluorophenyl)methanone;

[0038] (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0039] (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-trifluoromethoxyphenyl)methanone;

[0040] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone;

[0041] (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone;

[0042] (5-fluoro-2-methylphenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone;

[0043] (4-chlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0044] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(p-tolyl)methanone;

[0045] (4-Fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0046] (2,3-Dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone;

[0047] (4-(Chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0048] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3-trifluoromethylphenyl)methanone;

[0049] 3-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxyl)benzonitrile;

[0050] 4-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxyl)benzonitrile;

[0051] (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-hydroxyphenyl)methanone;

[0052] (3-(Chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone;

[0053] (4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(2-fluorophenyl)methanone;

[0054] (3,5-bis(trifluoromethyl)phenyl)(4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone;

[0055] (4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(phenyl)methanone;

[0056] (2,5-difluorophenyl)(4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone;

[0057] (2-Fluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone;

[0058] (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone;

[0059] (3-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone;

[0060] (2,5-difluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone;

[0061] The preparation method of the tacrine derivative is selected from one of route A, route B, route C or route D; wherein

[0062] Method A includes the following steps:

[0063] Step 1: Take anthranilic acid M6 and cyclohexanone M7 as raw materials, add phosphorus trichloride dropwise thereto for reaction, and finally obtain a light green solid product M8;

[0064] Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were added into a three-necked flask in sequence and reacted at reflux temperature to obtain a white solid product M11;

[0065] Step 3: The intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12;

[0066] Step 4: M8, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M3;

[0067] Step 5: Dissolve the intermediate M3 and trifluoroacetic acid in DCM in sequence, and obtain a light yellow transparent liquid product M4 after reaction;

[0068] Step 6: The intermediate M4, triethylamine and substituted benzyl bromide are sequentially added to DCM and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound Ii;

[0069]

[0070] Method B includes the following steps:

[0071] Step 1: Take anthranilic acid M6 and cyclohexanone M7 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M8;

[0072] Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were added into a three-necked flask in sequence and reacted at reflux temperature to obtain a white solid product M11;

[0073] Step 3: The intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12;

[0074] Step 4: M8, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction was completed; the crude product was separated by column chromatography to obtain a light yellow solid product M3;

[0075] Step 5: Dissolve the intermediate M3 and trifluoroacetic acid in DCM in sequence, and react to obtain a light yellow transparent liquid product M4;

[0076] Step 6: The intermediate M4, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound I-ii;

[0077]

[0078] Method C includes the following steps:

[0079] Step 1: Take anthranilic acid M6 and cyclopentanone M5 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M13;

[0080] Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were added into a three-necked flask in sequence and reacted at reflux temperature to obtain a white solid product M11;

[0081] Step 3: The intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12;

[0082] Step 4: M13, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M1;

[0083] Step 5: Dissolve the intermediate M1 and trifluoroacetic acid in DCM in sequence, and obtain a light yellow transparent liquid product M2 after reaction;

[0084] Step 6: The intermediate M2, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound I-iii;

[0085]

[0086] Method D comprises the following steps:

[0087] Step 1: Take anthranilic acid M6 and cycloheptanone M14 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M15;

[0088] Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were added into a three-necked flask in sequence and reacted at reflux temperature to obtain a white solid product M11;

[0089] Step 3: The intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12;

[0090] Step 4: M15, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M16;

[0091] Step 5: Dissolve the intermediate M16 and trifluoroacetic acid in DCM in sequence, and obtain a light yellow transparent liquid product M17 after reaction;

[0092] Step 6: The intermediate M17, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to obtain a crude product after the reaction; the crude product is separated by column chromatography to obtain the target compound I-iv;

[0093]

[0094] Among them, R is halogen, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkoxy, hydrogen, acyl, or nitro-substituted (C5-C6) aromatic ring.

[0095] The tacrine derivative can form a pharmaceutically acceptable salt with an acid; the pharmaceutically acceptable addition salt includes an inorganic acid addition salt and an organic acid addition salt, and the salts with the following acid addition are particularly preferred: one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, and benzoic acid.

[0096] The tacrine derivative, whose prodrug is a derivative of general formula I, has weak activity or no activity itself, and is converted into a corresponding biologically active form under physiological conditions (for example, by metabolism, solvent decomposition or other means) after administration.

[0097] The term "halogen" refers to one of fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight-chain or branched alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to a phenyl group with no substituent or with a substituent; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, and the ring system is aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4 )-triazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl; "saturated or partially saturated heterocyclic group" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, phthalimido and thiazolinyl.

[0098] A pharmaceutical composition containing a tacrine derivative or a pharmaceutically acceptable salt of a tacrine derivative, which is a composition of the tacrine derivative or the pharmaceutically acceptable salt of a tacrine derivative with a carrier and an excipient;

[0099] The carrier is of a common type available in the pharmaceutical field;

[0100] The excipients include oral preparations, injection preparations and local preparations, wherein the oral preparations are one or more of adhesives, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigments, and flavoring agents; the injection preparations are one or more of preservatives, solubilizers, and stabilizers; the local preparations are one or more of bases, diluents, lubricants, and preservatives. Pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0101] Beneficial effects of the present invention:

[0102] The present invention has found that the compound of the present invention has significant inhibitory activity of AChE through the enzyme activity test of AChE. Cell experiments show that when the compound concentration is 25 μM, the survival rate of PC12 cells is greater than 80%, indicating low cytotoxicity. When the H2O2 concentration is 200 μM, the cell survival rate is higher than 60%, indicating good antioxidant activity. It shows satisfactory anti-inflammatory activity in the LPS-induced NO production experiment. Therefore, the research results of this project are of great significance in AD treatment targets and drug development. DETAILED DESCRIPTION

[0103] The content of the present invention is further described below in conjunction with the embodiments, but the content of the present invention is not limited to the following embodiments.

[0104] The synthetic routes A, B, C and D mentioned below describe the preparation of the derivatives of formula I of the present invention. The raw materials used in the examples are all commercially available raw materials. All intermediate compounds and final compounds mentioned in the present invention are prepared by the methods described in routes A, B, C and D or similar methods, and the relevant structures have been confirmed.

[0105] Route A: Synthesis of Compound Ii

[0106] According to the compound of general formula I of the present invention, in this synthetic route, R is the corresponding group at the corresponding position of compound Ii; halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydrogen, acyl, nitro substituted (C5-C6) aromatic ring.

[0107]

[0108] Taking o-aminobenzoic acid M6 (20.0 g, 146 mmol) and cyclohexanone M7 (18 mL, 204 mmol) as raw materials, phosphorus trichloride (81.6 mL, 876 mmol) was added dropwise at -10°C to finally obtain a light green solid product M8 (29.7 g, 93.7%). N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence at 25°C and reacted at reflux temperature for 36 h to finally obtain a white solid product M11 (35.3 g, 92.2%). Intermediate M11 (35.0 g, 90 mmol) was dephthaloylated under the action of hydrazine hydrate (50 mL) to obtain M12 (18.2 g, 78.3%). At 25°C, M8 (5.0 g, 23 mmol), M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol) and potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask in sequence and the reaction solution was heated to 180°C. After the reaction was completed for 1 hour, a yellow oily liquid crude product (10.1 g) was obtained. The crude product was separated by column chromatography (dichloromethane: methanol = 100: 1) to obtain a light yellow solid product M3 (6.0 g, 59.4%). Intermediate M3 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in sequence and reacted at 25°C for 0.5 h. The light yellow transparent liquid product M4 (1.5 g, 65.2%) was obtained. At a temperature of -10°C, the intermediate M4 (0.1 g, 0.3 mmol), triethylamine (1 mL) and 0.33 mmol of substituted benzyl bromide were added to DCM (5 mL) in sequence and the temperature was raised to 25°C. After 5 hours, a crude product was obtained. The crude product was separated by column chromatography to obtain the target compound Ii.

[0109] Route B: Synthesis of Compound I-ii

[0110] According to the compound of general formula I of the present invention, in this synthetic route, R is the corresponding group at the corresponding position of compound I-ii; halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydrogen, acyl, nitro substituted (C5-C6) aromatic ring.

[0111]

[0112] Taking o-aminobenzoic acid M6 (20.0 g, 146 mmol) and cyclohexanone M7 (18 mL, 204 mmol) as raw materials, phosphorus trichloride (81.6 mL, 876 mmol) was added dropwise at -10°C to finally obtain a light green solid product M8 (29.7 g, 93.7%). N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence at 25°C and reacted at reflux temperature for 36 h to finally obtain a white solid product M11 (35.3 g, 92.2%). Intermediate M11 (35.0 g, 90 mmol) was dephthaloylated under the action of hydrazine hydrate (50 mL) to obtain M12 (18.2 g, 78.3%). At 25°C, M8 (5.0 g, 23 mmol), M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol) and potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask in sequence and the reaction solution was heated to 180°C. After the reaction was completed for 1 hour, a yellow oily liquid crude product (10.1 g) was obtained. The crude product was separated by column chromatography (dichloromethane: methanol = 100: 1) to obtain a light yellow solid product M3 (6.0 g, 59.4%). Intermediate M3 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in sequence and reacted at 25°C for 0.5 h. The light yellow transparent liquid product M4 (1.5 g, 65.2%) was obtained. At a temperature of -10°C, the intermediate M4 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 ml of substituted benzoic acid were added to tetrahydrofuran (5 mL) and the temperature was raised to 25°C. After 2 hours, a crude product was obtained. The crude product was separated by column chromatography to obtain the target compound I-ii.

[0113] Route C: Synthesis of Compound I-iii

[0114] According to the compound of general formula I of the present invention, in this synthetic route, R is the corresponding group at the corresponding position of compound I-iii; halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydrogen, acyl, nitro substituted (C5-C6) aromatic ring.

[0115]

[0116] Taking o-aminobenzoic acid M6 (20.0 g, 146 mmol) and cyclopentanone (M5) (19.4 mL, 219 mmol) as raw materials, phosphorus trichloride (40.8 mL, 438 mmol) was added dropwise at -10°C to finally obtain a light green solid product M13 (26.1 g, 88.2%). N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask at 25°C and reacted at reflux temperature for 36 h to finally obtain a white solid product M11 (35.3 g, 92.2%). Intermediate M11 (35.0 g, 90 mmol) was dephthaloylated under the action of hydrazine hydrate (50 mL) to obtain M12 (18.2 g, 78.3%). At 25°C, M13 (4.67 g, 23 mmol), M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol) and potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask in sequence and the reaction solution was heated to 180°C. After the reaction was completed for 1 hour, a yellow oily liquid crude product (9.8 g) was obtained. The crude product was separated by column chromatography (dichloromethane: methanol = 100: 1) to obtain a light yellow solid product M1 (5.5 g, 56.5%). Intermediate M1 (2.64 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in sequence and reacted at 25°C for 0.5 h. The light yellow transparent liquid product M2 (1.3 g, 64.4%) was obtained. At a temperature of -10°C, the intermediate M2 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 ml of substituted benzoic acid were added to tetrahydrofuran (5 mL) and the temperature was raised to 25°C. After 2 hours, a crude product was obtained. The crude product was separated by column chromatography to obtain the target compound I-iii.

[0117] Route D: Synthesis of Compound I-iv

[0118] According to the compound of general formula I of the present invention, in this synthetic route, R is the corresponding group at the corresponding position of compound I-iv; halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydrogen, acyl, nitro substituted (C5-C6) aromatic ring.

[0119]

[0120] Taking anthranilic acid M6 (20.0 g, 146 mmol) and cycloheptanone (M14) (27.3 mL, 219 mmol) as raw materials, phosphorus trichloride (40.8 mL, 438 mmol) was added dropwise at -10°C to finally obtain a light green solid product M15 (26.5 g, 78.5%). N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask at 25°C and reacted at reflux temperature for 36 h to finally obtain a white solid product M11 (35.3 g, 92.2%). Intermediate M11 (35.0 g, 90 mmol) was dephthaloylated under the action of hydrazine hydrate (50 mL) to obtain M12 (18.2 g, 78.3%). At 25 ° C, M15 (5.3 g, 23 mmol), M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol) and potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask in sequence and the reaction solution was heated to 180 ° C. After the reaction was completed for 1 hour, a yellow oily liquid crude product (10.4 g) was obtained. The crude product was separated by column chromatography (dichloromethane: methanol = 100: 1) to obtain a light yellow solid product M16 (5.2 g, 50.3%). Intermediate M16 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in sequence and reacted at 25 ° C for 0.5 h. The light yellow transparent liquid product M17 (1.4 g, 58.5%) was obtained. At a temperature of -10°C, the intermediate M17 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 ml of substituted benzoic acid were added to tetrahydrofuran (5 mL) and the temperature was raised to 25°C. After 2 hours, a crude product was obtained. The crude product was separated by column chromatography to obtain the target compound I-iv.

[0121] Example 1

[0122] Preparation of 1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol

[0123] Step 1: Preparation of intermediate 9-chloro-5,6,7,8-tetrahydroacridine (M8)

[0124] Add o-aminobenzoic acid (20.0 g, 146 mmol) and cyclohexanone (18 mL, 204 mmol) to a round-bottom flask, slowly add phosphorus oxychloride (81.6 mL) dropwise at -10 °C, and after the addition is complete, install a tail gas absorption device, heat the reaction solution to reflux, and react for 3 hours. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, pour the residual liquid into a large amount of water, and filter to obtain 29.7 g of a light green solid product with a yield of 93.7%, MS (ESI) m / z: 218 [M+H] + .

[0125] Step 2: Preparation of intermediate 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-hydroxypropyl]-1,1-dimethylethyl ester (M11)

[0126] At room temperature, N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence, refluxed, and reacted for 36 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a light yellow transparent oily liquid. Anhydrous ethanol (200 mL) was added to the residual liquid to completely dissolve the oily substance, and water was added thereto until a white solid precipitated. The mixture was filtered, the filter cake was washed with cold water, and dried to obtain 35.3 g of a white solid with a yield of 92.2%. MS (ESI) m / z: 390 [M+H] + .

[0127] Step 3: Preparation of intermediate 1-amino-3-N-(4-Bocpiperazine)-2-propanol (M12)

[0128] At room temperature, the intermediate M11 (35.0 g, 90 mmol) and hydrazine hydrate (50 mL) were dissolved in anhydrous ethanol (350 mL) in turn, and the reaction solution was heated to 80 ° C. and reacted for 2 h. After the reaction was completed, it was cooled to room temperature. Filtered and concentrated under reduced pressure to obtain a colorless transparent oily liquid, which was diluted with dichloromethane (200 mL), washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18.2 g of a white solid, with a yield of 78.3%, MS (ESI) m / z: 260 [M+H] + .

[0129] Step 4: Preparation of intermediate 4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxylic acid tert-butyl ester (M3)

[0130] At room temperature, intermediate M8 (5.0 g, 23 mmol), intermediate M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol), potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask, and the reaction solution was heated to 180 ° C. The reaction was completed for 1 h, and the reaction was cooled to room temperature. Ethyl acetate was added to the reaction solution, and after sufficient stirring, it was washed with saturated sodium carbonate aqueous solution, water, and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10.1 g of a yellow oily liquid. The crude product was separated by column chromatography (DCM: MeOH = 100: 1) to obtain 6.0 g of a light yellow solid, with a yield of 59.4%, MS (ESI) m / z: 441 [M+H] + .

[0131] Step 5: Preparation of intermediate 1-(piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)-2-propanol (M4)

[0132] At room temperature, the intermediate M3 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in turn, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a yellow oily liquid. Water (50 mL) was added to the residue, and the pH of the reaction solution was adjusted to 12 with a saturated sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (3×60 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.5 g of a light yellow transparent liquid with a yield of 65.2%. MS (ESI) m / z: 341 [M+H] + .

[0133] Step 6: Preparation of 1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol

[0134] Keep the temperature below -10 ° C, add intermediate M4 (0.1g, 0.3mmol), triethylamine (1mL), 0.33mmol o-fluorobenzyl bromide to DCM (5mL) in sequence. After the addition, warm the reaction solution to room temperature and react for 5h. After the reaction is completed, add the reaction solution dropwise to ice water with stirring. Solid precipitates, filter, wash the filter cake with ice water, and dry to obtain a crude product. The crude product is separated by column chromatography to obtain the target compound. White solid, yield 42.7%. MS (ESI) m / z: 449 [M + H] + 、447[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.30(d,J=8.6Hz,1H),7.79(d,J=8.4Hz,1H),7.72(t,J=7.6Hz,1 H),7.43(t,J=7.7Hz,1H),7.39–7.35(m,1H),7.33(q,J=5.8Hz,1H),7.17(q,J=8.6,7.9Hz ,2H),6.76(s,1H),5.12(s,1H),3.89(s,1H),3.79(d,J=13.0Hz,1H),3.70(dt,J=12.6,6 .2Hz,1H),3.51(s,2H),2.95(s,2H),2.67(s,2H),2.48–2.16(m,10H),1.85–1.77(m,4H).

[0135] Example 2

[0136] Preparation of 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)propan-2-ol

[0137] According to the synthesis method of step 1 in Example 1, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 1, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 1, M12 was prepared; according to the synthesis method of step 4 in Example 1, M3 was prepared; according to the synthesis method of step 5 in Example 1, M4 was prepared; according to the synthesis method of step 6 in Example 1, o-fluorobenzyl bromide was replaced with 2,4,5-trifluorobenzyl bromide to prepare 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)propan-2-ol, a white solid, with a yield of 43.5%. MS (ESI) m / z: 485 [M+H] + 、483[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=8.5Hz,1H),7.73(d,J=8.4Hz,1H),7.58(t,J= 7.6Hz,1H),7.55–7.48(m,1H),7.47–7.40(m,1H),7.35(t,J=7.6Hz,1H),5.88(s ,1H),5.01(s,1H),3.81(s,1H),3.61(d,J=12.9Hz,1H),3.53(q,J=6.1Hz,1H),3 .47(s,2H),2.91(s,2H),2.69(s,2H),2.46–2.14(m,10H),1.80(d,J=6.4Hz,4H).

[0138] Example 3

[0139] Preparation of 1-(4-(3,5-bis(trifluoromethyl)benzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol

[0140] According to the synthesis method of step 1 in Example 1, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 1, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 1, M12 was prepared; according to the synthesis method of step 4 in Example 1, M3 was prepared; according to the synthesis method of step 5 in Example 1, M4 was prepared; according to the synthesis method of step 6 in Example 1, o-fluorobenzyl bromide was replaced with 3,5-bistrifluoromethylbenzyl bromide to prepare 1-(4-(3,5-bis(trifluoromethyl)benzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol, a white solid, with a yield of 48.7%. MS (ESI) m / z: 567 [M+H] + 、565[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.20(d,J=8.5Hz,1H),7.98(d,J=12.0Hz,3H),7.74(d,J=8.5Hz,1H),7.61(t,J=7.6Hz,1H),7.38(t,J=7.7Hz,1H),6.07(s,1H ),5.03(s,1H),3.84(t,J=6.0Hz,1H),3.66(s,3H),3.56(dt,J=12.4,6.1Hz ,1H),2.92(s,2H),2.69(s,2H),2.48–2.18(m,10H),1.80(d,J=3.4Hz,4H).

[0141] Example 4

[0142] Preparation of 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)propan-2-ol

[0143] According to the synthesis method of step 1 in Example 1, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 1, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 1, M12 was prepared; according to the synthesis method of step 4 in Example 1, M3 was prepared; according to the synthesis method of step 5 in Example 1, M4 was prepared; according to the synthesis method of step 6 in Example 1, o-fluorobenzyl bromide was replaced with 4-(trifluoromethoxy)benzyl bromide to prepare 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)propan-2-ol, a white solid, with a yield of 52.1%. MS (ESI) m / z: 515 [M+H] + 、513[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.36(d,J=8.6Hz,1H),7.84–7.75(m,2H),7.50(t,J=7.7Hz,1H),7.40(d,J=8.4Hz,2H),7.31(d,J=8.1Hz,2H),7.10(s,1H),5 .17(s,1H),3.92(s,1H),3.86(d,J=13.0Hz,1H),3.77(q,J=6.4Hz,1H),3. 47(s,2H),2.97(s,2H),2.67(s,2H),2.37(d,J=53.2Hz,10H),1.83(s,4H).

[0144] Example 5

[0145] Preparation of 1-(4-benzylpiperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol

[0146] According to the synthesis method of step 1 in Example 1, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 1, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 1, M12 was prepared; and then according to the synthesis method of step 4 in Example 1, M3 was prepared; and then according to the synthesis method of step 5 in Example 1, M4 was prepared; and then according to the synthesis method of step 6 in Example 1, o-fluorobenzyl bromide was replaced with benzyl bromide to prepare 1-(4-benzylpiperazine-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol, a white solid, with a yield of 49.5%. MS (ESI) m / z: 431 [M+H] + 、429[MH] - , 1HNMR(600MHz,DMSO-d6)δ8.39(d,J=8.6Hz,1H),7.85–7.78(m,2H),7.51(t,J=6.7Hz,1H),7.35–7.19(m,6H),5.20(s,1H),3. 94(s,1H),3.90(d,J=13.4Hz,1H),3.82(q,J=6.4Hz,1H),3.46(s,2H),2.97(s,2H),2.67(s,2H),2.39(s,10H),1.83(s,4H).

[0147] Example 6

[0148] Preparation of 1-(4-(2,5-difluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol

[0149] According to the synthesis method of step 1 in Example 1, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 1, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 1, M12 was prepared; according to the synthesis method of step 4 in Example 1, M3 was prepared; according to the synthesis method of step 5 in Example 1, M4 was prepared; according to the synthesis method of step 6 in Example 1, o-fluorobenzyl bromide was changed to 2,5-difluorobenzyl bromide to prepare 1-(4-(2,5-difluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol, a white solid, with a yield of 55.5%. MS (ESI) m / z: 467.0 [M+H] +, 465 [MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.25(d,J=8.6Hz,1H),7.77(d,J=8.4Hz,1H),7.66(t,J=7.6Hz,1H),7.43–7.37(m,1H),7.26–7.12(m,3H),6.41(s,1H),5.0 8(s,1H),3.86(s,1H),3.72(d,J=13.1Hz,1H),3.63(s,1H),3.50(s,2H),2 .95–2.91(m,2H),2.68(s,2H),2.48–2.18(m,10H),1.81(d,J=6.4Hz,4H).

[0150] Example 7

[0151] Preparation of (2-fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazine-1-yl)methanone

[0152] Step 1: Preparation of intermediate 9-chloro-5,6,7,8-tetrahydroacridine (M8)

[0153] Add o-aminobenzoic acid (20.0 g, 146 mmol) and cyclohexanone (18 mL, 204 mmol) to a round-bottom flask, slowly add phosphorus oxychloride (81.6 mL) dropwise at -10 °C, and after the addition is complete, install a tail gas absorption device, heat the reaction solution to reflux, and react for 3 hours. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, pour the residual liquid into a large amount of water, and filter to obtain 29.7 g of a light green solid product with a yield of 93.7%, MS (ESI) m / z: 218 [M+H] + .

[0154] Step 2: Preparation of intermediate 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-hydroxypropyl]-1,1-dimethylethyl ester (M11)

[0155] At room temperature, N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence, refluxed, and reacted for 36 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a light yellow transparent oily liquid. Anhydrous ethanol (200 mL) was added to the residual liquid to completely dissolve the oily substance, and water was added thereto until a white solid precipitated. The mixture was filtered, the filter cake was washed with cold water, and dried to obtain 35.3 g of a white solid with a yield of 92.2%. MS (ESI) m / z: 390 [M+H] + .

[0156] Step 3: Preparation of intermediate 1-amino-3-N-(4-Bocpiperazine)-2-propanol (M12)

[0157] At room temperature, the intermediate M11 (35.0 g, 90 mmol) and hydrazine hydrate (50 mL) were dissolved in anhydrous ethanol (350 mL) in turn, and the reaction solution was heated to 80 ° C. and reacted for 2 h. After the reaction was completed, it was cooled to room temperature. Filtered and concentrated under reduced pressure to obtain a colorless transparent oily liquid, which was diluted with dichloromethane (200 mL), washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18.2 g of a white solid, with a yield of 78.3%, MS (ESI) m / z: 260 [M+H] + .

[0158] Step 4: Preparation of intermediate 4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxylic acid tert-butyl ester (M3)

[0159] At room temperature, add intermediate M8 (5.0 g, 23 mmol), intermediate M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol), potassium iodide (2.5 g, 26 mmol) to a round-bottom flask, heat the reaction solution to 180 ° C, react for 1 h, and cool to room temperature after the reaction is complete. Add ethyl acetate to the reaction solution, stir well, wash with saturated sodium carbonate aqueous solution, water, and saturated brine in turn, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 10.1 g of a yellow oily liquid. The crude product was separated by column chromatography (DCM: MeOH = 100: 1) to obtain 6.0 g of a light yellow solid, with a yield of 59.4%, MS (ESI) m / z: 441 [M+H] + .

[0160] Step 5: Preparation of intermediate 1-(piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)-2-propanol (M4)

[0161] At room temperature, the intermediate M3 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in turn, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a yellow oily liquid. Water (50 mL) was added to the residue, and the pH of the reaction solution was adjusted to 12 with a saturated sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (3×60 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.5 g of a light yellow transparent liquid with a yield of 65.2%. MS (ESI) m / z: 341 [M+H] + .

[0162] Step 6: Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-hydroxyphenyl)methanone

[0163] At -10°C, the intermediate M4 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 mL of o-fluorobenzoic acid were added to tetrahydrofuran (5 mL) in sequence. After the addition, the reaction solution was warmed to room temperature and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was added dropwise to ice water with stirring. Solid precipitated, filtered, the filter cake was washed with ice water, and dried to obtain a crude product. The crude product was separated by column chromatography to obtain the target compound. White solid, yield 45.3%. MS (ESI) m / z: 463 [M+H] + 、461[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.33(d,J=8.6Hz,1H),7.85(d,J=8.5Hz,1H),7.75–7.71(m,1H),7.50(d,J=1. 7Hz,2H),7.37(td,J=7.3,1.8Hz,1H),7.32–7.25(m,2H),6.72(s,1H),5.21(s,1H),3.95–3.89(m,1H), 3.82(d,J=13.0Hz,1H),3.69(d,J=6.5Hz,1H),3.57(s,2H),3.13(t,J=5.1Hz,2H),2.97(s,2H),2.71( d,J=6.8Hz,2H),2.47(s,1H),2.39(qd,J=12.8,4.5Hz,4H),2.30(dt,J=10.8,4.9Hz,1H),1.83(s,4H).

[0164] Example 8

[0165] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(2,4,5-trifluorophenyl)methanone

[0166] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 7, M12 was prepared; and then according to the synthesis method of step 4 in Example 7, M3 was prepared; and then according to the synthesis method of step 5 in Example 7, M4 was prepared; and then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 2,4,5-trifluorobenzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(2,4,5-trifluorophenyl)methanone, a white solid, with a yield of 42.3%. MS (ESI) m / z: 499 [M+H] + 、497[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.22(d,J=8.5Hz,1H),7.77(d,J=8.3Hz,1H),7.71–7.58(m,3H),7.42(t,J=7.7Hz,1H),6.04(s,1H),5.11(s,1H),3.87 (s,1H),3.68(s,1H),3.55(s,3H),3.15(s,2H),2.93(s,2H),2.72(s,2H ),2.45(s,1H),2.36(qd,J=12.7,6.2Hz,4H),2.29(s,1H),1.83(s,4H).

[0167] Example 9

[0168] Preparation of (2,4-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone

[0169] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 2,4-difluorobenzoic acid to prepare (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone, white solid, yield 43.5%. MS (ESI) m / z: 481 [M+H] + 、479[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.26(d,J=8.6Hz,1H),7.79(d,J=8.4Hz,1H),7.67(t,J=7.6Hz,1H),7.45(dt ,J=12.1,7.9Hz,2H),7.36(td,J=9.7,2.5Hz,1H),7.17(td,J=8.5,2.4Hz,1H),6.29(s,1H),5.14(s, 1H),3.89(s,1H),3.74(d,J=13.3Hz,1H),3.62(q,J=6.2Hz,1H),3.55(s,2H),3.13(s,2H),2.94(s,2 H),2.72(d,J=5.4Hz,2H),2.47(s,1H),2.37(qd,J=12.7,6.1Hz,4H),2.31–2.26(m,1H),1.83(s,4H).

[0170] Example 10

[0171] Preparation of (2,6-dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone

[0172] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 7, M12 was prepared; and then according to the synthesis method of step 4 in Example 7, M3 was prepared; and then according to the synthesis method of step 5 in Example 7, M4 was prepared; and then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 2,6-dichlorobenzoic acid to prepare (3-fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)ketone, white solid, yield 44.2%. MS (ESI) m / z: 513 [M+H] + 、511[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.34(d,J=8.6Hz,1H),7.84(d,J=8.4Hz,1H),7.73(t,J=7.7Hz,1 H),7.54(d,J=8.1Hz,2H),7.51–7.43(m,2H),6.77(s,1H),5.22(s,1H),3.92(s,1H),3.8 3(d,J=13.1Hz,1H),3.75–3.69(m,1H),3.55(d,J=18.5Hz,2H),3.02(t,J=5.1Hz,2H),2. 96(s,2H),2.71(d,J=5.5Hz,2H),2.37(dtd,J=36.7,12.1,11.5,6.1Hz,6H),1.83(s,4H).

[0173] Embodiment 11

[0174] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3,4,5-trifluorophenyl)methanone

[0175] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 7, M12 was prepared; and then according to the synthesis method of step 4 in Example 7, M3 was prepared; and then according to the synthesis method of step 5 in Example 7, M4 was prepared; and then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 3,4,5-trifluorobenzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3,4,5-trifluorophenyl)methanone, a white solid, with a yield of 51.2%. MS (ESI) m / z: 498 [M+H] + 、497[MH] - , 1H NMR (600MHz, DMSO-d6) δ8.27(d,J=8.5Hz,1H),7.80(d,J=7.2Hz,1H),7.67(t,J=7.6H z,1H),7.48–7.37(m,3H),6.31(s,1H),5.15(s,1H),3.89(s,1H),3.74(d,J=13.1Hz,1 H),3.62(dt,J=12.5,6.2Hz,1H),3.52(s,2H),3.23(s,2H),2.95(s,2H),2.72(d,J=5 .7Hz,2H),2.47(s,1H),2.38(qd,J=12.8,6.2Hz,4H),2.33–2.28(m,1H),1.83(s,4H).

[0176] Example 12

[0177] Preparation of (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazine-1-yl)methanone

[0178] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 3,5-bistrifluoromethylbenzoic acid to prepare (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone, white solid, yield 42.2%. MS (ESI) m / z: 581 [M+H] + 、579[MH] - , 1H NMR(600MHz,DMSO-d6)δ8.22–8.17(m,2H),8.10(s,2H),7.75(d,J=8.4Hz,1H),7 .60(t,J=7.6Hz,1H),7.40(t,J=7.7Hz,1H),5.80(s,1H),5.07(s,1H),3.85(t,J= 5.8Hz,1H),3.65(d,J=13.4Hz,1H),3.57(s,1H),3.55–3.50(m,2H),3.21(s,2H), 2.92(s,2H),2.73(d,J=4.3Hz,2H),2.47–2.33(m,1H),2.31(s,5H),1.83(s,4H).

[0179] Example 13

[0180] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-trifluoromethoxyphenyl)methanone

[0181] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-trifluoromethoxybenzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-trifluoromethoxyphenyl)methanone, white solid, yield 53.7%. MS (ESI) m / z: 529 [M+H] + 、527[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.27(d,J=8.6Hz,1H),7.80(d,J=8.5Hz,1H),7.67(t,J=7 .6Hz,1H),7.54–7.49(m,2H),7.43(t,J=8.6Hz,3H),6.32(s,1H),5.15(s,1H),3.9 2–3.87(m,1H),3.75(d,J=14.1Hz,1H),3.64–3.60(m,1H),3.54(s,2H),3.23(s,2 H), 2.95 (s, 2H), 2.72 (d, J = 6.0Hz, 2H), 2.38 (qd, J = 12.8, 6.2Hz, 6H), 1.83 (s, 4H).

[0182] Embodiment 14

[0183] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone

[0184] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with benzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone, white solid, yield 60.2%. MS (ESI) m / z: 445 [M+H] + 、443[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.37(d,J=8.6Hz,1H),7.88(d,J=8.5Hz,1H),7.76(t,J=7.7H z,1H),7.51(s,1H),7.44(d,J=5.4Hz,3H),7.36(d,J=6.4Hz,2H),6.95(s,1H),5.24(s ,1H),3.95(s,1H),3.87(d,J=13.3Hz,1H),3.75(d,J=6.7Hz,1H),3.54(s,2H),3.25( s,2H),2.98(s,2H),2.71(d,J=7.4Hz,2H),2.40(dd,J=11.0,6.1Hz,6H),1.83(s,4H).

[0185] Embodiment 15

[0186] Preparation of (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone

[0187] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 2,5-difluorobenzoic acid to prepare (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone, white solid, yield 60.7%. MS (ESI) m / z: 481 [M+H] + 、479[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.35(d,J=8.6Hz,1H),7.86(d,J=8.4Hz,1H),7.75(t,J=7.7Hz,1H),7.49(t,J =7.4Hz,1H),7.39–7.34(m,2H),7.31(ddd,J=8.0,5.0,2.8Hz,1H),6.81(s,1H),5.23(s,1H),3.95–3.9 2(m,1H),3.84(d,J=13.6Hz,1H),3.72(dt,J=12.6,6.2Hz,1H),3.56(s,2H),3.15(t,J=5.1Hz,2H),2. 98(s,2H),2.71(d,J=7.2Hz,2H),2.49(s,1H),2.40(qd,J=12.8,6.1Hz,4H),2.34(s,1H),1.84(s,4H).

[0188] Example 16

[0189] Preparation of (5-fluoro-2-methylphenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone

[0190] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 5-fluoro-2-methylbenzoic acid to prepare (5-fluoro-2-methylphenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone, white solid, yield 58.8%. MS (ESI) m / z: 477 [M+H] + 、475[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.27(d,J=8.5Hz,1H),7.81(d,J=7.3Hz,1H),7.68(t,J=7.3Hz,1H),7.47–7.42(m,1H),7. 29(dd,J=8.6,5.5Hz,2H),7.13(td,J=8.7,2.8Hz,1H),7.03(dd,J=8.9,2.8Hz,1H),6.37(s,1H),5.13(s,1H),3.89 (dt,J=10.9,6.1Hz,1H),3.78–3.73(m,1H),3.63(dt,J=12.3,5.8Hz,1H),3.53(s,2H),3.03(s,2H),2.95(s,2H), 2.71(d,J=5.5Hz,2H),2.44(s,1H),2.37(qd,J=12.8,6.2Hz,4H),2.26(d,J=8.0Hz,1H),2.15(s,3H),1.82(s,4H).

[0191] Embodiment 17

[0192] Preparation of (4-chlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone

[0193] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-chlorobenzoic acid to prepare (4-chlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone, white solid, yield 57.3%. MS (ESI) m / z: 479 [M+H] + 、477[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.26(d,J=8.5Hz,1H),7.79(d,J=9.7Hz,1H),7.67(t,J=7.6 Hz,1H),7.50(d,J=8.5Hz,2H),7.45(t,J=7.7Hz,1H),7.40(d,J=8.5Hz,2H),6.30(s, 1H),5.10(s,1H),3.92–3.86(m,1H),3.74(d,J=13.0Hz,1H),3.62(s,1H),3.52(s,2 H),3.22(s,2H),2.94(s,2H),2.72(d,J=5.5Hz,2H),2.48–2.32(m,6H),1.83(s,4H).

[0194] Embodiment 18

[0195] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(p-tolyl)methanone

[0196] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with p-toluic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(p-tolyl)methanone, white solid, yield 62.5%. MS (ESI) m / z: 459

[0197] [M+H] + 、457[MH] -, 1 H NMR(600MHz,DMSO-d6)δ8.16(d,J=8.5Hz,1H),7.74(d,J=8.4Hz,1H),7.61–7.57 (m,1H),7.41–7.37(m,1H),7.26–7.21(m,4H),5.70(s,1H),5.06(s,1H),3.88–3. 82(m,1H),3.63(d,J=13.0Hz,1H),3.54–3.46(m,3H),3.22(s,2H),2.91(s,2H), 2.73(d,J=3.6Hz,2H),2.46–2.33(m,4H),2.32(s,3H),2.26(s,2H),1.82(s,4H).

[0198] Embodiment 19

[0199] Preparation of (4-fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazine-1-yl)methanone

[0200] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-fluorobenzoic acid to prepare (4-fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone, white solid, yield 63.2%. MS (ESI) m / z: 463 [M+H] + 、461[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.18(d,J=8.5Hz,1H),7.75(d,J=8.4Hz,1H),7.60(t,J =7.5Hz,1H),7.46–7.38(m,3H),7.26(t,J=8.9Hz,2H),5.81(s,1H),5.08(s,1H) ,3.88–3.83(m,1H),3.65(d,J=13.3Hz,1H),3.52(t,J=7.8Hz,3H),3.24(s,2H) ,2.92(s,2H),2.73(d,J=4.0Hz,2H),2.36(qd,J=12.7,6.2Hz,6H),1.83(s,4H).

[0201] Embodiment 20

[0202] Preparation of (2,3-dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone

[0203] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 7, M12 was prepared; according to the synthesis method of step 4 in Example 7, M3 was prepared; according to the synthesis method of step 5 in Example 7, M4 was prepared; according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 2,3-dichlorobenzoic acid to prepare (2,3-dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone, white solid, yield 63.5%. MS (ESI) m / z: 513 [M+H] + 、511[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.29(d,J=8.6Hz,1H),7.83(d,J=8.4Hz,1H),7.70(d,J=7.7Hz, 2H),7.45(q,J=7.5Hz,2H),7.34(d,J=7.6Hz,1H),6.42(s,1H),5.21(s,1H),3.91(s,1H) ,3.77(d,J=12.9Hz,1H),3.66(s,1H),3.56(d,J=13.1Hz,2H),3.03(s,2H),2.96(s,2H) ,2.72(s,2H),2.48(s,1H),2.43–2.33(m,4H),2.32–2.27(m,1H),1.83(t,J=3.8Hz,4H).

[0204] Embodiment 21

[0205] Preparation of (4-(chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone

[0206] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-chloromethylbenzoic acid to prepare (4-(chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone, white solid, yield 45.7%. MS (ESI) m / z: 493 [M+H] + 、491[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.31(d,J=8.4Hz,1H),7.83(d,J=7.9Hz,1H),7.70(dt,J=14.0,7 .8Hz,1H),7.58–7.45(m,3H),7.41(d,J=6.4Hz,1H),7.38(d,J=8.2Hz,1H),6.57(s,1H), 5.19(s,1H),4.87–4.77(m,2H),3.92(s,1H),3.80(d,J=13.4Hz,1H),3.67(s,2H),3.54( s,2H),3.23(s,2H),2.96(s,2H),2.71(d,J=6.5Hz,2H),2.45–2.33(m,5H),1.83(s,4H).

[0207] Embodiment 22

[0208] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3-trifluoromethylphenyl)methanone

[0209] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 7, M12 was prepared; and then according to the synthesis method of step 4 in Example 7, M3 was prepared; and then according to the synthesis method of step 5 in Example 7, M4 was prepared; and then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 3-trifluoromethylbenzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3-trifluoromethylphenyl)methanone, a white solid, with a yield of 50.2%. MS (ESI) m / z: 513 [M+H] + 、511[MH]- , 1 H NMR(600MHz,DMSO-d6)δ8.29(d,J=8.5Hz,1H),7.84–7.79(m,2H),7.70(dd,J=1 3.5,7.0Hz,4H),7.46(t,J=7.7Hz,1H),6.42(s,1H),5.17(s,1H),3.94–3.87(m, 1H),3.77(d,J=13.0Hz,1H),3.64(s,1H),3.56(s,2H),3.22(s,2H),2.95(s,2H) ,2.72(d,J=5.8Hz,2H),2.39(qd,J=12.8,6.2Hz,5H),2.33(s,1H),1.83(s,4H).

[0210] Embodiment 23

[0211] Preparation of 3-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-formyl)benzonitrile

[0212] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 7, M12 was prepared; according to the synthesis method of step 4 in Example 7, M3 was prepared; according to the synthesis method of step 5 in Example 7, M4 was prepared; according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 3-cyanobenzoic acid to prepare 3-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-formyl)benzonitrile, white solid, yield 52.6%. MS (ESI) m / z: 470

[0213] [M+H] + 、468[MH] - , 1H NMR(600MHz,DMSO-d6)δ8.16(d,J=8.6Hz,1H),7.92(d,J=7.7Hz,1H),7.86(s,1H),7.72 (dd,J=20.4,8.1Hz,2H),7.65(t,J=7.7Hz,1H),7.58(t,J=7.6Hz,1H),7.39(t,J=7.6Hz ,1H),5.66(s,1H),5.06(s,1H),3.84(s,1H),3.61(s,1H),3.56–3.48(m,3H),3.20(s,2 H),2.92(s,2H),2.74(s,2H),2.47(s,1H),2.39–2.32(m,4H),2.29(s,1H),1.83(s,4H).

[0214] Embodiment 24

[0215] Preparation of 4-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-formyl)benzonitrile

[0216] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; and then according to the synthesis method of step 3 in Example 7, M12 was prepared; and then according to the synthesis method of step 4 in Example 7, M3 was prepared; and then according to the synthesis method of step 5 in Example 7, M4 was prepared; and then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-cyanobenzoic acid to prepare 4-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-formyl)benzonitrile, white solid, yield 59.6%. MS (ESI) m / z: 470 [M+H] + 、468[MH] - , 1 H NMR(600MHz,DMSO-d6)δ8.37(d,J=8.6Hz,1H),7.92(d,J=8.3Hz,2H),7.87(s,1H), 7.76(t,J=7.7Hz,1H),7.57(d,J=8.3Hz,2H),7.51(t,J=7.7Hz,1H),6.93(s,1H),5 .24(s,1H),3.95(s,1H),3.87(d,J=9.2Hz,1H),3.74(d,J=6.6Hz,1H),3.56(s,2H) ,3.19(s,2H),2.98(s,2H),2.71(d,J=7.3Hz,2H),2.49–2.29(m,6H),1.84(s,4H).

[0217] Embodiment 25

[0218] Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-methoxyphenyl)methanone

[0219] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 4-methoxybenzoic acid to prepare (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-methoxyphenyl)methanone, a white solid, with a yield of 48.8%. MS (ESI) m / z: 475 [M+H] + 、473[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.37(d,J=8.6Hz,1H),7.88(d,J=8.4Hz,1H),7.76(t,J =7.7Hz,1H),7.51(t,J=7.7Hz,1H),7.34(d,J=8.2Hz,2H),6.97(d,J=8.3Hz,2H) ,6.94(s,1H),5.25(s,1H),3.95(s,0H),3.87(d,J=12.7Hz,1H),3.79(s,3H),3. 76(s,0H),3.50(s,0H),2.98(s,1H),2.41(dd,J=21.1,9.1Hz,1H),1.84(s,5H).

[0220] Embodiment 26

[0221] Preparation of (3-(chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone

[0222] According to the synthesis method of step 1 in Example 7, the key intermediate M8 was prepared; according to the synthesis method of step 2 in Example 7, the intermediate M11 was prepared; then according to the synthesis method of step 3 in Example 7, M12 was prepared; then according to the synthesis method of step 4 in Example 7, M3 was prepared; then according to the synthesis method of step 5 in Example 7, M4 was prepared; then according to the synthesis method of step 6 in Example 7, o-fluorobenzoic acid was replaced with 3-chloromethylbenzoic acid to prepare (3-(chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone, a white solid, with a yield of 49.6%. MS (ESI) m / z: 493 [M+H] + 、491[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.28(t,J=8.0Hz,1H),7.80(d,J=10.2Hz,1H),7.68(t,J=7.6Hz,1H),7.55 –7.50(m,1H),7.49–7.40(m,3H),7.35(dd,J=20.9,8.3Hz,1H),6.34(s,1H),5.69(s,1H),5.15(s,1 H),4.80(s,1H),3.90(s,1H),3.75(s,1H),3.63(dt,J=13.4,6.7Hz,1H),3.53(s,2H),3.23(s,1H) ,3.10(s,1H),2.95(s,2H),2.72(d,J=5.6Hz,2H),2.37(td,J=12.6,11.9,6.0Hz,6H),1.83(s,4H).

[0223] Embodiment 27

[0224] Preparation of (4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(2-fluorophenyl)methanone

[0225] Step 1: Preparation of intermediate 9-chloro-2,3-dihydro-1H-cyclopenta[b]quinoline (M13)

[0226] Add o-aminobenzoic acid (20.0 g, 146 mmol) and cyclopentanone (19.4 g, 219 mmol) to a round-bottom flask, slowly add phosphorus oxychloride (40.8 mL, 438 mmol) dropwise at -10 °C, install a tail gas absorption device, heat the reaction solution to reflux, and react for 3 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate under reduced pressure, pour the residual liquid into a large amount of water, and filter to obtain 26.1 g of a light green solid product with a yield of 88.2%, MS (ESI) m / z: 204 [M+H] + .

[0227] Step 2: Preparation of intermediate 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-hydroxypropyl]-1,1-dimethylethyl ester (M11)

[0228] At room temperature, N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence, refluxed, and reacted for 36 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a light yellow transparent oily liquid. Anhydrous ethanol (200 mL) was added to the residual liquid to completely dissolve the oily substance, and water was added thereto until a white solid precipitated. The mixture was filtered, the filter cake was washed with cold water, and dried to obtain 35.3 g of a white solid with a yield of 92.2%. MS (ESI) m / z: 390 [M+H] + .

[0229] Step 3: Preparation of intermediate 1-amino-3-N-(4-Bocpiperazine)-2-propanol (M12)

[0230] At room temperature, the intermediate M11 (35.0 g, 90 mmol) and hydrazine hydrate (50 mL) were dissolved in anhydrous ethanol (350 mL) in turn, and the reaction solution was heated to 80 ° C. and reacted for 2 h. After the reaction was completed, it was cooled to room temperature. Filtered and concentrated under reduced pressure to obtain a colorless transparent oily liquid, which was diluted with dichloromethane (200 mL), washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18.2 g of a white solid, with a yield of 78.3%, MS (ESI) m / z: 260 [M+H] + .

[0231] Step 4: Preparation of intermediate tert-butyl 4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazine-1-carboxylate (M1)

[0232] At room temperature, intermediate M13 (4.67 g, 23 mmol), intermediate M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol), potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask, and the reaction solution was heated to 180 ° C. The reaction was completed for 1 h, and the reaction was cooled to room temperature. Ethyl acetate was added to the reaction solution, and after sufficient stirring, it was washed with saturated sodium carbonate aqueous solution, water, and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 9.8 g of a yellow oily liquid. The crude product was separated by column chromatography (DCM: MeOH = 100: 1) to obtain 5.5 g of a light yellow solid, with a yield of 56.5%, MS (ESI) m / z: 427 [M+H] + .

[0233] Step 5: Preparation of Intermediate 1-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-3-(piperazin-1-yl)propan-2-ol (M2)

[0234] At room temperature, the intermediate M1 (2.64 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in turn, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a yellow oily liquid. Water (50 mL) was added to the residue, and the pH of the reaction solution was adjusted to 12 with a saturated sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (3×60 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.3 g of a light yellow transparent liquid with a yield of 64.4%. MS (ESI) m / z: 327 [M+H] + .

[0235] Step 6: Preparation of (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-hydroxyphenyl)methanone

[0236] At -10°C, the intermediate M2 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 mL of o-fluorobenzoic acid were added to tetrahydrofuran (5 mL) in sequence. After the addition, the reaction solution was warmed to room temperature and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was added dropwise to ice water with stirring. Solid precipitated, filtered, the filter cake was washed with ice water, and dried to obtain a crude product. The crude product was separated by column chromatography to obtain the target compound. White solid, yield 42.7%. MS (ESI) m / z: 449 [M+H] + 、447[MH] - , 1H NMR(600MHz,DMSO-d6)δ8.31(d,J=8.6Hz,1H),7.76–7.70(m,2H),7.65(t,J=8.1Hz,1H),7.55–7.46(m,2H ),7.38(td,J=7.2,1.8Hz,1H),7.35–7.25(m,2H),5.06(s,1H),3.88(t,J=6.1Hz,1H),3.78–3.71(m,1H), 3.65(dt,J=13.8,7.0Hz,2H),3.60(s,1H),3.32(dt,J=14.7,7.2Hz,2H),3.26–3.18(m,1H),3.17(s,2H), 3.02(t,J=7.8Hz,2H), 2.46(dd,J=12.9,6.2Hz,2H), 2.39(dt,J=10.7,5.5Hz,3H), 2.10(p,J=7.6Hz,2H).

[0237] Embodiment 28

[0238] Preparation of (3,5-bis(trifluoromethyl)phenyl)(4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone

[0239] According to the synthesis method of step 1 in Example 27, the key intermediate M13 was prepared; according to the synthesis method of step 2 in Example 27, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 27, M12 was prepared; according to the synthesis method of step 4 in Example 27, M1 was prepared; according to the synthesis method of step 5 in Example 27, M2 was prepared; according to the synthesis method of step 6 in Example 27, o-fluorobenzoic acid was replaced with 3,5-bistrifluoromethylbenzoic acid to prepare (3,5-bis(trifluoromethyl)phenyl)(4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone, white solid, yield 56.7%. MS (ESI) m / z: 567 [M+H] + 、565[MH] -1H NMR (600MHz, DMSO-d6) δ8.21(s,1H),8.15(s,1H),8.11(s,2H),7.81(d,J=8.3Hz,1H),7.69(t,J=7. 6Hz,1H),7.60(s,1H),7.49(t,J=7.7Hz,1H),5.29(s,1H),3.92–3.86(m,1H),3.74(d,J=13.8Hz,1H ),3.63(ddt,J=20.3,14.0,6.5Hz,1H),3.32(dt,J=14.7,7.2Hz,2H),3.23(dd,J=17.6,10.1Hz,3H) ,3.03(s,2H),2.57(s,1H),2.45(d,J=6.1Hz,2H),2.40(q,J=7.7,6.8Hz,3H),2.09(p,J=7.6Hz,2H).

[0240] Embodiment 29

[0241] Preparation of (4-(3-((2,3-dihydro-1H-cyclopentane[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(phenyl)methanone

[0242] The key intermediate M13 was prepared according to the synthesis method of the step in Example 27; the intermediate M11 was prepared according to the synthesis method of step 2 in Example 26; M12 was prepared according to the synthesis method of step 3 in Example 26; M1 was prepared according to the synthesis method of step 4 in Example 26; M2 was prepared according to the synthesis method of step 5 in Example 26; and (4-(3-((2,3-dihydro-1H-cyclopentane[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(phenyl)methanone was prepared according to the synthesis method of step 6 in Example 26, replacing o-fluorobenzoic acid with benzoic acid, as white solid, with a yield of 58.8%. MS (ESI) m / z: 431 [M+H] + 、429[MH] -1H NMR (600MHz, DMSO-d6) δ8.23(d,J=8.5Hz,1H),7.72(d,J=9.7Hz,1H),7.63(t,J=7.6Hz,1H),7.44(dd,J= 5.1,2.0Hz,4H),7.36(dd,J=7.4,2.3Hz,2H),7.14(s,1H),5.01(s,1H),3.89–3.83(m,1H),3.70(dt,J=13 .5,5.4Hz,1H),3.59(dt,J=13.5,6.8Hz,3H),3.28(dt,J=14.7,7.2Hz,3H),3.20(dt,J=14.9,7.2Hz,2H), 2.95(t,J=7.8Hz,2H), 2.45(dd,J=12.8,6.1Hz,2H), 2.38(dd,J=12.8,6.0Hz,3H), 2.06(p,J=7.5Hz,2H).

[0243] Embodiment 30

[0244] Preparation of (2,5-difluorophenyl)(4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone

[0245] According to the synthesis method of step 1 in Example 27, the key intermediate M13 was prepared; according to the synthesis method of step 2 in Example 27, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 27, M12 was prepared; according to the synthesis method of step 4 in Example 27, M1 was prepared; according to the synthesis method of step 5 in Example 27, M2 was prepared; according to the synthesis method of step 6 in Example 27, o-fluorobenzoic acid was replaced with 2,5-difluorobenzoic acid to prepare (2,5-difluorophenyl)(4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone, white solid, yield 61.1%. MS (ESI) m / z: 467 [M+H] + 、465[MH] -1H NMR (600MHz, DMSO-d6) δ8.20(d,J=8.5Hz,1H),7.71(d,J=8.4Hz,1H),7.59(t,J=7.6Hz,1H),7.41(s,1H), 7.35(ddd,J=7.2,4.8,2.4Hz,2H),7.31(td,J=5.1,2.5Hz,1H),6.91(s,1H),5.00(s,1H),3.85(p,J=6.0Hz ,1H),3.71–3.64(m,1H),3.60(s,1H),3.57(q,J=6.6Hz,2H),3.28–3.23(m,2H),3.19(q,J=5.5,3.7Hz,3H) ,2.92(t,J=7.8Hz,2H),2.45(dd,J=12.8,5.9Hz,2H),2.37(dd,J=12.8,6.0Hz,3H),2.05(p,J=7.5Hz,2H).

[0246] Embodiment 31

[0247] Preparation of (2-fluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone

[0248] Step 1: Preparation of intermediate 11-chloro-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline (M15)

[0249] Add o-aminobenzoic acid (20.0 g, 146 mmol) and cycloheptanone (27.3 mL, 219 mmol) to a round-bottom flask, slowly add phosphorus oxychloride (40.8 mL, 438 mmol) dropwise at -10 °C, install a tail gas absorption device, heat the reaction solution to reflux, and react for 3 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate under reduced pressure, pour the residual liquid into a large amount of water, and filter to obtain 26.5 g of a light green solid product with a yield of 78.5%, MS (ESI) m / z: 232 [M+H] + .

[0250] Step 2: Preparation of intermediate 4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-hydroxypropyl]-1,1-dimethylethyl ester (M11)

[0251] At room temperature, N-(2,3-epoxypropyl)phthalamide M9 (20.0 g, 98 mmol), N-Boc piperazine (28.0 g, 150 mmol), triethylamine (30 mL) and tetrahydrofuran (200 mL) were added to a three-necked flask in sequence, refluxed, and reacted for 36 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a light yellow transparent oily liquid. Anhydrous ethanol (200 mL) was added to the residual liquid to completely dissolve the oily substance, and water was added thereto until a white solid precipitated. The mixture was filtered, the filter cake was washed with cold water, and dried to obtain 35.3 g of a white solid with a yield of 92.2%. MS (ESI) m / z: 390 [M+H] + .

[0252] Step 3: Preparation of intermediate 1-amino-3-N-(4-Bocpiperazine)-2-propanol (M12)

[0253] At room temperature, the intermediate M11 (35.0 g, 90 mmol) and hydrazine hydrate (50 mL) were dissolved in anhydrous ethanol (350 mL) in turn, and the reaction solution was heated to 80 ° C. and reacted for 2 h. After the reaction was completed, it was cooled to room temperature. Filtered and concentrated under reduced pressure to obtain a colorless transparent oily liquid, which was diluted with dichloromethane (200 mL), washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18.2 g of a white solid, with a yield of 78.3%, MS (ESI) m / z: 260 [M+H] + .

[0254] Step 4: Preparation of intermediate tert-butyl 4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazine-1-carboxylate (M16)

[0255] At room temperature, intermediate M15 (5.3 g, 23 mmol), intermediate M12 (12.0 g, 46 mmol), phenol (1.0 g, 6 mmol), potassium iodide (2.5 g, 26 mmol) were added to a round-bottom flask, and the reaction solution was heated to 180 ° C. The reaction was continued for 1 h. After the reaction was completed, the mixture was cooled to room temperature. Ethyl acetate was added to the reaction solution, and after sufficient stirring, the mixture was washed with saturated aqueous sodium carbonate solution, water, and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10.4 g of a yellow oily liquid. The crude product was separated by column chromatography (DCM: MeOH = 100: 1) to obtain 5.2 g of a light yellow solid with a yield of 50.3%. MS (ESI) m / z: 455 [M+H] + .

[0256] Step 5: Preparation of intermediate 1-(piperazin-1-yl)-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propan-2-ol (M17)

[0257] At room temperature, the intermediate M16 (3.0 g, 13 mmol) and trifluoroacetic acid (10 mL) were dissolved in DCM (30 mL) in turn, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a yellow oily liquid. Water (50 mL) was added to the residue, and the pH of the reaction solution was adjusted to 12 with a saturated sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (3×60 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.4 g of a light yellow transparent liquid with a yield of 58.5%. MS (ESI) m / z: 355 [M+H] + .

[0258] Step 6: Preparation of (2-fluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone

[0259] At -10°C, the intermediate M17 (0.1 g, 0.3 mmol), DIPEA (0.06 g, 0.4 mmol), HATU (0.12 g, 0.3 mmol) and 0.3 mL of o-fluorobenzoic acid were added to tetrahydrofuran (5 mL) in sequence. After the addition, the reaction solution was warmed to room temperature and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was added dropwise to ice water with stirring. Solid precipitated, filtered, the filter cake was washed with ice water, and dried to obtain a crude product. The crude product was separated by column chromatography to obtain the target compound. White solid, yield 48.9%. MS (ESI) m / z: 477 [M+H] + 、475[MH] - , 1 H NMR (600MHz, DMSO-d6) δ8.35(d,J=8.5Hz,1H),7.85(d,J=8.4Hz,1H),7.79(t,J=7.7Hz,1H) ,7.58(t,J=7.7Hz,1H),7.53–7.46(m,1H),7.37(td,J=7.3,1.8Hz,1H),7.33–7.26(m,3H),5 .14(s,1H),3.94(s,1H),3.72(d,J=14.2Hz,1H),3.56(s,3H),3.12(s,4H),2.93(d,J=6.4Hz ,2H),2.46(s,1H),2.35(d,J=32.7Hz,5H),1.85(d,J=5.9Hz,2H),1.74(s,2H),1.70(s,2H).

[0260] Embodiment 32

[0261] Preparation of (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone

[0262] According to the synthesis method of step 1 in Example 31, the key intermediate M15 was prepared; according to the synthesis method of step 2 in Example 31, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 31, M12 was prepared; according to the synthesis method of step 4 in Example 31, M16 was prepared; according to the synthesis method of step 5 in Example 31, M17 was prepared; according to the synthesis method of step 6 in Example 31, o-fluorobenzoic acid was replaced with 3,5-bistrifluoromethylbenzoic acid to prepare (3,5-bis(trifluoromethyl)phenyl)(4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone, white solid, yield 58.9%. MS (ESI) m / z: 595 [M+H] + 、593[MH] -1 H NMR (600MHz, DMSO-d6) δ8.22(d,J=8.8Hz,2H),8.11(s,2H),7.82(d,J=8.4Hz,1H),7.66(t,J= 7.4Hz,1H),7.50(t,J=8.3Hz,1H),5.99(s,1H),5.09(s,1H),3.88(dd,J=11.7,5.2Hz,1H),3.5 8(s,2H),3.51(d,J=8.9Hz,1H),3.38(dd,J=12.9,6.8Hz,2H),3.22(s,2H),3.13–3.09(m,2H), 2.93(q,J=6.0Hz,2H),2.38(qd,J=12.8,6.2Hz,5H),1.85(p,J=5.9Hz,2H),1.72–1.68(m,4H).

[0263] Embodiment 33

[0264] Preparation of (3-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone

[0265] According to the synthesis method of step 1 in Example 31, the key intermediate M15 was prepared; according to the synthesis method of step 2 in Example 31, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 31, M12 was prepared; according to the synthesis method of step 4 in Example 31, M16 was prepared; according to the synthesis method of step 5 in Example 31, M17 was prepared; according to the synthesis method of step 6 in Example 31, o-fluorobenzoic acid was replaced with benzoic acid to prepare (3-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cycloheptan[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone, white solid, yield 57.7%. MS (ESI) m / z: 459 [M+H] + 、457[MH] -1 H NMR (600MHz, DMSO-d6) δ8.23(d,J=8.5Hz,1H),7.82(d,J=8.4Hz,1H),7.67(t,J=7.5Hz,1H),7.50(t,J=7.6Hz,1H),7.47–7.40(m,3H),7.37–

[0266] 7.33(m,2H),6.09(s,1H),5.08(s,1H),3.89(s,1H),3.62–3.49(m,4H),3.22(s,2H),3.13–3.08 (m,2H),2.93(h,J=4.5Hz,2H),2.36(qd,J=12.8,6.0Hz,6H),1.85(d,J=5.9Hz,2H),1.69(s,4H).

[0267] Embodiment 34

[0268] Preparation of (2,5-difluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone

[0269] According to the synthesis method of step 1 in Example 31, the key intermediate M15 was prepared; according to the synthesis method of step 2 in Example 31, the intermediate M11 was prepared; according to the synthesis method of step 3 in Example 31, M12 was prepared; according to the synthesis method of step 4 in Example 31, M16 was prepared; according to the synthesis method of step 5 in Example 31, M17 was prepared; according to the synthesis method of step 6 in Example 31, o-fluorobenzoic acid was replaced with 2,5-difluorobenzoic acid to prepare (2,5-difluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cycloheptan[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone, white solid, yield 63.8%. MS (ESI) m / z: 495 [M+H] + 、493[MH] -1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=8.4Hz,1H),7.78(d,J=8.3Hz,1H),7.60(t,J=7.6Hz,1H),7. 45(t,J=7.6Hz,1H),7.35(dd,J=8.0,5.0Hz,2H),7.30(t,J=6.4Hz,1H),5.61(s,1H),5.03(s,1H ),3.85(s,1H),3.53(s,2H),3.43(d,J=12.4Hz,2H),3.13(s,2H),3.10–3.05(m,2H),2.96–2.88 (m,2H),2.44(s,1H),2.40–2.30(m,4H),2.28(s,1H),1.83(q,J=6.0Hz,2H),1.71–1.66(m,4H).

[0270] Biological Experiment Example 1

[0271] Acetylcholinesterase (AChE) inhibitory activity test of the compounds of the present invention

[0272] Test substance: Compound of general formula I in the present invention (Examples 1-34), concentration: 100 nM.

[0273] Comparative drugs: Published compounds Tacrine, Donepezil

[0274]

[0275] AChE inhibition activity test method:

[0276] AChE inhibitory activity was determined spectrophotometrically on a 96-well plate. First, 2 mg of the compound was diluted with DMSO to prepare a 10 mm / L stock solution, and then the prepared compound stock solution was diluted with Buffer to 100 nm / L for enzyme inhibition test. After dilution, vortexing was performed. Finally, the working solution was prepared and diluted to 1 mg / 100 ul. After preparation, 50 ul of the compound was injected into the 96-well plate with a pipette, followed by 50 ul of the enzyme. After placing it in a 37 ° C shaker for 10 minutes, 100 ul of the working solution was quickly added, and then it was placed in an ELISA reader for testing at a wavelength of 405 nm and calculating its inhibition rate.

[0277] Using Tacrine and donepezil as positive control drugs, the target compounds were tested for AChE inhibition rate. The results are shown in Table 1.

[0278] Table 1

[0279]

[0280]

[0281] Biological Experiment Example 2

[0282] In vitro neurotoxicity test of the compounds of the present invention

[0283] Alzheimer's disease is a neurodegenerative disease. In order to study whether the compound is toxic to nerve cells, the present invention tests the effect of the compound on nerve cells (PC12).

[0284] Test object: Compounds of general formula I in the present invention (Examples 7-26)

[0285] Test method:

[0286] 6000 PC12 cells were plated in each well of a 96-well plate, and a group of controls and blanks were set up. After one day of incubation, the compounds were administered at concentrations of 25 μM, 12.5 μM, and 6.25 μM, respectively, with three replicate wells in each group. One day later, 10 μL of CCK-8 was added to each well. After 3 hours, the cells were taken out of the incubator and shaken at 37°C for 5 minutes. The cells were tested on a microplate reader at 450 nm and their survival rates were calculated.

[0287]

Claims

1. A tacrine derivative, characterized in that: Its structure is shown in general formula I, specifically: Wherein, n1, n2, and n3 are integers arbitrarily selected from 1 to 4; X is a N or O atom; Y is a 5-10 membered saturated or partially saturated heterocyclic group, which is substituted by 1-3 heteroatoms selected from N, O and S; R 1 is one of C1-C5 alkyl, phenyl C1-C3 alkyl, 3-10-membered saturated or partially saturated cycloalkyl C1-C3 alkyl, 5-10-membered heterocyclic or heteroaryl C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 3-10-membered saturated or partially saturated cycloalkyl C0-C3 alkylformyl, 5-10-membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl; wherein phenyl, cycloalkyl, heterocyclic and heteroaryl are optionally substituted by 0-3 R 3 replace; R 2 is one of hydroxyl, thiol, amino, or an ester or amide formed by connecting with an acid; wherein the acid is arbitrarily selected from C1-C5 straight or branched alkyl formic acid, C1-C5 straight or branched alkyl sulfinic acid, C1-C5 straight or branched alkyl sulfonic acid, 5-10 membered heterocyclic C0-C3 alkyl formic acid, 5-10 membered heterocyclic C0-C3 alkyl sulfinic acid, 5-10 membered heterocyclic C0-C3 alkyl sulfonic acid, 5-10 membered heteroaryl C0-C3 alkyl formic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfinic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfonic acid; The R 3 Selected from halogen, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) acyl, nitro, cyano.

2. A tacrine derivative according to claim 1, characterized in that: In the general formula I, n1, n2, and n3 are integers arbitrarily selected from 1 to 2; X is a N or O atom; Y is selected from a 5-10 membered saturated or partially saturated heterocyclic group, wherein the heterocyclic group is substituted by 1-3 heteroatoms selected from N, O and S; R 1 is C1-C5 alkyl, phenyl C1-C3 alkyl, 5-10 membered heterocyclic or aromatic heterocyclic C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl; R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight or branched alkyl carboxylic acid, C1-C5 straight or branched alkyl sulfonic acid, 5-10 membered heterocyclyl C0-C3 alkyl carboxylic acid, 5-10 membered heterocyclyl C0-C3 alkyl sulfonic acid, 5-10 membered heteroaryl C0-C3 alkyl carboxylic acid, 5-10 membered heteroaryl C0-C3 alkyl sulfonic acid.

3. A tacrine derivative according to claim 2, characterized in that: In the general formula I, X is a N atom; Y is a 5-10 membered saturated or partially saturated heterocyclic group, which is substituted by 1-2 heteroatoms selected from N, O and S; R 1 is phenyl C1-C3 alkyl, C0-C3 alkylformyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl; R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight or branched chain alkylcarboxylic acid, 5-10 membered heterocyclic C0-C3 alkylcarboxylic acid.

4. A tacrine derivative according to claim 3, characterized in that: In the general formula I, R 1 is phenyl C1-C3 alkyl, phenyl C0-C3 alkylformyl, 5-10 membered heterocyclic or aromatic heterocyclic C0-C3 alkylformyl; R 2 It is a hydroxyl group or an ester formed by connecting with an acid, wherein the acid is arbitrarily selected from C1-C5 straight chain or branched chain alkyl carboxylic acid.

5. A tacrine derivative according to claim 4, characterized in that: In the general formula I, Y is a 5-10 membered saturated or partially saturated heterocyclic group, wherein the heterocyclic group contains 1-2 heteroatoms selected from N or O; R 1 is phenyl C1-C3 alkyl, phenyl C0-C3 alkylformyl; R 2 It is hydroxyl.

6. A tacrine derivative according to any one of claims 1 to 5, characterized in that: The halogen refers to fluorine, chlorine, bromine or iodine; Alkyl refers to a straight chain or branched chain alkyl group; Cycloalkyl refers to substituted or unsubstituted cycloalkyl; Aryl refers to a phenyl group with no or a substituent attached; Heteroaryl refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, the ring system is aromatic and is selected from one of imidazolyl, pyridyl, pyrazolyl, (1,2,3)- and (1,2,4)-triazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, and benzoxazolyl; The saturated or partially saturated heterocyclic group refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, and S, and is selected from one of pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, phthalimido and thiazolinyl.

7. A tacrine derivative according to any one of claims 1 to 6, characterized in that: It is one of the following compounds: 1-(4-(2-fluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol; 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(2,4,5-trifluorobenzyl)piperazin-1-yl)propan-2-ol; 1-(4-(3,5-bis(trifluoromethyl)benzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol; 1-((1,2,3,4-tetrahydroacridin-9-yl)amino)-3-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)propan-2-ol; 1-(4-Benzylpiperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol; 1-(4-(2,5-difluorobenzyl)piperazin-1-yl)-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propan-2-ol; (2-Fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(2,4,5-trifluorophenyl)methanone; (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone; (2,6-dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3,4,5-trifluorophenyl)methanone; (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-trifluoromethoxyphenyl)methanone; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone; (2,5-difluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone; (5-fluoro-2-methylphenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone; (4-chlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(p-tolyl)methanone; (4-Fluorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (2,3-Dichlorophenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)methanone; (4-(Chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(3-trifluoromethylphenyl)methanone; 3-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxyl)benzonitrile; 4-(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazine-1-carboxyl)benzonitrile; (4-(2-Hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)(4-hydroxyphenyl)methanone; (3-(Chloromethyl)phenyl)(4-(2-hydroxy-3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)pyrazin-1-yl)methanone; (4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(2-fluorophenyl)methanone; (3,5-bis(trifluoromethyl)phenyl)(4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone; (4-(3-((2,3-dihydro-1H-cyclopenta[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)(phenyl)methanone; (2,5-difluorophenyl)(4-(3-((2,3-dihydro-1H-cyclopentadienyl[b]quinolin-9-yl)amino)-2-hydroxypropyl)piperazin-1-yl)methanone; (2-Fluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone; (3,5-bis(trifluoromethyl)phenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone; (3-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)(phenyl)methanone; (2,5-difluorophenyl)(4-(2-hydroxy-3-((7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-yl)amino)propyl)piperazin-1-yl)methanone.

8. The method for preparing a tacrine derivative according to claim 7, characterized in that: The preparation method is selected from one of method A, method B, method C or method D; The method A comprises the following steps: Step 1: using anthranilic acid M6 and cyclohexanone M7 as raw materials, phosphorus trichloride is added dropwise thereto for reaction, and finally a light green solid product M8 is obtained; Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were sequentially added into a three-necked flask and reacted at reflux temperature to obtain a white solid product M11; Step 3: intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12; Step 4: M8, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M3; Step 5: Dissolve the intermediate M3 and trifluoroacetic acid in DCM in sequence, and obtain a light yellow transparent liquid product M4 after reaction; Step 6: The intermediate M4, triethylamine and substituted benzyl bromide are sequentially added to DCM and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound Ii; The reaction route is: Method B includes the following steps: Step 1: Take anthranilic acid M6 and cyclohexanone M7 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M8; Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were sequentially added into a three-necked flask and reacted at reflux temperature to obtain a white solid product M11; Step 3: intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12; Step 4: M8, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction was completed; the crude product was separated by column chromatography to obtain a light yellow solid product M3; Step 5: Dissolve the intermediate M3 and trifluoroacetic acid in DCM in sequence, and react to obtain a light yellow transparent liquid product M4; Step 6: The intermediate M4, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound I-ii; The reaction route is: Method C includes the following steps: Step 1: Take anthranilic acid M6 and cyclopentanone M5 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M13; Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were sequentially added into a three-necked flask and reacted at reflux temperature to obtain a white solid product M11; Step 3: intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12; Step 4: M13, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M1; Step 5: Dissolve the intermediate M1 and trifluoroacetic acid in DCM in sequence, and obtain a light yellow transparent liquid product M2 after reaction; Step 6: The intermediate M2, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to react to obtain a crude product; the crude product is separated by column chromatography to obtain the target compound I-iii; The reaction route is: Method D comprises the following steps: Step 1: Take anthranilic acid M6 and cycloheptanone M14 as raw materials, add phosphorus trichloride dropwise thereto, and finally obtain a light green solid product M15; Step 2: M9, N-Boc piperazine, triethylamine and tetrahydrofuran were sequentially added into a three-necked flask and reacted at reflux temperature to obtain a white solid product M11; Step 3: intermediate M11 is dephthalated under the action of hydrazine hydrate to obtain M12; Step 4: M15, M12, phenol and potassium iodide were added to a round-bottom flask in sequence, and the reaction solution was heated to obtain a yellow oily liquid crude product after the reaction; the crude product was separated by column chromatography to obtain a light yellow solid product M16; Step 5: The intermediate M16 and trifluoroacetic acid were dissolved in DCM in sequence, and after reaction, a light yellow transparent liquid product M17 was obtained; Step 6: The intermediate M17, DIPEA, HATU and substituted benzoic acid are sequentially added to tetrahydrofuran and the temperature is raised to obtain a crude product after the reaction; the crude product is separated by column chromatography to obtain the target compound I-iv; The reaction route is: Among them, R is halogen, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, C1-C6 alkoxy, hydrogen, acyl, or nitro-substituted (C5-C6) aromatic ring.

9. A pharmaceutical composition containing a tacrine derivative or a pharmaceutically acceptable salt of a tacrine derivative, characterized in that: It is a composition of the tacrine derivative or the pharmaceutically acceptable salt of the tacrine derivative according to claim 1, a carrier and an excipient; The excipients include oral preparations, injection preparations and local preparations, wherein the oral preparations are one or more of adhesives, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, and flavoring agents; the injection preparations are one or more of preservatives, solubilizers, and stabilizers; and the local preparations are one or more of bases, diluents, lubricants, and preservatives.

10. A pharmaceutical composition containing a tacrine derivative or a pharmaceutically acceptable salt of a tacrine derivative according to claim 9, characterized in that: The pharmaceutical composition is administered orally or parenterally, or is formulated into enteric-coated tablets.

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