Derivative with high isoflavone-O-alkylamine structure and application thereof

Abstract

The invention discloses a derivative with a high isoflavone-O-alkylamine structure and application thereof, the structural formula of the derivative is as follows: # imgabs0 #, and the derivative can be used as an acetylcholin esterase inhibitor and a beta-amyloid protein aggregation inhibitor for treating Alzheimer's disease and other nervous system diseases.

Description

Technical Field

[0001] The invention relates to the field of high isoflavone compound derivatives, in particular to a derivative with a high isoflavone-O-alkylamine structure and application thereof. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease. With the aging of the population, the incidence rate is increasing year by year, which not only seriously endangers the health of the elderly, but also brings huge economic and human burdens to families and society.

[0003] At present, the pathogenesis of Alzheimer's disease is still unclear, and the main hypotheses include cholinergic hypothesis, Aβ cascade hypothesis, Tau protein hyperphosphorylation hypothesis, oxidative stress hypothesis, metal ion hypothesis, inflammatory response hypothesis, gene mutation hypothesis, etc. The main clinical manifestations are cognitive dysfunction and memory loss, personality and behavior changes, decreased judgment, and loss of self-care ability.

[0004] Choline is an important neurotransmitter in the brain that can improve memory, attention and problem-solving ability. When choline intake is insufficient, it will lead to memory loss, lack of concentration and slow reaction. Choline supplementation can improve cognitive function. For this reason, choline is closely related to mental illnesses such as Alzheimer's disease, Parkinson's disease, schizophrenia, and depression. Studies have shown that the more acetylcholine is missing, the more severe the cognitive dysfunction of AD patients. Therefore, inhibiting the activity of acetylcholinesterase and increasing the content of acetylcholine can effectively improve cognitive function. In recent decades, the most active and effective field in the research of anti-Alzheimer's drugs is acetylcholinesterase inhibitors. In large-scale, multi-center, double-blind and placebo-controlled experiments, this type of substance has statistically significantly improved the cognitive ability and quality of life of AD patients, and the mechanism of action of acetylcholinesterase inhibitors is relatively clear. Therefore, it is still the target of many researchers looking for new drugs to treat Alzheimer's disease.

[0005] The acetylcholinesterase inhibitors currently approved for use by the U.S. Food and Drug Administration (FDA) include tacrine, donepezil, rivastigmine, and galantamine. Acetylcholinesterase inhibitors are generally suitable for patients with mild to moderate AD, which can improve the patient's symptoms but cannot cure the disease. AChEI has little effect on patients with advanced AD. However, the cost of using acetylcholinesterase inhibitors to treat AD is relatively low, so they are widely used.

[0006] Donepezil, as an acetylcholinesterase inhibitor, is currently the first-line drug for the treatment of Alzheimer's disease. Currently, many reports on the molecular structure of AD treatment mainly focus on the synthesis of donepezil analogs and the hybrid of donepezil pharmacophore coupled with tacrine molecular structure.

[0007] Among the many theories of AD pathological development, the Aβ cascade hypothesis is currently the most recognized by the academic community. Aβ originates from β-amyloid precursor protein (APP), and APP is cleaved into Aβ by β-secretase and γ-secretase. Aβ is easy to aggregate to form insoluble deposits, resulting in diffuse senile plaques. Factors such as genes, metabolism, and age can disrupt the Aβ generation process, leading to the deposition of a large number of senile plaques. The deposition of Aβ and senile plaques in the brain causes a series of pathological processes in the brain, causing cognitive impairment, changes in brain network functional connectivity, and brain structural damage characteristics, leading to the occurrence of AD. Therefore, inhibiting Aβ aggregation is naturally considered to be one of the breakthroughs for humans to break through AD. On June 7, 2021, the U.S. FDA approved Biogen's Aduhelm (Adulainumab) for the treatment of early Alzheimer's disease, which can selectively bind to β-amyloid protein and clear β-amyloid protein accumulation in the brains of patients with Alzheimer's disease. However, there is no clear evidence that the drug can slow down the clinical cognitive decline of patients with Alzheimer's disease, so there is great controversy. On January 6, 2023, the Alzheimer's disease drug lecanemab (trade name Leqembi) developed by Eisai and Biogen was approved by the US FDA. The results of the Phase 3 clinical trial showed that the drug can slow the rate of cognitive decline in Alzheimer's patients by 27%. It is the world's first breakthrough targeted drug targeting the source of Alzheimer's disease, aiming to fundamentally solve the cause and slow down cognitive decline. In January 2024, the drug was approved in China. The successful approval of Leqembi verifies the validity of the Aβ hypothesis, is a landmark event in drug development in the AD field, and is considered a new beginning for AD treatment.

[0008] At present, most of the drugs that have been marketed for the treatment of Alzheimer's disease are single-target compounds. Such as acetylcholinesterase inhibitors: rivastigmine, galantamine, donepezil, tacrine, huperzine A; N-methyl-D-aspartate receptor antagonists: memantine; low molecular weight acidic oligosaccharide compound GV-971 (Ganlutena capsules) targeting the brain-gut axis; aducanumab and lencanumab targeting β-amyloid protein and its aggregated plaques. Due to the complex pathogenesis of AD and the limitations of single-target drugs that only treat the symptoms but not the root cause, multi-target drugs can act simultaneously on different targets of the occurrence and development of the disease, and have the characteristics of small toxic side effects and significant effects, which have become the mainstream direction of designing anti-Alzheimer's drugs.

[0009] Flavonoids are secondary metabolites of plants, existing in leaves, flowers and fruits of plants, and are the main active ingredients of many medicinal plants. According to the differences in the degree of oxidation of the chain bridge, the connection position of the B ring, and whether the chain bridge forms a ring, flavonoids are divided into flavonoids, chalcones, isoflavones, homoisoflavonoids, anthocyanidins and aurone.

[0010] High isoflavone compounds are a special class of flavonoid compounds. The parent structure has one more carbon atom than isoflavones. It is a series of derivatives formed by the C3 position of chromone and chromanone connected to a benzyl group. This type of compound only exists in a few plants and has a low content. There are 8 types of reported high isoflavone structures, and the present invention uses V-type high isoflavones.

[0011] Pharmacological activity studies have shown that isoflavone compounds have anti-inflammatory, phosphorylation inhibition, estrogen-like, anti-irritant, anti-mutagenic, tumor cell toxicity, antifungal, vasodilation induction and hepatocyte protection and other biological activities, and have potential therapeutic effects on Alzheimer's disease. Therefore, it is necessary to develop a multi-target drug based on isoflavone compound derivatives to treat neurological diseases such as Alzheimer's disease. Summary of the invention

[0012] The present invention provides a derivative with a high isoflavone-O-alkylamine structure and application thereof, so as to solve the limitation problem of the single target drug for treating Alzheimer's disease and other nervous system diseases in the prior art that the drug only treats the symptoms but not the root cause.

[0013] In order to achieve the above object, the technical solution adopted by the present invention is:

[0014] The derivative having a high isoflavone-O-alkylamine structure has the following structural formula:

[0015]

[0016] In the structure, X is any one of F, Cl, Br, I, and methoxy; NR1R2 is any one of N-methylpiperazine, N-ethylpiperazine, N-phenylpiperazine, N-Boc piperazine, dimethylamine, diethylamine, dipropylamine, piperidine, 4-piperidylpiperidine, 4-benzylpiperidine, and tetrahydropyrrole; R3 is any one of H, Br, nitro, methyl, and methoxy; and n is any natural number from 1 to 8.

[0017] Furthermore, in the structural formula, X is any one of Cl, Br, and methoxy, NR1R2 is any one of N-methylpiperazine, N-Boc piperazine, and tetrahydropyrrole, R3 is methoxy, and n is any natural number from 3 to 7.

[0018] A use of the above derivative with a homoisoflavone-O-alkylamine structure as an acetylcholinesterase inhibitor.

[0019] A use of the above-mentioned derivative with a high isoflavone-O-alkylamine structure as a β-amyloid protein aggregation inhibitor.

[0020] A use of the above-mentioned derivative with a high isoflavone-O-alkylamine structure in treating Alzheimer's disease.

[0021] A use of the above-mentioned derivative with a high isoflavone-O-alkylamine structure in treating nervous system diseases including Alzheimer's disease.

[0022] In the present invention, the high isoflavone compound generated by the Claisen-Schmidt condensation reaction of flavonoid compounds with different substituted benzaldehydes can bind well to β-amyloid protein, has high specificity, and can pass through the blood-brain barrier. Under normal circumstances, β-amyloid protein is prone to self-aggregation, forming aggregates or plaques, causing a series of neurotoxicity. If a compound can bind to β-amyloid protein, it can be inferred that the compound should be able to inhibit this aggregation process to a certain extent.

[0023] Therefore, the present invention introduces O-alkylamine fragment analogs into the homoisoflavone skeleton to carry out structural design and optimization. Such compounds have good acetylcholinesterase inhibitory activity and also have high β-amyloid protein inhibitory activity, and provide new ideas for the treatment of Alzheimer's disease as multi-target drugs.

[0024] The present invention uses chromone and 3-methoxy-4-hydroxybenzaldehyde to react to construct a high isoflavone skeleton structure, introduces bromoalkanes with different carbon chains on the phenolic hydroxyl group through a substitution reaction, and then introduces different short-chain amine fragments. Alzheimer's disease is treated by targeting cholinesterase and amyloid protein. Experimental results show that the molecule of this structure has good acetylcholinesterase inhibitory activity and high β-amyloid protein inhibitory activity, and has good neuroprotective effect and anti-oxidative stress effect, and can be used for the treatment of amyloid plaque diseases such as Alzheimer's disease and cholinergic deficiency diseases.

[0025] At present, most of the drugs used in clinical treatment of Alzheimer's disease are acetylcholinesterase inhibitors, which are single-target drugs and treat the symptoms but not the root cause, and the effect lasts for a short time. The Aβ cascade hypothesis is the most recognized AD pathogenic mechanism in the academic community. Targeting β-amyloid protein is a hot topic of research at home and abroad, and it is expected to fundamentally treat AD. On the basis of previous work, the present invention introduces linker carbon chains and short amine fragments, which have both aggregation inhibition activity of β-amyloid protein and inhibitory activity of cholinesterase, and the overall molecule has a certain flexibility and is easy to enter the catalytic valley on the surface of acetylcholinesterase. This type of substance can effectively inhibit the self-aggregation of β-amyloid protein and the formation of senile plaques, reduce the neurotoxicity of Aβ cascade reaction, scavenge free radicals, and protect nerve cells. Therefore, it is a multi-target drug that can be used to treat Alzheimer's disease and other related diseases.

[0026] The compound of the present invention has a good effect of inhibiting acetylcholinesterase activity and amyloid protein aggregation activity, and behavioral experimental studies such as water maze have shown that it can effectively improve the memory and cognitive function of AD model mice.

[0027] The use of the compound of the present invention in preparing medicines is used to treat cognitive disorders such as senile dementia, cerebrovascular dementia, mild cognitive impairment, attention deficit disorder, and / or neurodegenerative dementia with abnormal protein aggregation, especially Alzheimer's disease.

[0028] The compounds of the present invention can be administered by different methods, such as oral administration in capsules or tablets, parenteral administration in sterile solutions or suspensions, and in some cases, intravenous injection in the form of solutions. The free base compounds of the present invention can be prepared and taken in the form of their pharmaceutically applicable acid addition salts. Pharmaceutically applicable acids include inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and similar inorganic acids) or organic acids (such as acetic acid, oxalic acid, maleic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, tartaric acid and similar organic acids), etc. DETAILED DESCRIPTION

[0029] The following examples further illustrate the present invention.

[0030] Example 1

[0031] This embodiment discloses a derivative having a high isoflavone-O-alkylamine structure, and its structural formula is shown below:

[0032]

[0033] In the structure, X is any one of F, Cl, Br, I, and methoxy, preferably any one of Cl, Br, and methoxy.

[0034] NR1R2 is any one of N-methylpiperazine, N-ethylpiperazine, N-phenylpiperazine, N-Boc piperazine, dimethylamine, diethylamine, dipropylamine, piperidine, 4-piperidylpiperidine, 4-benzylpiperidine and tetrahydropyrrole, preferably any one of N-methylpiperazine, N-Boc piperazine and tetrahydropyrrole.

[0035] R3 is any one of H, Br, nitro, methyl and methoxy, preferably methoxy.

[0036] n is any natural number from 1 to 8, preferably any natural number from 3 to 7.

[0037] Example 2

[0038] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0039] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0040]

[0041] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one as compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H). The reaction formula is:

[0042]

[0043] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 226 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 ml of acetonitrile were added to a round-bottom flask, and 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100°C for 5.5 hours. The acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the silica gel column was passed, eluted with petroleum ether: ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 66.7%. 1H NMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.08-4.01 (m, 2H), 3.87 (s, 3H), 2.40-2.28 (m, 6H), 1.85-1.78 (m, 2H), 1.58-1.42 (m, 6H). The reaction formula is:

[0044]

[0045] Example 3

[0046] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)butoxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0047] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0048]

[0049] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H). The reaction formula is:

[0050]

[0051] Next, compound 4 was subjected to a substitution reaction with N-methylpiperazine to prepare 6-chloro-3-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)butoxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 226 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 ml of acetonitrile were added to a round-bottom flask, and 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100°C for 5.5 h. The acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the mixture was passed through a silica gel column, eluted with petroleum ether: ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 40%. 1H NMR (500 MHz, Chloroform-d) δ7.88 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.89-6.84 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.00 (m, 2H), 3.87 (s, 3H), 2.46-2.25 (m, 13H), 1.85-1.76 (m, 2H), 1.52-1.45 (m, 2H). The reaction formula is:

[0052]

[0053] Example 4

[0054] This example synthesized a derivative 4-(4-(4-((6-chloro-4-oxochroman-3-ylidene)methyl)-2-methoxyphenoxy)butyl)piperazine-1-carboxylic acid tert-butyl ester, and the preparation process was as follows:

[0055] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0056]

[0057] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H). The reaction formula is:

[0058]

[0059] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl 4-(4-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)butyl)piperazine-1-carboxylate as a derivative of compound 5. The substitution reaction process is as follows: 226 mg (0.5 mmol) of 3-(4-(4-bromobutyloxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine, and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the mixture was reacted at 100° C. for 5.5 h. Acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was passed through a silica gel column and eluted with petroleum ether: ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 45%. 1H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.08-4.01 (m, 2H), 3.87 (s, 3H), 3.40-3.32 (m, 4H), 2.46-2.25 (m, 6H), 1.89-1.74 (m, 2H), 1.52-1.45 (m, 2H), 1.39 (s, 9H). The reaction formula is as follows:

[0060]

[0061] Example 5

[0062] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0063] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0064]

[0065] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.41 (m, 2H). The reaction formula is as follows:

[0066]

[0067] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100° C. for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1. The corresponding components were collected to obtain the product with a yield of 66.7%. 1H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.12-4.03 (m, 2H), 3.87 (s, 3H), 2.39-2.25 (m, 6H), 1.81-1.68 (m, 4H), 1.55-1.36 (m, 6H). The reaction formula is as follows:

[0068]

[0069] Example 6

[0070] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-((5-(4-methylpiperazin-1-yl)pentyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0071] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0072]

[0073] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.41 (m, 2H). The reaction formula is as follows:

[0074]

[0075] Next, compound 4 was subjected to a substitution reaction with N-methylpiperazine to prepare 6-chloro-3-(3-methoxy-4-((5-(4-methylpiperazine-1-yl)pentyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100° C. for 8 h. Acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 49%. 1HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.91-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.08-4.01 (m, 2H), 3.87 (s, 3H), 2.46-2.25 (m, 13H), 1.85-1.76 (m, 2H), 1.52-1.35 (m, 4H). The reaction formula is as follows:

[0076]

[0077] Example 7

[0078] This example synthesized a derivative 4-(5-(4-((6-chloro-4-oxochroman-3-ylidene)methyl)-2-methoxyphenoxy)pentyl)piperazine-1-carboxylic acid tert-butyl ester, and the preparation process was as follows:

[0079] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0080]

[0081] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.41 (m, 2H). The reaction formula is as follows:

[0082]

[0083] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl 4-(5-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)pentyl)piperazine-1-carboxylate as a derivative of compound 5. The substitution reaction process is as follows: 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100° C. for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 56%. 1HNMR (500MHz, Chloroform-d) δ7.90 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.07 (s, 2H), 4.08-4.01 (m, 2H), 3.87 (s, 3H), 3.40-3.30 (m, 4H), 2.46-2.25 (m, 6H), 1.85-1.76 (m, 2H), 1.50-1.35 (m, 4H), 1.32 (s, 9H). The reaction formula is as follows:

[0084]

[0085] Example 8

[0086] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0087] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0088]

[0089] Then, compound 3 was subjected to a substitution reaction with 1,6-dibromohexane to prepare 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The process of the substitution reaction is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 78%. 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.36 (m, 4H). The reaction formula is as follows:

[0090]

[0091] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the mixture was reacted at 90°C for 6 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the mixture was passed through a silica gel column, and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 66.7%. 1H NMR (500 MHz, Chloroform-d) δ 7.85 (s, 1H), 7.73 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.08-4.01 (m, 2H), 3.85 (s, 3H), 2.40-2.28 (m, 6H), 1.84-1.69 (m, 2H), 1.62-1.45 (m, 4H), 1.40-1.32 (m, 6H). The reaction formula is as follows:

[0092]

[0093] Example 9

[0094] This example synthesized a derivative 6-chloro-3-(3-methoxy-4-((6-(4-methylpiperazin-1-yl)hexyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0095] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0096]

[0097] Then, compound 3 was subjected to a substitution reaction with 1,6-dibromohexane to prepare 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one as compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100°C for 4 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 78%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.36 (m, 4H). The reaction formula is as follows:

[0098]

[0099] Next, compound 4 was subjected to a substitution reaction with N-methylpiperazine to prepare 6-chloro-3-(3-methoxy-4-((6-(4-methylpiperazine-1-yl)hexyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100° C. for 8 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the mixture was passed through a silica gel column, and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 50%. 1HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 5.10 (s, 2H), 4.08-4.01 (m, 2H), 3.84 (s, 3H), 2.40-2.25 (m, 13H), 1.83-1.68 (m, 2H), 1.41-1.34 (m, 6H). The reaction formula is as follows:

[0100]

[0101] Example 10

[0102] This example synthesized a derivative 4-(6-(4-((6-chloro-4-oxochroman-3-ylidene)methyl)-2-methoxyphenoxy)hexyl)piperazine-1-carboxylic acid tert-butyl ester, and the preparation process was as follows:

[0103] First, 6-chloro-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask in sequence, and the mixture is stirred at 80°C for 6.5 hours. After the reaction is completed, 25% sodium hydroxide solution is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92-6.88 (m, 2H), 6.82 (d, J = 8.1 Hz, 1H), 5.98 (br, 1H), 5.09 (s, 2H), 3.88 (s, 3H). The reaction formula is:

[0104]

[0105] Then, compound 3 was subjected to a substitution reaction with 1,6-dibromohexane to prepare 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one of compound 4. The substitution reaction process is as follows: 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 4 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 78%. 1 H NMR (500 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.40-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.36 (m, 4H). The reaction formula is as follows:

[0106]

[0107] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl 4-(6-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)hexyl)piperazine-1-carboxylate as a derivative of compound 5. The substitution reaction process is as follows: 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylidene)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100° C. for 7 h. Acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 45%. 1HNMR (500MHz, Chloroform-d) δ7.88 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 2H), 6.68 (d, J = 8.1 Hz, 1H), 5.09 (s, 2H), 4.08-4.01 (m, 2H), 3.87 (s, 3H), 3.38-3.30 (m, 4H), 2.46-2.25 (m, 6H), 1.81-1.70 (m, 2H), 1.45-1.41 (m, 2H), 1.39 (s, 9H), 1.38-1.32 (m, 4H). The reaction formula is as follows:

[0108]

[0109] Embodiment 11

[0110] This example synthesized a derivative 6-methoxy-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0111] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0112]

[0113] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one of compound 4. The substitution reaction process is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92-6.89 (m, 2H), 6.83 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.10 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.29 (m, 2H), 1.87-1.73 (m, 4H). The reaction formula is as follows:

[0114]

[0115] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-methoxy-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 223 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100°C for 5.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 62%. 1H NMR (500 MHz, Chloroform-d) δ7.75 (s, 1H), 7.38 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.95-6.87 (m, 2H), 6.82 (d, J = 9.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.20 (br, 1H), 5.10 (s, 2H), 4.08-4.00 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.40-2.25 (m, 6H), 1.82-1.76 (m, 2H), 1.55-1.40 (m, 6H). The reaction formula is:

[0116]

[0117] Example 12

[0118] This example synthesized a derivative 6-methoxy-3-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)butoxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0119] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0120]

[0121] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one of compound 4. The substitution reaction process is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92-6.89 (m, 2H), 6.83 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.10 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.29 (m, 2H), 1.87-1.73 (m, 4H). The reaction formula is as follows:

[0122]

[0123] Next, compound 4 was subjected to a substitution reaction with N-methylpiperazine to prepare 6-methoxy-3-(3-methoxy-4-(4-(4-methylpiperazine-1-yl)butoxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 223 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100°C for 8 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the mixture was passed through a silica gel column, and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 65%. 1HNMR (500MHz, Chloroform-d) δ7.78 (s, 1H), 7.38 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.08 (s, 2H), 4.08-4.01 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.46-2.25 (m, 13H), 1.85-1.76 (m, 2H), 1.52-1.45 (m, 2H). The reaction formula is as follows:

[0124]

[0125] Embodiment 13

[0126] This example synthesized a derivative 4-(4-(2-methoxy-4-((6-methoxy-4-oxochroman-3-ylidene)methyl)phenoxy)butyl)piperazine-1-carboxylic acid tert-butyl ester, and the preparation process was as follows:

[0127] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0128]

[0129] Then, compound 3 was subjected to a substitution reaction with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one of compound 4. The substitution reaction process is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene) chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 82%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92-6.89 (m, 2H), 6.83 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.10 (s, 2H), 4.10-4.02 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.29 (m, 2H), 1.87-1.73 (m, 4H). The reaction formula is as follows:

[0130]

[0131] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl 4-(4-(2-methoxy-4-((6-methoxy-4-oxobenzodihydropyran-3-ylidene)methyl)phenoxy)butyl)piperazine-1-carboxylate as a derivative of compound 5. The substitution reaction process is as follows: 223 mg (0.5 mmol) of 3-(4-(4-bromobutyloxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 178 mg (1 mmol) of N-Boc piperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100° C. for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 63%. 1HNMR (500MHz, Chloroform-d) δ7.76 (s, 1H), 7.37 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.82 (d, J = 9.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.10 (s, 2H), 4.08-4.01 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.31 (m, 4H), 2.45-2.27 (m, 6H), 1.87-1.77 (m, 2H), 1.50-1.45 (m, 2H), 1.38 (s, 9H). The reaction formula is:

[0132]

[0133] Embodiment 14

[0134] This example synthesized a derivative 6-methoxy-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0135] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0136]

[0137] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one of compound 4. The process of the substitution reaction is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 86%. 1 H NMR(500MHz,Chloroform-d)δ7.80(s,1H),7.38(s,1H),7.02(d,J=8.1Hz,1H),6.93-6.88(m,2H),6.84(d,J=9.1Hz,1H),6.79(d,J=8.1H z,1H),6.23(br,1H),5.08(s,2H),4.15-4.04(m,2H),3.90(s,3H),3.82(s,3H),3.41-3.29(m,2H),1.85-1.73(m,4H),1.54-1.41(m,2H).

[0138] The reaction formula is as follows:

[0139]

[0140] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-methoxy-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 230 mg (0.5 mmol) of 3-(4-(5-bromopentyloxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 69%. 1H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.39 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.95-6.86 (m, 2H), 6.83 (d, J = 9.1 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.08 (s, 2H), 4.08-4.01 (m, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 2.41-2.30 (m, 6H), 1.85-1.75 (m, 4H), 1.56-1.41 (m, 6H). The reaction formula is as follows:

[0141]

[0142] Embodiment 15

[0143] This example synthesized a derivative 6-methoxy-3-(3-methoxy-4-((5-(4-methylpiperazin-1-yl)pentyl)oxy)benzylidene)chroman-4-one, and the preparation process was as follows:

[0144] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0145]

[0146] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one as compound 4. The substitution reaction process is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the elution was performed with petroleum ether: ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 86%. 1 H NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.38 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.08 (s, 2H), 4.15-4.04 (m, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.41-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.41 (m, 2H). The reaction formula is as follows:

[0147]

[0148] Next, compound 4 was subjected to a substitution reaction with N-methylpiperazine to prepare 6-methoxy-3-(3-methoxy-4-((5-(4-methylpiperazine-1-yl)pentyl)oxy)benzylidene)chroman-4-one as a derivative of compound 5. The substitution reaction process is as follows: 230 mg (0.5 mmol) of 3-(4-(5-bromopentyloxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate was slowly added under stirring, and the reaction was carried out at 100° C. for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the mixture was passed through a silica gel column, and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 55%. 1HNMR (500MHz, Chloroform-d) δ7.79 (s, 1H), 7.37 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.10 (s, 2H), 4.10-4.02 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 2.47-2.29 (m, 13H), 1.82-1.73 (m, 2H), 1.54-1.40 (m, 4H). The reaction formula is as follows:

[0149]

[0150] Example 16

[0151] This example synthesized a derivative 4-(5-(2-methoxy-4-((6-methoxy-4-oxobenzopyran-3-ylidene)methyl)phenoxy)pentyl)piperazine-1-carboxylic acid tert-butyl ester, and the preparation process was as follows:

[0152] First, 6-methoxy-4-dihydrochromanone is used as compound 1 and 3-methoxy-4-hydroxybenzaldehyde is used as compound 2. Compound 1 and compound 2 are subjected to Claisen-Schmidt condensation reaction to obtain 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3. The reaction process of the Claisen-Schmidt condensation reaction is as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromanone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde and 10 ml of phosphoric acid are added to a round-bottom flask and stirred at 80°C for 6.5 hours. 25% sodium hydroxide is added to adjust the pH to 8-9, a large amount of precipitate is generated, which is filtered and dried to obtain a light yellow solid. The yield is 85%. 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.40 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.25 (br, 1H), 5.08 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H). The reaction formula is as follows:

[0153]

[0154] Then, compound 3 was subjected to a substitution reaction with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one of compound 4. The process of the substitution reaction is as follows: 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane and 15 ml of acetonitrile were added to a round-bottom flask, 253 mg (1.83 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100°C for 3.5 hours. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the silica gel column was passed, and the corresponding components were collected to obtain the product with a yield of 86%. 1 H NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.38 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.93-6.88 (m, 2H), 6.84 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.08 (s, 2H), 4.15-4.04 (m, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.41-3.29 (m, 2H), 1.85-1.73 (m, 4H), 1.54-1.41 (m, 2H). The reaction formula is as follows:

[0155]

[0156] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl 4-(5-(2-methoxy-4-((6-methoxy-4-oxobenzopyran-3-ylidene)methyl)phenoxy)pentyl)piperazine-1-carboxylate as a derivative of compound 5. The substitution reaction process is as follows: 230 mg (0.5 mmol) of 3-(4-(5-bromopentyloxy)-3-methoxybenzylidene)-6-methoxybenzopyran-4-one, 178 mg (1 mmol) of N-Boc piperazine and 15 ml of acetonitrile were added to a round-bottom flask, 208 mg (1.5 mmol) of potassium carbonate were slowly added under stirring, and the reaction was carried out at 100° C. for 5.5 h. The acetonitrile was removed under reduced pressure, water and dichloromethane were added, and after separation, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was passed through a silica gel column and eluted with petroleum ether:ethyl acetate 1:1, and the corresponding components were collected to obtain the product with a yield of 58%. 1HNMR (500MHz, Chloroform-d) δ7.79 (s, 1H), 7.48 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.95-6.89 (m, 2H), 6.85 (d, J = 9.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.23 (br, 1H), 5.08 (s, 2H), 4.08-4.01 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.40-3.31 (m, 4H), 2.49-2.26 (m, 6H), 1.87-1.75 (m, 2H), 1.55-1.43 (m, 4H), 1.39 (s, 9H). The reaction formula is as follows:

[0157]

[0158] Combining the preparation methods of Examples 2 to 16, it can be seen that the overall preparation process of the derivative with a high isoflavone-O-alkylamine structure disclosed in Example 1 is: using 6-X-4-dihydrochromanone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compound 1 and compound 2 are subjected to a Claisen-Schmidt condensation reaction to obtain 6-X-3-(4-hydroxy-3-methoxybenzylidene)chroman-4-one as compound 3; compound 3 is subjected to a substitution reaction with a dibromoalkane to obtain 3-(4-(n-bromooxy)-3-methoxybenzylidene)-6-Xbenzopyran-4-one as compound 4; finally, compound 4 is subjected to a substitution reaction with different short-chain amines to obtain compound 5, which is a derivative with a high isoflavone-O-alkylamine structure. The overall reaction process is shown in the following reaction formula:

[0159]

[0160] Example 17 Cholinesterase activity test

[0161] The modified Ellman method was used to test the cholinesterase inhibitory activity of the derivatives with high isoflavone-O-alkylamine structure prepared in Example 2-16, and the method was referred to the literature (Wang Keren. Synthesis of novel multi-target apigenin derivatives and their anti-Alzheimer's disease research [D]. Nanyang Normal University, 2019.). The specific experimental plan is as follows:

[0162] Acetylcholinesterase inhibitory activity assay: Take a 96-well plate and add 30 μL of thioacetylcholine (1.2 mmol / L), 40 μL of 0.1 mol·L -1A phosphate buffer solution with a pH of 7.4, 20 μL of samples of different concentrations (1 μM, 0.1 μM, 0.01 μM, 1 nM) (i.e., derivatives with high isoflavone-O-alkylamine structure prepared in Examples 2 to 16) and 10 μL of Drosophila acetylcholinesterase solution (0.2 units / mL), mixed and incubated at 37°C for 15 min. Then 30 μL of 0.2% 5,5-dithiobis(2-nitrobenzoic acid) (DTNB 0.6 mmol / L) was added to each reaction well. The color reaction was allowed to develop for 2.5 hours, and the absorbance (OD) of the solution in the 96-well plate at λ=405 nm was measured using an ELISA reader.

[0163] Butyrylcholinesterase inhibitory activity assay: Take a 96-well plate and add 30 μL of iodothiobutyrylcholine (1.2 mmol / L), 40 μL of 0.1 mol·L -1 A phosphate buffer solution with a pH of 7.4, 20 μL of samples of different concentrations (1 μM, 0.1 μM, 0.01 μM, 1 nM) (i.e., the high isoflavone-O-alkylamine structure derivatives prepared in Examples 2 to 16) and 10 μL of Drosophila butyrylcholinesterase solution (0.2 units / mL), mixed and incubated at 37°C for 15 minutes. Then 30 μL of 0.2% 5,5-dithiobis(2-nitrobenzoic acid) (DTNB 0.6 mmol / L) was added to each reaction well. The color reaction was allowed to develop for 2.5 hours, and the absorbance (OD) of the solution in the 96-well plate at λ=405 nm was measured using an ELISA reader.

[0164] The positive control used 20 μL of different concentrations (1 μM, 0.1 μM, 0.01 μM, 1 nM) of tacrine instead of the derivatives prepared in Examples 2 to 16. The control group used 20 μL of phosphate buffer instead of the derivatives prepared in Examples 2 to 16. The background group used 10 μL of phosphate buffer instead of the enzyme solution and 20 μL of phosphate buffer instead of the derivatives prepared in Examples 2 to 16. Each group of data was repeated 3 times and the average value was taken.

[0165] Calculate the inhibition rate = (A 对照组 -A 实验组 ) / (A 对照组 -A 背景组 )*100%, and the IC of each compound was calculated using Graph Pad Priam9.5 software 50 value.

[0166] The results are shown in Table 1:

[0167] Table 1 Inhibitory activity of high isoflavone-O-alkylamine structure derivatives prepared in Examples 2 to 16 on cholinesterase

[0168]

[0169]

[0170] It can be concluded from Table 1 that the derivative prepared in Example 14 has the best acetylcholinesterase inhibitory activity, and the derivatives prepared in Examples 11, 8, 15, 2, etc. also have relatively high acetylcholinesterase inhibitory activity.

[0171] Example 18 DPPH free radical scavenging experiment

[0172] The derivatives prepared in Example 2, Example 8, Example 11 and Example 14 were selected to examine the antioxidant capacity through DPPH free radical scavenging experiment. The method refers to: National Standard "DPPH and ABTS Method for Determination of Antioxidant Activity of Peptides", and the specific experimental scheme is as follows:

[0173] Weigh 5 mg of DPPH and dissolve it in 1 mL of anhydrous ethanol to prepare a 12 mM solution, and dilute it to 120 μM with anhydrous ethanol;

[0174] The derivatives prepared in Example 2, Example 8, Example 11 and Example 14 were respectively dissolved in DMSO to prepare a mother solution with a concentration of 10 mM, and then diluted with distilled water to 1 μM, 10 μM and 100 μM for testing;

[0175] In a 96-well plate, 50 μL of DPPH solution (120 μM) and 50 μL of samples (derivatives prepared in Examples 2, 8, 11 and 14) of different concentrations (1 μM, 10 μM, 100 μM) were added, mixed evenly, and allowed to stand at 37° C. in the dark for 30 min. The absorbance (OD) of the solution in the 96-well plate at λ=517 nm was then measured using an ELISA reader.

[0176] Ascorbic acid was used instead of the compound sample in the positive control, anhydrous ethanol was used instead of DPPH in the control group, and the sample solvent DMSO (1 μM, 10 μM, 100 μM) was used instead of the derivatives prepared in Examples 2, 8, 11 and 14 in the blank group. Each group of data was run three times in parallel and the average value was taken.

[0177]

[0178] P——DPPH scavenging rate; As——absorbance of the mixture of the test compound and DPPH; Ac——absorbance of the mixture of the test compound and anhydrous ethanol; Ab——absorbance of the mixture of DPPH and DMSO

[0179] The results are shown in Table 2:

[0180] Table 2 Scavenging rate of DPPH free radicals by the derivatives prepared in Example 2, Example 8, Example 11 and Example 14

[0181]

[0182]

[0183] As can be seen from Table 2, the free radical scavenging rates of the derivatives prepared in Examples 8 and 14 are relatively high, close to the results of the positive control ascorbic acid, indicating that the derivatives prepared in Examples 8 and 14 have good antioxidant effects.

[0184] Example 19 Inhibition of Aβ aggregation

[0185] The derivatives prepared in Example 2, Example 4, Example 8, Example 11 and Example 14 were selected, and the ability of the synthesized small molecule compounds to inhibit Aβ self-aggregation was determined by the thioflavin T method. The method was based on the literature (Wang Keren. Synthesis of novel multi-target apigenin derivatives and their anti-Alzheimer's disease research [D]. Nanyang Normal University, 2019.). Specifically, a black 96-well plate was taken, and 20 μL of Aβ was added successively. 1-42 The mixture was incubated in an incubator at 37°C for 24 h with 20 μL of samples of different concentrations (1 μM, 25 μM, 50 μM) (derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14), and then 160 μL of a buffer solution containing 5 μM thioflavin T was added, and the fluorescence value was immediately measured using a microplate reader (excitation wavelength was 446 nm, emission wavelength was 490 nm).

[0186] The blank group was treated with 20 μL buffer instead of Aβ 1-42 , 20 μL buffer was used to replace the sample (derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14); the control group used 20 μL buffer to replace the sample (derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14).

[0187] Each set of data was repeated 3 times and the average value was taken.

[0188]

[0189] P——inhibition rate; IFi——fluorescence value of experimental group; IFc——fluorescence value of control group; IF0——fluorescence value of blank group

[0190] The results are shown in Table 3:

[0191] Table 3 Inhibitory activity of the derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14 on Aβ self-aggregation

[0192] Example 2 Example 4 Example 8 Embodiment 11 Embodiment 14 1μM 30％ 10％ 82％ 22％ 80％ 25μM 62％ 20％ 90％ 49％ 92％ 50μM 80％ 35％ 95％ 60％ 97％

[0193] As shown in Table 3, the derivatives prepared in Examples 2, 8, 11 and 14 all have good inhibitory activity against Aβ self-aggregation. Among them, the derivatives prepared in Examples 8 and 14 showed good Aβ aggregation inhibitory activity (>80%) at a concentration of 1 μM.

[0194] Example 20: H2O2-induced PC 12 Protective effect on nerve cell damage

[0195] The derivatives prepared in Example 2, Example 4, Example 8, Example 11 and Example 14 were selected and the effects of the compounds on PC were evaluated by MTT method. 12 The method is based on the literature (Du Jiyu. Novel tryptanthrin derivatives: a multi-target ligand for the treatment of Alzheimer's disease [D]. Anhui Medical University, 2023.). Specifically, 5*10 3 PC 12 The cells were seeded into a 96-well plate, and after overnight incubation, the old culture medium was discarded, and fresh culture medium containing 10 μM of the derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14 was added, and the cells were cultured for 3 hours, and then exposed to H2O2 (250 μM) and incubated overnight. 20 μL of MTT solution (5 mg / ml) was added, incubated for 4 hours, the supernatant was removed, 150 μL of DMSO was added, and the shaker was placed for 10 to 15 minutes, and the absorbance at 492 nm was immediately measured using an ELISA reader.

[0196] The control group used PBS buffer instead of the derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14, and was not exposed to H2O2 for overnight incubation; the blank group used PBS buffer instead of the derivatives prepared in Example 2, Example 4, Example 8, Example 11, and Example 14, and was exposed to H2O2 for overnight incubation. Each group of data was repeated 3 times, and the average value was taken.

[0197] P——cell survival rate

[0198] The results are shown in Table 4:

[0199] Table 4 Protective effect of the derivatives prepared in Example 2, Example 4, Example 8, Example 11 and Example 14 on H2O2-induced neuronal cells

[0200] Example 2 Example 4 Example 8 Embodiment 11 Embodiment 14 Cell survival rate 40％ 20％ 65％ 40％ 68％

[0201] As can be seen from Table 4, the cell survival rates of the derivatives prepared in Example 11 and Example 14 were relatively high, both greater than 60%, indicating that these compounds have good neuroprotective effects.

[0202] Example 21 Water maze experiment

[0203] The water maze experiment was used to evaluate the effect of the prepared compound on improving the memory and cognitive ability of Alzheimer's disease mice. The experimental method was based on the literature (Li Xiaohui, Wang Yanxia, ​​Dong Yiyi, et al. Experimental study on the improvement of memory and cognitive ability of Alzheimer's disease mice by inhibiting acetylcholinesterase by curcumin derivative Cur20 [J]. Drug Evaluation Research, 2022, 45 (03): 449-454.). Specifically, the mice were divided into a positive control group, a drug group (derivative prepared in Example 14), and a model group. At the same time every day, the mice were gavaged with a 0.5% sodium carboxymethyl cellulose suspension of the derivative prepared in Example 14 (400 mg / kg·d) for a total of 7 days. From the 8th day, 30 minutes after gavage, scopolamine hydrobromide (200 μL) was intraperitoneally injected to establish an AD model. The drug was administered for a total of 16 days. Starting from the 11th day, the mice were subjected to a 5-day water maze experiment. The water maze consists of a pool with a diameter of 150 cm, a height of 50 cm, and a water temperature of 20°C, as well as a camera and a behavior analysis system. The water maze has an escape platform with a diameter of 10 cm placed at a depth of 30 cm and 1.5 cm from the water surface. The positioning navigation experiment was carried out in the first 4 days, with 4 training sessions per day and an interval of more than 0.5 h between each experiment. Each time, mice were randomly placed in the water from 4 different quadrants of the pool, and the latency of the mice to find the platform was automatically tracked and recorded. The time did not exceed 90 seconds, and the average latency per day was calculated. On the 5th day, the spatial exploration experiment began. The platform was removed and the mice were randomly placed in the water from the quadrant opposite the platform facing and close to the pool wall. The movement trajectory of the mice to find the original platform and the number of crossings on the original platform were recorded in 90 seconds. During the experiment, the platform position, experimental environment and reference objects remained basically unchanged.

[0204] Donepezil was used as a positive control drug; the model group used 0.5% sodium carboxymethylcellulose instead of drug solution and needed to be injected with scopolamine hydrobromide. There were 5 mice in each group to reduce experimental errors.

[0205] The incubation period statistics are shown in Table 5:

[0206] Table 5 Statistics of latency of each group in water maze experiment

[0207] Day 1 Day 2 Day 3 Day 4 Model Group 34.9s 44.8s 50.9s 58.3s Positive control group (donepezil) 35.5s 30.2s 27.2s 23.4s Experimental sample group (derivatives prepared in Example 14) 33.6s 30.5s 28.4s 24.5s

[0208] When conducting the positioning navigation experiment, it can be found from Table 5 that the latency of the model group mice on the 2nd to 4th day increased significantly, indicating that the model was successfully established. Compared with the model group, the latency of the experimental sample group (derivative prepared in Example 14) and the positive control group mice was significantly shortened, and as the training time increased, the escape latency of the experimental sample group (derivative prepared in Example 14) and the positive control group mice gradually shortened, and the two showed similar effects.

[0209] The statistical results of the number of times of crossing the original platform are shown in Table 6:

[0210] Table 6 Statistics of the number of times each group crossed the original platform in the water maze experiment

[0211]

[0212]

[0213] In the space exploration experiment, it can be found from Table 6 that the number of times the model group mice crossed the original platform was significantly reduced, and the crossing time was significantly increased. The number of times the platform was crossed by mice in the positive control group and the experimental sample group (derivatives prepared in Example 14) was significantly increased.

[0214] The results showed that the derivative prepared in Example 14 could reduce the escape latency of the water maze of AD mice, increase the number of platform crossings, and improve the spatial learning, memory and cognitive abilities of AD mice.

[0215] In summary, combined with the tests of Examples 17 to 21, it can be seen that the derivative with a high isoflavone-O-alkylamine structure disclosed in Example 1 has both cholinesterase inhibitory activity and β-amyloid protein aggregation inhibitory activity, and also has antioxidant stress and neuroprotective effects, and can be used as an acetylcholinesterase inhibitor and β-amyloid protein aggregation inhibitor, and is a multi-target drug for the treatment of Alzheimer's disease or other nervous system diseases.

[0216] The present invention is not limited to the specific details of the above-mentioned embodiments. Within the technical concept of the present invention and without departing from the design concept of the present invention, various modifications and improvements made to the technical solution of the present invention by technical personnel in this field should fall within the protection scope of the present invention. The technical contents for which protection is sought in the present invention have been fully recorded in the claims.

Claims

1. A derivative having a high isoflavone-O-alkylamine structure, characterized in that: Its structural formula is as follows: ， In the structure, X is any one of F, Cl, Br, I, and methoxy; NR1R2 is any one of N-methylpiperazine, N-ethylpiperazine, N-phenylpiperazine, N-Boc piperazine, dimethylamine, diethylamine, dipropylamine, piperidine, 4-piperidylpiperidine, 4-benzylpiperidine, and tetrahydropyrrole; R3 is any one of H, Br, nitro, methyl, and methoxy; and n is any natural number from 1 to 8.

2. The derivative having a high isoflavone-O-alkylamine structure according to claim 1, characterized in that: In the structural formula, X is any one of Cl, Br, and methoxy, NR1R2 is any one of N-methylpiperazine, N-Boc piperazine, and tetrahydropyrrole, R3 is a methoxy group, and n is any natural number from 3 to 7.

3. Use of the derivative having a homoisoflavone-O-alkylamine structure as claimed in claim 1 or 2 as an acetylcholinesterase inhibitor.

4. Use of the derivative having a homoisoflavone-O-alkylamine structure as claimed in claim 1 or 2 as an inhibitor of β-amyloid protein aggregation.

5. Use of the derivative having a high isoflavone-O-alkylamine structure as claimed in claim 1 or 2 in the treatment of Alzheimer's disease.

6. Use of the derivative having a homoisoflavone-O-alkylamine structure as claimed in claim 1 or 2 in the treatment of nervous system diseases including Alzheimer's disease.

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