Derivatives having high isoflavone-o-alkylamine structure and use thereof

Abstract

The application discloses a derivative with a high isoflavone-O-alkylamine structure and application thereof, and a structure formula of the derivative is shown in the following formula: the derivative can be used as an acetylcholinesterase inhibitor and a beta-amyloid protein aggregation inhibitor to treat Alzheimer's disease and other nervous system diseases.

Description

Technical Field

[0001] This invention relates to the field of high isoflavone compound derivatives, specifically a derivative having a high isoflavone-O-alkylamine structure and its applications. Background Technology

[0002] Alzheimer's disease (AD) is a neurodegenerative disease. With an aging population, its incidence rate is increasing year by year, seriously endangering the health of the elderly and imposing a huge economic and human resource burden on families and society.

[0003] The pathogenesis of Alzheimer's disease is not yet fully understood, but several theories exist, including the cholinergic hypothesis, the Aβ cascade hypothesis, the Tau protein hyperphosphorylation hypothesis, the oxidative stress hypothesis, the metal ion hypothesis, the inflammatory response hypothesis, and the gene mutation hypothesis. The main clinical manifestations include cognitive impairment and memory decline, personality and behavioral changes, impaired judgment, and loss of self-care abilities.

[0004] Choline is an important neurotransmitter in the brain, which can improve memory, attention, and problem-solving abilities. Insufficient choline intake can lead to memory decline, poor concentration, and slow reaction time; choline supplementation can improve cognitive function. Therefore, choline is closely related to mental illnesses such as Alzheimer's disease, Parkinson's disease, schizophrenia, and depression. Studies show that the greater the acetylcholine deficiency, the more severe the cognitive impairment in AD patients. Therefore, inhibiting acetylcholinesterase activity and increasing acetylcholine levels can effectively improve cognitive function. In recent decades, the most active and effective area of ​​research in anti-Alzheimer's drugs has been acetylcholinesterase inhibitors. In large-scale, multicenter, double-blind, placebo-controlled trials, these substances have shown statistically significant improvements in cognitive ability and quality of life in AD patients. Moreover, the mechanism of action of acetylcholinesterase inhibitors is relatively clear; therefore, they remain a target for many researchers searching for new drugs to treat Alzheimer's disease.

[0005] Currently, acetylcholinesterase inhibitors 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 Alzheimer's disease (AD), improving symptoms but not curing the disease. AChEIs have minimal efficacy for patients with advanced AD. However, the cost of using acetylcholinesterase inhibitors to treat AD is relatively low, hence their widespread use.

[0006] Donepezil, an acetylcholinesterase inhibitor, is currently a first-line drug for the treatment of Alzheimer's disease. Much of the current molecular structural reporting on AD treatment focuses on the synthesis of donepezil analogs and hybrids of donepezil pharmacophores coupled to thacrine molecules.

[0007] Among the many theories of Alzheimer's disease (AD) pathogenesis, the Aβ cascade hypothesis is currently the most widely accepted in academia. Aβ originates from β-amyloid precursor protein (APP), which is cleaved into Aβ by β-secretase and γ-secretase. Aβ easily aggregates to form insoluble deposits, resulting in diffuse senile plaques. Genetic, metabolic, and age-related factors can disrupt the Aβ production process, leading to the massive deposition of senile plaques. The deposition of Aβ and senile plaques in the brain triggers a series of pathological processes, causing cognitive impairment, changes in brain network connectivity, and structural brain damage, thus leading to AD. Therefore, inhibiting Aβ aggregation is naturally considered one of the breakthroughs in combating AD. On June 7, 2021, the US FDA approved Biogen's Aduhelm (adanulumab) for the treatment of early-stage Alzheimer's disease. It selectively binds to β-amyloid protein, clearing β-amyloid protein accumulation in the brains of Alzheimer's patients. However, there is no clear evidence that this drug can slow down clinical cognitive decline in Alzheimer's patients, thus remaining highly controversial. On January 6, 2023, lecanemab (trade name Leqembi), an Alzheimer's disease drug developed by Eisai and Biogen, received FDA approval in the United States. Phase 3 clinical trial results showed that the drug slowed the rate of cognitive decline in Alzheimer's patients by 27%. It is the world's first breakthrough targeted therapy targeting the root cause of Alzheimer's disease, aiming to fundamentally address the cause and slow cognitive decline. In January 2024, the drug was approved in China. The successful approval of Leqembi validated the effectiveness of the Aβ hypothesis, marking a significant event in AD drug development and considered a new beginning for AD treatment.

[0008] Currently, most marketed drugs for treating Alzheimer's disease are single-target compounds. Examples include acetylcholinesterase inhibitors such as levamisole, galantamine, donepezil, tacrine, and huperzine A; N-methyl-D-aspartate receptor antagonists such as memantine; low-molecular-weight acidic oligosaccharide compounds targeting the brain-gut axis such as GV-971 (mannostatin capsules); and adunatumab and lencanemab targeting β-amyloid protein and its aggregated plaques. Due to the complex pathogenesis of AD and the limitations of single-target drugs (treating only the symptoms), multi-target drugs, which can simultaneously act on different targets in the development and progression of the disease, and have fewer side effects and significant efficacy, have become the mainstream direction in designing anti-Alzheimer's drugs.

[0009] Flavonoids are secondary metabolites found in the leaves, flowers, and fruits of plants, and are the main active ingredients in many medicinal plants. Based on differences in the degree of oxidation of the chain bridges, the position of the B-ring connection, and whether the chain bridges form a ring, flavonoids are classified into several types, including flavones, chalcones, isoflavones, high isoflavones, anthocyanins, and hesperidins.

[0010] High isoflavone compounds are a special class of flavonoids. Their parent structure has one more carbon atom than that of isoflavones, and they are a series of derivatives formed by attaching a benzyl group to the C3 position of chromones and chromones. These compounds are found only in a few plants, and in low amounts. Eight structural types of high isoflavones have been reported; this invention uses type V high isoflavones.

[0011] Pharmacological activity studies have shown that high-isoflavone compounds possess a variety of biological activities, including anti-inflammatory, phosphorylation-inhibiting, estrogen-like, anti-stimulatory, antimutagenic, tumor cytotoxic, antifungal, vasodilatory, and hepatoprotective effects, suggesting potential therapeutic potential for Alzheimer's disease. Therefore, it is necessary to develop a multi-target drug based on high-isoflavone derivatives to treat Alzheimer's disease and other neurological disorders. Summary of the Invention

[0012] This invention provides a derivative with a high isoflavone-O-alkylamine structure and its application, in order to solve the limitation of existing single-target drugs for treating neurological diseases such as Alzheimer's disease, which only treat the symptoms and not the root cause.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] The structural formula of the derivative with a high isoflavone-O-alkylamine structure is shown below:

[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-Bocpiperazine, dimethylamine, diethylamine, dipropylamine, piperidine, 4-piperidinylpiperidine, 4-phenylmethylpiperidine, 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, or methoxy; NR1R2 is any one of N-methylpiperazine, N-Bocpiperazine, or tetrahydropyrrole; R3 is methoxy; and n is any natural number from 3 to 7.

[0018] Application of the above-mentioned derivative having a high isoflavone-O-alkylamine structure as an acetylcholinesterase inhibitor.

[0019] Application of the above-mentioned derivative having a high isoflavone-O-alkylamine structure as an inhibitor of β-amyloid aggregation.

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

[0021] The above-mentioned derivative having a high isoflavone-O-alkylamine structure has applications in the treatment of neurological diseases, including Alzheimer's disease.

[0022] In this invention, a high-isoflavonoid compound generated by Claisen-Schmidt condensation reaction of flavonoids with benzaldehydes of different substituted forms can bind well to β-amyloid protein with high specificity and can cross the blood-brain barrier. Under normal circumstances, β-amyloid protein readily aggregates, forming aggregates or plaques, causing a series of neurotoxic effects. 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 some extent.

[0023] Therefore, this invention introduces O-alkylamine fragment analogs into the high isoflavone skeleton and performs structural design and optimization. These compounds have good acetylcholinesterase inhibitory activity and also have high β-amyloid inhibitory activity, providing a new approach for the treatment of Alzheimer's disease as multi-target drugs.

[0024] This invention constructs a high-isoflavone backbone structure by reacting chromogen with 3-methoxy-4-hydroxybenzaldehyde. Different carbon chains of bromoalkane are introduced onto the phenolic hydroxyl group via substitution reactions, followed by the introduction of different short-chain amine fragments. This structure targets cholinesterase and amyloid protein for the treatment of Alzheimer's disease. Experimental results show that the molecule possesses good inhibitory activity against acetylcholinesterase and high inhibitory activity against β-amyloid protein, as well as good neuroprotective and antioxidant effects. It can be used to treat Alzheimer's disease and other amyloid plaque diseases, as well as cholinergic deficiency diseases.

[0025] Currently, most drugs used clinically to treat Alzheimer's disease are acetylcholinesterase inhibitors, which are single-target drugs that only treat the symptoms and not the root cause, with short-lasting effects. The Aβ cascade hypothesis is currently the most widely accepted pathogenic mechanism of AD, and targeting β-amyloid protein is a hot research topic both domestically and internationally, with the potential to fundamentally treat AD. Building upon previous work, this invention introduces a linker carbon chain and a short amine fragment, possessing both β-amyloid protein aggregation inhibitory activity and cholinesterase inhibitory activity. Furthermore, the overall molecule has a certain degree of flexibility, easily entering the catalytic pit 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 the 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 related diseases.

[0026] The compounds of this invention have a good inhibitory effect on acetylcholinesterase activity and amyloid protein aggregation activity. Behavioral experiments such as the water maze have shown that they can effectively improve the memory and cognitive functions of AD model mice.

[0027] The application of the compounds of this invention in the preparation of pharmaceuticals for the treatment of cognitive impairments such as Alzheimer's disease, vascular dementia, mild cognitive impairment, attention deficit disorder, and / or neurodegenerative dementia with abnormal protein aggregation, especially Alzheimer's disease.

[0028] The compounds of this invention can be administered by various methods, such as oral administration as capsules or tablets, non-gastrointestinal administration as sterile solutions or suspensions, and, in some cases, intravenous injection as solutions. The free basic compounds of this invention can be formulated and administered as pharmaceutically suitable acid addition salts. Pharmaceutically suitable 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, mesylic acid, salicylic acid, succinic acid, citric acid, tartaric acid, and similar organic acids). Detailed Implementation

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

[0030] Example 1

[0031] This embodiment discloses a derivative having a high isoflavone-O-alkylamine structure, the structural formula of which 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-Bocpiperazine, dimethylamine, diethylamine, dipropylamine, piperidine, 4-piperidinylpiperidine, 4-phenylmethylpiperidine, and tetrahydropyrrole, preferably any one of N-methylpiperazine, N-Bocpiperazine, and tetrahydropyrrole.

[0035] R3 can be any one of H, Br, nitro, methyl, or methoxy, with methoxy being preferred.

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

[0037] Example 2

[0038] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzyl)chroman-4-one was synthesized. The preparation process is as follows:

[0039] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0040]

[0041] Then, compound 3 was substituted with 1,4-dibromobutane to prepare 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one as compound 4. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. 253 mg (1.83 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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). The reaction equation is:

[0042]

[0043] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-(4-(pyrrolidine-1-yl)butoxy)benzyl)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 226 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1). The fractions were collected, yielding the product in 66.7% yield. 1¹H NMR (500MHz, 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), 4.08–4.01 (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 equation is:

[0044]

[0045] Example 3

[0046] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)butoxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0047] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0048]

[0049] Then, compound 3 was substituted with 1,4-dibromobutane to prepare compound 4, 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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). The reaction equation 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-methylpiperazin-1-yl)butoxy)benzyl)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 226 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected to give the product in 40% yield. 1¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0052]

[0053] Example 4

[0054] In this embodiment, a derivative, tert-butyl 4-(4-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)butyl)piperazine-1-carboxylate, was synthesized. The preparation process is as follows:

[0055] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0056]

[0057] Then, compound 3 was substituted with 1,4-dibromobutane to prepare compound 4, 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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). The reaction equation is:

[0058]

[0059] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare tert-butyl piperazine-1-carboxylate, a derivative of compound 5. The substitution reaction was performed as follows: In a round-bottom flask, 226 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine, and 15 mL of acetonitrile were added. Potassium carbonate (208 mg, 1.5 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. Acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 45%. 1¹H NMR (500MHz, 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 equations are as follows:

[0060]

[0061] Example 5

[0062] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0063] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0064]

[0065] Then, compound 3 was substituted with 1,5-dibromobutane to prepare compound 4, 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0066]

[0067] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-((5-(pyrrolidine-1-yl)pentyl)oxy)benzylene)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylene)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. Acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 66.7%. 1¹H NMR (500MHz, 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 equations are as follows:

[0068]

[0069] Example 6

[0070] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-((5-(4-methylpiperazin-1-yl)pentyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0071] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0072]

[0073] Then, compound 3 was substituted with 1,5-dibromobutane to prepare compound 4, 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are 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-methylpiperazin-1-yl)pentyl)oxy)benzylene)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzylene)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 8 h. Acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 49%. 1¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equations are as follows:

[0076]

[0077] Example 7

[0078] In this embodiment, a derivative, tert-butyl 4-(5-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)pentyl)piperazine-1-carboxylate, was synthesized. The preparation process is as follows:

[0079] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0080]

[0081] Then, compound 3 was substituted with 1,5-dibromobutane to prepare compound 4, 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 420 mg (1.83 mmol) of 1,5-dibromopentane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0082]

[0083] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare 4-(5-(4-(((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)pentyl)piperazine-1-carboxylic acid tert-butyl ester, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 232 mg (0.5 mmol) of 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. Acetonitrile was removed under reduced pressure, and water and dichloromethane were added. After separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to give the product, with a yield of 56%. 1¹H NMR (500MHz, Chloroform-d) δ 7.90 (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 equations are as follows:

[0084]

[0085] Example 8

[0086] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-((6-(pyrrolidin-1-yl)hexyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0087] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0088]

[0089] Then, compound 3 was substituted with 1,6-dibromohexane to prepare compound 4, 3-(4-((6-bromohexyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1). The fractions were collected, yielding the product (78%). 1 ¹H NMR (500MHz, 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 equations are as follows:

[0090]

[0091] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-chloro-3-(3-methoxy-4-((6-(pyrrolidine-1-yl)hexyl)oxy)benzylene)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylene)-6-chlorobenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 90 °C for 6 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1). The fractions were collected, yielding the product in 66.7% yield. 1¹H NMR (500MHz, 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 equations are as follows:

[0092]

[0093] Example 9

[0094] In this embodiment, a derivative 6-chloro-3-(3-methoxy-4-((6-(4-methylpiperazin-1-yl)hexyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0095] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0096]

[0097] Then, compound 3 was substituted with 1,6-dibromohexane to prepare 3-(4-((6-bromohexyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one as compound 4. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 4 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 78% yield. 1 ¹H NMR (500MHz, 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 equations are 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-methylpiperazin-1-yl)hexyl)oxy)benzylene)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzylene)-6-chlorobenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 8 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected to give the product in 50% yield. 1¹H NMR (500MHz, 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), 5.10 (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 equations are as follows:

[0100]

[0101] Example 10

[0102] In this embodiment, a derivative, tert-butyl 4-(6-(4-((6-chloro-4-oxobenzodihydropyran-3-ylidene)methyl)-2-methoxyphenoxy)hexyl)piperazine-1-carboxylate, was synthesized. The preparation process is as follows:

[0103] First, using 6-chloro-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were reacted via a Claisen-Schmidt condensation reaction to prepare 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 182 mg (1 mmol) of 6-chloro-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added sequentially to a round-bottom flask, and the mixture was stirred at 80 °C for 6.5 h. After the reaction was complete, a 25% sodium hydroxide solution was added to adjust the pH to 8–9, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, Chloroform-d) δ 7.88 (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 equation is:

[0104]

[0105] Then, compound 3 was substituted with 1,6-dibromohexane to prepare compound 4, 3-(4-((6-bromohexyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 193 mg (0.61 mmol) of 6-chloro-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 447 mg (1.83 mmol) of 1,6-dibromohexane, and 15 mL of acetonitrile were added. 253 mg (1.83 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 4 h. 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 fractions were collected to give the product in 78% yield. 1 ¹H NMR (500MHz, 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 equations are 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, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 240 mg (0.5 mmol) of 3-(4-((6-bromohexyl)oxy)-3-methoxybenzyl)-6-chlorobenzopyran-4-one, 187 mg (1 mmol) of N-Boc piperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 7 h. 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 product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 45%. 1¹H NMR (500MHz, 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), 6.68 (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 equations are as follows:

[0108]

[0109] Example 11

[0110] In this embodiment, a derivative 6-methoxy-3-(3-methoxy-4-(4-(pyrrolidin-1-yl)butoxy)benzyl)chroman-4-one was synthesized. The preparation process is as follows:

[0111] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0112]

[0113] Then, compound 3 was substituted with 1,4-dibromobutane to prepare compound 4, 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0114]

[0115] Next, compound 4 was subjected to a substitution reaction with tetrahydropyrrole to prepare 6-methoxy-3-(3-methoxy-4-(4-(pyrrolidine-1-yl)butoxy)benzyl)chroman-4-one, a derivative of compound 5. The substitution reaction was performed as follows: In a round-bottom flask, 223 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 mL of acetonitrile were added. Potassium carbonate (208 mg, 1.5 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 62% yield. 1¹H NMR (500MHz, Chloroform-d) δ 7.75 (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 equation is:

[0116]

[0117] Example 12

[0118] In this embodiment, a derivative 6-methoxy-3-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)butoxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0119] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0120]

[0121] Then, compound 3 was substituted with 1,4-dibromobutane to prepare compound 4, 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are 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-methylpiperazin-1-yl)butoxy)benzyl)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 223 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 8 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 65% yield. 1¹H NMR (500MHz, Chloroform-d) δ 7.78 (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 equations are as follows:

[0124]

[0125] Example 13

[0126] In this embodiment, a derivative, 4-(4-(2-methoxy-4-((6-methoxy-4-oxobenzodihydropyran-3-ylidene)methyl)phenoxy)butyl)piperazine-1-carboxylic acid tert-butyl ester, was synthesized. The preparation process is as follows:

[0127] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0128]

[0129] Then, compound 3 was substituted with 1,4-dibromobutane to prepare compound 4, 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,4-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 82% yield. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0130]

[0131] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare 4-(4-(2-methoxy-4-((6-methoxy-4-oxobenzodihydropyran-3-ylidene)methyl)phenoxy)butyl)piperazine-1-carboxylic acid tert-butyl ester, which is the derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 223 mg (0.5 mmol) of 3-(4-(4-bromobutoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one, 178 mg (1 mmol) of N-Boc piperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 63%. 1¹H NMR (500MHz, Chloroform-d) δ 7.76 (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 equation is:

[0132]

[0133] Example 14

[0134] In this embodiment, a derivative 6-methoxy-3-(3-methoxy-4-((5-(pyrrolidin-1-yl)pentyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0135] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0136]

[0137] Then, compound 3 was substituted with 1,5-dibromobutane to prepare compound 4, 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 86% yield. 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-(pyrrolidine-1-yl)pentyl)oxy)benzylene)chroman-4-one, a derivative of compound 5. The substitution reaction was performed as follows: In a round-bottom flask, 230 mg (0.5 mmol) of 3-(4-(5-bromopentoxy)-3-methoxybenzylene)-6-methoxybenzopyran-4-one, 72 mg (1 mmol) of tetrahydropyrrole, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1). The fractions were collected, yielding the product in 69% yield. 1¹H NMR (500MHz, 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 equations are as follows:

[0141]

[0142] Example 15

[0143] In this embodiment, a derivative 6-methoxy-3-(3-methoxy-4-((5-(4-methylpiperazin-1-yl)pentyl)oxy)benzylene)chroman-4-one was synthesized. The preparation process is as follows:

[0144] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0145]

[0146] Then, compound 3 was substituted with 1,5-dibromobutane to prepare 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one as compound 4. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 86% yield. 1 ¹H NMR (500MHz, 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 equations are 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-methylpiperazin-1-yl)pentyl)oxy)benzylene)chroman-4-one, which is a derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 230 mg (0.5 mmol) of 3-(4-(5-bromopentoxy)-3-methoxybenzylene)-6-methoxybenzopyran-4-one, 100 mg (1 mmol) of N-methylpiperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected to give the product in 55% yield. 1¹H NMR (500MHz, Chloroform-d) δ 7.79 (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 equations are as follows:

[0149]

[0150] Example 16

[0151] In this embodiment, a derivative, 4-(5-(2-methoxy-4-((6-methoxy-4-oxobenzopyran-3-ylidene)methyl)phenoxy)pentyl)piperazine-1-carboxylic acid tert-butyl ester, was synthesized. The preparation process is as follows:

[0152] First, using 6-methoxy-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 were subjected to a Claisen-Schmidt condensation reaction to prepare 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3. The Claisen-Schmidt condensation reaction was performed as follows: 178 mg (1 mmol) of 6-methoxy-4-dihydrochromone, 152 mg (1 mmol) of 3-methoxy-4-hydroxybenzaldehyde, and 10 mL of phosphoric acid were added to a round-bottom flask and stirred at 80 °C for 6.5 h. The pH was adjusted to 8–9 by adding 25% sodium hydroxide, resulting in a large amount of precipitate. This precipitate was filtered, dried, and a pale yellow solid was obtained. The yield was 85%. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0153]

[0154] Then, compound 3 was substituted with 1,5-dibromobutane to prepare compound 4, 3-(4-((5-bromopentyl)oxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one. The substitution reaction was performed as follows: In a round-bottom flask, 190 mg (0.61 mmol) of 6-methoxy-3-(4-hydroxy-3-methoxybenzyl)chroman-4-one, 394 mg (1.83 mmol) of 1,5-dibromobutane, and 15 mL of acetonitrile were added. Potassium carbonate (253 mg, 1.83 mmol) was slowly added with stirring, and the reaction was carried out at 100 °C for 3.5 h. 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 product was obtained by column chromatography with petroleum ether:ethyl acetate (1:1) as elution. The fractions were collected, yielding the product in 86% yield. 1 ¹H NMR (500MHz, 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 equations are as follows:

[0155]

[0156] Next, compound 4 was subjected to a substitution reaction with N-Boc piperazine to prepare 4-(5-(2-methoxy-4-((6-methoxy-4-oxobenzopyran-3-ylidene)methyl)phenoxy)pentyl)piperazine-1-carboxylic acid tert-butyl ester, which is the derivative of compound 5. The substitution reaction was carried out as follows: In a round-bottom flask, 230 mg (0.5 mmol) of 3-(4-(5-bromopentoxy)-3-methoxybenzyl)-6-methoxybenzopyran-4-one, 178 mg (1 mmol) of N-Boc piperazine, and 15 mL of acetonitrile were added. 208 mg (1.5 mmol) of potassium carbonate was slowly added with stirring, and the reaction was carried out at 100 °C for 5.5 h. 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 product was passed through a silica gel column and eluted with petroleum ether:ethyl acetate in a 1:1 ratio. The corresponding components were collected to obtain the product, with a yield of 58%. 1¹H NMR (500MHz, Chloroform-d) δ 7.79 (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 equations are as follows:

[0157]

[0158] As can be seen from the preparation methods in Examples 2-16, the overall preparation process of the derivative with a high isoflavone-O-alkylamine structure disclosed in Example 1 is as follows: Using 6-X-4-dihydrochromone as compound 1 and 3-methoxy-4-hydroxybenzaldehyde as compound 2, compounds 1 and 2 are subjected to a Claisen-Schmidt condensation reaction to obtain 6-X-3-(4-hydroxy-3-methoxybenzyl)chromone-4-one as compound 3; compound 3 is then reacted with a dibromoalkane via a substitution reaction to obtain 3-(4-(n-bromooxy)-3-methoxybenzyl)-6-Xbenzopyran-4-one as compound 4; finally, compound 4 is reacted with different short-chain amines via substitution reactions to obtain compound 5, which is the 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 structures prepared in Examples 2-16, following the method described in 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 scheme is as follows:

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

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

[0164] The positive control used 20 μL of tacrine at different concentrations (1 μM, 0.1 μM, 0.01 μM, 1 nM) instead of the derivatives prepared in Examples 2-16. The control group used 20 μL of phosphate buffer instead of the derivatives prepared in Examples 2-16. 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 2-16. Data from each group were repeated in triplicate, 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 The IC50 of each compound was calculated using Graph Pad Priam 9.5 software, multiplied by 100%. 50 value.

[0166] The results are shown in Table 1:

[0167] Table 1. Inhibitory activity of cholinesterase against derivatives with high isoflavone-O-alkylamine structures prepared in Examples 2-16.

[0168]

[0169]

[0170] As can be seen from Table 1, the derivative prepared in Example 14 showed the best inhibition of acetylcholinesterase activity, and the derivatives prepared in Examples 11, 8, 15, and 2 also had high acetylcholinesterase inhibitory activity.

[0171] Example 18 DPPH Free Radical Scavenging Experiment

[0172] The derivatives prepared in Examples 2, 8, 11, and 14 were selected, and their antioxidant capacity was investigated using a DPPH free radical scavenging assay. The method followed the national standard "Determination of Antioxidant Activity of Peptides: DPPH and ABTS Methods," and the specific experimental protocol is as follows:

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

[0174] The derivatives prepared in Examples 2, 8, 11 and 14 were dissolved in DMSO to prepare a 10 mM stock solution, which was 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 at different concentrations (1 μM, 10 μM, 100 μM) (derivatives prepared in Examples 2, 8, 11, and 14) were added, mixed thoroughly, and incubated at 37°C in the dark for 30 min. The absorbance (OD) of the solution in the 96-well plate was then measured using a microplate reader at λ = 517 nm.

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

[0177]

[0178] P – DPPH scavenging rate; As – absorbance of the analyte mixed with DPPH; Ac – absorbance of the analyte mixed with anhydrous ethanol; Ab – absorbance of the DPPH mixed with DMSO.

[0179] The results are shown in Table 2:

[0180] Table 2 shows the scavenging rates of DPPH free radicals of the derivatives prepared in Examples 2, 8, 11, and 14.

[0181]

[0182]

[0183] As shown in Table 2, the derivatives prepared in Examples 8 and 14 exhibited high free radical scavenging rates, approaching the results of the positive control ascorbic acid. This indicates that the derivatives prepared in Examples 8 and 14 possess good antioxidant activity.

[0184] Example 19 Inhibition of Aβ Aggregation

[0185] The derivatives prepared in Examples 2, 4, 8, 11, and 14 were selected, and the ability of the synthesized small molecule compounds to inhibit Aβ self-aggregation was determined using the thiosulfate T method. The method followed the literature (Wang Keren. Synthesis of Novel Multi-Target Apigenin Derivatives and Their Anti-Alzheimer's Disease Study [D]. Nanyang Normal University, 2019). Specifically, 20 μL of Aβ was added sequentially to a black 96-well plate. 1-42 (25 μM) and 20 μL of samples of different concentrations (1 μM, 25 μM, 50 μM) (derivatives prepared in Examples 2, 4, 8, 11, and 14) were incubated at 37°C for 24 h in an incubator. Then, 160 μL of buffer containing 5 μM thioflavone T was added, and the fluorescence value was immediately measured using an ELISA reader (excitation wavelength 446 nm, emission wavelength 490 nm).

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

[0187] Each set of data was analyzed three 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 Examples 2, 4, 8, 11, and 14 against Aβ self-aggregation.

[0192] Example 2 Example 4 Example 8 Example 11 Example 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 exhibited good inhibitory activity against Aβ self-aggregation. Among them, the derivatives prepared in Examples 8 and 14 showed excellent Aβ aggregation inhibition activity (>80%) at a concentration of 1 μM.

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

[0195] The derivatives prepared in Examples 2, 4, 8, 11, and 14 were selected, and their effects on PC were evaluated using the MTT assay. 12 Neuroprotective effects on cells. Methods were based on the literature (Du Jiyu. Novel tryptophan derivative: A multi-target ligand for the treatment of Alzheimer's disease [D]. Anhui Medical University, 2023). Specifically, 5*10 cells per well were used. 3 Cell density will PC 12 Cells were seeded into 96-well plates and incubated overnight. The old culture medium was discarded, and fresh culture medium containing 10 μM of the derivatives prepared in Examples 2, 4, 8, 11, and 14 was added. Cells were cultured for 3 hours, then exposed to H2O2 (250 μM) overnight. 20 μL of MTT solution (5 mg / ml) was added, and incubation was continued for 4 hours. The supernatant was removed, and 150 μL of DMSO was added. The cells were shaken for 10–15 minutes, and the absorbance at 492 nm was immediately measured using a microplate reader.

[0196] The control group used PBS buffer instead of the derivatives prepared in Examples 2, 4, 8, 11, and 14, and did not incubate overnight under H2O2. The blank group used PBS buffer instead of the derivatives prepared in Examples 2, 4, 8, 11, and 14, and did not require overnight incubation under H2O2. Data from each group were repeated in triplicate, and the average value was taken.

[0197] P – Cell survival rate

[0198] The results are shown in Table 4:

[0199] Table 4. Protective effects of the derivatives prepared in Examples 2, 4, 8, 11, and 14 against H2O2-induced neuroprotection.

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

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

[0202] Example 21: Water Maze Experiment

[0203] The water maze test was used to evaluate the effect of the prepared compound on improving memory and cognitive abilities in 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 abilities in Alzheimer's disease mice by curcumin derivative Cur20 through inhibition of acetylcholinesterase [J]. Drug Evaluation Research, 2022, 45(03):449-454.). Specifically, the mice were divided into a positive control group, a drug group (the derivative prepared in Example 14), and a model group. The mice were administered 0.5% sodium carboxymethyl cellulose suspension of the derivative prepared in Example 14 by gavage (400 mg / kg·d) at the same time every day for 7 days. Starting from the 8th day, scopolamine hydrobromide (200 μL) was injected intraperitoneally 30 min after gavage to establish the AD model. The drug was administered for a total of 16 days. Starting from the 11th day, the mice were subjected to the water maze test for 5 days. The water maze consisted of a pool with a diameter of 150cm, a height of 50cm, and a water temperature of 20℃, along with cameras and a behavior analysis system. An escape platform with a diameter of 10cm was placed in the water at a depth of 30cm and 1.5cm above the surface. For the first four days, a navigation experiment was conducted, with four training sessions per day and at least 0.5 hours between each session. Mice were randomly placed into the water from four different quadrants of the pool each time. The latency period for the mice to find the platform was automatically tracked and recorded, not exceeding 90 seconds, and the average latency period for each day was calculated. On the fifth day, a spatial exploration experiment began. The platform was removed, and mice were randomly placed into the water from the quadrant opposite the platform, facing and close to the pool wall. The movement trajectory of the mice finding the original platform and the number of times they traversed the original platform were recorded within 90 seconds. During the experiment, the platform position, experimental environment, and reference points remained essentially unchanged.

[0204] Donepezil was used as a positive control; the model group used 0.5% sodium carboxymethyl cellulose instead of the drug solution and required injection of scopolamine hydrobromide. Five mice were used in each group to reduce experimental error.

[0205] The statistical results of the incubation period are shown in Table 5:

[0206] Table 5. Latency period statistics for each group in the 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] As shown in Table 5 during the navigation and positioning experiment, the latency of the model group mice increased significantly from day 2 to day 4, indicating successful model establishment. Compared with the model group, the latency of the experimental sample group (the derivative prepared in Example 14) and the positive control group mice was significantly shortened. Moreover, with the extension of training time, the escape latency of the experimental sample group (the derivative prepared in Example 14) and the positive control group mice gradually shortened, showing similar effects.

[0209] The statistics of the number of times the original platform was crossed are shown in Table 6:

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

[0211]

[0212]

[0213] Table 6 shows that in the space exploration experiment, the number of times the model group mice crossed the original platform was significantly reduced, while the crossing time was significantly increased. The number of platform crossings was significantly increased in the positive control group and the experimental sample group (the derivative prepared in Example 14).

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

[0215] In summary, based on the tests conducted in Examples 17-21, it can be seen that the derivative with a high isoflavone-O-alkylamine structure disclosed in Example 1 possesses both cholinesterase inhibitory activity and β-amyloid aggregation inhibitory activity, as well as antioxidant stress and neuroprotective effects. It can be used as an acetylcholinesterase inhibitor and a β-amyloid aggregation inhibitor, making it a multi-target drug for the treatment of Alzheimer's disease or other neurological diseases.

[0216] This invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this invention and without departing from the design idea of ​​this invention, all modifications and improvements made by those skilled in the art to the technical solutions of this invention should fall within the protection scope of this invention. The technical content for which protection is sought in this invention has been fully described in the claims.

Claims

1. A derivative having a high isoflavone-O-alkylamine structure, characterized in that, Its structural formula is shown below: ， ， ， 。 2. The application of a derivative having a high isoflavone-O-alkylamine structure as described in claim 1 in the preparation of an acetylcholinesterase inhibitor.

3. The application of a derivative having a high isoflavone-O-alkylamine structure as described in claim 1 in the preparation of a β-amyloid aggregation inhibitor.

4. The use of a derivative having a high isoflavone-O-alkylamine structure as described in claim 1 in the preparation of a drug for treating Alzheimer's disease.

Images