Composition for prevention or treatment of neurodegenerative diseases comprising novel chalcone derivative compound as active ingredient

Abstract

The present invention relates to a novel chalcone derivative compound and a composition for the prevention or treatment of neurodegenerative diseases, comprising same as an active ingredient. The present invention can fundamentally eliminate the cause of neurotransmission dysfunction by simultaneously inhibiting the activities of two hyperactivated cholinesterases, unlike conventional symptomatic therapies that focus on the control of peripheral symptoms for various neurodegenerative diseases caused by a decrease in acetylcholine concentration, including Alzheimer's disease.

Description

Composition for preventing or treating degenerative brain diseases comprising a novel chalcone derivative compound as an active ingredient

[0001] The present invention relates to a chalcone compound and its cyclic derivatives, indenone and tetralone compounds, which can be used as excellent pharmacological agents for various degenerative brain diseases including Alzheimer's disease by simultaneously inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

[0002] Alzheimer's disease (AD) is one of the most common neurodegenerative brain diseases in the elderly, with approximately 50 million patients worldwide and a steadily increasing number. It primarily affects people aged 60 to 70 years or older and is characterized by memory loss, behavioral disorders, and language disorders. Although AD can be caused by aging, smoking, depression, lack of physical activity, social isolation, and diabetes, the exact pathogenesis of AD is not fully understood. The main characteristics of AD are reported to be the formation and accumulation of amyloid beta (Aβ) plaques, the accumulation of tau protein, and a decline in neurotransmission due to a decrease in acetylcholine concentration.

[0003] When transmembrane APP (amyloid precursor protein) is degraded by α-secretase and γ-secretase, Aβ fragments are not formed. However, when transmembrane APP is degraded by β-secretase and γ-secretase, Aβ fragments such as Aβ40 and Aβ42 are formed. Aβ plaques formed by the aggregation of Aβ fragments accumulate in axons, dendrites, etc., causing neurological dysfunction and synapse loss, resulting in cognitive impairment.

[0004] Tau protein, a protein that stabilizes microtubules, is primarily expressed in neurons and helps stabilize axons and maintain their shape. In AD patients, tau protein is hyperphosphorylated, reducing its affinity for microtubules. Tau detaches from microtubules and aggregates into loosely tangled paired helical filaments (PHFs) and tightly packed straight filaments (SFs). The aggregation of PHFs and SFs forms neurofibrillary tangles (NFTs). NFTs accumulate in axons and dendrites, damaging neurons and leading to cognitive impairment.

[0005] When a presynaptic neuron is stimulated, choline acetyltransferase (ChAT) synthesizes the neurotransmitter acetylcholine from choline and acetyl-CoA, and acetylcholine is transported to the cell membrane in the form of vesicles by vesicular acetylcholine transporter (VAChT) and secreted to the postsynaptic neuron. After depolarization, the secreted acetylcholine is rapidly broken down by acetylcholine esterase (AChE) into choline and acetate, and the choline is reabsorbed and reused by the choline transporter 1 (CHT1). In the brain, acetylcholine is a neurotransmitter involved in important processes such as memory, concentration, sensation, and learning. Therefore, a decrease in acetylcholine is known to cause memory decline and cognitive impairment, which are characteristics of AD patients, and the expression of acetylcholine and ChAT, which synthesizes acetylcholine, is reduced in AD patients. Therefore, inhibiting the activity of AChE to increase the concentration of acetylcholine may be an important therapeutic target for AD.

[0006] Human cholinesterases exist in two forms: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE and BuChE are proteins with similar structures, sharing 65% of their amino acid sequences, and they degrade acetylcholine into choline and acetate. AChE and BuChE have a narrow, deep-lying structure, consisting of a peripheral anionic site (PAS) at the entrance and a catalytic anionic site (CAS) located internally, which degrades acetylcholine. The PAS of AChE and BuChE interacts with Aβ fragments, promoting amyloid plaque formation.

[0007] In AD patients, both AChE and BuChE activities are increased, and when AChE inhibitors are used, AChE activity is suppressed while BuChE activity increases. Therefore, simultaneous inhibition of AChE and BuChE is considered an effective treatment strategy.

[0008] Currently, FDA-approved drugs used to treat AD include tacrine, donepezil, rivastigmine, galantamine, memantine, and aduganumab. Tacrine, an AChE inhibitor approved in 1993, is no longer used due to hepatotoxicity and lack of therapeutic efficacy. Donepezil and galantamine are AChE inhibitors, and rivastigmine is a simultaneous AChE and BuChE inhibitor, but is used in patch form due to severe side effects when administered orally. Memantine is a drug that inhibits the N-methyl-D-aspartate receptor (NMDAR), and aduganumab is an antibody that targets amyloid plaques. The currently used drugs only delay the progression of dementia to some extent and lack therapeutic efficacy. Therefore, the need for the development of drugs that can fundamentally treat AD is greatly increasing.

[0009]

[0010] Numerous papers and patents are referenced and cited throughout this specification. The disclosures of these cited papers and patents are incorporated herein by reference in their entirety to provide a clearer understanding of the state of the art and the scope of the invention.

[0011]

[0012] The present inventors have diligently researched and developed an effective therapeutic composition capable of fundamentally eliminating the cause of various neurodegenerative diseases caused by a decrease in the concentration of the neurotransmitter acetylcholine. As a result, the present invention was completed by discovering that a chalcone derivative compound of Chemical Formula 1, described below, simultaneously inhibits acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), which are acetylcholine hydrolases, thereby blocking excessive acetylcholine degradation and efficiently restoring neurotransmission function.

[0013] Accordingly, the purpose of the present invention is to provide a novel chalcone derivative compound and a composition for preventing or treating degenerative neurological diseases comprising the same as an active ingredient.

[0014] Other objects and advantages of the present invention will become more apparent from the detailed description, claims and drawings below.

[0015]

[0016] According to one aspect of the present invention, the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0017] Chemical Formula 1

[0018]

[0019] In the above chemical formula,

[0020] R1 and R2 are each independently hydrogen, C1-C3 alkyl or C1-C3 alkoxy, or R1 and R2 are combined with each other to form a 5- to 6-membered heterocycloalkene ring;

[0021] R3 and R4 are each independently hydrogen or C1-C3 alkyl, or R3 and R4 combine with each other to form cyclopentanone or cyclohexanone;

[0022] A1 and A2 are each independently carbon or nitrogen;

[0023] L1 is a 5- to 6-membered heterocycloalkylene ring which is directly bonded or unsubstituted or substituted with C1-C3 alkyl;

[0024] n is an integer from 1 to 3;

[0025] R5 is unsubstituted or C6-C substituted with C1-C3 alkyl or halogen 10 It's Aryl.

[0026] The present inventors have diligently researched and developed an effective therapeutic composition capable of fundamentally eliminating the etiology of various neurodegenerative diseases caused by decreased acetylcholine concentration and consequently impaired neurotransmission function. As a result, they discovered that the chalcone derivative compound of Chemical Formula 1 can effectively restore neurotransmission function impaired due to decreased acetylcholine by simultaneously inhibiting the activity of AChE and BuChE, which are acetylcholine hydrolases.

[0027] The term “alkyl” as used herein means a straight-chain or branched saturated hydrocarbon group, and includes, for example, methyl, ethyl, propyl, isopropyl, etc. C1-C3 alkyl means an alkyl group having an alkyl unit having 1 to 3 carbon atoms, and when C1-C3 alkyl is substituted, the carbon number of the substituent is not included.

[0028] In this specification, the term “alkoxy” means a radical formed by the removal of hydrogen from an alcohol, for example, C1-C3 alkoxy means a radical formed by the removal of hydrogen from an alcohol having 1 to 3 carbon atoms.

[0029] As used herein, the term “heterocycloalkyl” refers to a saturated carbon ring containing oxygen, sulfur, or nitrogen as a heteroatom within the ring. Specifically, the heteroatom is nitrogen or oxygen, and more specifically, oxygen. The number of heteroatoms is 1-3, specifically 1-2. “Heterocycloalkyl of a 5-membered or 6-membered ring” refers to a ring in which the sum of the numbers of carbons and heteroatoms constituting the ring is 5 or 6. The term “heterocycloalkene” refers to an unsaturated carbon ring containing a double bond between carbons in the aforementioned heterocycloalkyl ring. The double bond may be 1 or 2, specifically 1. In the chemical formula 1 of the present invention, R1 and R2 are bonded to each other to form a 5- to 6-membered heterocycloalkene ring, which means that the ring formed by R1 and R2 bonded to a phenyl group is fused with a phenyl group and includes a double bond forming a phenyl ring.

[0030] As used herein, the term “halogen” refers to a halogen group element including fluoro, chloro, bromo, and iodo. Specifically, the halogen is fluoro.

[0031] As used herein, the term “aryl” means a monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and has aromaticity.

[0032]

[0033] According to a specific embodiment of the present invention, R1 and R2 are each independently hydrogen or C1-C3 alkoxy, or R1 and R2 combine with each other to form dioxol. More specifically, R1 and R2 are not hydrogen at the same time.

[0034] According to a specific embodiment of the present invention, A1 and A2 are not nitrogen at the same time.

[0035] According to a specific embodiment of the present invention, when A1 or A2 bonded to L1 is nitrogen, L1 is a direct bond, and when A1 or A2 bonded to L1 is carbon, L1 is a heterocycloalkylene of a 5-6 membered ring which is unsubstituted or substituted with C1-C3 alkyl. When A1 or A2 bonded to L1 is nitrogen, it is obvious that an ammonium cation is formed according to the octet rule.

[0036] More specifically, when A1 and A2 are both carbon, L1 is a 5-6 membered heterocycloalkylene ring which is unsubstituted or substituted with C1-C3 alkyl, and more specifically, a 6-membered heterocycloalkylene ring which is substituted with C1-C3 alkyl.

[0037] According to a specific embodiment of the present invention, the heterocycloalkylene of the 5- to 6-membered ring is selected from the group consisting of piperazinylene, piperidinylene, pyrrolidinylene, and morpholinylene, and more specifically, piperazinylene.

[0038]

[0039] According to a specific embodiment of the present invention, R5 is C6 aryl which is unsubstituted or substituted with halogen, and more specifically, C6 aryl which is unsubstituted or substituted with fluoro.

[0040] According to a specific embodiment of the present invention, the compound represented by the above-described chemical formula 1 is selected from the group consisting of compounds represented by the following chemical formulas 2 to 25:

[0041] Chemical Formula 2

[0042]

[0043] Chemical Formula 3

[0044]

[0045] Chemical Formula 4

[0046]

[0047]

[0048] Chemical Formula 5

[0049]

[0050] Chemical Formula 6

[0051]

[0052] Chemical Formula 7

[0053]

[0054] Chemical Formula 8

[0055]

[0056] Chemical Formula 9

[0057]

[0058] Chemical Formula 10

[0059]

[0060] Chemical Formula 11

[0061]

[0062] Chemical Formula 12

[0063]

[0064] Chemical Formula 13

[0065]

[0066] Chemical Formula 14

[0067]

[0068] Chemical Formula 15

[0069]

[0070] Chemical Formula 16

[0071]

[0072] Chemical Formula 17

[0073]

[0074] Chemical Formula 18

[0075]

[0076] Chemical Formula 19

[0077]

[0078] Chemical Formula 20

[0079]

[0080] Chemical Formula 21

[0081]

[0082] Chemical Formula 22

[0083]

[0084] Chemical Formula 23

[0085]

[0086] Chemical Formula 24

[0087]

[0088] Chemical Formula 25

[0089]

[0090] According to another aspect of the present invention, the present invention provides a composition for preventing or treating a degenerative neurological disease, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0091] As used herein, the term "neurodegenerative diseases" encompasses diseases that cause irreversible structural and functional degeneration in brain tissue and its constituent cells. Specifically, neurodegenerative diseases that can be prevented or treated using the composition of the present invention encompass various neurological diseases caused by a decline in neurotransmission function due to a decrease in acetylcholine concentration.

[0092] The term “prevention” as used herein means inhibiting the occurrence of a disease or condition in a subject who has not been diagnosed as having the disease or condition but is susceptible to such disease or condition.

[0093] As used herein, the term “treatment” means (a) suppressing the development of a disease, condition, or symptom; (b) alleviating the disease, condition, or symptom; or (c) eliminating the disease, condition, or symptom. When the composition of the present invention is administered to a subject, it simultaneously inhibits AChE and BChE, which are acetylcholine hydrolases, thereby blocking excessive degradation of acetylcholine, thereby suppressing the development of symptoms caused by decreased neurotransmission function, eliminating them, or alleviating them. Therefore, the composition of the present invention can be a composition for treating these diseases on its own, or can be administered together with other pharmacological ingredients and used as a therapeutic adjuvant for the diseases. Accordingly, the terms “treatment” or “therapeutic agent” as used herein include the meaning of “therapeutic aid” or “therapeutic adjuvant.”

[0094] As used herein, the term “administration” or “administer” refers to directly administering a therapeutically effective amount of the composition of the present invention to a subject so that the same amount is formed in the body of the subject.

[0095] In the present invention, the term “therapeutically effective amount” means the content of a composition in which the pharmacological ingredient in the composition is contained in an amount sufficient to provide a therapeutic or preventive effect to a subject to whom the pharmaceutical composition of the present invention is to be administered, and includes a “prophylactically effective amount”.

[0096] The term “subject” as used herein includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus macaque. Specifically, the subject of the present invention is a human.

[0097] As used herein, the term “pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, alkaline earth metals such as magnesium, and ammonium.

[0098] According to a specific embodiment of the present invention, the neurodegenerative disease is Alzheimer's disease, argyrophilic grain disease (AGD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism (PSP-P), Richardson syndrome, Pick's disease, Niemann-Pick disease, Rasmussen's syndrome, Parkinson's disease, atypical parkinsonism in Guadeloupe, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), progressive subcortical gliosis, primary progressive aphasia, globular glial tauopathy, Lytico-Bodig disease, neurodegeneration with brain iron accumulation, pantothenate kinase-associated neurodegeneration (PKAN), postencephalitic parkinsonism, chronic traumatic encephalopathy;CTE), Familial British dementia, Familial Danish dementia, Huntington's disease, Down's syndrome, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, leukotauopathy, amyotrophic lateral sclerosis (ALS), cerebral amyloid angiopathy, senile dementia of the neurofibrillary tangle type, motor neuron disease with neurofibrillary tangles, diffuse neurofibrillary tangles with calcification, corticobasal degeneration, primary age-related tauopathy tauopathy) and traumatic brain injury.;

[0099] According to a specific embodiment of the present invention, the composition inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), or a combination thereof.

[0100] The term “inhibition” as used herein means to measurably inhibit the expression level of AChE and BuChE or their inherent biological activity (i.e., hydrolysis activity of acetylcholine) compared to a control group, specifically to inhibit the concentration of acetylcholine in a body to a degree that significantly restores the concentration, and more specifically to inhibit it by 30% or more, even more specifically by 50% or more, and most specifically by 70% or more compared to a control group.

[0101] When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.

[0102] Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0103] The pharmaceutical composition of the present invention can be administered orally or parenterally, and specifically, can be administered orally, intravenously, or intracerebroventricularly.

[0104] The appropriate dosage of the pharmaceutical composition of the present invention may be prescribed in various ways depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. The preferred dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg / kg for adults.

[0105] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by inserting it into a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and the like. In this case, the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersing agent or stabilizer.

[0106] According to another aspect of the present invention, the present invention provides a method for preventing or treating a degenerative neurological disease, comprising administering to a subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0107] The chalcone derivative compound of chemical formula 1 used in the present invention and the neurodegenerative disease that can be improved or prevented through the same have already been described above, so their description is omitted to avoid excessive duplication.

[0108]

[0109] According to another aspect of the present invention, the present invention provides a functional food composition for improving or preventing degenerative brain diseases, comprising the compound of the present invention or a food-related salt thereof as an active ingredient.

[0110] The chalcone derivative compound of chemical formula 1 used in the present invention and the neurodegenerative disease that can be improved or prevented through the same have already been described above, so their description is omitted to avoid excessive duplication.

[0111] In this specification, the term “food-acceptable salt” means a salt in a form that can be used in a food composition among salts in which cations and anions are bonded by electrostatic attraction, and specific examples thereof include the examples of “pharmaceutically acceptable salts” described above.

[0112] When the composition of the present invention is manufactured as a food composition, it may contain not only the compound of the present invention as an active ingredient, but also carbohydrates, seasonings, and flavoring agents that are commonly added during food manufacturing. Examples of carbohydrates include, but are not limited to, monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents [thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.]) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is manufactured as a drink, in addition to the pine bark extract, which is an active ingredient of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, Eucommia ulmoides extract, jujube extract, licorice extract, etc. can be additionally included.

[0113] According to another aspect of the present invention, the present invention provides a functional food composition for inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) or a combination thereof, comprising the compound of the present invention or a food-chemically acceptable salt thereof as an active ingredient.

[0114] The chalcone derivative compound of chemical formula 1 used in the present invention and its food-related acceptable salt have already been described above, so their description is omitted to avoid excessive duplication.

[0115]

[0116] The features and advantages of the present invention are summarized as follows:

[0117] (a) The present invention provides a novel chalcone derivative compound and a composition for preventing or treating a degenerative neurological disease comprising the same as an active ingredient.

[0118] (b) The present invention can fundamentally eliminate the cause of the decline in neurotransmission function by simultaneously inhibiting the activity of two overactive cholinesterase enzymes, moving away from the conventional symptomatic treatment that focused on controlling peripheral symptoms for various degenerative neurodegenerative diseases caused by a decrease in the concentration of acetylcholine, including Alzheimer's disease.

[0119]

[0120] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0121]

[0122] Example

[0123] Reagents and instruments

[0124] Compounds and reagents used in the experiment were purchased from Aldrich Chemical Co., Acros, and TCI. Melting points were measured using a standard digital melting point meter (Model No: IA9100) and a capillary tube. TLC plates were Kieselgel 60 F. 254(Art.5715) (Merck) was used, and silica gel 60 (0.040-0.063 mm ASTM) from Merck was used for column chromatography. All solvents were used directly without distillation. HPLC (Shimadzu LC-20AD, Shimadazu Lc-2050C) analysis was performed using a column, SunFire C18 (4.6 nm 150 nm, 5 nm); mobile phase, conditions: 40-90% acetonitrile 0-15 min, 100% acetonitrile 15-25 min, 40-90% acetonitrile 25-30 min isocratic using A (water), B (acetonitrile), flow rate; 1.0 mL / min; Detection was performed under diode array detector (Shimadzu Spd-M20A) conditions, and the compound purity was expressed as percentage (%) and the retention time was expressed in minutes (min). NMR spectra were recorded using Varian AS 00( 1 H-NMR is 400 MHz, 13 C-NMR was performed at 100 MHz using tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are given in ppm, and coupling constants (J) are given in hertz (Hz).

[0125]

[0126] Design of target compounds

[0127] Based on the structure of donepezil, an AChE inhibitor, we aimed to discover a compound structure that could simultaneously inhibit BuChE while having superior inhibitory activity. In order to introduce the quaternary ammonium ion of acetylcholine, pyridinium and methylpiperazinium were introduced to the piperidine moiety of donepezil, and 3,4-dimethoxy acetophenone, tetralone, methylenedioxy, and methylenedioxy indanone were introduced to the indanone moiety of donepezil, and the inhibitory activity against AChE and BuChE was evaluated.

[0128]

[0129]

[0130] Schematic diagram of the compound synthesis process

[0131] Compounds C30 to C49 were obtained in 17-90% yields using pyridine derivatives, benzyl bromide, and 4-fluorobenzyl bromide, and all synthesized compounds were 1 H department 13 The structures were confirmed by instrumental analytical methods including C-NMR. Compounds C50 to C53 were obtained in 73-91% yields using methyl piperazine derivatives and benzyl bromide, and all synthesized compounds were 1 H department 13 The structure was confirmed by spectroscopic methods including C-NMR.

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] Synthesis of each individual compound

[0138] General synthesis of chalcone derivatives

[0139] Method 1: Acetophenone derivative / indanone / tetralone derivative (1.00 equiv.) was added to ethanol, and 50% NaOH (1.00 equiv.) and an aldehyde derivative (1.0 equiv.) were added. The mixture was stirred at room temperature or 0°C. After the reaction was completed, the desired compound was obtained through an appropriate treatment process. When a solid was formed, the mixture was filtered under reduced pressure, washed with water and EtOH, and the filtrate was extracted with water and ethyl acetate. If a solid was not formed, the mixture was extracted with water and ethyl acetate, the organic layer was separated, and the moisture in the organic layer was removed with anhydrous MgSO4 and filtered. The organic solvent was distilled off under reduced pressure, and the remaining residue was separated and purified by silica gel column chromatography and dried under vacuum.

[0140] Method 2: A tetralone derivative (1.00 equiv.) and p-toluenesulfonic acid (1.50 equiv.) were added to toluene, and a benzaldehyde derivative (1.50 equiv.) was added, followed by refluxing and stirring at high temperature. After the reaction was completed, the compound was cooled to room temperature, extracted with a 10% aqueous solution of Na2CO3, water, and ethyl acetate, and the organic layer was separated. The moisture in the organic layer was removed with anhydrous MgSO4, and filtered. The organic solvent was distilled off under reduced pressure, and the remaining residue was separated and purified by silica gel column chromatography and dried under vacuum.

[0141]

[0142] (E)-1-(3,4-dimethoxyphenyl)-3-(pyridin-3-yl)prop-2-en-1-one (C04)

[0143] 3,4-Dimethoxyacetophenone (500 mg, 2.77 mmol), pyridin-3-aldehyde (297 mg, 2.77 mmol), EtOH (20 mL), 50% NaOH dissolved in water (0.33 mL, 4.16 mmol) was reacted at room temperature (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:1) to obtain a yellow solid (302 mg, 40.48%). R f 0.10 (ethyl acetate:n-hexane = 1:1); HPLC: R T 3.27 min (purity: 92.15%, 0.5% TFA dissolved in water: ACN = 50:50); 1 H-NMR (DMSO-d6, 400MHz) δ 3.87(s, 3H), 3.88(s, 3H), 7.12(d,J=8.4 Hz, 1H), 7.49(dd,J=8.2, 5.0 Hz, 1H), 7.63(d,J=2.0 Hz, 1H), 7.74(d,J=15.6 Hz, 1H), 7.94 (dd,J=8.4, 2.0 Hz, 1H), 8.10(d,J=15.6 Hz, 1H), 8.36 (ddd,J=8.0, 1.8 Hz, 1H), 8.61(dd,J=4.6, 1.8 Hz, 1H), 9.04(d,J=2.0 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 55.6, 55.8, 110.8, 110.9, 123.6, 123.8, 123.8, 130.2, 130.6, 135.1, 139.6, 148.8, 150.2, 150.8, 153.4, 187.1 ppm.

[0144]

[0145] (E)-1-(3,4-dimethoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (C05)

[0146] 3,4-Dimethoxy acetophenone (200 mg, 1.11 mmol), pyridin-4-aldehyde (118 mg, 1.11 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.08 mL, 1.11 mmol) was reacted at 0°C (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 10:1) to obtain a yellow solid (103 mg, 34.46%). mp 123.1~123.8°C; R f 0.14 (ethyl acetate); HPLC: R T 2.36 min (purity: 97.34%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400MHz) δ 3.80 (s, 3H), 3.87 (s, 3H), 7.13 (d,J= 8.8 Hz, 1H), 7.62 (d,J= 2.5 Hz, 1H), 7.65 (d,J= 15.6 Hz, 1H), 7.84 (d,J= 4.8, 2.0 Hz, 2H), 7.95 (ddJ= 8.4, 2.0 Hz, 1H), 8.17 (d,J= 15.6 Hz, 1H), 8.67 (dd,J= 4.4, 2.0 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 13 C-NMR (DMSO-d6, 100 MHz) 55.6, 55.8, 110.7, 110.9, 122.5, 123.8, 126.3, 130.0, 140.1, 141.9, 148.9, 150.3, 153.6, 187.2 ppm.

[0147]

[0148] (E)-5,6-dimethoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-indene-1-one (C07)

[0149] 5,6-Dimethoxy-1-indanone (300 mg, 1.56 mmol), pyridin-3-aldehyde (167 mg, 1.56 mmol), EtOH (15 mL), 50% NaOH dissolved in water (0.19 mL, 2.34 mmol) was reacted at 0°C (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 5:1) to obtain a pale yellow solid (228 mg, 51.95%). mp 164.9~166.0°C; R f 0.38 (ethyl acetate:n-hexane = 5:1); HPLC: R T 3.11 min (purity: 95.63%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400 MHz) δ 3.84 (s, 3H), 3.91 (s, 3H), 4.05 (d, J = 1.6 Hz, 2H), 7.22 (s, 1H), 7.25 (s, 1H), 7.46 (dd, J = 1.8 Hz, 1H), 7.52 (dd,J=7.8, 4.6 Hz, 1H), 8.16(ddd,J=8.0, 2.0 Hz, 1H), 8.60(dd,J=4.8, 1.6 Hz, 1H), 8.94(d,J=2.4 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 31.4, 55.6, 56.0, 104.6, 108.0, 123.9, 127.5, 129.7, 131.0, 136.7, 137.9, 145.2, 149.4, 149.7, 151.4, 155.5, 191.4 ppm.

[0150]

[0151] (E)-5,6-dimethoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-indene-1-one (C08)

[0152] 5,6-Dimethoxy-1-indanone (300 mg, 1.56 mmol), pyridine-4-carboxyaldehyde (502 mg, 4.68 mmol), EtOH (15 mL), 50% NaOH dissolved in water (0.12 mL, 1.56 mmol) was reacted at 0°C (2 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate) to obtain a pale yellow solid (285 mg, 64.94%). mp 194.8–197.7°C; R f 0.22 (ethyl acetate); HPLC: R T 7.52 min (purity: 99.43%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400 MHz) δ 3.84 (s, 3H), 3.91 (s, 3H), 4.07 (d, J = 1.6 Hz, 2H), 7.21 (s, 1H), 7.24 (s, 1H), 7.38 (s, 1H), 7.68(dd,J=6.0, 1.6 Hz, 2H), 8.68(dd,J=6.0, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.4, 55.7, 56.0, 104.6, 108.0, 124.1, 128.1, 129.6, 140.3, 142.1, 145.4, 149.4, 150.2, 155.7, 191.4 ppm.

[0153]

[0154] (E)-5-methoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-indene-1-one (C10)

[0155] 5-Methoxy-1-indanone (200 mg, 1.23 mmol), pyridin-3-aldehyde (396 mg, 3.70 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.10 mL, 1.23 mmol) was reacted at 0°C (1 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:1) to obtain a white solid (229 mg, 74.09%). mp 162.9 ~164.1°C; R f 0.35 (ethyl acetate); HPLC: R T 5.77 min (purity: 95.22%, 0.5% TFA dissolved in water: ACN = 60:40); 1 H-NMR (DMSO-d6, 400 MHz) δ 3.90 (s, 3H), 4.13 (d,J= 1.2 Hz, 2H), 7.05 (dd,J=8.4, 2.4 Hz, 1H), 7.19 (d,J=2.0 Hz, 1H), 7.49 (dd,J=2.0 Hz, 1H), 7.53 (dd,J=8.2, Hz, 1H), 7.75 (d,J=8.4 Hz, 1H), 8.17 (ddd,J=8.4, 1.6 Hz, 1H), 8.60(d,J=4.8, 1.6 Hz, 1H), 8.95(d,J=2.0 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 31.8, 55.8, 110.1, 155.6, 123.9, 125.6, 128.0, 130.3, 131.0, 136.8, 137.7, 149.8, 151.5, 153.1, 165.1, 191.2 ppm.

[0156]

[0157] (E)-5-methoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-indene-1-one (C11)

[0158] 5-Methoxy-1-indanone (200 mg, 1.23 mmol), pyridine-4-carboxyaldehyde (660 mg, 6.17 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.10 mL, 1.23 mmol) was reacted at 0°C (30 min), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 3:1) to obtain a white solid (50 mg, 16.18%). mp 166.8~168.3°C; R f 0.28 (ethyl acetate); HPLC: R T 6.11 min (purity: 96.38%, water: ACN = 60:40); 1 H-NMR (DMSO-d6, 400MHz) δ 3.91(s, 3H), 4.14(d,J=2.0 Hz, 2H), 7.06(dd,J=8.4, 2.4 Hz, 1H), 7.19(d,J=2.0 Hz, 1H), 7.41(dd,J=2.2 Hz, 1H), 7.69(dd,J=4.4, 1.6 Hz, 2H), 7.76(d,J=8.4 Hz, 1H), 8.69(dd,J=4.4, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.8, 55.9, 110.1, 115.7, 124.1, 125.8, 128.5, 130.1, 140.2, 142.1, 150.3, 153.2, 165.3, 181.2 ppm.

[0159]

[0160] (E)-6-methoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-indene-1-one (C13)

[0161] 6-Methoxy-1-indanone (200 mg, 1.24 mmol), pyridin-3-aldehyde (133 mg, 1.24 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.15 mL, 1.85 mmol) was reacted at room temperature (30 min), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:3) to obtain a white solid (247 mg, 79.27%). mp 162.2-163.3℃; R f 0.24 (ethyl acetate:n-hexane = 1:3); HPLC: R T 4.50 min (purity: 95.53%, 0.5% TFA in water:ACN = 60:40 solution); 1 H-NMR (DMSO-d6, 400MHz) δ 3.85(s, 3H), 4.09(d,J=2.4 Hz, 2H), 7.27(d,J=2.4 Hz, 1H), 7.32(dd,J=8.4, 2.4 Hz, 1H), 7.53(dd,J=8.2, 5.0 Hz, 1H), 7.56(dd,J=2.0 Hz, 1H), 7.59 (d,J=8.4 Hz, 1H), 8.19(ddd,J=8.0, 2.0 Hz, 1H), 8.61(dd,J=4.8, 1.6 Hz, 1H), 8.97(d,J=2.4 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 31.1, 55.5, 105.7, 123.8, 123.0, 127.6, 129.3, 130.8, 137.0, 137.8, 138.2, 142.7, 150.0, 151.7, 159.2, 192.9 ppm.

[0162]

[0163] (E)-6-methoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-indene-1-one (C14)

[0164] 6-Methoxy-1-indanone (200 mg, 1.23 mmol), pyridine-4-carboxyaldehyde (396 mg, 3.70 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.10 mL, 1.23 mmol) was reacted at 0°C (1 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:3) to obtain a white solid (272 mg, 88.00%). mp 177.0-178.3°C; R f 0.15 (ethyl acetate: n-hexane = 1:1); HPLC: R T 6.64 min (purity: 99.48%, 0.5% TFA:ACN dissolved in water = 60:40); 1 H-NMR (DMSO-d6, 400MHz) δ 3.85(s, 3H), 4.11(d,J=2.0Hz, 2H), 7.28(d,J=2.8Hz, 1H), 7.34(dd,J=8.4, 2.8Hz, 1H), 7.48(dd,J=2.0Hz, 1H), 7.59(d,J=8.4Hz, 1H), 7.72(ddd,J=4.6, 1.6Hz, 2H), 8.70(ddd,J=4.6, 1.6Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.0, 55.6, 105.7, 124.1, 124.2, 127.6, 129.7, 138.0, 140.2, 141.9, 142.8, 150.3, 159.3, 192.9 ppm

[0165]

[0166] (E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)prop-2-en-1-one (C16)

[0167] 3,4-(Methylenedioxy)acetophenone (500 mg, 3.05 mmol), pyridin-3-aldehyde (979 mg, 9.14 mmol), EtOH (20 mL), 50% NaOH (0.24 3.05 mmol) dissolved in water were reacted at 0°C (2.5 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:3) to obtain a pale yellow solid (584 mg, 75.61%). mp 140.8–142.6°C; R f 0.23 (ethyl acetate:n-hexane = 1:1); HPLC: R T 3.38 min (purity: 99.34%, 0.5% TFA:ACN dissolved in water = 70:30); 1 H-NMR (DMSO-d6, 400MHz) δ 6.17(s, 2H), 7.11(d,J=8.0 Hz, 1H), 7.49(dd,J=8.0, 4.8 Hz, 1H), 7.68(d,J=2.0 Hz, 1H), 7.73(d,J=15.6 Hz, 1H), 7.89(dd,J=8.0, 1.6 Hz, 1H), 8.07 (d,J=15.6 Hz, 1H), 8.36(ddd,J=8.4, 2.0 Hz, 1H), 8.61(dd,J=4.8, 1.6 Hz, 1H), 9.02(d,J=2.4 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 102.1, 108.0, 108.2, 123.8, 123.9, 125.3, 130.6, 139.9, 148.0, 150.3, 150.9, 151.7 186.7 ppm.

[0168]

[0169] (E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(pyridin-4-yl)prop-2-en-1-one (C17)

[0170] 3,4-(Methylenedioxy)acetophenone (500 mg, 3.05 mmol), pyridine-4-carboxyaldehyde (326 mg, 3.05 mmol), EtOH (20 mL), and 50% NaOH dissolved in water (0.37 mL, 4.57 mmol) were reacted at 0°C (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:3) to obtain a pale yellow solid (457 mg, 58.97%). mp 153.2~155.2°C; R f 0.23 (ethyl acetate:n-hexane = 1:1); HPLC: R T 3.17 min (purity: 97.17%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400MHz) δ 6.18(s, 2H), 7.11(d,J=8.4 Hz, 1H), 7.64(d,J=15.6 Hz, 1H), 7.68(d,J=2.0 Hz, 1H), 7.84(dd,J=4.8, 1.6 Hz, 2H), 7.90(dd,J=8.2, 1.8 Hz, 1H), 8.14(d,J=15.6 Hz, 1H), 8.66(dd,J=4.8, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 102.2, 108.0, 108.2, 122.5, 125.5, 126.2, 131.8, 140.4, 141.9, 148.1, 150.3, 151.9, 186.8 ppm.

[0171]

[0172] (E)-6-Ethoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one (C19)

[0173] 6-Ethoxy-1-indanone (100 mg, 0.57 mmol), pyridine-4-carboxyaldehyde (182 mg, 1.70 mmol), EtOH (5 mL), and 50% NaOH dissolved in water (0.05 mL, 0.57 mmol) were reacted at 0°C (1 h), then filtered under reduced pressure to obtain a white solid (133 mg, 89.27%). R f 0.58 (ethyl acetate); HPLC: R T 5.99 min (purity: 98.20%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400 MHz) δ 1.35 (t, J = 6.8 Hz, 3H), 4.09 (m, 2H), 4.11 (q, J = 6.8 Hz, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.47(dd,J=2.4 Hz, 1H), 7.58(d,J=8.4 Hz, 1H), 7.71(dd,J=4.6, 1.4 Hz, 2H), 8.69(dd,J=4.6, 1.4 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 14.5, 31.0, 63.5, 106.2, 124.2, 124.4, 127.6, 129.7, 138.0, 140.3, 141.9, 142.7, 150.3, 158.5, 192.9 ppm.

[0174]

[0175] (E)-5-methoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-2,3-dihydro-1H-indene-1-one (C20)

[0176] 5-Methoxy-1-indanone (50 mg, 0.31 mmol), 4-(4-methylpiperazinyl)benzaldehyde (63 mg, 0.31 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.04 mL, 0.46 mmol) was used for the reaction at room temperature (19 h), then the mixture was filtered under reduced pressure to obtain a yellow solid (67 mg, 62.03%). mp 190.8~192.6℃ DEG; R f 0.63 (MeOH:DCM=1:9); HPLC: R T 3.29 min (purity: 97.67%, 0.5% TFA dissolved in water: ACN = 60:40); 1 H-NMR (DMSO-d6, 400 MHz) δ 2.32 (m, 3H), 2.54 (m, 3H), 3.89 (s, 3H), 4.00 (s, 2H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.19(d,J=2.4 Hz, 1H), 7.37(s, 1H), 7.62(d,J=8.8 Hz, 2H), 7.69(d,J=8.4 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 32.1, 45.5, 46.7, 54.2, 55.7, 110.1, 114.5, 115.2, 124.7, 125.1, 131.0, 131.4, 132.1, 132.2, 151.4, 152.5, 164.5, 191.5 ppm.

[0177]

[0178] (E)-5-Ethoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-2,3-dihydro-1H-indene-1-one (C21)

[0179] 5-Ethoxy-1-indanone (50 mg, 0.28 mmol), 4-(4-methylpiperazinyl)-benzaldehyde (58 mg, 0.28 mmol), EtOH (10 mL), 50% NaOH dissolved in water (0.03 mL, 0.43 mmol) was used for the reaction at room temperature (24 h), then reduced pressure and filtered to obtain a yellow solid (91 mg, 89.67%). mp 225.0~227.4℃; R f 0.59 (MeOH:DCM=1:9); HPLC: R T 4.71 min (purity: 99.36%, 0.5% TFA dissolved in water: ACN = 60:40); 1 H-NMR (DMSO-d6, 400 MHz) δ 1.38 (t, J = 7.0 Hz, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 3.29 (m, 4H), 3.99 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 6.99(dd,J=8.8, 2.4 Hz, 1H), 7.03(d,J=8.8 Hz, 2H), 7.16(d,J=2.0 Hz, 1H), 7.36(s, 1H), 7.61(d,J=8.8 Hz, 2H), 7.67(d,J=8.0 Hz, 1H).

[0180]

[0181] (E)-6-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (C22)

[0182] 6-Methoxy-1-tetralone (100 mg, 0.57 mmol), pyridine-4-carboxyaldehyde (182 mg, 1.70 mmol), EtOH (5 mL), 50% NaOH dissolved in water (0.05 mL, 0.57 mmol) was reacted at 0°C (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 5:1) to obtain a white solid (46 mg, 30.42%). R f 0.38 (ethyl acetate:n-hexane = 5:1); HPLC: R T4.74 min (purity: 99.63%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400MHz) δ 2.94(m, 2H), 3.04(m, 2H), 3.86(s, 3H), 6.93(d,J=2.4 Hz, 1H), 6.07(dd,J=8.6, 2.6 Hz, 1H), 7.47(dd,J= 4.8, 1.6 Hz, 1H), 7.57(s, 1H), 7.95(d,J=8.8 Hz, 1H), 8.65(dd,J= 4.8, 1.6 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 26.7, 28.2, 55.6, 112.4, 113.9, 123.9, 126.0, 130.0, 131.8, 139.1, 142.8, 146.3, 149.9, 163.5, 185.0 ppm.

[0183]

[0184] 2-(hydroxy(pyridin-4-yl)methyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (C23)

[0185] 6-Methoxy-1-tetralone (100 mg, 0.57 mmol), pyridine-4-carboxyaldehyde (182 mg, 1.70 mmol), 50% NaOH (5 mL) dissolved in water (0.05 mL, 0.57 mmol) were reacted at 0°C (3 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 5:1) to obtain a white solid (14 mg, 8.67%). R f 0.23 (ethyl acetate:n-hexane =5:1); 1H-NMR (DMSO-d6, 400MHz) δ 1.60 (m, 1H), 1.81 (m, 1H), 2.77 (m, 1H), 2.87 (m, 2H), 3.82 (s, 3H), 5.53 (d,J= 10.8 Hz, 2H), 6.84 (d,J= 2.4 Hz, 1H), 6.91 (dd,J= 8.8, 2.8 Hz, 1H), 7.38 (dd,J= 4.8, 1.6 Hz, 2H), 7.89 (d,J= 8.8 Hz, 1H), 8.52 (dd,J= 4.4, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 21.1, 28.1, 53.2, 55.5, 68.6, 112.4, 113.4, 121.2, 126.1, 129.1, 147.0, 149.2, 153.7, 163.1, 195.4 ppm.

[0186]

[0187] (E)-7-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (C24)

[0188] 7-Methoxy-1-tetralone (200 mg, 1.13 mmol), pyridine-4-carboxyaldehyde (365 mg, 3.40 mmol), EtOH (5 mL), 50% NaOH dissolved in water (0.09 mL, 1.13 mmol) was reacted at 0°C (1.5 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 3:1) to obtain a white solid (265 mg, 88.39%). R f 0.43 (ethyl acetate:n-hexane = 3:1); HPLC: R T 5.20 min (purity: 99.63%, 0.5% TFA dissolved in water: ACN = 70:30); 1H-NMR (DMSO-d6, 400MHz) δ 2.90 (m, 2H), 3.04 (m, 2H), 3.82 (s, 3H), 7.20 (dd,J=8.4, 2.8 Hz, 1H), 7.33 (d,J=8.4 Hz, 1H), 7.45(d,J=2.8Hz, 1H), 7.49(dd,J=4.4, 1.6Hz, 2H), 7.61(s, 1H), 8.59(dd,J=4.4, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 26.8, 27.0, 55.3, 110.1, 121.3, 123.9, 130.0, 132.5, 133.3, 136.2, 138.9, 142.7, 149.9, 158.2, 186.3 ppm.

[0189]

[0190] (E)-6,7-dimethoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (C25)

[0191] 6,7-Dimethoxy-1-tetralone (200 mg, 0.97 mmol), pyridine-4-carboxyaldehyde (312 mg, 2.91 mmol), EtOH (15 mL), 50% NaOH dissolved in water (0.08 mL, 0.08 mmol) was reacted at 0°C (4 h), then reduced pressure and filtered to obtain a yellow solid (214 mg, 74.70%). R f 0.38 (ethyl acetate); HPLC: R T 11.21 min (purity: 97.533%, 0.5% TFA dissolved in water: ACN = 65:35); 1 H-NMR (DMSO-d6, 400MHz) δ 2.91(m, 2H), 3.04(m, 2H), 3.81(s, 3H), 3.88(s, 3H), 6.97(s, 1H), 7.45(s, 1H), 7.47(dd,J=4.6, 1.0Hz, 2H), 7.56(s, 1H), 8.65(d,J=4.4, 1.6 Hz, 2H); 13C-NMR (DMSO-d6, 100 MHz) 26.9, 27.5, 55.5, 55.9, 108.9, 110.8, 123.4, 123.9, 125.4, 131.6, 138.8, 139.0, 142.9, 149.9, 153.8, 185.0 ppm.

[0192]

[0193] 2-(hydroxy(pyridin-4-yl)methyl)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (C26)

[0194] 6,7-Dimethosy-1-tetralone (200 mg, 0.97 mmol), pyridine-4-carboxyaldehyde (312 mg, 2.91 mmol), EtOH (15 mL), 50% NaOH dissolved in water (0.08 mL, 0.08 mmol) was reacted at 0°C (2 h), and the residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:1) to obtain a white solid (136 mg, 44.74%). R f 0.28 (ethyl acetate); 1 H-NMR (DMSO-d6, 400 MHz) δ 1.59 (m, 1H), 1.99 (m, 1H), 2.79 (m, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 5.50 (d, J = 4.8 Hz, 1H), 5.54(d,J=2.4Hz, 1H), 6.86(s, 1H), 7.39 (dd,J=4.4, 1.6Hz, 2H), 7.39(s, 1H), 8.52(dd,J=4.4, 1.6Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 21.4, 27.4, 52.9, 55.4, 55.7, 68.7, 108.3, 110.9, 121.2, 125.4, 139.2, 147.5, 149.2, 153.3, 153.7, 195.3 ppm.

[0195]

[0196] (E)-6-methoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-3,4-dihydronaphthalen-1(2H)-one (C27)

[0197] 6-Methoxy-1-tetralone (50 mg, 0.28 mmol), 4-(4-methylpiperazinyl)benzaldehyde (58 mg, 0.28 mmol), p-toluenesulfonic acid (81 mg, 0.43 mmol), and toluene (5 mL) were reacted at 110°C (18 h), and then recrystallized from ethyl acetate and n-hexane to obtain a yellow solid (45 mg, 44.34%). mp 167.2–168.9°C; R f 0.08 (MeOH:DCM=1:30); HPLC: R T 7.23 min (purity: 96.38%, 0.5% TFA dissolved in water: ACN = 35:65); 1 H-NMR (DMSO-d6, 400 MHz) δ 2.22 (s, 3H), 2.44 (m, 4H), 2.90 (m, 2H), 3.07 (m, 2H), 3.25 (m, 4H), 3.84 (s, 3H), 6.89 (d, J = 2.8 Hz, 1H), 6.93(dd,J=8.8, 2.4 Hz, 1H), 6.99(d,J=8.8 Hz, 2H), 7.42(d,J=8.8 Hz, 2H), 7.60(s, 1H), 7.90(d,J=8.8 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 26.8, 28.2, 45.7, 47.1, 54.4, 55.5, 112.2, 113.5, 114.3, 125.0, 126.6, 129.7, 131.5, 131.9, 135.6, 145.6, 151.0, 163.0, 185.2 ppm;

[0198]

[0199] (E)-6-Ethoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-3,4-dihydronaphthalen-1(2H)-one (C28)

[0200] 6-Ethoxy-1-tetralone (50 mg, 0.26 mmol), 4-(4-methylpiperazinyl)-benzaldehyde (54 mg, 0.26 mmol), p-toluene sulfonic acid (75 mg, 0.39 mmol), and toluene (5 mL) were reacted at 110°C (16 h), and then recrystallized from ethyl acetate and n-hexane to obtain a yellow solid (48 mg, 49.04%). mp 153.6–154.8°C; R f 0.08 (MeOH: DCM = 1:30); HPLC: R T 7.28 min (purity: 95.99%, 0.5% TFA dissolved in water: ACN =60:40); 1 H-NMR (DMSO-d6, 400 MHz) δ 1.35 (t, J = 7.2 Hz, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 2.89 (m, 2H), 3.07 (m, 2H), 3.25 (m, 4H), 4.13(q,J=7.2 Hz, 2H), 6.87(d,J= 2.4 Hz, 1H), 6.91(dd,J=8.6, 2.6 Hz, 1H), 6.99(d,J= 8.8 Hz, 2H), 7.42(d,J= 8.4 Hz, 2H), 7.59(s, 1H), 7.88(d,J=8.8 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 14.5, 26.8, 28.2, 45.7, 47.1, 54.4, 63.5, 112.6, 1113.8, 114.3, 125.0, 126.5, 129.7, 131.5, 131.9, 135.6, 145.6, 150.9, 162.3, 185.2 ppm.

[0201]

[0202] (E)-6-(pyridin-4-ylmethylene)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (C29)

[0203] 5,6-Methylenedioxy-1-indanone (150 mg, 0.85 mmol), pyridine-4-carboxyaldehyde (273 mg, 2.55 mmol), EtOH (15 mL), 50% NaOH dissolved in water (0.07 mL, 0.85 mmol) was reacted at 0°C (2 h), then filtered under reduced pressure to obtain a pale yellow solid (189 mg, 83.82%). R f 0.37 (ethyl acetate); HPLC: R T 2.70 min (purity: 98.34%, 0.5% TFA dissolved in water: ACN = 70:30); 1 H-NMR (DMSO-d6, 400MHz) δ 4.05(s, 2H), 6.20(s, 2H), 7.17(s, 1H), 7.21(s, 1H), 7.37(dd,J=2.0 Hz, 1H), 7.67(dd,J=4.4, 1.6 Hz, 2H), 8.77(dd,J=4.4, 1.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.7, 102.2, 102.6, 105.9, 124.1, 128.4, 131.5, 140.1, 142.0, 147.9, 148.3, 149.5, 150.2, 154.3, 191.0 ppm.

[0204]

[0205] General synthesis of pyridinium bromide and methylpiperazin-1-ium bromide derivatives

[0206] Substituted pyridine and substituted 1-methylpiperazine (1.00 equiv.) were added to ethyl ether and dichloromethane, benzyl bromide (2.00 equiv.) was added, and the mixture was stirred at room temperature or while heating. When a solid was formed, it was filtered under reduced pressure, or distilled under reduced pressure, recrystallized from ethyl acetate and dichloromethane, filtered under reduced pressure, and dried under vacuum.

[0207]

[0208] (E)-1-Benzyl-3-(3-(3,4-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)pyridin-1-ium bromide (C30)

[0209] (E)-1-(3,4-dimethoxyphenyl)-3-(pyridin-3-yl)prop-2-en-1-one (50 mg, 0.19 mmol), ethyl ether (10 mL), and benzyl bromide (35 mg, 0.20 mmol) were used. The reaction was carried out at room temperature for 24 h, 40°C (8 h), and then under reduced pressure and filtered to obtain a yellow solid (64 mg, 76.50%). mp 244.1~246.7°C; 1 H-NMR (DMSO-d6, 400MHz) δ 3.87(s, 3H), 3.90(s, 3H), 5.87(s, 2H), 7.17(d,J=8.4 Hz, 1H), 7.47(m, 3H), 7.59(m, 3H), 7.81(d,J= 15.6 Hz, 1H), 7.98(dd,J=8.4, 2.0 Hz, 1H), 8.26(dd,J=6.0, 2.0 Hz, 1H), 8.34 (d,J= 15.6 Hz, 1H), 9.17(m, 2H), 9.79(s, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 55.7, 55.9, 63.7, 110.7, 111.0, 124.1, 128.4, 128.7, 128.8, 129.2, 129.2, 129.4, 129.7, 134.0, 135.2, 135.6, 143.7, 145.0, 149.0, 153.9, 186.6 ppm.

[0210]

[0211] (E)-1-Benzyl-4-(3-(3,4-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)pyridin-1-ium bromide (C31)

[0212] (E)-1-(3,4-dimethoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (40 mg, 0.15 mmol), ethyl ether (10 mL), and benzyl bromide (50 mg, 0.30 mmol) were reacted at 40°C (2d), then filtered under reduced pressure to obtain a yellow solid (48 mg, 72.67%). mp 195.9–196.8°C; R f 0.22(MeOH : DCM = 1:9); 1 H-NMR (DMSO-d6, 400MHz) δ 3.87 (s, 3H), 3.90 (s, 3H), 5.83 (s, 2H), 7.16 (d, J = 8.4Hz, 1H), 7.47 (m, 3H), 7.56 (m, 2H), 7.61(d,J=2.0Hz, 1H), 7.80(d,J=15.6Hz, 1H), 8.00(dd,J=8.4, 2.0Hz, 1H), 8.46(d,J=15.6Hz, 1H), 8.62(d,J=6.8Hz, 2H), 9.27(d,J=6.8Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz)55.7, 56.0, 62.9, 110.7, 111.0, 124.4, 126.1, 126.7, 128.6, 128.7, 129.2, 129.6, 132.6, 134.4, 136.3, 145.0, 149.0. 151.0, 154.1, 186.7 ppm.

[0213]

[0214] (E)-1-Benzyl-3-((5,6-dimethoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)pyridin-1-ium bromide (C32)

[0215] (E)-5,6-dimethoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-indene-1-one (50 mg, 0.18 mmol), ethyl ether (10 mL), dichloromethane (5 mL), and benzyl bromide (33 mg, 0.20 mmol) were used for the reaction at 50°C (24 h), then the mixture was reduced in pressure and filtered to obtain a yellow solid (29 mg, 35.62%). mp 236.0~237.8°C;1 H-NMR (DMSO-d6, 400MHz) δ 3.85(s, 3H), 3.94(s, 3H), 4.13(d,J=1.6 Hz, 2H), 5.90(s, 2H), 7.19(s, 1H), 7.28(s, 1H), 7.47 (m, 3H), 7.58(m, 3H), 8.26(dd,J=8.2, 6.4 Hz, 1H), 8.90(d,J=8.4 Hz, 1H), 9.16(d,J=6.0 Hz, 1H), 9.57(s, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 31.0, 55.7, 56.2, 63.8, 104.8, 107.9, 123.5, 128.5, 128.9, 129.2, 129.3, 129.5, 134.0, 135.8, 142.4, 143.7, 145.0, 145.5, 145.8, 149.6, 156.1, 190.8 ppm.

[0216]

[0217] (E)-1-Benzyl-4-((5,6-dimethoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)pyridin-1-ium bromide (C33)

[0218] (E)-5,6-dimethoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-indene-1-one (50 mg, 0.18 mmol), ethyl ether (10 mL), dichloromethane (5 mL), and benzyl bromide (61 mg, 0.36 mmol) were used for the reaction at 40°C (24 h), then the mixture was reduced in pressure and filtered to obtain a light brown solid (14 mg, 17.19%). mp 225.6~227.9°C; 1 H-NMR (DMSO-d6, 400 MHz) δ 3.85 (s, 3H), 3.94 (s, 3H), 4.18 (d, J = 1.6 Hz, 2H), 5.85 (s, 2H), 7.19 (s, 1H), 7.29 (s, 1H), 7.45 (m, 3H), 7.56(m, 3H), 8.40(d,J=6.8 Hz, 2H), 9.23(d,J=6.8 Hz, 2H); 13C-NMR (DMSO-d6, 100 MHz) 31.4, 55.8, 56.2, 62.8, 104.8, 107.9, 124.1, 124.8, 128.1, 128.8, 129.2, 129.4, 134.4, 144.6, 145.8, 146.5, 149.7, 150.2, 151.3, 156.4, 190.7 ppm.

[0219]

[0220] (E)-1-Benzyl-3-((5-methoxy-1-oxo-1H-indene-2(3H)-ylidene) methyl)pyridin-1-ium bromide (C34)

[0221] (E)-5-methoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one (50 mg, 0.20 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (68 mg, 0.40 mmol) were used for the reaction at 40°C (24 h), and then the mixture was filtered under reduced pressure to obtain a white solid (65 mg, 76.96%). mp 206.8~209.5°C; 1 H-NMR (DMSO-d6, 400MHz) δ 3.92 (s, 3H), 4.21 (d,J=1.2 Hz, 2H), 5.93 (s, 2H), 7.08 (dd,J=8.4, 2.4 Hz, 1H), 7.17(d,J=2.0 Hz, 1H), 7.45(m, 3H), 7.58(dd,J=2.2 Hz, 1H), 7.62 (dd,J= 7.8, 1.8 Hz, 2H), 7.79 (d,J=8.4 Hz, 1H), 8.27(dd, 8.2, 6.2 Hz, 1H), 8.92 (d,J=8.4 Hz, 1H), 9.18(d,J=5.6 Hz, 1H), 9.61(s, 1H); 13C-NMR (DMSO-d6, 100 MHz) 31.4, 56.0, 63.7, 110.1, 115.8, 123.9, 126.1, 128.4, 128.9, 129.2, 129.4, 129.8, 134.0, 135.6, 142.2, 143.8, 145.0, 153.1, 165.6, 190.6 ppm.

[0222]

[0223] (E)-1-Benzyl-4-((5-methoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)pyridin-1-ium bromide (C35)

[0224] (E)-5-methoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one (27 mg, 0.11 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (37 mg, 0.21 mmol) were used for the reaction at 40°C (48 h), then the mixture was reduced in pressure and filtered to obtain a white solid (12 mg, 25.83%). mp 243.0~245.1°C; 1 H-NMR (DMSO-d6, 400 MHz) δ 3.92 (s, 3H), 4.25 (d, J = 1.2 Hz, 2H), 5.86 (s, 2H), 7.09 (dd, J = 8.6, 2.2 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.45(m, 3H), 7.57(m, 3H), 7.80(d,J=8.4 Hz, 1H), 8.42(d,J=6.8 Hz, 2H), 9.25(d,J=6.8 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.8, 56.0, 62.8, 110.1, 116.0, 125.2, 126.3, 128.1, 128.7, 129.2, 129.4, 129.8, 134.4, 144.7, 146.4, 151.2, 153.3, 165.9, 190.5 ppm.

[0225]

[0226] (E)-1-Benzyl-3-((6-methoxy-1-oxo-1H-indene-2(3H)-ylidene) methyl)pyridin-1-ium bromide (C36)

[0227] (E)-6-methoxy-2-(pyridin-3-ylmethylene)-2,3-dihydro-1H-inden-1-one (50 mg, 0.20 mmol), ethyl ether (10 mL), dichloromethane (5 mL), and benzyl bromide (68 mg, 0.40 mmol) were used. After reaction at 40°C (72 h), the mixture was reduced in pressure and filtered to obtain an orange solid (31 mg, 36.70%). mp 238.4~241.7°C; 1 H-NMR (DMSO-d6, 400MHz) δ 3.86 (s, 3H), 4.15 (d,J= 1.6 Hz, 2H), 5.91 (s, 2H), 7.31 (d,J= 2.4 Hz, 1H), 7.37 (dd,J= 8.4, 2.8 Hz, 1H), 7.48 (m, 3H), 7.62 (m, 3H), 7.67 (dd,J= 2.0 Hz, 1H), 8.27 (dd,J=8.2, 6.2 Hz, 1H), 8.93 (d,J= 8.4 Hz, 1H), 9.17 (d,J= 6.0 Hz, 1H), 9.58 (s, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 30.7, 55.6, 63.8, 105.9, 124.5, 125.1, 127.5, 128.5, 128.9, 239.2, 129.5, 134.0, 135.5, 137.8, 142.1, 142.7, 144.0, 145.2, 146.0, 159.4, 192.5 ppm.

[0228]

[0229] (E)-1-Benzyl-4-((6-methoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)pyridin-1-ium bromide (C37)

[0230] (E)-6-methoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one (50 mg, 0.20 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (68 mg, 0.40 mmol) were used for the reaction at 40°C (40 h), then the mixture was reduced in pressure and filtered to obtain a yellow solid (55 mg, 65.12%). mp 193.5~195.6°C; 1 H-NMR (DMSO-d6, 400MHz) δ 3.85 (s, 3H), 4.21 (d,J= 1.2 Hz, 2H), 5.87 (s, 2H), 7.31 (d,J= 2.4 Hz, 1H), 7.38 (dd,J= 8.4, 2.8 Hz, 1H), 7.46 (m, 3H), 7.57 (m, 3H), 7.66 (s, 1H), 8.44 (d,J= 6.8 Hz, 2H), 9.25 (d,J= 6.8 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.1, 55.6, 62.9, 105.9, 124.9, 126.3, 127.6, 128.3, 128.7, 129.2, 129.4, 134.3, 137.6, 142.9, 144.7, 146.1, 151.0, 159.4, 192.5 ppm.

[0231]

[0232] (E)-3-(3-(Benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)-1-benzylpyridin-1-ium bromide (C38)

[0233] (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(pyridin-3-yl)prop-2-en-1-one (50 mg, 0.20 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (68 mg, 0.34 mmol) were used for the reaction at 40°C (48 h), and then the reaction mixture was filtered under reduced pressure to obtain a yellow solid (52 mg, 61.29%). mp 243.4~245.2°C: 1H-NMR (DMSO-d6, 400MHz) δ 5.87(s, 2H), 6.20 (s, 2H), 7.16(d,J=8.4 Hz, 1H), 7.45(m, 3H), 7.59(dd,J=7.8, 1.8 Hz, 2H), 7.68(d,J=2.0 Hz, 1H), 7.80 (d,J=15.6 Hz, 1H), 7.91 (dd,J=8.0, 1.6 Hz, 1H), 8.27 (dd,J=7.2 Hz, 1H), 8.29(d,J=15.6 Hz, 1H), 9.15(d,J=8.4 Hz, 1H), 9.18(d,J=6.4 Hz, 1H), 9.77(s, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 63.7, 102.3, 107.9, 108.3, 125.8, 128.3, 128.4, 128.8, 129.2, 129.4, 131.4, 134.0, 135.5, 143.8, 144.6, 144.9, 148.2, 152.2, 186.3 ppm.

[0234]

[0235] (E)-4-(3-(Benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-1-yl)-1-benzylpyridin-1-ium bromide (C39)

[0236] (E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(pyridin-4-yl)prop-2-en-1-one (50 mg, 0.20 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (68 mg, 0.34 mmol) were used for the reaction at 40°C (48 h), and then the mixture was filtered under reduced pressure to obtain a yellow solid (68 mg, 80.01%). mp 232.9~234.2°C; 1H-NMR (DMSO-d6, 400MHz) δ 5.83(s, 2H), 6.20(s, 2H), 7.16(d,J=8.4 Hz, 1H), 7.46(m, 3H), 7.55(dd,J=7.8, 1.8 Hz, 2H), 7.69(d,J=2.0 Hz, 1H), 7.79(d,J=15.6 Hz, 1H), 7.93(dd,J=8.2, 1.8 Hz, 1H), 8.42(d,J=15.6Hz, 1H), 8.60(d,J=7.2Hz, 2H), 9.27(d,J=7.2Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 63.0, 102.4, 108.0, 108.3, 126.1, 126.7, 128.6, 129.2, 129.3, 131.3, 132.5, 134.3, 136.5, 145.0, 148.3, 150.9, 152.4, 186.3 ppm.

[0237]

[0238] (E)-1-Benzyl-4-((6-ethoxy-1-oxo-1H-indene-2(3H)-ylidene) methyl)pyridin-1-ium bromide (C40)

[0239] (E)-6-Ethoxy-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-inden-1-one (50 mg, 0.19 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (97 mg, 0.57 mmol) were reacted at 50°C (16 h), then filtered under reduced pressure to obtain a yellow solid (64 mg, 77.20%). mp 192.9~195.6°C; 1H-NMR (DMSO-d6, 400 MHz) δ 1.35 (t, J = 6.8 Hz, 3H), 4.12 (q, J = 6.8 Hz, 2H), 4.20 (d, J = 1.6 Hz, 2H), 5.88 (s, 2H), 7.28 (d, J = 2.8 Hz, 1H), 7.36 (dd,J=8.6, 2.6Hz, 1H), 7.46(m, 3H), 7.58(m, 3H), 7.65(dd,J=2.2Hz, 1H), 8.44(d,J=6.8 Hz, 2H), 9.26(d,J=6.8 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 14.5, 31.1, 62.8, 63.6, 106.4, 125.2, 126.2, 127.7, 128.3, 128.7, 129.2, 129.4, 134.4, 137.6, 142.8, 144.7, 146.1, 151.0, 158.6, 192.5 ppm.

[0240]

[0241] (E)-1-Benzyl-4-((6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (C41)

[0242] (E)-6-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (20 mg, 0.08 mmol), ethyl ether (3 mL), dichloromethane (3 mL), benzyl bromide (38 mg, 0.23 mmol) were used for the reaction at 40°C (20 h), then the mixture was filtered under reduced pressure to obtain a pale yellow solid (26 mg, 74.48%). mp 164.2~168.1°C; R f 0 (MeOH : DCM =1:9); 1H-NMR (DMSO-d6, 400MHz) δ 2.97 (m, 2H), 3.09 (m, 2H), 3.89 (s, 3H), 5.85 (s, 2H), 6.96 (d,J= 2.4 Hz, 1H), 6.99 (dd,J= 8.8, 2.8 Hz, 1H), 7.46 (m, 3H), 7.57 (dd,J= 7.8, 1.8 Hz, 2H), 7.70 (s, 1H), 7.97 (d,J= 8.8 Hz, 1H), 8.24 (d,J= 6.8 Hz, 2H), 9.20 (d,J= 6.8 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 26.9, 27.8, 55.7, 62.8, 112.5, 114.2, 125.6, 128.3, 128.7, 128.8, 129.2, 129.4, 130.3, 134.3, 144.0, 144.4, 146.5, 152.3, 163.9, 184.4 ppm.

[0243]

[0244] (E)-1-(4-fluorobenzyl)-4-((6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (C42)

[0245] (E)-6-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (30 mg, 0.11 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (64 mg, 0.34 mmol) were reacted at 47°C, then (2d) the reaction mixture was reduced in pressure and filtered to obtain a yellow solid (34 mg, 68.03%). mp 166.6~168.1°C; 1H-NMR (DMSO-d6, 400MHz) δ 2.97(m, 2H), 3.09 (m, 2H), 3.87(s, 3H), 5.84(s, 2H), 6.98(m, 2H), 7.32(dd,J=9.0 Hz, 2H), 7.68(m, 3H), 7.97(d,J=8.8 Hz, 1H), 8.24(d,J=6.8 Hz, 2H), 9.20 (d,J=6.8 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 26.9, 27.8, 55.7, 61.9, 112.5, 114.2, 116.0, 116.2, 125.6, 128.3, 128.7, 130.2, 130.5, 130.5, 131.4, 131.5, 144.0, 144.3, 146.5, 152.3, 161.3, 163.8, 184.4 ppm.

[0246]

[0247] 1-Benzyl-4-(hydroxy(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)pyridin-1-ium bromide (C43)

[0248] 2-(Hydroxy(pyridin-4-yl)methyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (50 mg, 0.18 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (91 mg, 0.53 mmol) were used for the reaction at 40°C (20 h), then the mixture was reduced in pressure and filtered to obtain a pale yellow solid (45 mg, 55.02%). mp 179.2~181.9°C; 1H-NMR (DMSO-d6, 400MHz) δ 1.58(m, 1H), 2.00(m, 1H), 2.84(m, 2H), 2.99(m, 1H), 3.83(s, 3H), 5.73(brs, 1H), 5.83(s, 2H), 6.08(d,J=4.8 Hz, 1H), 6.85(d,J=2.4 Hz, 1H), 6.92(dd,J=8.8, 2.4 Hz, 1H), 7.46 (m, 3H), 7.56 (dd,J=7.8, 1.4 Hz, 2H), 7.89(d,J=8.8 Hz, 1H), 8.17(d,J=6.6 Hz, 2H), 9.14(d,J=6.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 21.8, 28.5, 53.3, 56.0, 63.1, 69.3, 112.9, 114.0, 125.9, 126.1, 129.3, 129.7, 129.7, 129.8, 134.8, 144.5, 147.4, 163.8, 165.8, 194.9 ppm.

[0249]

[0250] (E)-1-Benzyl-4-((7-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (C44)

[0251] (E)-7-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (50 mg, 0.19 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (97 mg, 0.57 mmol) were used for the reaction at 50°C (16 h), then the mixture was reduced in pressure and filtered to obtain a yellow solid (37 mg, 44.63%). mp 166.1~169.1°C; 1H-NMR (DMSO-d6, 400MHz) δ 2.93(m, 2H), 3.01(m, 2H), 3.82 (s, 3H), 5.87(s, 2H), 7.24(dd,J=8.4, 2.8 Hz, 1H), 7.36(d,J=8.4 Hz, 1H), 7.48(m, 4H), 7.58 (dd,J=8.0, 2.0 Hz, 2H), 7.74(s, 1H), 8.26(d,J=7.0 Hz, 2H), 9.23(d,J=7.0 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 26.7, 27.0, 55.4, 62.8, 110.1, 121.8, 128.3, 128.8, 129.2, 129.4, 129.4, 130.2, 133.0, 134.3, 136.3, 143.6, 144.5, 152.1, 158.3, 185.8 ppm.

[0252]

[0253] (E)-1-(4-fluorobenzyl)-4-((7-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (C45)

[0254] (E)-7-methoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (50 mg, 0.19 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (107 mg, 0.57 mmol) were reacted at 43°C (2d), then the mixture was filtered under reduced pressure to obtain an orange solid (62 mg, 71.82%). mp 167.5~173.5°C; 1 H-NMR (DMSO-d6, 400 MHz) δ 2.93 (m, 2H), 3.08 (m, 2H), 3.82 (s, 3H), 5.85 (s, 2H), 7.35 (m, 4H), 7.45 (d, J = 2.8 Hz, 1H), 7.68 (dd,J=8.8, 5.6 Hz, 2H), 7.73(s, 1H), 8.25(d,J=6.8 Hz, 2H), 9.21 (d,J=6.8 Hz, 2H); 13C-NMR (DMSO-d6, 100 MHz) 26.7, 27.0, 55.4, 62.0, 110.1, 116.0, 116.2, 121.8, 128.3, 129.4, 130.2, 130.5, 131.4, 131.5, 133.0, 136.3, 143.6, 144.4, 152.1, 158.3, 161.4, 163.8, 185.8 ppm.

[0255]

[0256] (E)-1-Benzyl-4-((6,7-dimethoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)pyridin-1-ium bromide (C46)

[0257] (E)-6,7-Dimethoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (20 mg, 0.07 mmol), ethyl ether (3 mL), dichloromethane (3 mL), and benzyl bromide (35 mg, 0.20 mmol) were used for the reaction at 40°C (20 h), then the mixture was reduced in pressure and filtered to obtain a yellow solid (22 mg, 67.39%). mp 172.8~177.5°C; 1 H-NMR (DMSO-d6, 400MHz) δ 2.94 (m, 2H), 3.09 (m, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 5.85 (s, 2H), 7.00 (s, 1H), 7.46 (m, 4H), 7.57 (dd,J= 8.0, 1.6 Hz, 2H), 7.68 (s, 1H), 8.25 (d,J= 6.6 Hz, 2H), 9.20 (d,J= 6.6 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 27.1, 27.3, 55.6, 55.9, 62.8, 108.9, 110.8, 125.0, 128.3, 128.6, 128.8, 129.2, 129.4, 134.3, 139.1, 144.0, 144.4, 148.2, 152.3, 154.2, 184.3 ppm.

[0258]

[0259] (E)-4-((6,7-dimethoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)-1-(4-fluorobenzyl)pyridin-1-ium bromide (C47

[0260] (E)-6,7-Dimethoxy-2-(pyridin-4-ylmethylene)-3,4-dihydronaphthalen-1(2H)-one (50 mg, 0.17 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (96 mg, 0.51 mmol) were reacted at 43°C (2d), then the mixture was filtered under reduced pressure to obtain an orange solid (57 mg, 69.22%). mp 129.1~132.6°C; 1 H-NMR (DMSO-d6, 400 MHz) δ 2.94 (m, 2H), 3.08 (m, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 5.84 (s, 2H), 7.00 (s, 1H), 7.32 (dd, J = 8.8 Hz, 2H), 7.44(s, 1H), 7.67(m, 3H), 8.24(d,J=7.0 Hz, 2H), 9.19(d,J=7.0 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 27.2, 27.3, 55.6, 56.0, 62.0, 108.9, 110.8, 116.0, 116.2, 125.0, 128.3, 128.6, 130.5, 131.4, 131.5, 139.1, 144.0, 144.3, 148.2, 152.4, 154.2, 161.4, 184.3 ppm.

[0261]

[0262] 1-Benzyl-4-((6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(hydroxy)methyl) pyridin-1-ium bromide (C48)

[0263] 2-(Hydroxy(pyridin-4-yl)methyl)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (50 mg, 0.17 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (87 mg, 0.51 mmol) were reacted at 40°C (18 h), then filtered under reduced pressure to obtain a yellow solid (64 mg, 77.72%). mp 183.2~185.6°C; 1 H-NMR(DMSO-d6, 400MHz) δ 1.09 (m, 1H), 1.58 (m, 1H), 2.81 (m, 2H), 2.99 (m, 1H), 3.78 (s, 3H), 3.83 (s, 3H), other peaks 13 C-NMR (DMSO-d6, 100 MHz) 21.7, 27.4, 52.6, 54.9, 55.5, 55.8, 62.6, 68.9, 108.2, 110.8, 125.0, 125.5, 128.8, 128.8, 129.3, 129.4, 134.3, 139.2, 144.0, 147.6, 153.5, 165.3, 194.4 ppm.

[0264]

[0265] (E)-1-Benzyl-4-((5-oxo-5H-indeno[5,6-d][1,3]dioxole-6(7H)-ylidene)methyl)pyridin-1-ium bromide (C49)

[0266] (E)-6-(Pyridin-4-ylmethylene)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (50 mg, 0.19 mmol), ethyl ether (5 mL), dichloromethane (5 mL) and benzyl bromide (97 mg, 0.57 mmol) were reacted at 52°C (36 h), then filtered under reduced pressure to obtain a yellow solid (73 mg, 90.47%). mp 250.8~254.3°C; 1H-NMR (DMSO-d6, 400MHz) δ 4.16 (d,J= 2.0 Hz, 2H), 5.86 (s, 2H), 6.23 (s, 2H), 7.19 (s, 1H), 7.25 (s, 1H), 7.41~7.49 (m, 3H), 7.54~7.57 (m, 3H), 8.40 (d,J= 7.0 Hz, 2H), 9.24 (d,J= 7.0 Hz, 2H); 13 C-NMR (DMSO-d6, 100 MHz) 31.7, 62.8, 102.3, 102.9, 105.8, 125.0, 128.1, 128.7, 129.2, 129.3, 131.1, 134.4, 144.6, 146.1, 148.3, 148.6, 151.1, 155.0, 190.3 ppm.

[0267]

[0268] (E)-1-Benzyl-4-(4-((5-methoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)phenyl)-1-methyl piperazin-1-ium bromide (C50)

[0269] (E)-5-Methoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-one (40 mg, 0.11 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (59 mg, 0.34 mmol) were reacted at 55°C (18 h), and then recrystallized from dichloromethane and ethyl acetate to obtain a yellow solid (52 mg, 91.00%). mp 241.2~243.3°C; 1H-NMR (DMSO-d6, 400MHz) δ 3.07 (s, 3H), 3.48~3.65 (m, 6H), 3.89 (s, 3H), 3.86~3.94 (m, 2H), 4.03 (s, 2H), 4.73 (s, 2H), 7.03 (dd,J= 8.6, 2.2 Hz, 1H), 7.12 (d,J= 8.8 Hz, 2H), 7.19 (d,J= 2.4 Hz, 1H), 7.41 (s, 1H), 7.52~7.61 (m, 5H), 7.69 (d,J= 8.8 Hz, 2H), 7.71 (d,J=8.4 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 32.1, 40.9, 44.7, 55.8, 58.1, 66.8, 110.2, 115.0, 115.2, 125.2, 126.0, 127.4, 128.9, 130.4, 130.9, 131.7, 132.1, 132.3, 133.2, 150.0, 152.6, 164.6, 191.5 ppm.

[0270]

[0271] (E)-1-Benzyl-4-(4-((5-ethoxy-1-oxo-1H-indene-2(3H)-ylidene)methyl)phenyl)-1-methyl piperazin-1-ium bromide (C51)

[0272] (E)-5-Ethoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-2,3-dihydro-1H-inden-1-one (40 mg, 0.11 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (57 mg, 0.33 mmol) were reacted at 50°C, and then (4d) recrystallized from dichloromethane and ethyl acetate to obtain a yellow solid (48 mg, 81.79%). mp 252.6~255.0°C; 1H-NMR (DMSO-d6, 400MHz) δ 1.38 (t,J= 7.0 Hz, 3H), 3.08 (s, 3H), 3.48~3.65 (m, 6H), 3.85~3.94 (m, 2H), 4.02 (s, 2H), 4.17 (q,J= 7.0 Hz, 2H), 4.73 (s, 2H), 7.01 (dd,J= 8.2, 2.2 Hz, 1H), 7.12 (d,J= 8.8 Hz, 2H), 7.16 (d,J= 2.0 Hz, 1H), 7.40 (s, 1H), 7.53~7.61 (m, 5H), 7.69 (d,J= 8.8 Hz, 3H); 13 C-NMR (DMSO-d6, 100 MHz) 14.5, 32.1, 40.9, 44.7, 58.1, 63.8, 66.8, 110.6, 115.0, 115.5, 125.2, 126.0, 127.4, 129.0, 130.4, 130.7, 131.6, 132.1, 132.3, 133.2, 150.0, 152.6, 163.9, 191.5 ppm.

[0273]

[0274] (E)-1-Benzyl-4-(4-((6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl) phenyl)-1-methylpiperazin-1-ium bromide (C52)

[0275] (E)-6-methoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-3,4-dihydronaphthalen-1(2H)-one (20 mg, 0.06 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (28 mg, 0.17 mmol) were reacted at 45°C (18 h), and then recrystallized from dichloromethane and ethyl acetate to obtain a yellow solid (25 mg, 78.10%). mp 212.3~214.0°C; 1H-NMR (DMSO-d6, 400MHz) δ 2.83~2.93 (m, 2H), 3.07 (s, 3H), 3.05~3.10 (m, 2H), 3.45~3.52 (m, 4H), 3.58~3.66 (m, 2H), 3.85 (s, 3H), 3.84~3.89 (m, 2H), 4.72 (s, 2H), 6.90 (d,J=2.8 Hz, 1H), 6.95(dd,J= 8.4, 2.8 Hz, 1H), 7.09(d,J=8.8 Hz, 2H), 7.50(d,J=8.8 Hz, 2H), 7.52~7.64 (m, 6H), 7.91(d,J=8.8 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 26.7, 28.2, 41.2, 44.7, 55.5, 58.2, 66.9, 112.3, 113.6, 114.2, 114.9, 126.4, 127.4, 129.0, 129.7, 130.4, 131.5, 132.8, 133.2, 135.2, 145.7, 149.4, 163.1, 185.3 ppm.

[0276]

[0277] (E)-1-Benzyl-4-(4-((6-ethoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl)phenyl)-1-methylpiperazin-1-ium bromide (C53)

[0278] (E)-6-Ethoxy-2-(4-(4-methylpiperazin-1-yl)benzylidene)-3,4-dihydronaphthalen-1(2H)-one (25 mg, 0.07 mmol), ethyl ether (5 mL), dichloromethane (5 mL), and benzyl bromide (34 mg, 0.20 mmol) were reacted at 50°C (16 h), and recrystallized from dichloromethane and ethyl acetate to obtain a yellow solid (28 mg, 73.06%). mp 213.3~215.2°C; 1H-NMR (DMSO-d6, 400 MHz) δ1.35 (t, J = 7.0 Hz, 3H), 2.82 - 2.91 (m, 2H), 3.07 (s, 3H), 3.005 - 3.09 (m, 2H), 3.47 - 3.52 (m, 4H), 3.59~3.62(m, 2H), 3.85~3.90(m, 2H), 4.13(q,J=7.0 Hz, 2H), 4.72(s, 2H), 6.88(d,J=2.8 Hz, 1H), 6.93 (dd,J=6.4, 2.0 Hz, 1H), 7.08(d,J=9.2 Hz, 2H), 7.49(d,J=8.8 Hz, 2H), 7.53~ 7.63(m, 6H), 7.89(d,J=8.8 Hz, 1H); 13 C-NMR (DMSO-d6, 100 MHz) 14.5, 26.8, 28.2, 41.1, 44.7, 58.2 63.5, 66.9, 112.7, 113.8, 114.2, 114.9, 126.4, 127.4, 128.9, 129.8, 130.4, 131.5, 132.8, 133.2, 135.1, 145.6, 149.4, 162.4, 185.2 ppm.

[0279] Structure of each compound (C30-C53) Compound (chemical formula) Structure Compound (chemical formula) Structure C30 (2) C31 (3) C32 (4) C33 (5) C34 (6) C35 (7) C36 (8) C37 (9) C38 (10) C39 (11) C40 (12) C41 (13) C42 (14) C43 (15) C44 (16) C45 (17) C46 (18) C47 (19) C48 (20) C49 (21) C50 (22) C51 (23) C52 (24) C53 (25)

[0280]

[0281] Evaluation of the cholinesterase inhibitory activity of each compound

[0282] In vitro experiments were conducted to measure the degree of inhibition of hAChE (human acetylcholinesterase) and hBuChE (human butyrylcholinesterase). Pyridine and piperidine derivatives, which are precursors of the pyridinium structure, showed no cholinesterase inhibitory activity, while C30-C53 compounds showed excellent AChE and / or BuChE inhibitory activity. In particular, some compounds, including C35, showed superior AChE inhibitory activity compared to donepezil.

[0283]

[0284] compound C30-C53 Evaluation of cholinesterase inhibitory activity of compound IC 50 (nM) Compound IC 50(nM)hAChEhBChEhAChEhBChEDonepezil29.65±1.393410±160Donepezil28.53±0.843380±150C30377.3±11.963650±130C4024.39±1.041450±20C313.38±0.152280±40C4 141.53±1.25780±20C3240.97±0.773810±150C4290.24±0.871740±20C337.53± 0.361670±40C432320±80>10000C3485.24±1.712880±100C44126.43±3.831110 ±10C357.11±0.22560±10C45147.87±0.991480±20C3635.68±0.942170±70C4620.6±0.351570±50C3731.17±1.17270±4C47147.87±0.991480±20C38244.26±3 .232350±70C48637.03±6.88>10000C395.21±0.152390±110C4920.83±0.37630 ±20C501320±10400±3C511170±10150±3C522460±501130±10C531740±40760±20

[0285]

[0286] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula 1: Chemical Formula 1 In the above chemical formula, R1 and R2 are each independently hydrogen, C1-C3 alkyl or C1-C3 alkoxy, or R1 and R2 are combined with each other to form a 5- to 6-membered ring heterocycloalkene; R3 and R4 are each independently hydrogen or C1-C3 alkyl, or R3 and R4 combine with each other to form cyclopentanone or cyclohexanone; A1 and A2 are each independently carbon or nitrogen; L1 is a 5- to 6-membered heterocycloalkylene ring which is directly bonded or unsubstituted or substituted with C1-C3 alkyl; n is an integer from 1 to 3; R5 is unsubstituted or C6-C substituted with C1-C3 alkyl or halogen 10 It's Aryl.

2. A compound characterized in that in paragraph 1, R1 and R2 are each independently hydrogen or C1-C3 alkoxy, or R1 and R2 combine with each other to form dioxol.

3. A compound characterized in that in paragraph 1, A1 and A2 are not nitrogen at the same time.

4. A compound characterized in that in the first paragraph, when A1 or A2 bonded to L1 is nitrogen, L1 is a direct bond, and when A1 or A2 bonded to L1 is carbon, L1 is a heterocycloalkylene of a 5-6 membered ring that is unsubstituted or substituted with C1-C3 alkyl.

5. A compound according to claim 4, characterized in that the heterocycloalkylene of the 5- to 6-membered ring is selected from the group consisting of piperazinylene, piperidinylene, pyrrolidinylene, and morpholinylene.

6. A compound according to claim 1, wherein R5 is an unsubstituted or halogen-substituted C6 aryl.

7. In the first paragraph, the compound represented by the chemical formula 1 is a compound characterized in that it is selected from the group consisting of compounds represented by the following chemical formulas 2 to 25: Chemical Formula 2 Chemical Formula 3 Chemical Formula 4 Chemical Formula 5 Chemical Formula 6 Chemical Formula 7 Chemical Formula 8 Chemical Formula 9 Chemical Formula 10 Chemical Formula 11 Chemical Formula 12 Chemical Formula 13 Chemical Formula 14 Chemical Formula 15 Chemical Formula 16 Chemical Formula 17 Chemical Formula 18 Chemical Formula 19 Chemical Formula 20 Chemical Formula 21 Chemical Formula 22 Chemical Formula 23 Chemical Formula 24 Chemical Formula 25 8. A composition for preventing or treating a degenerative neurological disease, comprising a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. In the 8th paragraph, the neurodegenerative disease is Alzheimer's disease, argyrophilic grain disease (AGD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism (PSP-P), Richardson syndrome, Pick's disease, Niemann-Pick disease, Rasmussen's syndrome, Parkinson's disease, atypical parkinsonism in Guadeloupe, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), progressive subcortical gliosis, primary progressive aphasia, globular glial tauopathy, Lytico-Bodig disease, neurodegeneration with brain iron accumulation, pantothenate kinase-associated neurodegeneration (PKAN), postencephalitic parkinsonism, chronic traumatic encephalopathy;CTE), Familial British dementia, Familial Danish dementia, Huntington's disease, Down's syndrome, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, leukotauopathy, amyotrophic lateral sclerosis (ALS), cerebral amyloid angiopathy, senile dementia of the neurofibrillary tangle type, motor neuron disease with neurofibrillary tangles, diffuse neurofibrillary tangles with calcification, corticobasal degeneration, primary age-related tauopathy A composition characterized by being selected from the group consisting of tauopathy and traumatic brain injury.; 10. In the 8th paragraph, the composition is characterized in that it inhibits acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) or a combination thereof.

11. A functional food composition for improving or preventing degenerative brain disease, comprising a compound of any one of claims 1 to 7 or a food-based salt thereof as an active ingredient.

12. A functional food composition for inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) or a combination thereof, comprising as an active ingredient a compound of any one of claims 1 to 7 or a food-related acceptable salt thereof.

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