CN114591312B

CN114591312B - Sulfone and sulfoxide compounds, preparation method and medical application thereof

Info

Publication number: CN114591312B
Application number: CN202210261801.8A
Authority: CN
Inventors: 徐进宜; 徐盛涛; 刘玉林; 李文龙; 章海燕; 朱哲英; 刘洁; 姚鸿; 朱华健
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2022-03-17
Filing date: 2022-03-17
Publication date: 2023-07-28
Anticipated expiration: 2042-03-17
Also published as: CN114591312A

Abstract

The invention relates to a sulfone and sulfoxide compound, a preparation method and medical application thereof, wherein the compound has acetylcholinesterase inhibition capability and therapeutic activity on dementia symptoms, and also discloses a medicinal composition containing the compound, and application of the compound or medicinal salt thereof or the composition containing the compound in preparation of medicaments for treating Alzheimer disease and related dementia symptoms.

Description

Sulfone and sulfoxide compounds, preparation method and medical application thereof

Technical Field

The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to a sulfone and sulfoxide compound, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound serving as an acetylcholinesterase inhibitor, in particular to the preparation of medicines for treating Alzheimer's disease, parkinsonism, epilepsy and schizophrenia.

Background

Alzheimer's Disease (AD) is the most common progressive neurodegenerative disease. Clinically, AD patients are characterized by an omnidirectional demented appearance, including other symptoms such as hypomnesis, language problems, behavioral disorders, and the like. According to the report of alzheimer's disease in the world in 2019, nearly 80% of people worry about suffering from AD at some time, and 25% consider that people cannot prevent AD. The pathogenesis of AD is complex and remains incompletely understood, but several assumptions about AD pathophysiology have been proposed to facilitate drug development, including low levels of acetylcholine (ACh), amyloid- β (aβ) deposition, tau protein aggregation, oxidative stress, and the like.

Cholinesterase is a key enzyme in biological nerve conduction, and cholinesterase is classified into acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) according to the specificity of its catalytic substrate. AChE catalyzes the cleavage reaction of acetylcholine, resulting in ACh deficiency and failure of nerve signal transduction, and thus in decline of cognitive function, memory capacity loss, and clinical manifestation of senile dementia symptoms in patients. AChE inhibitor can inhibit AChE activity, delay ACh hydrolysis speed, improve synaptic gap ACh level, and ensure nerve signal normal conduction, thereby exerting therapeutic effect on senile dementia.

Cholinergic hypothesis was the earliest proposed hypothesis, indicating that the pathogenesis of AD and corresponding dysfunction is associated with low ACh levels. Thus, increasing the level of ACh in the brain by inhibiting AChE is considered a good strategy for treating AD. This hypothesis has prompted successful development of AChE inhibitors as drugs. Clinically, current treatment options for AD patients are mainly limited to 5 AChE inhibitors: tacrine, donepezil, rivastigmine, galanthamine, huperzine a and 1N-methyl-D-aspartate receptor antagonist: memantine. Unfortunately, these drugs, while improving symptoms such as cognitive deterioration, hypomnesis, etc., do not fully meet the therapeutic needs of patients. Thus, there is a great clinical need to develop more potent and novel AChE inhibitors with additional functions for the treatment of AD.

Alkenyl sulfones, like chalcones, activate Nrf2 and induce expression of Nrf 2-dependent antioxidant enzymes such as NAD (P) H quinone oxidoreductase 1 (NQO 1) and heme oxygenase 1 (HO-1) to exert antioxidant and anti-inflammatory activity. Therefore, it is considered as a potential neuroprotective fragment and has been applied to design a variety of novel neuroprotective agents for the treatment of neurodegenerative diseases. The study integrates alkenyl sulfone and sulfonyl functional groups into the structure of the anti-AD drug donepezil, so that a series of novel molecules with anti-AChE, anti-oxidation and neuroprotective activities are obtained, and the novel molecules have the potential of treating AD.

Disclosure of Invention

An object of the present invention is to provide two kinds of sulfone and sulfoxide compounds represented by general formula (general formula I and general formula II) or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for the preparation of two sulfone and sulfoxide compounds of the general formula (formula I and formula II).

It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a sulfone and sulfoxide compound selected from the group consisting of formula I and formula II, and pharmaceutically acceptable salts thereof.

It is still another object of the present invention to provide an AChE inhibitor comprising a sulfone and sulfoxide compound selected from the group consisting of general formula I and general formula II, and pharmaceutically acceptable salts thereof.

It is still another object of the present invention to provide the use of the sulfone and sulfoxide compounds of general formula I and general formula II, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them in the treatment of dementia symptoms. Wherein the dementia symptoms belong to, but are not limited to, central nervous system degenerative diseases such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, parkinson's disease, or Huntington's disease. The technical scheme is as follows: based on the above object, the present invention provides a sulfone and sulfoxide compound represented by the general formula I or the general formula II:

wherein:

n is an integer from 0 to 3, where n is preferably 1, 2 or 3;

m is an integer from 0 to 3, wherein m is preferably 0, 1 or 2;

x is SO or SO ₂ The method comprises the steps of carrying out a first treatment on the surface of the Preferably SO ₂ ；

Represents a single bond or a double bond;

R ₁ is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, -O [ (CH) ₂ ) _q O] _r R ₆ 1 to 4 identical or different substituents in phenyl, benzyl, benzyloxy and 3-12 membered heterocyclic groups; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; r is R ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and hydroxymethyl; q is 1, 2, 3 or 4; r is 1, 2, 3 or 4; t is 1, 2, 3 or 4;

preferably, R ₁ Is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, carboxyl and-O [ (CH) ₂ ) _q O] _r R ₆ 1 to 3 substituents which are the same or different; r is R ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2, 3 or 4;

more preferably, R ₁ Is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, hydroxy and-O [ (CH) ₂ ) _q O] _r R ₆ 1 to 2 substituents which are the same or different; r is R ₆ Selected from C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2 or 3;

R ₂ is substituted or unsubstituted C ₃ -C ₁₀ Cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ Cycloalkenyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C ₆ -C ₁₂ An aryl group; the R is ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, C ₆ -C ₁₀ Aryl and 1, 2, 3, 4 or 5 substituents, which may be the same or different, in a 3-to 12-membered heterocyclic group; or at said C ₆ -C ₁₂ Two adjacent substituents on the aryl group together with the carbon atoms on their adjacent aromatic rings form C ₃ -C ₇ Cycloalkyl, C ₃ -C ₇ Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclyl group independently contains 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

preferably, R ₂ Is substituted or unsubstituted C ₃ -C ₈ Cycloalkyl or substituted or unsubstituted C ₆ -C ₁₂ An aryl group; the R is ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ 1-5 substituents which are the same or different in cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, phenyl, naphthyl and 3-12 membered heterocyclic groups; or at said C ₆ -C ₁₂ Two adjacent substituents on the aryl group together with the carbon atoms on their adjacent aromatic rings form C ₃ -C ₇ Cycloalkyl, C ₃ -C ₇ Cycloalkenyl or 3-7 membered heterocyclylThe method comprises the steps of carrying out a first treatment on the surface of the The heterocyclic group contains 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen;

more preferably, R ₂ Is C ₃ -C ₈ A cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; the R is ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C substituted with halogen ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl group, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ 1 to 5 substituents which may be the same or different in alkynyl, cyano, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, sulfonyl and phenyl, or two adjacent substituents on said phenyl together with the carbon atom on the benzene ring adjacent thereto form

Most preferably, R ₂ Is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or substituted or unsubstituted phenyl, the substituents of the substituted phenyl may be selected from halogen, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl, ethoxycarbonyl and 1 to 5 identical or different substituents of the propoxycarbonyl or two adjacent substituents on the phenyl together with the carbon atoms on the phenyl ring adjacent thereto form

R ₃ Selected from hydrogen or fluorine;

R ₄ and R is ₅ Each independently selected from hydrogen, carboxyl, C ₁ -C ₄ Alkoxycarbonyl and C ₁ -C ₄ An alkyl group; or R is ₄ And R is ₅ Are joined together to form C ₁ -C ₄ An alkylene group;

preferably, R ₄ And R is ₅ Each independently selected from the group consisting of hydrogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, and 2-methylpropyl; or R is ₄ And R is ₅ Together linked to form a methylene, ethylene or propylene group;

in the present invention, the halogen is F, cl, br or I.

In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.

In the present invention, the term "C ₁ -C ₆ Alkyl "refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.

In the present invention, the term "C ₁ -C ₆ Alkoxy "refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

In the present invention, the term "C ₂ -C ₆ Alkenyl "refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond and includes, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

In the present invention, the term "C ₂ -C ₆ Alkynyl "refers to a straight or branched chain alkynyl group containing one triple bond having 2 to 6 carbon atoms and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

In the present invention, the term "C ₃ -C ₁₀ Cycloalkyl "refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cycloHexyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like. The term "C ₃ -C ₈ Cycloalkyl "," C ₃ -C ₇ Cycloalkyl ", and" C ₃ -C ₆ Cycloalkyl "has similar meaning.

In the present invention, the term "C ₃ -C ₁₀ Cycloalkenyl "refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring and includes, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl, and the like. The term "C ₃ -C ₇ Cycloalkenyl "has similar meaning.

In the present invention, the term "C ₆ -C ₁₂ Aryl "refers to an aromatic cyclic group having 6 to 12 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain a heteroatom in the ring. The term "C ₆ -C ₁₀ Aryl "has similar meaning.

In the present invention, the term "3-12 membered heterocyclic group" means a saturated or unsaturated 3-12 membered cyclic group containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen in the ring, such as a dioxolyl group and the like. The term "3-7 membered heterocyclyl" has similar meaning.

In a preferred embodiment, the sulfone and sulfoxide compounds of the structures of the general formulae I and II are sulfone compounds of the general formulae III and IV, respectively:

wherein R is ¹ Each independently selected from hydrogen, halogen, C ¹ -C ⁶ Alkyl, C substituted by halogen ¹ -C ⁶ Alkyl, C ¹ -C ⁶ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, carboxyl or-O [ (CH) ₂ ) _q O] _r R ₆ One or more of the following; wherein R is ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2, 3 or 4;

preferably, R ₁ Each independently selected from hydrogen, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, halogen substituted C ₁ -C ₃ Alkoxy, hydroxy or-O [ (CH) ₂ ) _q O] _r R ₆ One or more of the following; wherein R is ₆ Selected from C ₁ -C ₃ Alkyl and halogen substituted C ₁ -C ₃ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1 or 2.

R ₂ Is thatOr C ₃ -C ₇ Cycloalkyl, R ₇ Represents each independently selected from H, halogen, nitro, cyano, C ₁ -C ₄ Alkyl, halogen substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, phenyl or C ₁ -C ₄ One or more of alkoxycarbonyl groups, or two adjacent R' s ₇ Together with the carbon atoms of its adjacent benzene rings> v is 1, 2, 3, 4 or 5.

Preferably, R ₂ Is thatCyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, R ₇ Independently selected from H, -F, -Br, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl,one or more of ethoxycarbonyl or propoxycarbonyl, or two adjacent R ₇ Together with the carbon atoms of the benzene rings adjacent thereto form +.>v is 1, 2, 3, 4 or 5.

R ₃ Selected from hydrogen or fluorine.

The halogen is F, cl, br or I.

In a more preferred embodiment of the present invention, the compounds of the general formulae I and II according to the invention are preferably the following specific compounds:

In another aspect, the present invention provides a process for preparing compounds of formula I and formula II, which is carried out according to scheme 1 below.

Scheme 1:

wherein R is ₁ ,R ₂ ,R ₃ ,R ₄ ,R ₅ X, m, n and t are as defined above for formula I and formula II.

Step a, adding the raw material 1 into dimethyl sulfoxide, stirring and heating, adding sodium hydride, continuously stirring, cooling, and adding trimethyl sulfoxide iodide; and reacting at 100 ℃ to obtain the epoxy intermediate 2.

Step b: dissolving the intermediate 2 into dichloromethane, cooling to-10 ℃, adding 1-10 equivalents of hydrogen fluoride pyridine solution, continuing to react until the raw materials disappear, and separating and purifying to obtain the intermediate 3.

Step c, dissolving the intermediate 3 into dichloromethane, adding a dess-martin oxidant to oxidize an alcohol hydroxyl group into an aldehyde group, and separating and purifying to obtain an intermediate 4.

And d, dissolving the corresponding substituted benzene in dichloromethane and protecting nitrogen. Adding chloromethylsulfonic acid in ice bath, stirring at room temperature. Separating and purifying to obtain an intermediate 6.

Step e, add intermediate 6 and 35% hcl to a three-necked flask. Metallic lead and zinc were added while stirring at 60 ℃. The reaction was continued for 1 hour. Separating and purifying to obtain an intermediate 7.

Step f potassium carbonate is added to a solution of intermediate 7 in acetonitrile and stirred. Diethyl p-toluenesulfonyloxy methylphosphonate was added and reacted at 50 ℃. Separating and purifying to obtain an intermediate 8.

Step g, dissolving intermediate 8 in methanol, adding sodium hydroxide and reacting to hydrolyze at 80 ℃. The reaction mixture was concentrated in vacuo and the pH was adjusted to 3.0 with hydrochloric acid. Separating and purifying to obtain an intermediate 9.

Step h, adding one drop of pyridine into a solution of the intermediate 9 in dichloromethane, slowly dropwise adding oxalyl chloride under an ice bath, and reacting at room temperature. The solvent and excess oxalyl chloride were removed in vacuo, the resulting crude product was dissolved in anhydrous dichloromethane, aluminum trichloride was added in an ice bath and reacted at room temperature. Separating and purifying to obtain an intermediate 10.

Step i triethyliodosilane was added to a solution of intermediate 10 in trifluoroacetic acid and the reaction was refluxed for 48 hours. Isolation and purification yields intermediate 11.

Step j, intermediate 11 is dissolved in dichloromethane, and m-chloroperoxybenzoic acid is added and reacted at room temperature. Isolation and purification yields intermediate 12.

Step k, dissolving the intermediate 12 in anhydrous tetrahydrofuran, dropwise adding 2.5M n-hexane solution of n-butyllithium at-78 ℃ under nitrogen protection, and gradually heating the reaction to 0 ℃ and stirring for 1 hour. After detection of the silyl ether, the reaction was cooled again to-78 ℃, n-butyllithium was added, and after stirring for 0.5 hour, intermediate 4 was added dropwise to the reaction mixture, and the reaction was continued. Separating and purifying to obtain an intermediate 13.

Step l trifluoroacetic acid was added to intermediate 13 and reacted at room temperature in dichloromethane. The solvent was evaporated in vacuo to give the corresponding product trifluoroacetate hydrochloride, which was continuously dissolved in acetonitrile, potassium carbonate and the corresponding bromide were added sequentially, and the reaction was allowed to react at room temperature. Separating and purifying to obtain a product 14.

Step m, 14 was dissolved in methanol, pd-C was added and the reaction was carried out overnight at room temperature. And separating and purifying to obtain a product 15.

And N, adding potassium carbonate into a solution of 15 in acetonitrile, adding N-fluoro-bis-benzene sulfonamide, and reacting at room temperature. The product 16 is obtained by separation and purification.

The pharmaceutically acceptable salt can be prepared by reacting the sulfone and sulfoxide compounds with inorganic acid or organic acid, wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid, and the organic acid is citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, sulfanilic acid, 2-acetoxybenzoic acid or hydroxyethaneyellow acid.

The use of the compounds disclosed herein or pharmaceutically acceptable salts thereof or the compositions of the present invention in AChE inhibitor drugs is also within the scope of the present invention.

The application of the compound or the pharmaceutically acceptable salt thereof disclosed in the application to the preparation of the anti-dementia symptom medicament is also within the protection scope of the invention. The dementia symptoms belong to, but are not limited to, central nervous system degenerative diseases such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, parkinson's disease, or Huntington's disease.

The invention also discloses a pharmaceutical composition which contains a therapeutically effective amount of one or more selected from the compounds of the general formula I and the general formula II, pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials are optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and/or diluents.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols and the like, and may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterilization apparatus for injection or infusion.

Detailed Description

The invention will be further illustrated in the following examples. These examples are only intended to illustrate the invention but not to limit it in any way. The starting materials used in the present invention are commercially available unless otherwise specified.

Example 1 preparation of (E) -2- ((1- (2-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-1)

1.1 Synthesis of 6-t-butoxycarbonyl-1-oxa-6-azaspiro [2.5] octane

130mL of dimethyl sulfoxide (DMSO) was added to a 250mL eggplant-shaped bottle, stirred and heated, 5g of NaH solid was weighed and added to the DMSO solution, stirring was continued for 12 hours, and cooled to room temperature. 25g of trimethylsulfoxide iodide was added thereto and stirred at room temperature for 24 hours. 25-t-butoxycarbonyl piperidone, which had been previously dissolved in DMSO, was added to the reaction solution, and the reaction was monitored by Thin Layer Chromatography (TLC) with stirring for another 12 hours. 100-200mL of water is added after the reaction is finished, 100mL of Ethyl Acetate (EA) is extracted for 3 times, 30mL of saturated saline water is used for washing the organic layer for three times, and the organic layer is dried by spin to obtain 28g of colorless liquid which is 6-tert-butoxycarbonyl-1-oxa-6-azaspiro [2.5]]Octane. ¹ H NMR(500MHz,Chloroform-d)δ3.64(ddd,J＝12.3,5.3,2.7Hz,1H),3.53(ddd,J＝12.4,5.3,2.6Hz,1H),3.39(s,1H),2.09(ddd,J＝12.4,5.3,2.7Hz,1H),1.92(ddd,J＝12.3,5.3,2.6Hz,1H)；LRMS(EI)m/z 214(M ⁺ )。

1.2 Synthesis of (4-fluoro-1-t-butoxycarbonyl-substituted piperazin-4-yl) methanol

28g of 6-tert-butoxycarbonyl-1-oxa-6-azaspiro [2.5 ]]Octane is dissolved in 100mL of Dichloromethane (DCM), cooled, and 70% hydrogen fluoride pyridine solution 120mL is added for reaction for 12 hours, after the reaction is finished, water and methylene chloride are used for extraction for three times, petroleum Ether (PE) is Ethyl Acetate (EA) =4:1, the mixture is passed through a column, and 21g of a basic colorless liquid product is obtained after spin drying, and the basic colorless liquid product is (4-fluoro-1-Boc substituted piperazine-4-yl) methanol. ¹ H NMR(500MHz,Chloroform-d)δ3.65(d,J＝6.5Hz,1H),3.63–3.53(m,3H),3.44(ddd,J＝12.4,6.7,4.0Hz,2H),3.35(t,J＝6.6Hz,1H),2.15(dddd,J＝25.1,12.4,6.6,3.9Hz,2H),2.00(dddd,J＝25.1,12.4,6.6,4.0Hz,2H)；LRMS(EI)m/z 234(M ⁺ )。

1.3 Synthesis of 4-fluoro-1-tert-butoxycarbonyl substituted piperazine-4-carbaldehyde

3.5g of (4-1-tert-butoxycarbonyl-substituted piperazin-4-yl) methanol was dissolved in 20mL of an organic solvent, 16g of dess-Martin oxidant was added thereto, and the mixture was stirred at room temperature for 14 hours, whereby the reaction was completed. 50mL of methylene chloride is added, water is added for extraction, saturated sodium bicarbonate solution is washed for three times, and the mixture is dried and spun to obtain 3.2g of white liquid which is 4-fluoro-1-tert-butoxycarbonyl substituted piperazine-4-formaldehyde. ¹ H NMR(500MHz,Chloroform-d)δ9.62(s,1H),3.68(td,J＝6.0,1.2Hz,4H),2.25–2.09(m,4H),1.51(s,9H)；LRMS(EI)m/z 232(M ⁺ )。

1.4 Synthesis of 3, 4-dimethoxy benzene sulfonyl chloride

1.5g of 3, 4-dimethoxy (1.7 mmol) are dissolved in dichloromethane and blanketed with nitrogen. 1.24g of chloromethylsulfonic acid was added under ice bath, and the reaction was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (3X 30 mL). The combined organics were dried over anhydrous sodium sulfateA layer. The reaction mixture was concentrated under reduced pressure. Petroleum ether ethyl acetate=4:1 column chromatography gives 1.95g of white liquid as 3, 4-dimethoxybenzene-1-sulfonyl chloride. ¹ H NMR(500MHz,Chloroform-d)δ7.61(dd,J＝9.7,2.2Hz,1H),7.34(d,J＝2.2Hz,1H),7.08(d,J＝9.6Hz,1H),3.84(d,J＝4.4Hz,6H)；LRMS(EI)m/z 237(M ⁺ )。

1.5 Synthesis of 3, 4-dimethoxy benzene mercaptan

1g of 3, 4-dimethoxybenzenesulfonyl chloride, 10ml of 35% HCl was added to a 100ml three-necked flask. While stirring at 60 ℃, 100mg of metallic lead and 150mg of zinc were added. After the addition, the reaction was carried out at 70℃for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (4X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure. Petroleum ether: ethyl acetate=3:1, to give 610mg of a white solid as 3, 4-dimethoxybenzenethiol. ¹ H NMR(500MHz,Chloroform-d)δ6.96(dd,J＝7.3,2.2Hz,1H),6.89(d,J＝2.3Hz,1H),6.75(d,J＝7.3Hz,1H),5.02(s,1H),3.84(d,J＝2.9Hz,6H)；LRMS(EI)m/z 171(M ⁺ )。

1.6 Synthesis of ethyl 2- ((3, 4-dimethoxyphenyl) thio) acetate

6.42g of potassium carbonate was added to a solution of 6.60g of 3, 4-dimethoxybenzenethiol in anhydrous acetonitrile (30 mL), and 7.77g of ethyl bromoacetate was added dropwise. After stirring the reaction at room temperature for 3 hours, the reaction mixture was concentrated in vacuo, extracted with DCM (50 ml×3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Vacuum concentrating, petroleum ether: ethyl acetate=4:1 purification gave 9.04g of a white liquid as ethyl 2- ((3, 4-dimethoxyphenyl) thio) acetate. ¹ H NMR(500MHz,Chloroform-d)δ7.04(dd,J＝8.1,2.2Hz,1H),6.91(d,J＝2.3Hz,1H),6.87(d,J＝8.1Hz,1H),4.17(q,J＝6.6Hz,2H),3.84(d,J＝2.9Hz,6H),3.70(s,2H),1.24(t,J＝6.5Hz,3H)；LRMS(EI)m/z 229(M ⁺ )。

1.7 Synthesis of 2- ((3, 4-dimethoxyphenyl) thio) acetic acid

3.5g of ethyl 2- ((3, 4-dimethoxyphenyl) thio) acetate was dissolved in methanol (30 mL), sodium hydroxide (20 mL, 10%) was added and stirred at 80℃for 1 hour. The reaction mixture was concentrated in vacuo and neutralized with HCl (1 mol/L) to adjust the pH to 3.0. The mixture was then filtered and the filtrate was washed with water to give 3.05g of a white solid, 2- ((3, 4-dimethoxyphenyl) thio) acetic acid. ¹ H NMR(500MHz,Chloroform-d)δ7.04(dd,J＝8.1,2.2Hz,1H),6.91(d,J＝2.3Hz,1H),6.87(d,J＝8.1Hz,1H),3.88–3.82(m,8H)；LRMS(EI)m/z 229(M ⁺ )。

1.8 Synthesis of 5, 6-dimethoxy benzo [ b ] thiophen-3 (2H) -one

To a solution of 2.5g of 2- ((3, 4-dimethoxyphenyl) thio) acetic acid in dichloromethane (30 mL) was added a drop of pyridine, 2.78g of oxalyl chloride was slowly added dropwise under ice bath, and the reaction was stirred at room temperature for 1h. The solvent and excess oxalyl chloride were removed in vacuo. The resulting crude product was dissolved in dry dichloromethane (30 mL) and 2.92g of aluminum trichloride was added to the solution under an ice bath. The reaction was stirred at room temperature for 8 hours and extracted with dichloromethane (50 ml. Times.3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentrated in vacuo and the crude product recrystallised to give 1.5g of a white solid as 5, 6-dimethoxy benzo [ b ]]Thiophen-3 (2H) -one. ¹ H NMR(500MHz,Chloroform-d)δ7.44(s,1H),7.16(s,1H),4.33(s,2H),3.88(d,J＝0.7Hz,6H)；LRMS(EI)m/z 211(M ⁺ )。

1.9 Synthesis of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene

5.53g triethyliodosilane (0.15 mL) was added to 3.2g 5, 6-dimethoxy benzo [ b ]]The thiophen-3 (2H) -one was refluxed in 15ml of trifluoroacetic acid solution for 48 hours. The reaction mixture was concentrated in vacuo, extracted with dichloromethane (50 ml×3), the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentrated in vacuo to give 2.1g of a white solid as 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] ]Thiophene. ¹ H NMR(500MHz,Chloroform-d)δ6.96(s,1H),6.82(t,J＝1.0Hz,1H),3.84(d,J＝3.8Hz,6H),3.38–3.28(m,2H),3.04(dddd,J＝6.0,4.9,3.8,1.1Hz,2H)；LRMS(EI)m/z 197(M ⁺ )。

1.10 Synthesis of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide

1.5g of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ]]Thiophene was dissolved in dichloromethane, 1.98-g m-CPBA was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, extracted with dichloromethane (50 ml×3), the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentrating in vacuum to obtain crude product, passing petroleum ether: ethyl acetate=2:1 purification by column gave 1.3g as a pale yellow solid, 5, 6-dimethoxy-2, 3-dihydrobenzo [ b]Thiophene 1, 1-dioxide. ¹ H NMR(500MHz,Chloroform-d)δ7.41(s,1H),6.89(d,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.73(dd,J＝9.1,7.3Hz,1H),3.65(dd,J＝9.1,7.3Hz,1H),3.14(dddd,J＝9.0,7.1,4.9,0.9Hz,2H)；LRMS(EI)m/z 229(M ⁺ )。

1.11 Synthesis of 1-Boc (E) -4- ((5, 6-dimethoxy-1, 1-dioxobenzo [ b ] thiophene-2 (3H) -ethylene) methyl) -4-fluoropiperidine-1-carboxylate

200mg of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ]]Thiophene 1, 1-dioxide dissolved in anhydrous tetrahydrofuran with N ₂ To protect, 350. Mu.L of a 2.5M solution of n-butyllithium was added dropwise at-78℃and after half an hour, 95mg of methylchlorosilane was added, and the reaction was gradually warmed to 0℃and stirred for 1 hour. After detection of the silyl ether by TLC, the reaction was cooled again to-78℃and 350. Mu.L of n-butyllithium was added thereto, followed by stirring for half an hour, and then, 243mg of 4-fluoro-1-t-butoxycarbonyl-substituted piperazine-4-carbaldehyde was dropped into the reaction mixture. After stirring the reaction for 2 hours, it was quenched with saturated ammonium chloride, extracted with dichloromethane (20 ml×3), the organic layer was washed with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and purified by column chromatography (DCM/CH ₃ OH, 30:1) to give a white solid, 1-tert-Ding Yang carbonyl (E) -4- ((5, 6-dimethoxy-1, 1-dioxobenzo [ b)]Thiophene-2 (3H) -ethylene) methyl) -4-fluoropiperidine-1-carboxylate. ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.02(t,J＝1.0Hz,1H),6.26(t,J＝0.9Hz,1H),3.84(d,J＝2.4Hz,6H),3.74–3.65(m,3H),3.57(ddd,J＝12.3,7.4,4.8Hz,2H),3.31(t,J＝1.0Hz,1H),2.20–2.06(m,2H),1.98(dddd,J＝24.9,12.4,7.4,4.8Hz,2H)；LRMS(EI)m/z 442(M ⁺ )。

1.12 Synthesis of (E) -2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-1)

150mg of 1-tert-butoxycarbonyl (E) -4- ((5, 6-dimethoxy-1, 1-dioxobenzo [ b)]Thiophene-2 (3H) -ethylene) methyl) -4-fluoropiperidine-1-carboxylate was dissolved in 5mL of dichloromethane, 2.5mL of trifluoroacetic acid was added thereto, and the reaction was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to give the corresponding product trifluoroacetate hydrochloride which was continued to dissolve in acetonitrile (10 mL), 146mg of potassium carbonate and 100mg of 2-fluorobenzyl were added, and the reaction was stirred at room temperature for 0.5 hours. The reaction mixture was extracted with dichloromethane (20 mL. Times.3) and the salt was usedThe combined organic layers were washed with water and dried over anhydrous sodium sulfate. Concentrated in vacuo and purified by column chromatography (DCM/CH ₃ OH, 30:1) to yield 110mg of a white solid in 74% yield as the desired product F-1. ¹ H NMR(500MHz,Chloroform-d)δ7.35–7.25(m,2H),7.17–7.09(m,2H),7.02(t,J＝1.0Hz,1H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.69(dd,J＝8.3,1.0Hz,3H),3.31(t,J＝1.0Hz,1H),2.83–2.72(m,4H),2.11–1.90(m,4H)；LRMS(EI)m/z 450(M ⁺ )。

Example 2 preparation of (E) -2- ((4-fluoro-1- (3-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-2)

The 2-fluorobenzyl bromide is replaced by 3-fluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 1, the target product F-2 is obtained with a yield of 70%, ¹ H NMR(CDCI3,400MHz)δ7.28(s,1H),7.17(s,1H),6.95(m 1H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.33(td,J＝7.8,5.0Hz,1H),7.10(ddt,J＝7.8,2.2,1.0Hz,1H),7.08–7.00(m,3H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,5H),3.69(t,J＝1.0Hz,1H),3.55(t,J＝1.0Hz,2H),3.31(t,J＝1.0Hz,1H),2.83–2.69(m,4H),2.11–1.90(m,4H)；LRMS(EI)m/z 450(M ⁺ )。

example 3 preparation of (E) -2- ((4-fluoro-1- (4-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-3)

The 2-fluorobenzyl bromide is replaced by 4-fluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 1, the target product F-3 is obtained with the yield of 56%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.21(ddt,J＝8.1,5.0,1.0Hz,2H),7.06–6.99(m,3H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.69(t,J＝1.0Hz,1H),3.52(t,J＝1.0Hz,2H),3.31(t,J＝1.0Hz,1H),2.82–2.70(m,4H),2.11–1.90(m,4H)；LRMS(EI)m/z 450(M ⁺ )。

example 4 (E) -2- ((1- (2, 4-difluorobenzyl) -4-fluoropiperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-4)

The 2-fluorobenzyl bromide is replaced by 2, 4-difluorobenzyl bromide, and the other required raw materials, reagents and preparation method are the same as those in example 1, so as to obtainThe yield of the target product F-4 is 76%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.36–7.29(m,1H),7.02(t,J＝1.0Hz,1H),6.90(dtd,J＝14.4,7.9,2.7Hz,2H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(dd,J＝10.3,1.0Hz,3H),3.31(t,J＝1.0Hz,1H),2.83–2.72(m,4H),2.11–1.90(m,4H)；LRMS(EI)m/z 468(M ⁺ )。

example 5 (E) -2- ((1- (2, 5-difluorobenzyl) -4-fluoropiperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-5)

2-fluorobenzyl bromide is replaced by 2, 5-difluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as those in example 1, the target product F-5 is obtained with the yield of 72%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.10–6.99(m,3H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,4H),3.71–3.65(m,2H),3.31(t,J＝1.0Hz,1H),2.83–2.72(m,3H),2.11–1.90(m,3H)；LRMS(EI)m/z 468(M ⁺ )。

example 6 (E) -2- ((1- (3, 5-difluorobenzyl) -4-fluoropiperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-6)

The 2-fluorobenzyl bromide is replaced by 3, 5-difluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as those in example 1, the target product F-6 is obtained with the yield of 64%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.02(t,J＝1.0Hz,1H),6.95–6.87(m,3H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.69(t,J＝1.0Hz,1H),3.53(t,J＝0.9Hz,2H),3.31(t,J＝1.0Hz,1H),2.82–2.70(m,4H),2.11–1.90(m,4H)；LRMS(EI)m/z 468(M ⁺ )。

example 7 (E) -2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-7)

2-fluorobenzyl bromide is replaced by benzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 1, the target product F-7 is obtained with 89% of yield, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.33–7.22(m,3H),7.02(d,J＝1.0Hz,1H),6.24(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.69(t,J＝1.0Hz,1H),3.51(s,2H),3.31(t,J＝1.0Hz,1H),2.82–2.70(m,4H),2.01(ddddd,J＝37.4,25.1,12.2,7.1,4.9Hz,4H)；LRMS(EI)m/z 432(M ⁺ )。

example 8 (E) -2- ((1- (2-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-8)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as those in example 1 to obtain the target product F-8 with a yield of 77%, ¹ H NMR(500MHz,Chloroform-d)δ7.35–7.25(m,2H),7.17–7.09(m,2H),7.02(t,J＝1.0Hz,1H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.75–3.69(m,2H),3.66(dd,J＝13.6,1.1Hz,1H),3.22(q,J＝0.9Hz,1H),2.85–2.70(m,3H),2.36(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.3,8.1,5.4Hz,2H),1.48(ddt,J＝12.3,8.2,5.5Hz,2H)；LRMS(EI)m/z 432(M ⁺ )。

example 9 (E) -2- ((1- (3-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-9)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as those of example 2 to obtain the target product F-9 with a yield of 76%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.33(td,J＝7.8,5.0Hz,1H),7.10(ddt,J＝7.7,2.2,1.0Hz,1H),7.08–7.00(m,3H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(q,J＝1.1Hz,1H),3.55(t,J＝1.0Hz,2H),3.22(q,J＝0.9Hz,1H),2.86(ddd,J＝12.4,8.1,5.5Hz,2H),2.80(dtt,J＝8.6,5.3,0.9Hz,1H),2.69(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.5,8.2,5.4Hz,2H),1.48(ddt,J＝12.3,8.2,5.5Hz,2H)；LRMS(EI)m/z 432(M ⁺ )。

example 10 (E) -2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-10)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as those of example 3 to obtain the target product F-10 with a yield of 83%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.21(ddt,J＝8.1,5.0,1.1Hz,2H),7.06–6.99(m,3H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(q,J＝1.1Hz,1H),3.52(t,J＝1.0Hz,2H),3.22(q,J＝0.9Hz,1H),2.86(ddd,J＝12.3,8.1,5.5Hz,2H),2.80(dtt,J＝8.6,5.3,0.9Hz,1H),2.69(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.5,8.2,5.4Hz,2H),1.49(ddt,J＝12.5,8.2,5.4Hz,2H)；LRMS(EI)m/z 432(M ⁺ )。

example 11 (E) -2- ((1- (2, 4-difluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-11)

The 4-fluoro-1-tert-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-tert-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as in example 4 to obtain the target product F-11 with a yield of 69%, ¹ H NMR(500MHz,Chloroform-d)δ7.36–7.29(m,2H),7.02(t,J＝1.0Hz,1H),6.90(dtd,J＝14.4,7.9,2.7Hz,2H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(dd,J＝6.5,1.0Hz,3H),3.22(q,J＝0.9Hz,1H),2.80(dtdt,J＝8.6,5.3,2.0,1.0Hz,1H),2.79–2.73(m,1H),2.73(dd,J＝7.6,4.9Hz,1H),2.36(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.3,8.1,5.4Hz,2H),1.48(ddt,J＝12.3,8.2,5.5Hz,2H)；LRMS(EI)m/z 450(M ⁺ )。

example 12 (E) -2- ((1- (2, 5-difluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-12)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as those in example 5 to obtain the target product F-12 with a yield of 59%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.10–7.01(m,3H),7.02(s,1H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(q,J＝1.1Hz,1H),3.65(d,J＝0.9Hz,2H),3.22(q,J＝0.9Hz,1H),2.80(dtdt,J＝8.6,5.3,2.0,1.0Hz,1H),2.74(ddd,J＝12.5,8.2,5.5Hz,2H),2.36(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.3,8.1,5.4Hz,2H),1.48(ddt,J＝12.3,8.2,5.5Hz,2H)；LRMS(EI)m/z 450(M ⁺ )。

example 13 (E) -2- ((1- (3, 5-difluorobenzyl) piperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-13)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as in example 6 to obtain the target product F-13 with a yield of 93%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.02(t,J＝1.0Hz,1H),6.95–6.87(m,3H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(q,J＝1.1Hz,1H),3.52(t,J＝0.9Hz,2H),3.22(q,J＝0.9Hz,1H),2.86(ddd,J＝12.5,8.1,5.5Hz,2H),2.80(dtt,J＝8.6,5.3,0.9Hz,1H),2.70(ddd,J＝12.3,8.2,5.5Hz,2H),1.78(ddt,J＝12.5,8.2,5.5Hz,2H),1.48(ddt,J＝12.3,8.2,5.4Hz,2H)；LRMS(EI)m/z 450(M ⁺ )。

Example 14 (E) -2- ((1-Benzylpiperidin-4-yl) methylene) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-14)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as in example 7 to obtain the target product F-14 with 73% yield, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.33–7.22(m,3H),7.02(d,J＝1.0Hz,1H),6.19(dt,J＝8.6,1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.70(q,J＝1.1Hz,1H),3.49(d,J＝0.8Hz,2H),3.22(q,J＝0.9Hz,1H),2.86(ddd,J＝12.4,8.2,5.5Hz,2H),2.80(dtt,J＝8.6,5.3,0.9Hz,1H),2.69(ddd,J＝12.5,8.2,5.5Hz,2H),1.78(ddt,J＝12.5,8.2,5.5Hz,2H),1.49(ddt,J＝12.5,8.2,5.4Hz,2H)；LRMS(EI)m/z 414(M ⁺ )。

example 15- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-15)

3mg Pd-C was added to a solution of F-1 (30 mg,0.07 mmol) in MeOH (10 mL) and the reaction was carried out in H ₂ The reaction was carried out for 2 hours under an atmosphere. The reaction solution was filtered and concentrated in vacuo to give F-15 (27 mg,0.06 mmol), yield 88%, ¹ H NMR(500MHz,Chloroform-d)δ7.35–7.25(m,3H),7.17–7.09(m,2H),6.91(t,J＝1.1Hz,1H),3.84(d,J＝2.4Hz,7H),3.70(d,J＝1.1Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.81–2.75(m,1H),2.78–2.73(m,1H),2.73–2.69(m,1H),2.72–2.66(m,1H),2.20–2.01(m,2H),2.00–1.80(m,4H)；LRMS(EI)m/z 452(M ⁺ )。

example 16- ((4-fluoro-1- (3-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-16)

F-1 is replaced by F-2, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-16 is obtained with the yield of 84%, ¹ H NMR(500MHz,Chloroform-d)δ7.33(td,J＝7.8,4.9Hz,1H),7.10(ddq,J＝7.8,2.2,1.2Hz,1H),7.06(ddt,J＝5.8,2.2,1.2Hz,1H),7.06–7.00(m,1H),6.91(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,7H),3.56(t,J＝1.0Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.78–2.65(m,4H),2.20–2.01(m,2H),2.00–1.79(m,4H)；LRMS(EI)m/z 452(M ⁺ )。

example 17- ((4-fluoro-1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-17)

F-1 is replaced by F-3, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-17 is obtained with 77% of yield, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.21(ddt,J＝8.1,5.0,1.1Hz,2H),7.06–6.99(m,2H),6.91(t,J＝1.1Hz,1H),3.84(d,J＝2.4Hz,7H),3.52(t,J＝1.0Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.78–2.65(m,4H),2.20–2.01(m,2H),2.00–1.79(m,4H)；LRMS(EI)m/z 452(M ⁺ )。

Example 18- ((4-fluoro-1- (2, 4-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-18)

F-1 is replaced by F-4, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-18 is obtained with a yield of 81%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.32(dddd,J＝7.8,6.0,3.6,1.1Hz,1H),6.95–6.88(m,2H),6.91–6.84(m,1H),3.84(d,J＝2.4Hz,7H),3.71(d,J＝1.0Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.81–2.75(m,1H),2.78–2.73(m,1H),2.73–2.69(m,1H),2.72–2.66(m,1H),2.20–2.01(m,2H),2.00–1.80(m,4H)；LRMS(EI)m/z 470(M ⁺ )。

example 19- ((4-fluoro-1- (2, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-19)

F-1 is replaced by F-5, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-19 is obtained, the yield is 83%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.10–6.99(m,3H),6.91(t,J＝1.1Hz,1H),3.84(d,J＝2.4Hz,7H),3.67(d,J＝0.9Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.81–2.75(m,1H),2.78–2.73(m,1H),2.73–2.69(m,1H),2.72–2.66(m,1H),2.20–2.01(m,2H),2.00–1.80(m,4H)；LRMS(EI)m/z 470(M ⁺ )。

example 20- ((4-fluoro-1- (3, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-20)

F-1 is replaced by F-6, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-20 is obtained with the yield of 84%, ¹ H NMR(500MHz,Chloroform-d)δ7.34(s,1H),6.95–6.87(m,4H),3.84(d,J＝2.4Hz,7H),3.53(t,J＝0.9Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.78–2.65(m,4H),2.20–2.01(m,2H),2.00–1.79(m,4H)；LRMS(EI)m/z 470(M ⁺ )。

example 21- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-21)

F-1 is replaced by F-7, the rest required raw materials, reagents and preparation method are the same as in example 15, the target product F-21 is obtained with the yield of 54%, ¹ H NMR(500MHz,Chloroform-d)δ7.35–7.22(m,3H),6.91(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.52(d,J＝0.8Hz,2H),3.19(ddd,J＝12.3,7.7,0.9Hz,1H),2.99(ddd,J＝12.5,7.8,1.0Hz,1H),2.78–2.65(m,4H),2.19–2.01(m,2H),2.00–1.79(m,4H)；LRMS(EI)m/z 434(M ⁺ )。

example 22 (. + -.) 2-fluoro-2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzothiophene 1, 1-dioxide (F-22)

Potassium carbonate (661mg, 4.81 mmol) was added to a solution of 15 (1.41 g,3.21 mmol) in acetonitrile (20 mL), followed by N-fluorobis-benzenesulfonamide (1.7 g,5.39 mmol). After stirring at room temperature for 1h, extracted with dichloromethane (50 mL. Times.3), the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give F-22 in 80% yield, ¹ H NMR(500MHz,Chloroform-d)δ7.44(s,1H),7.35–7.25(m,1H),7.17–7.09(m,1H),3.84(d,J＝2.4Hz,3H),3.70(d,J＝1.1Hz,1H),3.31–3.12(m,1H),2.80–2.69(m,2H),2.30(d,J＝1.4Hz,0H),2.01–1.80(m,2H)；LRMS(EI)m/z 470(M ⁺ )。

example 23 2-fluoro-2- ((4-fluoro-1- (3-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzothiophene 1, 1-dioxide (F-23)

F-15 is replaced by F-16, the rest required raw materials, reagents and preparation method are the same as in example 22, the target product F-23, 84%, ¹ H NMR(500MHz,Chloroform-d)δ7.44(s,1H),7.33(td,J＝7.8,5.0Hz,1H),7.10(ddt,J＝7.7,2.2,1.0Hz,1H),7.07–7.00(m,1H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,4H),3.56(t,J＝1.0Hz,1H),3.31–3.12(m,1H),2.72(t,J＝4.8Hz,3H),2.30(d,J＝1.4Hz,1H),2.01–1.80(m,3H)；LRMS(EI)m/z 470(M ⁺ )。

example 24 2-fluoro-2- ((4-fluoro-1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzothiophene 1, 1-dioxide (F-24)

F-15 is replaced by F-17, the rest required raw materials, reagents and preparation method are the same as in example 22, the target product F-24, 76%, ¹ H NMR(500MHz,Chloroform-d)δ7.21(ddt,J＝8.1,5.0,1.1Hz,1H),7.06–6.96(m,2H),3.84(d,J＝2.4Hz,3H),3.52(t,J＝1.0Hz,1H),3.31–3.12(m,1H),2.72(t,J＝4.8Hz,2H),2.30(d,J＝1.4Hz,0H),2.01–1.80(m,2H)；LRMS(EI)m/z 470(M ⁺ )。

example 25- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -2-fluoro-5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-25)

F-15 is replaced by F-21, the rest required raw materials, reagents and preparation method are the same as those of example 25, the target product F-25 is obtained with the yield of 70%, ¹ H NMR(500MHz,Chloroform-d)δ7.32–7.28(m,1H),7.29(s,2H),7.30–7.24(m,1H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,4H),3.52(d,J＝0.8Hz,1H),3.31–3.17(m,1H),2.72(t,J＝4.8Hz,3H),2.30(d,J＝1.5Hz,1H),2.01–1.80(m,3H)；LRMS(EI)m/z 452(M ⁺ )。

Example 26 2-fluoro-2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-26)

The 4-fluoro-1-t-butoxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-t-butoxycarbonyl substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation method are the same as in example 22 to obtain the target product F-26 with a yield of 78%, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.35–7.25(m,2H),7.17–7.09(m,2H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.75–3.62(m,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.80(ddd,J＝12.5,7.0,4.8Hz,2H),2.38(ddd,J＝12.5,6.9,4.9Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.96–1.86(m,1H),1.86–1.72(m,3H)；LRMS(EI)m/z 452(M ⁺ )。

example 27 2-fluoro-2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-27)

The 2-fluorobenzyl bromide is replaced by 3-fluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-27 is obtained with the yield of 74%, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.33(td,J＝7.8,5.0Hz,1H),7.10(ddt,J＝7.8,2.2,1.0Hz,1H),7.06(ddt,J＝5.8,2.2,1.2Hz,1H),7.06–7.00(m,1H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.55(t,J＝1.0Hz,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.72(ddd,J＝12.5,6.9,4.9Hz,2H),2.33(ddd,J＝12.3,6.7,5.0Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.97–1.86(m,1H),1.86–1.73(m,4H)；LRMS(EI)m/z 452(M ⁺ )。

example 28 2-fluoro-2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-28)

The 2-fluorobenzyl bromide is replaced by 4-fluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-28 is obtained with a yield of 70%, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.21(ddt,J＝8.1,5.0,1.1Hz,2H),7.06–7.00(m,2H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.52(t,J＝1.0Hz,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.72(ddd,J＝12.5,6.9,4.9Hz,2H),2.34(ddd,J＝12.5,6.7,5.0Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.97–1.86(m,1H),1.86–1.73(m,4H)；LRMS(EI)m/z 452(M ⁺ )。

example 29 2-fluoro-2- ((1- (2, 4-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-29)

2-fluorobenzyl bromide is replaced by 2, 4-difluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-29 is obtained with 66 percent of yield, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.32(dtt,J＝7.9,5.1,1.1Hz,1H),6.98(t,J＝1.0Hz,1H),6.90(dtd,J＝14.4,7.9,2.7Hz,2H),3.84(d,J＝2.4Hz,6H),3.68(d,J＝1.1Hz,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.80(ddd,J＝12.5,7.0,4.8Hz,2H),2.38(ddd,J＝12.5,6.9,4.9Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.96–1.86(m,1H),1.86–1.72(m,4H)；LRMS(EI)m/z 470(M ⁺ )。

Example 30 2-fluoro-2- ((1- (2, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-30)

2-fluorobenzyl bromide is replaced by 2, 5-difluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-30 is obtained with 67% yield, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),7.10–6.96(m,2H),3.84(d,J＝2.4Hz,3H),3.66(d,J＝0.9Hz,1H),3.32–3.20(m,1H),2.80(ddd,J＝11.9,6.9,4.7Hz,1H),2.45(ddd,J＝12.4,6.8,4.8Hz,1H),2.09(ddd,J＝25.1,7.1,1.0Hz,1H),1.97–1.86(m,1H),1.86–1.72(m,2H)；LRMS(EI)m/z 470(M ⁺ )。

example 31 2-fluoro-2- ((1- (3, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-31)

The 2-fluorobenzyl bromide is replaced by 3, 5-difluorobenzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-31 is obtained with the yield of 62%, ¹ H NMR(500MHz,Chloroform-d)δ7.45(s,1H),6.98(t,J＝1.0Hz,1H),6.95–6.87(m,3H),3.84(d,J＝2.4Hz,6H),3.52(t,J＝0.9Hz,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.72(ddd,J＝12.5,6.9,4.9Hz,2H),2.34(ddd,J＝12.5,6.7,5.0Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.97–1.86(m,1H),1.86–1.73(m,4H)；LRMS(EI)m/z 470(M ⁺ )。

example 32- ((1-Benzylpiperidin-4-yl) methyl) -2-fluoro-5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-32)

2-fluorobenzyl bromide is replaced by benzyl bromide, the rest required raw materials, reagents and preparation method are the same as in example 26, the target product F-32 is obtained with 69 percent of yield, ¹ H NMR(500MHz,Chloroform-d)δ7.29(s,3H),7.33–7.22(m,3H),6.98(t,J＝1.0Hz,1H),3.84(d,J＝2.4Hz,6H),3.48(d,J＝0.8Hz,2H),3.28(dd,J＝3.1,0.9Hz,1H),3.27–3.18(m,1H),2.72(ddd,J＝12.5,6.9,4.9Hz,2H),2.34(ddd,J＝12.5,6.7,5.0Hz,2H),2.11(dd,J＝7.1,1.1Hz,1H),2.06(dd,J＝7.2,1.0Hz,1H),1.96–1.86(m,1H),1.86–1.73(m,4H)；LRMS(EI)m/z 434(M ⁺ )。

example 33 [ tablet ]

Taking the above formula, and preparing into tablets by a conventional method.

The following are the results of pharmacological experiments on some of the compounds of the present invention:

in vitro enzyme activity inhibition experiments of partial Compounds on AChE

1. Experimental method

Method for determining AChE inhibitory activity of a compound:

experimental principle: AChE is placed in the optimal enzyme reaction condition and reaction system, a substrate is added to a reaction template, and the enzyme activity is detected by a colorimetric method through the reaction of the enzyme and the substrate.

Experimental materials: all compound samples were formulated with dimethyl sulfoxide (DMSO) to 10 ^-2 The mol/L solution is gradually diluted to the required concentration by DMSO; AChE zymogen is mouse zymogen cortical.

The testing method comprises the following steps: sample addition contains PB, H ₂ O, S-ACh, DTNB, adding appropriate amount of enzyme into each tube except blank holes, reacting at room temperature for 20 min, adding SDS into each hole to terminate the reaction, and adding appropriate amount of enzyme into blank holes. The absorbance value (OD 450 nm) of each well is read by an enzyme-labeled instrument, and the inhibition rate and IC are calculated ₅₀ 。

2. Experimental results

TABLE 1 inhibition of acetylcholinesterase by certain compounds of the invention

/>

Analysis of results in the evaluation of biological Activity, we selected the marketed drug Donepezil as the positive control for its acetylcholinesterase inhibitory Activity IC ₅₀ The value was 10.8nM. From the data already obtained in the above table, it can be seen that all the partial compounds newly synthesized have better inhibitory activity on acetylcholinesterase than the positive control compound Donepezil; IC in which multiple compounds are directed to acetylcholinesterase ₅₀ The value is less than 5nM, which is obviously better than the positive control drug Donepezil (IC) ₅₀ =10.8 nM). This shows that the compounds of the present invention have a good potential.

In vivo experiments of the ability of partial Compounds to penetrate the blood brain Barrier

1. Experimental method

Experimental instrument: the ACQUITY UPLC I-Class Plus ultra-high performance liquid chromatography system is provided with a Xex TQ-XS triple quadrupole mass spectrometer, and the operation software is MassLynx V4.2 (Woltty technologies Co., ltd.); one ten million electronic analytical balance (model XS105DU, mertrel tolidol corporation), vortex mixer (model G560E, SCIENTIFIC INDUSTRIES corporation), high-speed centrifuge (model TGL-16B, shanghai's pavilion scientific instrumentation), high-speed refrigerated centrifuge (model CT15RE, HITACHI corporation), refrigerator (model MPR-312DCN-PC, loose cold chain (major company), medical low-temperature cabinet (model MDF-U54V, panasonic Healthcare co., ltd.), and the like.

Liquid chromatography conditions: the chromatographic column is ACQUITY UPLC BEH C liquid chromatographic column (specification: 2.1X105 mm,1.7 μm) with a column temperature of 45deg.C; mobile phase A is 0.1% formic acid water solution, mobile phase B is acetonitrile; verapamil hydrochloride is used as an internal standard for determination. Gradient elution conditions were 0-1.2min:20-60% of B,1.2-1.5min:60-95% B,1.5-1.8min:95% B,1.8-2.5min:95-20% B; the flow rate was 0.5ml/min.

Mass spectrometry conditions: the ion source is an electrospray ionization source (ESI), the positive ion scanning mode is adopted for detection, the flow rate of desolvation gas (nitrogen) is 1000L/h, the desolvation gas temperature is 500 ℃, and the capillary voltage is 3.0kV. The scanning mode is multi-reaction monitoring (MRM). The Cone voltage (Cone) was 40V and the Collision energy (Collision) was 30eV.

Subject animal information: adult female ICR mice weighing about 25-35g were supplied by the Qinglong mountain animal breeding farm in Nanjing, and had a production license number of SCXK (Su) 2017-0001.

The experimental method comprises the following steps: animals fasted for 12h before the test and were free to drink water. The medicine is fasted and forbidden within 2 hours after administration, and the medicine is drunk and fed freely after 2 hours. The test compounds were administered by intraperitoneal injection at a dose of 15mg/kg, and the mice were sacrificed by femoral artery bleeding 0.5h, 1h, 2h and 4h after administration, while taking about 300 μl of blood, followed by rapid removal of brain tissue, rinsing with physiological saline, and then blotting the surface with filter paper for 4 animals at each time point. All collected whole blood samples were placed in heparin sodium anticoagulation tubes and centrifuged at 8000rpm for 5min to separate plasma. All samples were stored at-70 ℃. During testing, 10 μl of mouse plasma sample is precisely sucked into a 1.5ml Eppendorf tube, 100 μl of acetonitrile solution of 2ng/ml verapamil hydrochloride is added, vortex oscillation is carried out for 5min, centrifugation is carried out at 15000rpm for 5min, 90 μl of supernatant is taken for UPLC-MS/MS measurement, and relevant pharmacokinetic parameters are calculated by adopting WinNonlin version 6.4.4 pharmacokinetics professional software after data are obtained.

2. Experimental results

TABLE 2 concentration in plasma and brain tissues after intraperitoneal administration of example 27

Analysis of results: it can be seen from table 2 that the compound of example 27 had a distribution in both plasma and brain tissue, and that the content of example 27 in plasma decreased rapidly over time, and showed a relatively steady and slowly decreasing trend in brain tissue, especially during 1-4 hours, and that the content of example 27 in brain tissue remained steady. The cerebral blood distribution ratio B/P after 0.5h administration was 4.167, the cerebral blood distribution ratio B/P after 0.5h administration was 5.240, the B/P after 1h was 6.325, the B/P after 2h was 8.397, and the B/P after 4h was 8.467, so that the cerebral blood ratio of the compound concentration also increased with the lapse of time. Thus, example 27 has the ability to penetrate the BBB and is less likely to be excreted by brain tissue after penetration of the BBB, and thus can exert an anti-AD therapeutic effect better.

EXAMPLE 27 evaluation of the Activity of scopolamine mice on improvement of learning memory disorder model

1. Experimental method

Animal and materials required for experiment: the experimental mice were adult ICR female mice (8-10 weeks, body weight 25-35 g), from Zhejiang university of industry; the modeling agent is scopolamine hydrobromide, which is purchased from Aba Ding Shiji company; the positive drug was donepezil hydrochloride, purchased from the company a Ding Shiji; example 27 was synthesized by applicant; the buffer (blank solvent) was 10% dmso+20% hydroxypropyl beta cyclodextrin in PBS buffer.

120 mice were selected and randomly divided into six groups, namely a normal control group, a model control group, a 5mg/kg donepezil hydrochloride group, a 0.1mg/kg example 27 group, a 0.3mg/kg example 27 group and a 1mg/kg example 27 group, and each group comprises 20 mice, and the experimental method is as follows:

animals were given adaptive training on the first day. The mice are placed in the bright room back to the hole, so that the mice can freely move between the bright room and the dark room, and no current stimulus is given to the two rooms for 5min. The study experiments were performed following the following day of intragastric administration of each group of mice. During detection, the mouse is placed in the bright room back to the hole, and a timer is started. The animals were shocked (0.19 mA) by entering the darkroom through the tunnel portal, the time was the latency, and if not already entering the darkroom for 5min, the latency was recorded as 300s, and the number of times the mice were kept dark (wrong) into the darkroom within 5min was recorded. The third day a memory experiment was performed. After the camera bellows is electrified, the mice are placed in the darkroom back to the hole, the incubation period of each mouse is still recorded, and the darkness avoiding (error) times of the mice entering the darkroom within 5 minutes are recorded.

TABLE 3 evaluation results of the improved Activity of example 27 on scopolamine mice model of learning memory impairment

Analysis of results: the results of the passive avoidance test are detailed in the table, and through single factor analysis of variance, in the learning test, each group has no statistical difference in latency (p=0.212) and has statistical difference in error frequency (p=0.0055), and compared with the model control group, the number of errors of the normal control group mice is remarkably reduced (p=0.0038); in the memory test: each group had statistical differences in latency and number of errors. The latency of the normal control mice was significantly increased (p=0.0003) compared to the model control mice, and the number of errors was significantly reduced in the normal control, donepezil hydrochloride and 0.1, 0.3mg/kg mice of example 27 (P <0.0001, p=0.021, p=0.002, p=0.0041). The experimental result shows that the 0.1mg/kg and 0.3mg/kg of the compound preparation in the example 27 can obviously improve the memory disorder of mice caused by scopolamine, and the 0.1mg/kg dose effect is better than the treatment effect of donepezil at 5 mg/kg.

EXAMPLE 27 assay for cytochrome P450s inhibition

1. Experimental method

Animal and materials required for experiment: diclofenac, dextromethorphan, midazolam, testosterone, tolbutamide, labetalol and human liver microsomes, all purchased from the company ala Ding Shiji; example 27 was synthesized by the applicant.

Four specific probe substrates (CYP 2C9, 5. Mu.M diclofenac; CYP2D6, 5. Mu.M dextromethorphan; CYP3A4-M, 2.5. Mu.M midazolam and CYP3A4-T, 50. Mu.M testosterone) were used to evaluate the inhibition of cytochrome P450 in human liver microsomes (HLM, 0.25 mg/mL) in the presence of various concentrations of test compound (0.05-20. Mu.M). After pre-incubation for 10 minutes at 37℃20. Mu.L of NADPH was added to a final concentration of 10mM and the reaction was started. The mixture was incubated at 37℃for 10 minutes, and then the reaction was stopped by adding 400. Mu.L of cold stop solution (200 ng/mL of tolbutamide and 200ng/mL of labetalol in acetonitrile). After the reaction was terminated, the plate was centrifuged and the supernatant was analyzed by LC/MS.

TABLE 4 evaluation results of cytochrome P450s inhibition in example 27

Analysis of results: the results in Table 4 show that example 27 has a weak inhibitory effect on CYP2C9, CYP2D6, CYP3A4-M and CYP3A4-T, corresponding IC ₅₀ Values above 20 μm indicate that example 27 has a lower probability of causing drug interactions in the metabolic pathway in vivo, and has better safety and drug-forming properties.

Claims

1. A sulfone and sulfoxide compound having the structure of formula I or formula II, or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:

wherein:

n is an integer of 0 to 3;

m is an integer of 0 to 3;

x is SO or SO ₂ ；

Represents a single bond or a double bond;

R ₁ is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, -O [ (CH) ₂ ) _q O] _r R ₆ 1 to 4 identical or different substituents in phenyl, benzyl, benzyloxy and 3-12 membered heterocyclic groups; wherein the heterocyclic group contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; r is R ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl and hydroxymethyl; q is 1, 2, 3 or 4; the method comprises the steps of carrying out a first treatment on the surface of the r is 1, 2, 3 or 4; t is 1, 2, 3 or 4;

R ₂ is substituted or unsubstituted C ₃ -C ₁₀ Cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ Cycloalkenyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C ₆ -C ₁₂ Aryl, said R ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, C ₆ -C ₁₀ Aryl and 1, 2, 3, 4 or 5 substituents, which may be the same or different, in a 3-to 12-membered heterocyclic group; or (b)Is at the C ₆ -C ₁₂ Two adjacent substituents on the aryl group together with the carbon atoms on their adjacent aromatic rings form C ₃ -C ₇ Cycloalkyl, C ₃ -C ₇ Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclyl group independently contains 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen;

R ₃ selected from hydrogen or fluorine;

the halogen is F, cl, br or I.

2. The sulfone and sulfoxide compound according to claim 1, wherein n is 1, 2 or 3, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof.

3. The sulfone and sulfoxide compound according to claim 1, wherein m is 0, 1 or 2, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof.

4. The sulfone and sulfoxide compound according to claim 1, wherein X is SO, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof ₂ 。

5. The sulfone and sulfoxide compound according to claim 1, wherein the sulfone and sulfoxide compound is selected from the group consisting of Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt and a mixture thereof,

n is an integer of 0 to 3;

m is an integer of 0 to 3;

x is SO or SO ₂ ；

R ₁ Is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, carboxyl and-O [ (CH) ₂ ) _q O] _r R ₆ 1 to 3 substituents which are the same or different; r is R ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2, 3 or 4;

R ₂ is substituted or unsubstituted C ₃ -C ₈ Cycloalkyl or substituted or unsubstituted C ₆ -C ₁₂ An aryl group; the R is ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, halogen substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₈ 1-5 substituents which are the same or different in cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, phenyl, naphthyl and 3-12 membered heterocyclic groups; or alternatively

At said C ₆ -C ₁₂ Two adjacent substituents on the aryl group together with the carbon atoms on their adjacent aromatic rings form C ₃ -C ₇ Cycloalkyl, C ₃ -C ₇ Cycloalkenyl or 3-7 membered heterocyclyl; the heterocyclic group contains 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen;

R ₃ selected from hydrogen or fluorine;

R ₄ and R is ₅ Each independently selected from the group consisting of hydrogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl, and 2-methylpropyl; or R is ₄ And R is ₅ Together linked to form a methylene, ethylene or propylene group;

the halogen is F, cl, br or I.

6. The sulfone and sulfoxide compound according to claim 5, wherein n is 1, 2 or 3, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof.

7. The sulfone and sulfoxide compound according to claim 5, wherein m is 0, 1 or 2, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof.

8. The sulfone and sulfoxide compound according to claim 5, wherein X is SO ₂ 。

9. The sulfone and sulfoxide compound according to claim 5, wherein the sulfone and sulfoxide compound is selected from the group consisting of Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt and a mixture thereof,

n is an integer of 0 to 3;

m is an integer of 0 to 3;

x is SO or SO ₂ ；

R ₁ Is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C substituted with halogen ₁ -C ₆ Alkoxy, hydroxy and-O [ (CH) ₂ ) _q O] _r R ₆ 1 to 2 substituents which are the same or different; r is R ₆ Selected from C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2 or 3;

R ₂ is C ₃ -C ₈ A cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group; the R is ₂ Wherein the substituents are selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C substituted with halogen ₁ -C ₆ Alkoxy, C ₁ -C ₆ Alkoxycarbonyl group, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ 1 to 5 substituents which may be the same or different in alkynyl, cyano, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, sulfonyl and phenyl, or two adjacent substituents on said phenyl together with the carbon atom on the benzene ring adjacent thereto form

R ₃ Selected from hydrogen or fluorine;

the halogen is F, cl, br or I.

10. The sulfone and sulfoxide compound according to claim 9, or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein n is 1, 2 or 3.

11. The sulfone and sulfoxide compound according to claim 9, wherein m is 0, 1 or 2, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or a mixture thereof.

12. The sulfone and sulfoxide compound according to claim 9, wherein X is SO, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof ₂ 。

13. The sulfone and sulfoxide compound according to claim 9, wherein the sulfone and sulfoxide compound is selected from the group consisting of Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt and a mixture thereof,

n is an integer of 0 to 3;

m is an integer of 0 to 3;

x is SO or SO ₂ ；

R ₁ Is selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, C substituted with halogen ₁ -C ₆ Alkoxy, hydroxy and-O [ (CH) ₂ ) _q O] _r R ₆ 1 to 2 substituents which are the same or different; r is R ₆ Selected from C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3;

R ₂ is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or substituted or unsubstituted phenyl, the substituents of the substituted phenyl may be selected from halogen, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl, ethoxycarbonyl and 1 to 5 identical or different substituents of the propoxycarbonyl or two adjacent substituents on the phenyl together with the carbon atoms on the phenyl ring adjacent thereto form

R ₃ Selected from hydrogen or fluorine;

the halogen is F, cl, br or I.

14. The sulfone and sulfoxide compound according to claim 13, or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein n is 1, 2 or 3.

15. The sulfone and sulfoxide compound according to claim 13, or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein m is 0, 1 or 2.

16. The sulfone and sulfoxide compound according to claim 13, wherein X is SO, or a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof ₂ 。

17. Sulfone and sulfoxide compounds or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salts or mixtures thereof, wherein the sulfone and sulfone compounds have the structure of the following general formula (III) or (IV):

wherein R is ₁ Each independently selected from hydrogen, halogen, C ₁ -C ₆ Alkyl, C substituted by halogen ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, cyano, nitro, amino, hydroxy, carboxyl or-O [ (CH) ₂ ) _q O] _r R ₆ One or more of the following; wherein R is ₆ Selected from hydrogen, halogen, C ₁ -C ₆ Alkyl and halogen substituted C ₁ -C ₆ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2, 3 or 4;

R ₂ is thatOr C ₃ -C ₇ Cycloalkyl, R ₇ Each independently selected from H, halogen, nitro, cyano, C ₁ -C ₄ Alkyl, halogen substituted C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy, halogen substituted C ₁ -C ₆ Alkoxy, phenyl or C ₁ -C ₄ One or more of alkoxycarbonyl groups, or two adjacent R' s ₇ Together with the carbon atoms of its adjacent benzene rings> v is 1, 2, 3, 4 or 5;

R ₃ selected from hydrogen or fluorine.

18. The sulfone compound according to claim 17, wherein the sulfone compound is a Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or a mixture thereof,

R ₁ each independently selected from hydrogen, halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ Alkoxy, halogen substituted C ₁ -C ₃ Alkoxy, hydroxy or-O [ (CH) ₂ ) _q O] _r R ₆ One or more of the following; wherein R is ₆ Selected from C ₁ -C ₃ Alkyl and halogen substituted C ₁ -C ₃ An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1 or 2;

R ₂ is thatCyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, R ₇ Independently selected from H, -F, -Br, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, and triOne or more of fluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, or two adjacent R ₇ Together with carbon atoms on the benzene rings adjacent theretov is 1, 2, 3, 4 or 5;

R ₃ selected from hydrogen or fluorine.

19. A sulfone and sulfoxide compound or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein the sulfone and sulfoxide compound is selected from the group consisting of:

20. the sulfone and sulfoxide compound or the Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof according to any one of claims 1 to 19, wherein the pharmaceutically acceptable salt is prepared by reacting the sulfone and sulfoxide compound with an inorganic acid or an organic acid, wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid, and the organic acid is citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, sulfanilic acid, 2-acetoxybenzoic acid or hydroxyethaneyellow acid.

21. A composition comprising a sulfone and sulfoxide compound of any one of claims 1-19, or optionally one or more of its Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, and a pharmaceutically acceptable carrier.

22. Use of a sulfone and sulfoxide compound according to any one of claims 1 to 19 or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof or a composition according to claim 21 for the preparation of an AChE inhibitor drug.

23. Use of a sulfone and sulfoxide compound according to any one of claims 1 to 19 or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof or a composition according to claim 21 in the manufacture of a medicament for the treatment and/or prophylaxis of neurological disorders associated with AChE.

24. The use according to claim 23, wherein the AChE-related neurological disorder comprises alzheimer's disease, frontotemporal dementia, dementia with lewy bodies, parkinson's disease or huntington's disease.