CN114591312A - Sulfone and sulfoxide compounds, preparation method and medical application thereof - Google Patents

Abstract

The invention relates to sulfone and sulfoxide compounds, a preparation method and medical application thereof, wherein the compounds have acetylcholinesterase inhibition capability and therapeutic activity on dementia symptoms, the invention also discloses a medicinal composition containing the compounds, and application of the compounds or medicinal salts thereof or the composition containing the compounds 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 field of medicinal chemistry and pharmacotherapeutics, in particular to sulfone and sulfoxide compounds, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds as acetylcholinesterase inhibitors, especially the application of the compounds in preparing medicaments for treating Alzheimer disease, Parkinson syndrome, epilepsy and schizophrenia.

Background

Alzheimer's Disease (AD) is the most common progressive neurodegenerative disease. Clinically, AD patients are characterized by an overall presentation of dementia, including hypomnesis, speech problems, behavioral disturbances, and other symptoms. According to the ' 2019 report of world alzheimer's disease ', nearly 80% of people are concerned about AD at some time, and 25% of people consider that they cannot prevent AD. The pathogenesis of AD is complex and yet incompletely understood, but several hypotheses about the pathophysiology of AD have been proposed to facilitate drug development, including low levels of acetylcholine (ACh), amyloid- β (Α β) deposition, Tau protein aggregation, oxidative stress, and the like.

Cholinesterase is a key enzyme in biological nerve conduction, and is classified into acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) according to the specificity of catalytic substrates. AChE catalyzes the cleavage reaction of acetylcholine, resulting in ACh deficiency and failure of nerve signal conduction, which in turn leads to the decline of cognitive function and memory loss of patients, and clinically manifested as senile dementia. The AChE inhibitor can inhibit AChE activity, delay ACh hydrolysis speed, improve level of synaptic cleft ACh, and ensure normal conduction of nerve signals, thereby exerting therapeutic effect on senile dementia.

The cholinergic hypothesis was the earliest proposed hypothesis and suggests that the pathogenesis of AD and the corresponding dysfunction are associated with low levels of ACh. Therefore, increasing levels of ACh in the brain by inhibiting AChE is considered a good strategy for treating AD. This hypothesis prompted the successful development of AChE inhibitors as drugs. Clinically, the current treatment options for AD patients are mainly limited to 5 AChE inhibitors: tacrine, donepezil, rivastigmine, galantamine, huperzine a and 1N-methyl-D-aspartate receptor antagonist: memantine. Unfortunately, these drugs, while improving cognitive deterioration, memory loss, and the like, do not fully satisfy the therapeutic needs of the patient. Therefore, there is an urgent clinical need to develop more potent and novel AChE inhibitors with additional functions for the treatment of AD.

Like chalcones, alkenyl sulfones may activate Nrf2 and induce expression of Nrf2 dependent antioxidant enzymes such as nad (p) H quinone oxidoreductase 1(NQO1) and heme oxygenase 1(HO-1) for antioxidant and anti-inflammatory activity. Therefore, it is considered to be a potential neuroprotective fragment and has been applied to design a variety of novel neuroprotective agents for the treatment of neurodegenerative diseases. In the research, alkenyl sulfone and sulfone functional groups are fused into the structure of the anti-AD drug donepezil, so that a series of novel molecules with anti-AChE, anti-oxidation and neuroprotection activities are obtained, and the potential of treating AD is achieved.

Disclosure of Invention

The invention aims to provide two sulfone and sulfoxide compounds shown in general formulas (general formula I and general formula II) or pharmaceutically acceptable salts thereof.

The invention also aims to provide a preparation method of the sulfone and sulfoxide compounds shown in the two general formulas (general formula I and general 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 compounds of formula I and formula II, and pharmaceutically acceptable salts thereof.

Still another object of the present invention is to provide an AChE inhibitor, which comprises sulfone and sulfoxide compounds selected from formula I and formula II, and pharmaceutically acceptable salts thereof.

The invention also aims to provide application of the sulfone and sulfoxide compounds shown in the general formulas I and II, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same in treating dementia symptoms. Wherein the dementia symptoms belong to but are not limited to central nervous system degenerative diseases such as Alzheimer's disease, fronto-temporal lobe dementia, dementia with Lewy bodies, Parkinson's disease, Huntington's disease, and the like. The technical scheme is as follows: based on the above purposes, the sulfone and sulfoxide compound shown in the general formula I or II or pharmaceutically acceptable salt thereof is as follows:

wherein:

n is an integer from 0 to 3, wherein 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 SO₂(ii) a Preferably SO₂；

Represents a single bond or a double bond;

R₁is selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, sulfonyl, -O [ (CH)₂)_qO]_rR₆1-4 identical or different substituents in phenyl, benzyl, benzyloxy and 3-12 membered heterocyclic group; wherein said heterocyclyl contains from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; r₆Selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl and hydroxymethyl; q is 1, 2,3 or 4; r is 1, 2,3 or 4; t is 1, 2,3 or 4;

preferably, R₁Is selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₁-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, carboxyl and-O [ (CH)₂)_qO]_rR₆1 to 3 identical or different substituents; r₆Selected from hydrogen, halogen, C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2,3 or 4;

more preferably, R₁Is selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy, hydroxy and-O [ (CH)₂)_qO]_rR₆1 to 2 identical or different substituents; r₆Is selected from C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2 or 3;

R₂is substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₃-C₁₀Cycloalkenyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C₆-C₁₂An aryl group; said R is₂Wherein the substituent is selected from halogen and C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl, halogen-substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₈Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, sulfonyl, C₆-C₁₀1, 2,3, 4 or 5 substituents in aryl and 3-12 membered heterocyclyl which may be the same or different; or at said C₆-C₁₂Two adjacent substituents on the aryl group and carbon atoms on the adjacent aromatic ring form C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclic group independently contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen;

preferably, R₂Is substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₆-C₁₂An aryl group; the R is₂Wherein the substituent is selected from halogen and C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl, halogen-substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₈1 to 5 substituents which may be the same or different in cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, sulfonyl, phenyl, naphthyl and 3-12 membered heterocyclic group; or at said C₆-C₁₂Two adjacent substituents on the aryl group together with the carbon atoms of the aromatic ring to which they are adjacent form C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkenyl or 3-7 membered heterocyclyl; the heterocyclic group contains 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen;

more preferably, R₂Is C₃-C₈A substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group; said R is₂Wherein the substituent is selected from halogen and C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen-substituted C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₂-C₆Alkenyl radical, C₂-C₆1-5 same or different substituents in alkynyl, cyano, nitro, nitryl, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfonyl and phenyl, or two adjacent substituents on the phenyl and carbon atoms on the adjacent benzene ring form the structure

Most preferably, the first and second substrates are,R₂is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or substituted or unsubstituted phenyl, and the substituent of the substituted phenyl can be 1-5 same or different substituents 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 propoxycarbonyl, or two adjacent substituents on the phenyl and the carbon atom on the adjacent benzene ring form the same substituent

R₃Selected from hydrogen or fluorine;

R₄and R₅Each independently selected from hydrogen, carboxyl, C₁-C₄Alkoxycarbonyl and C₁-C₄An alkyl group; or R₄And R₅Are connected together to form C₁-C₄An alkylene group;

preferably, R₄And R₅Each independently selected from hydrogen, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl and 2-methylpropyl; or R₄And R₅Taken together to form methylene, ethylene or propylene groups;

in the present invention, the halogen is F, Cl, Br or I.

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

In the present invention, the term "C₁-C₆Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like; preferred are ethyl and propylIsopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

In the present invention, the term "C₁-C₆Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.

In the present invention, the term "C₂-C₆The alkenyl group "means a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, but is not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.

In the present invention, the term "C₂-C₆Alkynyl "refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond, including without limitation ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

In the present invention, the term "C₃-C₁₀Cycloalkyl "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 "C₃-C₈Cycloalkyl group "," C₃-C₇Cycloalkyl ", and" C₃-C₆Cycloalkyl "has similar meaning.

In the present invention, the term "C₃-C₁₀Cycloalkenyl "refers to cyclic alkenyl groups having 3 to 10 carbon atoms in the ring and includes, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecenyl, and the like. The term "C₃-C₇Cycloalkenyl "has a similar meaning.

In the present invention, the term "C₆-C₁₂Aryl "refers to an aromatic ring group having 6 to 12 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring. The term "C₆-C₁₀Aryl "has a 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, for example, dioxolanyl and the like. The term "3-7 membered heterocyclyl" has a similar meaning.

In a preferred embodiment, the sulfones and sulfoxides with structures represented by formula I and formula II are sulfones represented by the following formula III and formula IV, respectively:

wherein R is¹Each independently selected from hydrogen, halogen, C¹-C⁶Alkyl, C substituted by halogen¹-C⁶Alkyl radical, C¹-C⁶Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, carboxyl or-O [ (CH)₂)_qO]_rR₆One or more of; wherein R is₆Selected from hydrogen, halogen, C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2,3 or 4;

preferably, R₁Each independently selected from hydrogen, halogen, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halogen substituted C₁-C₃Alkoxy, hydroxy or-O [ (CH)₂)_qO]_rR₆One or more of; wherein R is₆Is selected from C₁-C₃Alkyl and halogen substituted C₁-C₃An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1 or 2.

R₂Is composed of

Or C₃-C₇Cycloalkyl radical, R₇Each independently selected from H, halogen, nitro, cyano, C₁-C₄Alkyl, halogen substituted C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen substituted C₁-C₆Alkoxy, phenyl or C₁-C₄One or more of alkoxycarbonyl groups, or two adjacent R groups₇Together with the carbon atoms of the benzene rings adjacent thereto

v is 1, 2,3, 4 or 5.

Preferably, R₂Is composed of

Cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, R₇Independently selected from one or more of H, -F, -Br, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, or two adjacent R₇Together with the carbon atoms of the benzene rings adjacent thereto

v is 1, 2,3, 4 or 5.

R₃Selected from hydrogen or fluorine.

The halogen is F, Cl, Br or I.

In a more preferred embodiment of the invention, the compounds of formula I and formula II of the invention are preferably the following specific compounds:

in another aspect, the present invention provides a method for preparing compounds represented by formula I and formula II, which is performed according to scheme 1 below.

Scheme 1:

wherein R is₁,R₂,R₃,R₄,R₅X, 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, then cooling, and adding trimethyl sulfoxide iodide; reacting at 100 ℃ to obtain an epoxy intermediate 2.

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

And step c, dissolving the intermediate 3 into dichloromethane, adding a dess-Martin oxidant to oxidize alcoholic hydroxyl into aldehyde group, and separating and purifying to obtain an intermediate 4.

And d, dissolving the corresponding substituted benzene in dichloromethane, and protecting with nitrogen. Chlorosulfonic acid was added in an ice bath, and the reaction was stirred at room temperature. Separating and purifying to obtain an intermediate 6.

Step e intermediate 6 and 35% HCl were added to a three-neck flask. While stirring at 60 ℃, metallic lead and zinc were added. The reaction was continued for 1 hour. Separating and purifying to obtain an intermediate 7.

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

Step g, intermediate 8 is dissolved in methanol, added with sodium hydroxide and reacted at 80 ℃ for hydrolysis. 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, a drop of pyridine was added to a solution of intermediate 9 in dichloromethane, oxalyl chloride was slowly added dropwise in an ice bath, and the reaction was carried out at room temperature. The solvent and excess oxalyl chloride were removed in vacuo and the resulting crude product was dissolved in anhydrous dichloromethane and aluminum trichloride was added in an ice bath and reacted at room temperature. Separating and purifying to obtain an intermediate 10.

Step i triiodosilane was added to a solution of intermediate 10 in trifluoroacetic acid and the reaction was refluxed for 48 hours. Separating and purifying to obtain an intermediate 11.

Step j intermediate 11 was dissolved in dichloromethane, m-chloroperoxybenzoic acid was added and reacted at room temperature. Separating and purifying to obtain the intermediate 12.

And step k, dissolving the intermediate 12 in anhydrous tetrahydrofuran, dropping 2.5M n-butyllithium n-hexane solution and methyl chlorosilane at the temperature of-78 ℃ under the protection of nitrogen, gradually heating the reaction to 0 ℃ and stirring for 1 hour. After the silyl ether detection, the reaction was cooled to-78 ℃ again, n-butyllithium was added, and after stirring for 0.5 hour, the intermediate 4 was dropped into the reaction mixture to continue the reaction. Separating and purifying to obtain an intermediate 13.

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

Step m, dissolving 14 in methanol, adding Pd-C, and reacting at room temperature overnight. Separating and purifying to obtain the product 15.

And step N, adding potassium carbonate into a solution of 15 in acetonitrile, adding N-fluoro-bis-benzenesulfonamide, and reacting at room temperature. Separating and purifying to obtain the product 16.

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, p-aminobenzene sulfonic acid, 2-acetoxybenzoic acid or glycollic acid.

The application of the compound disclosed in the application or the pharmaceutically acceptable salt thereof or the composition disclosed in the invention in the AChE inhibitor medicine is also within the protection scope of the invention.

The application of the compound or the pharmaceutically acceptable salt thereof disclosed in the application to the preparation of the anti-dementia medicament is also in 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, fronto-temporal dementia, dementia with Lewy bodies, Parkinson's disease, Huntington's disease, and the like.

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

The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions, and aerosols, and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

Detailed Description

The invention will be further illustrated in the following examples. These examples are intended to illustrate the invention, but not to limit it in any way. The starting materials used in the present invention are not particularly specified, and all of them are commercially available.

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)

Synthesis of 1.16-tert-butyloxycarbonyl-1-oxa-6-azaspiro [2.5] octane

130mL of dimethyl sulfoxide (DMSO) was added to a 250mL eggplant-shaped bottle, and the mixture was stirred and heated, 5g of NaH solid was weighed and added to the DMSO solution, and stirring was continued for 12 hours, followed by cooling to room temperature. To the mixture was added 25g of trimethylsulfoxonium iodide, and the mixture was stirred at room temperature for 24 hours. 25g N-tert-Butoxycarbonylpiperidone dissolved in DMSO was added to the reaction solution, and the reaction was further stirred for 12 hours and monitored by Thin Layer Chromatography (TLC). After the reaction, 100-200mL of water was added, 100mL of Ethyl Acetate (EA) was extracted 3 times, 30mL of saturated brine was used to wash the organic layer three times, and the organic layer was spin-dried to obtain 28g of a colorless liquid which was 6-t-butoxycarbonyl-1-oxa-6-azaspiro [2.5]]Octane.¹H 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-tert-butoxycarbonyl-substituted piperazin-4-yl) methanol

28g of 6-tert-butoxycarbonyl-1-oxa-6-azaspiro [2.5]]Dissolving octane in 100mL of Dichloromethane (DCM), cooling, adding 120mL of 70% hydrogen fluoride pyridine solution, reacting for 12 hours, extracting with water and dichloromethane three times after the reaction is finished, passing Petroleum Ether (PE), Ethyl Acetate (EA) 4:1 through a column, and spin-drying to obtain 21g of a basically colorless liquid product which is (4-fluoro-1-Boc substituted piperazine-4-yl) methanol.¹H 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⁺)。

Synthesis of 1.34-fluoro-1-tert-butoxycarbonyl-substituted piperazine-4-carbaldehyde

3.5g of (4-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 to complete the reaction. Adding 50mL of dichloromethane, adding water for extraction, washing with saturated sodium bicarbonate solution for three times, drying, and spin-drying to obtain 3.2g of white liquid which is 4-fluoro-1-tert-butoxycarbonyl substituted piperazine-4-formaldehyde.¹H 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⁺)。

1.43 Synthesis of 4-Dimethoxybenzenesulfonyl chloride

1.5g of 3, 4-dimethoxy (1.7mmol) are dissolved in dichloromethane under nitrogen. 1.24g of chloromethanesulfonic acid was added under ice-cooling, 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 organic layers were dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure. Petroleum ether ethyl acetate 4:1 column chromatography gave 1.95g of white liquid as 3, 4-dimethoxybenzene-1-sulfonyl chloride.¹H 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⁺)。

Synthesis of 53, 4-dimethoxybenzenethiol

1g of 3, 4-dimethoxybenzenesulfonyl chloride, 10ml of 35% HCl were charged into 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: passing the ethyl acetate-3: 1 column to obtain a white solid 610mg is 3, 4-dimethoxy benzenethiol.¹H 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⁺)。

1.62 Synthesis of ethyl- ((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 (30mL), and 7.77g of ethyl bromoacetate was added dropwise. After the reaction was stirred at room temperature for 3 hours, the reaction mixture was concentrated in vacuo, extracted with DCM (50mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Vacuum concentration, petroleum ether: ethyl acetate 4:1 gave 9.04g of white liquid as ethyl 2- ((3, 4-dimethoxyphenyl) thio) acetate.¹H 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⁺)。

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

3.5g of ethyl 2- ((3, 4-dimethoxyphenyl) thio) acetate were dissolved in methanol (30mL), sodium hydroxide (20mL, 10%) was added and stirred at 80 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and neutralized with HCl (1mol/L) to adjust the pH to 3.0. The mixture was then filtered and the filtrate washed with water to give 3.05g of a white solid as 2- ((3, 4-dimethoxyphenyl) thio) acetic acid.¹H 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⁺)。

Synthesis of 85, 6-dimethoxybenzo [ b ] thiophen-3 (2H) -one

To a solution of 2.5g 2- ((3, 4-dimethoxyphenyl) thio) acetic acid in dichloromethane (30mL) was added one drop of pyridine, 2.78g oxalyl chloride was slowly added dropwise under ice bath, and the reaction was stirred at room temperature for 1 h. The solvent and excess oxalyl chloride were removed in vacuo. The resulting crude product was dissolved in dry dichloromethane (30mL), and 2.92g of aluminum trichloride was added to the solution under 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. Concentration in vacuo and recrystallization of the crude product gave 1.5g of a white solid as 5, 6-dimethoxybenzo [ b ]]Thiophen-3 (2H) -ones.¹H 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⁺)。

Synthesis of 95, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene

5.53g of triiodosilane (0.15mL) was added to 3.2g of 5, 6-dimethoxybenzo [ b ]]Thiophene-3 (2H) -ketone in 15ml trifluoroacetic acid solution, reaction reflux for 48 hours. The reaction mixture was concentrated in vacuo, extracted with dichloromethane (50mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentrated in vacuo to give 2.1g of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] solid as a white solid]Thiophene.¹H 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⁺)。

Synthesis of 105, 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, 1.98g 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 (50mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration in vacuo afforded the crude product, which was purified by petroleum ether: purification on a 2:1 column with ethyl acetate gave 1.3g of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] as a pale yellow solid]Thiophene 1, 1-dioxide.¹H 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⁺)。

Synthesis of 111-tert-Butoxycarbonyl (E) -4- ((5, 6-dimethoxy-1, 1-dioxobenzo [ b ] thiophene-2 (3H) -ethylidene) methyl) -4-fluoropiperidine-1-carboxylate

200mg of 5, 6-dimethoxy-2, 3-dihydrobenzo [ b ]]Dissolving thiophene 1, 1-dioxide in anhydrous tetrahydrofuran with N₂Protection, 350 mu L of 2.5M n-butyllithium solution is dripped at the temperature of minus 78 ℃, 95mg of methylchlorosilane is added after half an hour, the reaction is gradually heated to 0 ℃ and stirred for 1 hour. After detection of the silyl ether by TLC, the reaction was cooled again to-78 ℃, 350 μ L of n-butyllithium was added, stirred for half an hour, and 243mg of 4-fluoro-1-tert-butoxycarbonyl substituted piperazine-4-carbaldehyde was added dropwise to the reaction mixture. After the reaction was stirred for 2 hours, it was quenched with saturated ammonium chloride, extracted with dichloromethane (20mL × 3), and 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)₃OH, 30:1) to obtain a white solid which is 1-tert-butyloxycarbonyl (E) -4- ((5, 6-dimethoxy-1, 1-dioxybenzo [ b)]Thiophene-2 (3H) -ethylene) methyl) -4-fluoropiperidine-1-carboxylate.¹H 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-dioxybenzo [ b ]]Thiophene-2 (3H) -ethylene) methyl) -4-fluoropiperidine-1-carboxylate was dissolved in 5mL of dichloromethane, and 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 trifluoroacetic acid hydrochloride, which was continuously dissolved in acetonitrile (10mL), 146mg of potassium carbonate and 100mg of 2-fluorobenzyl bromide were added, and the reaction was stirred at room temperature for 0.5 hour. The reaction mixture was extracted with dichloromethane (20mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentrated in vacuo and chromatographed (DCM/CH)₃OH, 30:1) to obtain 110mg of white solid with yield of 74 percent, which is the target product F-1.¹H 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 the 3-fluorobenzyl bromide, the other needed raw materials, reagents and preparation methods are the same as the example 1, the target product F-2 is obtained, the yield is 70 percent,¹H 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)

2-fluorobenzyl bromide is replaced by 4-fluorobenzyl bromide, the other needed raw materials, reagents and preparation methods are the same as example 1, the target product F-3 is obtained, the yield is 56 percent,¹H 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)

2-fluorobenzyl bromide is replaced by 2, 4-difluorobenzyl bromide, and the other needed raw materials, reagents and preparation methods are the same as those of example 1, so that the target product F-4 is obtained with the yield of 76%,¹H 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, and the other needed raw materials, reagents and preparation methods are the same as those of example 1, so that the target product F-5 is obtained with the yield of 72%,¹H 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 the 3, 5-difluorobenzyl bromide, and the other needed raw materials, reagents and preparation methods are the same as the example 1, so that the target product F-6 is obtained with the yield of 64 percent,¹H 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)

The 2-fluorobenzyl bromide is replaced by benzyl bromide, and the other needed raw materials, reagents and preparation methods are the same as example 1, so that the target product F-7 is obtained with the yield of 89%,¹H 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)

Replacing 4-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde with 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, and obtaining the target product F-8 with the yield of 77 percent by using the other required raw materials, reagents and preparation methods in the same manner as in example 1,¹H 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)

Will 4The-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde is replaced by 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, the other required raw materials, reagents and preparation method are the same as example 2, the target product F-9 is obtained, the yield is 76%,¹H 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)

Replacing 4-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde with 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, and obtaining the target product F-10 with the yield of 83 percent by using the other required raw materials, reagents and preparation methods in the same manner as in example 3,¹H 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)

Replacing 4-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde with 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, and obtaining the target product F-11 with the yield of 69 percent by using the other needed raw materials, reagents and preparation methods in the same manner as in example 4,¹H 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)

Replacing 4-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde with 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, and obtaining the target product F-12 with the yield of 59 percent by using the other needed raw materials, reagents and preparation methods in the same manner as in example 5,¹H 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)

Replacing 4-fluorine-1-tert-butyloxycarbonyl substituted piperazine-4-formaldehyde with 1-tert-butyloxycarbonyl substituted piperidine-4-formaldehyde, and obtaining the target product F-13 with 93% yield by the same preparation method as the example 6 with the rest of the required raw materials, reagents and reagents,¹H 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-tert-butyloxycarbonyl-substituted piperazine-4-formaldehyde is replaced by 1-tert-butyloxycarbonyl-substituted piperidine-4-formaldehyde, and the other required raw materials, reagents and preparation methods are the same as in the example7 to obtain a target product F-14 with the yield of 73 percent,¹H 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 152- ((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(30mg, 0.07mmol) in MeOH (10mL) and the reaction was taken up in H₂The reaction was carried out under an atmosphere for 2 hours. The reaction solution was filtered and concentrated in vacuo to give F-15(27mg,0.06mmol), 88% yield,¹H 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 162- ((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, and the rest needed raw materials, reagents and preparation methods are the same as example 15, so that the target product F-16 is obtained with the yield of 84 percent,¹H 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 172- ((4-fluoro-1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-17)

Replacement of F-1To obtain F-3, the other needed raw materials, reagents and preparation methods are the same as example 15, the target product F-17 is obtained, the yield is 77 percent,¹H 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 182- ((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, and the rest needed raw materials, reagents and preparation methods are the same as example 15, so that the target product F-18 is obtained with the yield of 81 percent,¹H 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 192- ((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 other needed raw materials, reagents and preparation methods are the same as example 15, the target product F-19 is obtained, the yield is 83 percent,¹H 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 202- ((4-fluoro-1- (3, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-20)

Replacing F-1 with F-6, obtaining the target product F-20 by using the same raw materials, reagents and preparation method as the example 15, and collectingThe rate is 84 percent,¹H 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 212- ((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 other needed raw materials, reagents and preparation methods are the same as example 15, the target product F-21 is obtained, the yield is 54 percent,¹H 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 (665mg,4.81mmol) was added to a solution of 15(1.41g,3.21mmol) in acetonitrile (20mL), and N-fluorobisbenzenesulfonamide (1.7g,5.39mmol) was added. After stirring at room temperature for 1 hour, extraction was performed 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,¹H 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 232-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, and the other required raw materials, reagents and preparation methods are the same as those of the raw materialsExample 22, the target product F-23, 84%,¹H 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 242-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, and the rest needed raw materials, reagents and preparation methods are the same as example 22 to obtain a target product F-24, 76 percent,¹H 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 252- ((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 other needed raw materials, reagents and preparation methods are the same as example 25, the target product F-25 is obtained, the yield is 70 percent,¹H 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 262-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-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 methods are the same as example 22, to obtain the target product F-26 with a yield of 78%,¹H 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 272-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 the 3-fluorobenzyl bromide, and the rest needed raw materials, reagents and preparation methods are the same as the example 26, so that the target product F-27 is obtained with the yield of 74 percent,¹H 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 282-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 the 4-fluorobenzyl bromide, the other needed raw materials, reagents and preparation methods are the same as the example 26, the target product F-28 is obtained, the yield is 70 percent,¹H 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 292-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, and the rest of the required raw materials, reagents and preparation methods are the same as those of example 26, so that the target product F-29 is obtained with the yield of 66%,¹H 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 302-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, and the rest needed raw materials, reagents and preparation methods are the same as those of example 26, so that the target product F-30 is obtained with the yield of 67 percent,¹H 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 312-fluoro-2- ((1- (3, 5-difluorobenzyl) piperidin-4-yl) methyl) -5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-31)

2-fluorobenzyl bromide is replaced by 3, 5-difluorobenzyl bromide, and the rest needed raw materials, reagents and preparation methods are the same as those of example 26, so that the target product F-31 is obtained with the yield of 62%,¹H 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 322- ((1-Benzylpiperidin-4-yl) methyl) -2-fluoro-5, 6-dimethoxy-2, 3-dihydrobenzo [ b ] thiophene 1, 1-dioxide (F-32)

The 2-fluorobenzyl bromide is replaced by benzyl bromide, and the other needed raw materials, reagents and preparation methods are the same as those of example 26, so that the target product F-32 is obtained with the yield of 69 percent,¹H 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 [ tablets ]

The above formula is taken, and the tablets are prepared by a conventional method.

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

in-vitro enzyme activity inhibition experiment of partial compounds on AChE

1. Experimental method

Method for determining AChE inhibitory activity of compounds:

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

Experimental materials: all compound samples were made up to 10 in dimethyl sulfoxide (DMSO)^-2Gradually diluting the mol/L solution to the required concentration by DMSO; AChE zymogen is mouse cortical zymogen.

The test method comprises the following steps: sample addition containing PB and H₂O, S-ACh, DTNB, adding appropriate amount of enzyme into each tube except blank hole, reacting at room temperature for 20 min, adding SDS into each hole to terminate reaction, and adding appropriate amount of enzyme into blank hole. Reading the absorbance value (OD450 nm) of each hole by using a microplate reader, and calculating the inhibition rate and IC₅₀。

2. Results of the experiment

TABLE 1 inhibition of acetylcholinesterase by some of the compounds of the invention

Analysis of results in the evaluation of biological Activity, we selected the marketed drug, Donepzil, as a positive control, whose acetylcholinesterase inhibitory activity IC₅₀The value was 10.8 nM. From the data already obtained in the above table, it can be seen that all the partial compounds newly synthesized have better acetylcholinesterase inhibitory activity than the positive control compound Donepezil; IC of a plurality of compounds therein to acetylcholinesterase₅₀The value is less than 5nM and is obviously superior to the positive control drug Donepzil (IC)₅₀10.8 nM). This indicates that the compounds of the present invention have good potential.

In vivo testing of the ability of some Compounds to penetrate the blood brain Barrier

1. Experimental methods

An experimental instrument: an ACQUITY UPLC I-Class Plus ultra performance liquid chromatography system equipped with a Xevo TQ-XS triple quadrupole mass spectrometer with MassLynx V4.2 (Watts technologies, Inc.); one in ten million electronic analytical balances (model XS105DU, mertler-toledo), vortex mixer (model G560E, SCIENTIFIC INDUSTRIES), high speed centrifuge (model TGL-16B, shanghai' an kiosks scientific instruments), high speed refrigerated centrifuge (model CT15RE, HITACHI), refrigerator (model MPR-312DCN-PC, matsushitic cold chain (dawn) inc.), medical cryobox (model MDF-U54V, Panasonic Healthcare co., Ltd.), etc.

Liquid chromatography conditions: the chromatographic column is ACQUITY UPLC BEH C18 liquid chromatographic column (specification: 2.1 × 50mm, 1.7 μm), and the column temperature is 45 deg.C; the mobile phase A is 0.1% formic acid water solution, and the mobile phase B is acetonitrile; and selecting verapamil hydrochloride as an internal standard for determination. Gradient elution conditions were 0-1.2 min: 20-60% of B, 1.2-1.5 min: 60-95% B, 1.5-1.8 min: 95% B, 1.8-2.5 min: 95-20% of B; the flow rate was 0.5 ml/min.

Mass spectrum conditions: the detection is carried out by UPLC-MS/MS, an ion source is an electrospray ionization source (ESI), the detection is carried out in a positive ion scanning mode, the flow rate of desolvation gas (nitrogen) is 1000L/h, the temperature of the desolvation gas is 500 ℃, and the capillary voltage is 3.0 kV. The scanning mode is Multiple Reaction Monitoring (MRM). The Cone voltage (Cone) was 40V and the Collision energy (Collision) was 30 eV.

And (3) test animal information: adult female ICR mice, the weight of which is about 25-35g, are provided by the Qinglongshan breeding farm in Nanjing, and the production license number is SCXK (Su) 2017-0001.

The experimental method comprises the following steps: animals were fasted for 12h before the experiment and had free access to water. After the administration, the patient is fasted and deprived of water for 2 hours, and after 2 hours, the patient is free to drink water and is given food. A total of 16 mice were given test compounds by intraperitoneal injection at a dose of 15mg/kg, and were sacrificed by femoral artery bleeding at 0.5h, 1h, 2h and 4h after administration while taking about 300 μ l of blood, followed by rapid removal of brain tissue, rinsing with physiological saline, and then blotting off surface water with filter paper for 4 animals at each time point. All collected whole blood samples were placed in heparin sodium anticoagulation tubes, centrifuged at 8000rpm for 5min, and plasma was fractionated. All samples were stored at-70 ℃. During testing, 10 mu l of mouse plasma sample is precisely absorbed into a 1.5ml Eppendorf tube, 100 mu l of 2ng/ml acetonitrile solution of verapamil hydrochloride is added, vortex oscillation is carried out for 5min, centrifugation is carried out for 5min at 15000rpm, 90 mu l of supernatant is taken for UPLC-MS/MS measurement, and relevant pharmacokinetic parameters are calculated by adopting WinNonlin version 6.4 pharmacokinetic professional software after data are obtained.

2. Results of the experiment

Table 2 example 27 concentrations in plasma and brain tissue following intraperitoneal administration

And (4) analyzing results: as can be seen from Table 2, after example 27 was administered, the compound had a distribution in both plasma and brain tissue, and over time, the amount of example 27 in plasma decreased rapidly and showed a more steady and slow decrease in brain tissue, especially the amount of example 27 in brain tissue remained steady during 1-4 h. The brain blood distribution ratio B/P value after 0.5h of administration was 4.167, the brain blood distribution ratio B/P value after 0.5h of administration was 5.240, the B/P value after 1h was 6.325, the B/P value after 2h was 8.397, and the B/P value after 4h was 8.467, so the brain blood ratio of the compound concentration also increased with time. Therefore, example 27 has the ability to penetrate the BBB and is less likely to be excreted to the brain tissue after penetrating the BBB, and thus can exert a better therapeutic effect against AD.

Example 27 evaluation of improving Activity on mouse model of learning and memory disorder caused by scopolamine

1. Experimental methods

Animals and materials required for the experiment: the experimental mice are adult ICR female mice (8-10 weeks, weight 25-35g) from Zhejiang university of industry; the molding agent is scopolamine hydrobromide, purchased from the company of Aladdin reagent; the positive drug is donepezil hydrochloride, purchased from the company Aladdin reagent; example 27 was synthesized by applicants; the buffer (blank solvent) was 10% DMSO + 20% hydroxypropyl β cyclodextrin in PBS buffer.

Selecting 120 mice, randomly dividing the mice 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, wherein the experimental method comprises the following steps of:

animals were given adaptive training the first day. Placing the mouse in the bright room with its back facing the opening, allowing the mouse to move freely between the bright room and the dark room, and keeping the two rooms without current stimulation for 5 min. The study experiments were performed the following day after gavage administration in each group of mice. During detection, the mouse is placed in a bright room with the back facing the opening, and a timer is started at the same time. The animal passed through the opening and entered the darkroom and was shocked by electricity (0.19mA), and the latency was recorded, if it did not enter the darkroom for 5min, the latency was recorded as 300s, and the number of times of avoiding darkness (error) that the mouse entered the darkroom within 5min was recorded. The memory experiment was performed on the third day. And after the dark box is electrified, putting the mice into a bright room with the back facing to the opening, still recording the latency of each mouse, and simultaneously recording the number of times of avoiding darkness (errors) when the mice enter the dark room within 5 min.

TABLE 3 EXAMPLE 27 evaluation results of improving Activity on scopolamine induced mouse model of learning and memory impairment

And (4) analyzing results: the passive avoidance test results are detailed in the table, and through one-factor anova, 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 the error frequency of the mice in the normal control group is significantly reduced compared with that in the model control group (P ═ 0.0038); in a memory test: groups were statistically different in latency and number of errors. Compared with the model control group, the incubation period of the mice in the normal control group is obviously increased (P is 0.0003), and the error frequency of the mice in the normal control group, the donepezil hydrochloride group and the 0.1 and 0.3mg/kg example 27 groups is obviously reduced (P <0.0001, P is 0.021, P is 0.002, and P is 0.0041). The experimental result shows that the 0.1mg/kg and 0.3mg/kg of example 27 can both significantly improve the mouse dysmnesia caused by scopolamine, and the 0.1mg/kg dosage effect is superior to the treatment effect of donepezil at 5 mg/kg.

EXAMPLE 27 determination of cytochrome P450s inhibition

1. Experimental methods

Animals and materials required for the experiment: diclofenac, dextromethorphan, midazolam, testosterone, tolbutamide, labetalol, and human liver microsomes, all purchased from alatin reagent; example 27 was synthesized by the applicant.

Inhibition of cytochrome P450 was assessed in human liver microsomes (HLM, 0.25mg/mL) using four specific probe substrates (CYP2C9, 5 μ M diclofenac; CYP2D6, 5 μ M dextromethorphan; CYP3a4-M, 2.5 μ M midazolam and CYP3a4-T, 50 μ M testosterone) in the presence of various concentrations of test compound (0.05-20 μ M). After preincubation at 37 ℃ for 10 minutes, 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 (200ng/mL tolbutamide and 200ng/mL labetalol in acetonitrile). After the reaction was terminated, the plates were centrifuged and the supernatant was analyzed by LC/MS/MS.

TABLE 4 evaluation results of cytochrome P450s inhibition in example 27

And (4) analyzing results: the results in Table 4 show that example 27 has a weak inhibitory effect on CYP2C9, CYP2D6, CYP3A4-M and CYP3A4-T, and the corresponding IC₅₀Values greater than 20 μ M indicate that example 27 has a lower probability of causing drug interactions in vivo metabolic pathways, and has better safety and drug-forming properties.

Claims (10)

1. A sulfone and sulfoxide compound with a structure shown in a general formula I or a general formula II, or a Z-isomer, an E-isomer, a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture thereof:

wherein:

n is an integer from 0 to 3, wherein 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 SO₂(ii) a Preferably SO₂；

Represents a single bond or a double bond;

R₁is selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxyl, sulfonyl, -O [ (CH)₂)_qO]_rR₆1-4 identical or different substituents in phenyl, benzyl, benzyloxy and 3-12 membered heterocyclic group; wherein, the heterocyclic ringThe radical contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen; r₆Selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl and hydroxymethyl; q is 1, 2,3 or 4; (ii) a r is 1, 2,3 or 4; t is 1, 2,3 or 4;

R₂is substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted C₃-C₁₀Cycloalkenyl group, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C₆-C₁₂Aryl radical of formula R₂Wherein the substituent is selected from halogen and C₁--C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl, halogen-substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₈Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, sulfonyl, C₆-C₁₀1, 2,3, 4 or 5 substituents in aryl and 3-12 membered heterocyclyl which may be the same or different; or at said C₆-C₁₂Two adjacent substituents on the aryl group and carbon atoms on the adjacent aromatic ring form C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclic group independently contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen;

R₃selected from hydrogen or fluorine;

R₄and R₅Each independently selected from hydrogen, carboxyl, C₁-C₄Alkoxycarbonyl and C₁-C₄An alkyl group; or R₄And R₅Are connected together to form C₁-C₄An alkylene group;

the halogen is F, Cl, Br or I.

2. The sulfone and sulfoxide compound of claim 1, or the Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof, or mixture thereof,

n is an integer from 0 to 3, wherein 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 SO₂(ii) a Preferably SO₂；

R₁Is selected from hydrogen, halogen, C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₁-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, carboxyl and-O [ (CH)₂)_qO]_rR₆1 to 3 same or different substituents in (1); r₆Selected from hydrogen, halogen, C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2,3 or 4;

R₂is substituted or unsubstituted C₃-C₈Cycloalkyl or substituted or unsubstituted C₆-C₁₂An aryl group; the R is₂Wherein the substituent is selected from halogen and C₁-C₆Alkyl, halogen substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl, halogen-substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₈Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, sulfonyl, phenyl, naphthyl and 1 to 5 substituents which may be the same or different in a 3-12 membered heterocyclic group; or at said C₆-C₁₂Two adjacent substituents on the aryl group together with the carbon atoms of the adjacent aromatic ring form C₃-C₇Cycloalkyl radical, C₃-C₇Cycloalkenyl or 3-7 membered heterocyclyl; the heterocyclic group contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen;

R₃selected from hydrogen or fluorine;

R₄and R₅Each independently selected from hydrogen, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl and 2-methylpropyl; or R₄And R₅Taken together to form methylene, ethylene or propylene groups;

the halogen is F, Cl, Br or I.

3. The sulfone and sulfoxide compound of claim 2, or the Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof, or mixture thereof,

n is an integer from 0 to 3, wherein 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 SO₂(ii) a Preferably SO₂；

R₁Is selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen-substituted C₁-C₆Alkoxy, hydroxy and-O [ (CH)₂)_qO]_rR₆1 to 2 identical or different substituents; r₆Is selected from C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2 or 3;

R₂is C₃-C₈A substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group; the R is₂Wherein the substituent is selected from halogen and C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen-substituted C₁-C₆Alkoxy radical, C₁-C₆Alkoxycarbonyl group, C₂-C₆Alkenyl radical, C₂-C₆1-5 same or different substituents in alkynyl, cyano, nitro, nitryl, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, sulfonyl and phenyl, or two adjacent substituents on the phenyl and the carbon atom on the adjacent benzene ringAre formed jointly

R₃Selected from hydrogen or fluorine;

R₄and R₅Each independently selected from hydrogen, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl and 2-methylpropyl; or R₄And R₅Taken together to form methylene, ethylene or propylene groups;

the halogen is F, Cl, Br or I.

4. The sulfone and sulfoxide compound of claim 3, or the Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof, or mixture thereof,

n is an integer from 0 to 3, wherein n is preferably 1, 2 or 3.

m is an integer of 0 to 3, wherein m is preferably 0, 1 or 2.

X is SO or SO₂(ii) a Preferably SO₂。

R₁Is selected from hydrogen, halogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen-substituted C₁-C₆Alkoxy, hydroxy and-O [ (CH)₂)_qO]_rR₆1 to 2 identical or different substituents; r₆Is selected from C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3;

R₂is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or substituted or unsubstituted phenyl, and the substituent of the substituted phenyl can be selected from 1 to 5 of 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 propoxycarbonylIdentical or different substituents, or two adjacent substituents on the phenyl radical together with the carbon atoms of the adjacent phenyl ring

R₃Selected from hydrogen or fluorine;

R₄and R₅Each independently selected from the group consisting of hydrogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methyl, ethyl, propyl, isopropyl, butyl and 2-methylpropyl; or R₄And R₅Taken together to form methylene, ethylene or propylene groups;

the halogen is F, Cl, Br or I.

5. The sulfone and sulfoxide compound of claim 4, or the Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, wherein said sulfone compound has the following general formula:

wherein R is₁Each independently selected from hydrogen, halogen, C₁-C₆Alkyl, C substituted by halogen₁-C₆Alkyl radical, C₁-C₆Alkoxy, halogen substituted C₁-C₆Alkoxy radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano, nitro, amino, hydroxy, carboxyl or-O [ (CH)₂)_qO]_rR₆One or more of; wherein R is₆Selected from hydrogen, halogen, C₁-C₆Alkyl and halogen substituted C₁-C₆An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1, 2,3 or 4;

R₂is composed of

Or C₃-C₇Cycloalkyl radical, R₇Each independently selected from H, halogen, nitro, cyano, C₁-C₄Alkyl, halogen substituted C₁-C₄Alkyl radical, C₁-C₄Alkoxy, halogen substituted C₁-C₆Alkoxy, phenyl or C₁-C₄One or more of alkoxycarbonyl groups, or two adjacent R₇Together with the carbon atoms of the benzene rings adjacent thereto

v is 1, 2,3, 4 or 5;

R₃selected from hydrogen or fluorine.

6. The sulfone compound of claim 5, or Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof,

R₁each independently selected from hydrogen, halogen, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, halogen substituted C₁-C₃Alkoxy, hydroxy or-O [ (CH)₂)_qO]_rR₆One or more of; wherein R is₆Is selected from C₁-C₃Alkyl and halogen substituted C₁-C₃An alkyl group; q is 1, 2 or 3; r is 1, 2 or 3; t is 1 or 2.

R₂Is composed of

Cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, R₇Independently selected from the group consisting of H, -F, -Br, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, methyl, ethyl, propyl, isopropyl, butyl, n-or n-butyl, n-or n-butyl, n-or n-butyl, n-or n,One or more of 2-methylpropyl, methoxy, ethoxy, propoxy, phenyl, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl, or two adjacent R₇Together with the carbon atoms of the benzene ring adjacent thereto

v is 1, 2,3, 4 or 5.

R₃Selected from hydrogen or fluorine.

7. The sulfone and sulfoxide compound of claim 1, or the Z-, E-, racemate, R-, S-, or pharmaceutically acceptable salt thereof, wherein said sulfone and sulfoxide compound is selected from the group consisting of:

8. the sulfone and sulfoxide compound of any of claims 1-7, or the Z-, E-, racemate, R-, S-, or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is prepared by reacting the sulfone and sulfoxide compound with an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid, or with an organic acid selected from 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, p-aminobenzenesulfonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, salicylic acid, glutamic acid, and mixtures thereof, 2-acetoxybenzoic acid or glycolic acid.

9. A composition comprising the sulfone and sulfoxide compound of any one of claims 1-7 or one or more of Z-isomer, E-isomer, racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof, and a pharmaceutically acceptable carrier.

10. Use of the sulfone and sulfoxide compound of any one of claims 1-7, or the Z-, E-, racemate, R-, S-, or pharmaceutically acceptable salt thereof, or the mixture thereof, or the composition of claim 9, for the preparation of AChE inhibitor drugs; preferably, in the treatment and/or prevention of AChE associated nervous system diseases in drugs, more preferably, the AChE associated nervous system diseases including Alzheimer's disease, fronto-temporal lobe dementia, Lewy body dementia, Parkinson's disease or Huntington's disease.