CN117088895A - Scutellarin compound and preparation method and application thereof - Google Patents

Abstract

The present invention provides a new compound represented by formula (I) and its preparation method and use. The compound represented by formula (I) has excellent antioxidant and Aβ protein deposition inhibition properties, and can achieve multi-targeted treatment of Alzheimer's disease.

Description

A scutellariae aglycone compound and its preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a scutellariae aglycone compound and a preparation method and application thereof.

Background Art

Alzheimer’s disease (AD) has become a global human health problem. As human life expectancy increases, the incidence of AD is also increasing. It is estimated that by 2050, the number of AD patients worldwide will reach 152 million. AD is a slowly progressive and ultimately fatal degenerative brain disease that places tremendous economic and emotional pressure on patients and their families. Unfortunately, current drug-based treatments can only moderately improve learning and memory, and there is no effective treatment to reduce or prevent the progression of AD. Therefore, developing new treatments for AD has become a major challenge in modern medicine. Although the pathogenesis of AD is not fully understood, the pathological development of AD is closely related to the abnormal accumulation of amyloid-β (Aβ), tau protein, reactive oxygen species (ROS), metal ions, and neuroinflammation.

Aβ is produced by proteolysis of amyloid precursor protein (APP). β-secretase (β-site APP cleavage enzyme, BACE) cleaves the N-terminus of the protein, and then γ-secretase cleaves the carboxyl terminal fragment (CTFβ) of the protein to form Aβ peptide. The amyloid hypothesis holds that during the development of AD, Aβ-peptide is transformed into β-sheet structure, monomer, oligomer, and finally into fibers in the form of α-helical structure. The accumulation of Aβ aggregates accelerates the progression of AD by stimulating a series of neurotoxic pathways such as apoptosis, inflammation, synaptic and neuronal damage. As the main pathological marker of AD, inhibiting Aβ deposition is considered to be a potential therapeutic strategy for AD.

Due to the brain's high demand for oxygen and lack of antioxidant defense systems, the brain is very vulnerable to oxidative stress (OS). A large amount of evidence shows that excessive production of ROS leads to OS, and OS plays a key role in the pathogenesis and pathophysiology of AD. OS in the early stages of AD may be necessary to initiate other pathological mechanisms of AD, such as Aβ and tau-induced neurotoxicity. Therefore, clearing or preventing the formation of ROS may help prevent the progression of AD. AD is a neuroinflammatory disease, and neuroinflammation plays an important role in its pathogenesis.

In November 2019, the original anti-AD new drug mannitol sodium capsule (GV-971) jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Shanghai Green Valley Pharmaceutical was approved for marketing. GV-971 (mannooligosaccharide diacid) treats AD by reshaping the balance of intestinal flora, inhibiting the abnormal increase of specific metabolites of intestinal flora, and reducing peripheral and central inflammatory effects. Another example is aducanumab (trade name Aduhelm), a new Alzheimer's drug developed by Biogen and approved by the FDA in 2021. Clinical studies have shown that it can selectively bind to β-amyloid protein, thereby clearing the accumulation of β-amyloid protein in the brains of Alzheimer's patients. It can be seen from the recently approved drugs that drugs that target anti-inflammatory and inhibit Aβ deposition have great potential.

On the other hand, in view of the complex pathogenesis and pathological manifestations of AD, multi-target-directed ligands (MTDLs) combine two or more related pharmacophore fragments to simultaneously act on multiple pathogenic pathways of AD, exerting better therapeutic effects than single-target drugs, and may open up a new therapeutic approach for the treatment of AD.

Traditional Chinese medicine plays a certain role in the prevention and treatment of AD. As early as 1436, the book "Southern Yunnan Materia Medica" included the folk medicinal plant for the treatment of cerebral palsy, Erigeron breviscapus. Erigeron breviscapus, also known as Erigeron asarum, is a plant of the Asteraceae family. Its roots or whole plants are used as medicine. It is mainly distributed in the southwest of our province and has the effects of dispelling wind and cold, promoting blood circulation and relieving pain. Scutellarin, also known as scutellarin (Scu), is the most important active ingredient in the traditional Chinese medicine Erigeron breviscapus, accounting for more than 90% of the content of scutellarin. Its chemical name is 4,5,6-trihydroxyflavone-7-glucuronide (the structural formula is shown in formula (a)).

It is confirmed in the prior art that baicalin has multiple pharmacological activities such as anti-oxidation, anti-inflammatory, vasodilation, antiplatelet, anticoagulation, and myocardial protection. Studies have found that baicalin can alleviate the damage of learning and memory ability of AD rats induced by Aβ _25-35 , significantly reduce the superoxide dismutase (SOD) activity, monoamine oxidase (MAO) activity, IL-1β, IL-6 and TNF-α levels in the brain tissue of AD rats, and inhibit the apoptosis of neurons, which has the effect of improving cognition. Baicalin effectively inhibits oligomerization and fiber formation by binding to Aβ ₄₂ , and reduces the cytotoxicity of SH-SY5Y cells induced by Aβ oligomers, which has a beneficial effect on intervening the development or progression of AD-like neuropathology. However, baicalin has poor pharmacokinetic properties, its solubility in water is only 0.16 mg/mL, it is eliminated quickly in the body, and its biological half-life is only (2.27±0.58) min. The poor solubility and low bioavailability of scutellarin have greatly limited its clinical application. Studies on the in vivo metabolism of scutellarin have found that scutellarin is hydrolyzed into scutellarin in the intestine, and its oral bioavailability is three times that of scutellarin, and it has better biological activity than scutellarin.

This study designed and synthesized a series of compounds by modifying baicalin, hoping to design multi-target anti-AD drug molecules with antioxidant, anti-inflammatory and Aβ deposition inhibition effects.

Summary of the invention

In a first aspect, the present invention provides a compound represented by formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs,

In formula (I),

R ₁ is selected from -C1-6 alkyl, -C1-6 alkyl-C6-20 aryl, -C6-20 aryl, -C6-20 aryl-3 to 10-membered heterocyclyl; wherein C6-20 aryl and C3-10 heterocyclyl are optionally substituted by one, two or more R _a ;

R ₂ is selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy;

_R3 is selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy;

R ₄ is selected from H, hydroxyl, halogen;

R ₅ is selected from H, hydroxyl, halogen;

_Ra is selected from H, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy.

In some embodiments, R ₁ is selected from -C1-6 alkyl, -C1-6 alkyl-C6-10 aryl, -C6-10 aryl, -C6-10 aryl-3 to 6-membered heterocyclyl; wherein C6-10 aryl, 3 to 6-membered heterocyclyl are optionally substituted by one, two or more _Ra ;

Preferably, R ₁ is selected from -C1-3 alkyl, -C1-3 alkyl-C6-10 aryl, -C6-10 aryl, -C6-10 aryl-3 to 6-membered heterocyclyl; wherein the C6-10 aryl, 3 to 6-membered heterocyclyl is optionally substituted by one, two or more R _a ;

Further preferably, R ₁ is selected from -C1-3 alkyl, -C1-3 alkyl-C6 aryl, -C6 aryl, -C6 aryl-6-membered heterocyclic group; wherein the C6 aryl and the 6-membered heterocyclic group are optionally substituted by one, two or more _Ra .

In some embodiments, the 6-membered heterocyclyl contains 1-3 heteroatoms, such as piperazinyl and piperidinyl.

In some embodiments, R ₁ is selected from methyl, ethyl, propyl, -methylene-phenyl, -methylene-biphenyl, phenyl, biphenyl, -phenyl-piperazinyl, -biphenyl-piperazinyl; wherein phenyl, biphenyl, piperazinyl are optionally substituted with one, two or more _Ra .

In some embodiments, _Ra is selected from H, hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy.

In some embodiments, R ₁ is selected from methyl, ethyl, phenyl, benzyl, halogen-substituted phenyl, hydroxy-substituted phenyl, methoxy-substituted phenyl, ethylpiperazinyl-substituted phenyl.

In some embodiments, _R2 is selected from hydroxyl.

In some embodiments, R ₃ is selected from hydroxy.

In some embodiments, _R4 is selected from H.

In some embodiments, R ₅ is selected from H.

In some embodiments, the compound represented by formula (I) is selected from the following compounds:

In a second aspect, the present invention provides a method for preparing the compound represented by the above formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, the preparation method comprising the following steps:

(1) The compound of formula SM reacts with BF ₃ ·Et ₂ O to generate the compound of formula A;

(2) the compound of formula A is reacted to produce a compound of formula B;

(3) the compound of formula B is reacted to produce a compound of formula C;

(4) reacting the compound of formula C with the compound R ₁ —NH ₂ to obtain the compound of formula I;

Wherein, R ₁ , R ₂ , R ₃ and R ₄ have the above-mentioned definitions.

In some embodiments, in step (1), the solvent is AcOH.

In some embodiments, in step (2), the reaction is carried out under N,N-dimethylformamide dimethyl acetal (DMF-DMA) conditions;

And/or, the reaction solvent is acetone.

In some embodiments, in step (3), the reaction is carried out under BBr ₃ conditions;

And/or, the reaction solvent is dichloromethane.

In some embodiments, in step (4), the reaction is carried out under HCHO conditions;

And/or, the reaction solvent is methanol.

The SM compound, boron trifluoride ether complex BF ₃ ·Et ₂ O, DMF-DMAC, BBr ₃ , HCHO, and 4-(4-ethyl-1-piperazinyl)aniline are commercially available compounds or can be obtained by those skilled in the art using conventional techniques.

In a third aspect, the present invention provides a pharmaceutical composition, comprising a compound represented by the above formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs.

In some embodiments, the pharmaceutical composition optionally comprises at least one additional active ingredient.

In some embodiments, additional active ingredients include cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, huperzine A), N-methyl-D-aspartate receptor antagonists (e.g., memantine), mannitol sodium capsules (GV-971), and Aduhelm.

In some embodiments, the pharmaceutical composition optionally comprises at least one pharmaceutically acceptable excipient.

In some embodiments, pharmaceutically acceptable excipients include pharmaceutically acceptable carriers, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, excipients, flocculants and deflocculating agents, filter aids, release retardants and other pharmaceutical excipients.

In some embodiments, the compound represented by the above formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs are prepared with pharmaceutical excipients such as pharmaceutically acceptable carriers, diluents or excipients into tablets, capsules, powders, granules, solutions, emulsions, suspensions, etc., which are suitable for oral and parenteral administration.

In some embodiments, methods of administration include, but are not limited to, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and peroral routes.

In some embodiments, the preparation can be administered, but not limited to, by infusion, bolus injection, percutaneous absorption, etc. The preparation can be prepared by a preparation method known in the art.

In a fourth aspect, the present invention provides the use of the compound represented by the above formula (I), its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, and the above pharmaceutical compositions in the preparation of drugs for the treatment and/or treatment of Alzheimer's disease.

Beneficial Effects

The present invention provides a novel compound represented by formula (I), which has activities such as anti-oxidation and inhibition of Aβ protein deposition, and can achieve multi-target treatment of Alzheimer's disease.

Definitions and Explanations of Terms Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and/or claims of this application.

Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-40" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. It should be understood that in the one, two or more used herein when describing substituents, "more" should refer to an integer ≥ 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner. The substituents may be, but are not limited to, =O, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, etc.

In addition, it should be noted that, unless otherwise clearly indicated, the description method "...independently selected" used in the present invention should be understood in a broad sense, meaning that the individuals described are independent of each other and can be independently selected from the same or different specific groups. In more detail, the description method "...independently selected" can mean that in different groups, the specific options expressed by the same symbols do not affect each other; it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C _1-6 alkyl" specifically refers to the independently disclosed C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl or C ₆ alkyl.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

"Hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes should be understood to include those atoms having the same atomic number but different mass numbers. For example, hydrogen isotopes include protium, tritium and deuterium, carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, oxygen isotopes include ¹⁶ O and ¹⁸ O, etc.

The "halogen" of the present invention refers to fluorine, chlorine, bromine, and iodine. The "halogenated" of the present invention refers to substitution with fluorine, chlorine, bromine, or iodine.

The "C1-6 alkyl" of the present invention refers to a straight or branched chain group containing 1 to 6 carbon atoms, and further preferably a straight or branched chain group containing 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

The "C1-6 alkoxy group" of the present invention refers to an -O-C1-6 alkyl group. The C1-6 alkyl group has the above-mentioned definition.

The "3 to 10 membered heterocyclyl" of the present invention refers to a group of a 3 to 10 membered non-aromatic ring system having 1 to 4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as valence permits. The heterocyclyl group can be saturated or can be partially unsaturated. Each example of a heterocyclyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

The "C6-20 aryl" of the present invention refers to an aromatic system containing 6 to 20 carbon atoms, which may include a monocyclic or fused polycyclic ring, preferably an aromatic system containing a monocyclic or fused bicyclic ring, preferably containing 6 to 12 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, and indanyl. The aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

"Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.

"Tautomers" refer to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

"Nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

"Prodrug" means a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see the following: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

The term "metabolite" as used herein refers to a product obtained by metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

Pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in a chain or ring which are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, diglucoside. Sugar acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention with sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of the group -COOH formed with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol.

In addition, the basic nitrogen-containing group can be quaternized with the following reagents: lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, hydrogen sulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc. Since the compounds of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salts include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. To this end, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or the cation of the base required for salt formation in the pharmaceutically acceptable salt can vary within a large range, for example, it can be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

The "solvate" of the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense. The solvent refers to a solvent known to or easily determined by a person skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or an alternative thereof.

The "ester" of the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce a parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with an appropriate group, such as, but not limited to, an alkyl group, an arylalkyl group, etc.

The "pharmaceutical composition" of the present invention refers to a mixture comprising any one of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers and/or one or more other drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used to prepare a drug for the treatment and/or prevention of a disease mediated by one or more kinases.

The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.

The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

The term "treat", as used herein, refers to ameliorating the disease or disorder (i.e., slowing, arresting or reducing the development of the disease or at least one clinical symptom thereof); or to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient; or regulating the disease or disorder physically (e.g., symptoms), physiologically (e.g., physical parameters), or both; or preventing or delaying the onset, occurrence and progression of the disease or disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a graph showing the results of an Aβ _1-42 aggregation inhibition assay using the ThT binding assay.

Figure 2. Evaluation of in vitro anti-inflammatory activity.

Figure 3. DPPH free radical scavenging ability measurement results.

Figure 4. Synthesis route of compounds of formula (I).

DETAILED DESCRIPTION

The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1

5,6-Dihydroxy-9-methyl-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S1)

The synthetic route is shown in Figure 4.

Step 1:

10 g of 3,4,5-trimethoxyphenol (54.3 mmol) and 60 mL of glacial acetic acid were added to a three-necked flask in succession. Under nitrogen protection, 25 ml of BF ₃ ·Et ₂ O solution was added, and the mixture was refluxed and stirred at 80°C for 16 h. After the reaction was completed by TLC detection, the mixture was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate/water. The organic phases were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO _4. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography to obtain 8 g of compound A.

Step 2:

Weigh 3 g of compound A (13.3 mmol), DMF-DMA (N,N-dimethylformamide dimethyl acetal) (3.86 g, 32.3 mmol), and 30 ml of toluene into a three-necked flask, protect with nitrogen, reflux and stir at 90°C for 6 h. After the reaction is completed by TLC detection, cool to room temperature, add water to quench the reaction, extract three times with ethyl acetate/water, combine the organic phases, wash with saturated brine, dry over anhydrous _{Na2SO4 ,} remove the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 2.2 g of compound B.

Step 3:

4.57 g of compound B (19.2 mmol) and 65 ml of dichloromethane were added into a three-necked flask successively. Under nitrogen protection, 21.6 g of BBr ₃ (86.63 mmol) was added in an ice bath and stirred overnight. After the reaction was completed by TLC detection, the mixture was cooled to room temperature and water was added to quench the reaction. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to obtain 2 g of compound C.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.5 mmol), 0.28 g of 25% methylamine aqueous solution (2.2 mmol), and 6 mL of methanol were added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After the reaction was completed by TLC detection, the mixture was cooled to room temperature and filtered to obtain the corresponding crude compound S1. Methanol was added for pulping and purification, and 0.30 g of the corresponding pure compound S1 was obtained by filtration, with a yield of 77.9%.

The structures of compounds A, B, and C are shown below:

Example 2

9-Ethyl-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S2)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.15 g of 70% ethylamine aqueous solution (2.2 mmol), and 6 mL of methanol were added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After the reaction was completed by TLC detection, the mixture was cooled to room temperature and filtered to obtain the corresponding crude compound S2. Methanol was added for pulping and purification, and 0.20 g of the corresponding pure compound S2 was obtained by filtration, with a yield of 50.2%.

Example 3

5,6-Dihydroxy-9-phenyl-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S3)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.20 g of aniline (2.2 mmol), and 6 mL of methanol were weighed and added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S3. Methanol was added for pulping and purification, and the corresponding pure compound S3 0.38 g was obtained by filtration, with a yield of 79.2%.

Example 4

9-[4-(4-Ethylpiperazin-1-yl)phenyl]-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazepine-4-one (Compound S4)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.45 g of 4-(4-ethyl-1-piperazinyl)aniline (2.2 mmol), and 6 mL of methanol were weighed and added into a pressure bottle, stirring was started, and stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S4. Methanol was added for pulping and purification, and the corresponding pure compound S4 0.41 g was obtained by filtration, with a yield of 62.6%.

Example 5

9-Benzyl-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S5)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.24 g of benzylamine (2.2 mmol), and 6 mL of methanol were weighed and added into a pressure bottle, stirring was started, and stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S5. Methanol was added for pulping and purification, and the corresponding pure compound S5 0.35 g was obtained by filtration, with a yield of 69.6%.

Example 6

9-(4-Fluorophenyl)-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S6)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.24 g of p-fluoroaniline (2.2 mmol), and 6 mL of methanol were added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S6. Methanol was added for pulping and purification, and the corresponding pure compound S6 0.35 g was obtained by filtration, with a yield of 68.8%.

Example 7

5,6-Dihydroxy-9-(4-hydroxyphenyl)-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S7)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.24 g of 4-aminophenol (2.2 mmol), and 6 mL of methanol were weighed and added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S7. Methanol was added for pulping and purification, and the corresponding pure compound S7 0.35 g was obtained by filtration, with a yield of 69.2%.

Example 8

5,6-Dihydroxy-9-(4-methoxyphenyl)-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazacyclohexan-4-one (Compound S8)

Step 1:

Same as step 1 of Example 1.

Step 2:

Same as step 2 of Example 1.

Step 3:

Same as step 3 of Example 1.

Step 4:

0.3 g of compound C (1.5 mmol), 0.85 g of 37% formaldehyde aqueous solution (10.4 mmol), 0.27 g of 4-methoxyaniline (2.2 mmol), and 6 mL of methanol were weighed and added to a pressure bottle, and stirring was started. Stirring was continued at room temperature overnight. After TLC detection, the reaction was cooled to room temperature and filtered to obtain the corresponding crude compound S8. Methanol was added for pulping and purification, and the corresponding pure compound S8 0.38 g was obtained by filtration, with a yield of 72.1%.

Experimental Example 1: ThT binding assay to measure Aβ _1-42 aggregation inhibition test

Experimental principle: Thioflavin T (ThT) is a benzothiazole dye, the most commonly used dye for detecting amyloid aggregation. ThT can specifically recognize the filamentous structure produced by Aβ during the aggregation process and bind to it and show enhanced fluorescence. The intensity of fluorescence is related to the aggregation degree of Aβ aggregates. Therefore, by detecting the fluorescence intensity with a fluorescence spectrophotometer or a multifunctional microplate reader, the inhibition of the compound on the self-aggregation of Aβ _1-42 can be calculated.

1. Experimental Materials

Compounds: Example compounds S1, S2, S3, S4, S5, S6, S7, S8; Comparative example scutellarin

2. Experimental Methods

All compounds were screened at a concentration of 50 μM, and the experiment was set up with 3 replicate wells and 3 independent experiments.

10 μL of a series of test compounds (50 μM, final concentration) or PBS and 10 μL Aβ _1-42 (25 μM, final concentration) were incubated at 37°C in the dark for 24 h. After incubation, 20 μL of the sample was extracted into a black 96-well plate, diluted to 200 μL with 180 μL of glycine-sodium hydroxide buffer (50 mM, pH 8.5) containing 5 μM ThT, and the fluorescence intensity was measured with a multifunctional microplate reader after low-speed shaking for 5 min. (Excitation wavelength is 450 nm, emission wavelength is 490 nm).

The inhibition percentage of autoinduced aggregation (I _Aβ1-42 , %) was calculated using the following formula.

I _Aβ1-42 (%)=1-(Fs/F ₀ )×100%

Fs: fluorescence intensity of the sample group after background subtraction; F ₀ : fluorescence intensity of the blank group after background subtraction.

3. Experimental results, see Table 1 and Figure 1.

Table 1. Inhibitory effects of different compounds on Aβ _1-42 self-induced aggregation

From the experimental results in Table 1, it can be seen that except for compound S1, the inhibition rates of the other compounds on self-induced Aβ _1-42 aggregation at a concentration of 50 μM are all greater than 50%, especially compound S7, which has stronger inhibitory activity on Aβ _1-42 than the positive control drug scutellarin. Based on the fact that Aβ _1-42 deposition plays a very important role in the formation and progression of AD, the S series compounds of the present invention have great potential in the treatment of Alzheimer's disease.

Experimental Example 2. Evaluation of in vitro anti-inflammatory activity

1 Experimental Materials

Compounds: Example compounds S1, S2, S3, S4, S5, S6, S7, S8; Comparative example scutellarin

2 Experimental methods

This experiment intends to use a mouse macrophage-like cell line (RAW264.7) as a model. First, the MTT method is used to test whether the compound is cytotoxic to RAW264.7 (the maximum administration concentration is 500 μM), and the interference of the compound on cell growth activity is eliminated. The drug concentration when the cell survival rate is >90% is taken, and the NO content in the culture medium is determined by the Griess method.

(1) MTT assay to detect the effects of various compounds on RAW264.7 cell viability

100 μL RAW264.7 cell suspension (cell density of 5×10 ³ cells/well) was inoculated into each well of a 96-well plate, and the plate was placed at 37°C and 5% CO ₂ for 24 hours before administration. The background well, test group, and blank group were set up with 3 replicates, and 8 sample solutions of different concentrations were added to the test group (DMEM medium was added to the blank group). After 24 hours of continuous culture, 20 μL MTT solution (5 mg/mL) was added to each well. After incubation in the incubator for 4 hours, crystals were formed, the supernatant was removed, 150 μL DMSO was added to each well, and the plate was shaken at a low speed for 15 minutes to fully dissolve the crystals. The absorbance of each well at 490 nm was measured on an ELISA reader, and the cell survival rate was calculated according to the following formula.

Cell survival rate = (OD _s - OD _r )/(OD ₀ - OD _r )×100%

OD _s : absorbance of the sample group; OD _r : absorbance of the background group; OD ₀ : absorbance of the blank group.

(2) Griess method was used to detect the effects of various compounds on LPS-induced NO release in RAW264.7 cells

100 μL RAW264.7 cell suspension (cell density 5×10 ⁴ cells/well) was inoculated into each well of a 96-well plate, and the plate was placed in a 37°C, 5% CO ₂ incubator for 24 hours. LPS (1 μg/mL) was added for 1 hour, and then the drug was administered. After 24 hours of continuous culture, 50 μL of the cell supernatant was transferred to another 96-well cell culture plate, and 50 μL of Griess A and B reagents were added. The plate was reacted in the dark for 10 minutes, and the OD value was measured at 540 nm. The concentration of NO was calculated based on the standard curve prepared with NaNO ₂ .

The experiment set up a blank group (addition of DMEM culture medium, without LPS stimulation), an LPS model group (addition of DMEM culture medium, with LPS stimulation), a positive drug group (scutellaria baicalensis, with LPS stimulation), and a test group (10 μM drug, with LPS stimulation), each with 3 replicate wells.

3 Experimental results

MTT assay was used to detect the effects of various compounds on RAW264.7 cell viability

The MTT assay showed that when the concentration of compounds S1-S8 was 10 μM, the cell survival rate was greater than 90%. Therefore, under this condition, the NO expression rate of S1-S8 was determined.

(1) Griess method was used to detect the effects of various compounds on LPS-induced NO release in RAW264.7 cells

Table 2. Effects of different compounds on LPS-induced NO release in RAW264.7 cells

The experimental results are shown in Table 2 and Figure 2. It can be seen from the experimental results that the inhibition of NO expression by compounds S1, S2, S3, and S4 is weak, while the inhibition of NO by compounds S6, S7, and S8 is more prominent, all of which are stronger than the positive control drug scutellarin, especially compound S7, which has an inhibition of NO of 50%. The NO experiment confirms that the scutellarin modified S series compounds of the present invention have good anti-inflammatory effects and can effectively combat the progression of Alzheimer's disease through anti-inflammatory pathways.

Experimental Example 3 Determination of Antioxidant Activity - Determination of ABTS Free Radical Scavenging Ability

Experimental principle: 2,2'-hydrazine-bis(3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS) is mixed with potassium persulfate solution to form blue-green ABTS ⁺ cationic free radicals. In the presence of antioxidants, the free radicals are scavenged, causing the solution to fade, and then the absorbance value change of the reaction solution at 734nm is measured. The smaller the absorbance of the reaction solution, the stronger the scavenging ability of the free radical scavenger. This principle can be used to measure the antioxidant activity of the compound.

1 Experimental Materials

Compounds: Examples S1, S2, S3, S4, S5, S6, S7, S8; Comparative Example Scutellarin

2 Experimental methods

All compounds and positive control drugs were prepared by isocratic dilution method with DMSO as solvent to prepare 400, 200, 100, 50, 25, 12.5, and 6.25 μM test solutions. Three replicate wells were set up for the experiment, and the experiment was performed independently three times.

Accurately weigh 38.4 mg of ABTS powder and dilute it to 10 ml with deionized water to obtain a 7 mmol/L ABTS solution for use; take 13.4 mg of potassium persulfate and dilute it to 10 ml with deionized water to obtain a 4.96 mmol/L potassium persulfate solution for use; mix the ABTS solution and the potassium persulfate solution in a ratio of 1:1, react at room temperature in the dark for 16 hours, and then dilute it about 23 times with deionized water. The ABTS solution is prepared and used immediately so that the absorbance of the solution at 734 nm is 0.7±0.02 to obtain the ABTS ⁺ working solution.

Take 20 μL of a series of test compounds or DMSO and mix them evenly with 180 μL ABTS solution or deionized water. After reacting for 6 minutes at room temperature and away from light, use an enzyme reader to measure the absorbance at 734 nm.

The scavenging rate of ABTS free radicals (I _ABTS , %) was calculated using the following formula.

I _ABTS (%)=(1-(A _s -A _r )/A ₀ )×100%

A0: absorbance of blank group; Ar: absorbance of reference group; As: absorbance of sample group.

The experimental results are shown in Table 3 and Figure 3. It can be seen from the experimental results that all compounds have stronger DPPH scavenging ability than baicalin, especially compounds S4 and S7. Oxidation is the core event of the initiation of Alzheimer's disease and an important inducing factor for the subsequent occurrence and development. Antioxidation has a positive effect on intervening in the progression of Alzheimer's disease. The baicalin-modified S series compounds of the present invention have very excellent antioxidant effects and can actively combat the occurrence and progression of Alzheimer's disease.

Table 3. Effects of different compounds on scavenging DPPH free radicals

The inventors of the present invention designed and synthesized a new multi-target anti-Alzheimer's drug molecule, and evaluated its inhibitory Aβ protein deposition, anti-inflammatory and antioxidant activities. From the summary of experimental results (Table 4), it can be seen that the compounds of the present invention, compounds S1-S8, have multiple target activities such as inhibiting amyloid protein aggregation, reducing NO expression, and scavenging free radicals, and can combat the progression of Alzheimer's disease through the above targets. In particular, compound S7 has better inhibitory effects on amyloid protein aggregation, reducing NO expression, and scavenging free radicals than the control drug scutellariae, and has great potential for development into an anti-Alzheimer's drug.

Table 4. Effects of different compounds on the inhibition of Aβ _1-42 auto-induced aggregation, LPS-induced NO release in RAW264.7 cells, and scavenging of DPPH free radicals

The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (9)

1. A compound of formula (I), stereoisomers, tautomers, isotopic labels, nitroxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof,

In the formula (I) of the present invention,

R ₁ selected from-C1-6 alkyl, -C1-6 alkyl-C6-20 aryl, -C6-20 aryl-3 to 10 membered heterocyclyl; wherein C6-20 aryl, C3-10 heterocyclyl are optionally substituted with one, two or more R _a Substitution;

R ₂ selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy;

R ₃ selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy;

R ₄ selected from H, hydroxy, halogen;

R ₅ selected from H, hydroxy, halogen;

R _a selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy.

2. The compound of claim 1, a stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,

R ₁ selected from-C1-6 alkyl, -C1-6 alkyl-C6-10 aryl, -C6-10 aryl-3 to 6 membered heterocyclyl; wherein C6-10 aryl, 3-to 6-membered heterocyclyl are optionally substituted with one, two or more R _a Substitution;

preferably, R ₁ Selected from-C1-3 alkyl, -C1-3 alkyl-C6-10 aryl, -C6-10 aryl-3 to 6 membered heterocyclyl; wherein C6-10 aryl, 3-to 6-membered heterocyclyl are optionally substituted with one, two or more R _a Substitution;

further preferably, R ₁ Selected from-C1-3 alkyl, -C1-3 alkyl-C6 aryl, -C6 aryl-6 membered heterocyclyl; wherein C6 aryl, 6 membered heterocyclyl are optionally substituted with one, two or more R _a And (3) substitution.

3. The compound of claim 1 or 2, a stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,

R ₁ selected from methyl, ethyl, propyl, -methylene-phenyl, -methylene-biphenyl, phenyl, biphenyl, -phenyl-piperazinyl, -biphenyl-piperazinyl; wherein phenyl, biphenyl, piperazinyl are optionally substituted with one, two or more R _a Substitution;

preferably, R _a Selected from H, hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy.

4. A compound, stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof according to claim 1-3,

R ₁ selected from methyl, ethyl, phenyl, benzyl, halogen substituted phenyl, hydroxy substituted phenyl, methoxy substituted phenyl, ethylpiperazinyl substituted phenyl.

5. The compound, stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof according to claim 1-4,

R ₂ selected from hydroxyl groups;

and/or R ₃ Selected from hydroxyl groups;

and/or R ₄ Selected from H;

and/or R ₅ Selected from H.

6. The compound, stereoisomer, tautomer, isotopic label, nitroxide, solvate, polymorph, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of any one of claims 1 to 5, wherein the compound of formula (I) is selected from the group consisting of:

7. a process for the preparation of a compound of formula (I), a stereoisomer, a tautomer, an isotopic label, a nitroxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, according to any one of claims 1 to 6, comprising the steps of:

(1) SM compounds and BF ₃ ·Et ₂ O reacts to generate a compound of formula A;

(2) Reacting the compound of formula A to form a compound of formula B;

(3) Reacting the compound of formula B to form a compound of formula C;

(4) Compounds of formula C and R ₁ -NH ₂ Reacting to obtain a compound of formula I;

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ Having the definition of any one of claims 1 to 6.

8. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer, a tautomer, an isotopic label, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, according to any one of claims 1 to 6.

9. Use of a compound of formula (I), a stereoisomer, a tautomer, an isotopic label, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or prodrug thereof, as defined in any one of claims 1 to 6, for the preparation of a medicament for the treatment and/or prophylaxis of alzheimer's disease.