A scutellarein compound, its preparation method and application

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a scutellarein compound, a preparation method thereof and an application thereof. Background Art

[0002] Alzheimer's disease (AD) has become a global human health problem. With the extension of human lifespan, the incidence of Alzheimer's disease is also increasing continuously. It is estimated that by 2050, the number of global Alzheimer's disease patients will reach 152 million. AD is a slowly progressive and ultimately fatal neurodegenerative disease, bringing huge economic and emotional pressures to patients and their families. Unfortunately, current drug-based treatments can only moderately improve learning and memory, and there is no effective treatment method to reduce or stop the progression of AD. Therefore, developing new therapies for AD has become a major challenge in modern medicine. Although the pathogenesis of AD is not fully understood, it is closely related to the pathological development of AD, including abnormal accumulation of amyloid-β (Aβ), tau protein, reactive oxygen species (ROS), metal ions, and neuroinflammation, etc.

[0003] Aβ is produced by proteolytic cleavage of amyloid precursor protein (APP). 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 sequentially transforms from an α-helical structure into a β-sheet structure, monomer, oligomer, and finally forms fibrils in the process of AD development. 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 a potential treatment strategy for AD.

[0004] Due to the high demand for oxygen in the brain and the lack of antioxidant defense system, the brain is very vulnerable to oxidative stress (OS). A large amount of evidence shows that excessive generation of ROS leads to OS, and OS plays a key role in the pathogenesis and pathophysiology of AD. OS in the early stage of AD may be necessary to initiate other pathological mechanisms of AD, such as Aβ- and tau-induced neurotoxicity. Therefore, scavenging or preventing the formation of ROS may help to stop the progression of AD. As a neuroinflammatory disease, neuroinflammation plays an important role in the pathogenesis of AD.

[0005] In November 2019, GV-971 (sodium oligomannate), an original anti-AD new drug jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Shanghai Green Valley Pharmaceutical Co., Ltd. in China, was approved for marketing. GV-971 (mannooligosaccharic acid) treats AD by reshaping the balance of the gut microbiota, inhibiting the abnormal increase of specific metabolites of the gut microbiota, and reducing peripheral and central inflammation. Another example is aducanumab (trade name Aduhelm), an Alzheimer's new 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 β-amyloid protein accumulation in the brains of Alzheimer's patients. It can be seen from the recently approved drugs that drugs targeting anti-inflammation and inhibiting Aβ deposition have great potential.

[0006] 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 and act on multiple pathogenic pathways of AD simultaneously, showing better efficacy than single-target drugs, which may open up a new treatment approach for the treatment of AD.

[0007] Traditional Chinese medicine in China has a certain function in the prevention and treatment of AD. As early as 1436, the medicinal plant Erigeron breviscapus, which is used to treat cerebral palsy folk, was included in the book Compendium of Materia Medica of Yunnan. Erigeron breviscapus, also known as Erigeron breviscapus var. scaberulus, is a plant of the genus Erigeron in the Compositae family. It is used as medicine with its roots or whole herbs. It is mainly distributed in the southwestern region of our province and has the effects of dispelling wind and cold, promoting blood circulation and dredging collaterals to relieve pain, etc. Scutellarin, also known as scutellarin (Scu), is the most important active ingredient of 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)).

[0008] It has been confirmed in the prior art that scutellarin has a variety of pharmacological activities such as antioxidant, anti-inflammatory, vasodilatory, antiplatelet, anticoagulant, and myocardial protection. Studies have found that scutellarin can relieve the 25-35 damage to the learning and memory ability of AD rats induced by Aβ, significantly reduce the activities of superoxide dismutase (SOD), monoamine oxidase (MAO), IL-1β, IL-6 and TNF-α levels in the brain tissue of AD rats, and can inhibit the apoptosis of neurons, showing the effect of improving cognition. Scutellarin acts on Aβ 42Combination can effectively inhibit oligomerization and fiber formation, reduce the cytotoxicity of Aβ oligomers on SH-SY5Y cells, and has a beneficial effect on intervening in the development or progression of AD-like neuropathology. However, scutellarin has poor pharmacokinetic properties. Its solubility in water is only 0.16 mg / mL, it is rapidly eliminated in vivo, and its biological half-life is only (2.27 ± 0.58) min. The poor solubility and low bioavailability of scutellarin greatly limit its clinical application. The in vivo metabolism study of scutellarin found that scutellarin is hydrolyzed to scutellarein in the intestine. Its oral bioavailability is 3 times that of scutellarin and it has better biological activity compared with scutellarin.

[0009]

[0010] In this study, a series of compounds were designed and synthesized by modifying scutellarein, with the expectation of designing drug molecules with multi-target anti-AD effects such as antioxidant, anti-inflammatory and inhibition of Aβ deposition. Summary of the Invention

[0011] 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,

[0012]

[0013] In formula (I),

[0014] R1 is selected from -C1-6 alkyl, -C1-6 alkyl-C6-20 aryl, -C6-20 aryl, -C6-20 aryl-3 to 10-membered heterocyclic group; wherein the C6-20 aryl and C3-10 heterocyclic group are optionally substituted by one, two or more R a substituted;

[0015] R2 is selected from H, hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy;

[0016] R3 is selected from H, hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy;

[0017] R4 is selected from H, hydroxyl, halogen;

[0018] R5 is selected from H, hydroxyl, halogen;

[0019] R a is selected from H, hydroxyl, halogen, C1-6 alkyl, C1-6 alkoxy.

[0020] In some embodiments, R1 is selected from -C1-6 alkyl, -C1-6 alkyl-C6-10 aryl, -C6-10 aryl, -C6-10 aryl-3 to 6-membered heterocyclic group; wherein the C6-10 aryl and 3 to 6-membered heterocyclic group are optionally substituted with one, two or more R a substituted;

[0021] Preferably, R1 is selected from -C1-3 alkyl, -C1-3 alkyl-C6-10 aryl, -C6-10 aryl, -C6-10 aryl-3 to 6-membered heterocyclic group; wherein the C6-10 aryl and 3 to 6-membered heterocyclic group are optionally substituted with one, two or more R a substituted;

[0022] More preferably, R1 is selected from -C1-3 alkyl, -C1-3 alkyl-C6 aryl, -C6 aryl, -C6 aryl-6-membered heterocyclic group; wherein the C6 aryl and 6-membered heterocyclic group are optionally substituted with one, two or more R a substituted.

[0023] In some embodiments, the 6-membered heterocyclic group contains 1-3 heteroatoms, such as piperazinyl and piperidinyl.

[0024] In some embodiments, R1 is selected from methyl, ethyl, propyl, -methylene-phenyl, -methylene-biphenyl, phenyl, biphenyl, -phenyl-piperazinyl, -biphenyl-piperazinyl; wherein the phenyl, biphenyl and piperazinyl are optionally substituted with one, two or more R a substituted.

[0025] In some embodiments, R a is selected from H, hydroxy, halogen, C1-3 alkyl, C1-3 alkoxy.

[0026] In some embodiments, R1 is selected from methyl, ethyl, phenyl, benzyl, halogen-substituted phenyl, hydroxy-substituted phenyl, methoxy-substituted phenyl, ethylpiperazinyl-substituted phenyl.

[0027] In some embodiments, R2 is selected from hydroxy.

[0028] In some embodiments, R3 is selected from hydroxy.

[0029] In some embodiments, R4 is selected from H.

[0030] In some embodiments, R5 is selected from H.

[0031] In some embodiments, the compounds represented by formula (I) are selected from the following compounds:

[0032]

[0033] 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, and the preparation method includes the following steps:

[0034] (1) React the compound of formula SM with BF3·Et2O to form the compound of formula A;

[0035] (2) React the compound of formula A to form the compound of formula B;

[0036] (3) React the compound of formula B to form the compound of formula C;

[0037] (4) React the compound of formula C with the compound R1-NH2 to obtain the compound of formula I;

[0038]

[0039] Among them, R1, R2, R3, and R4 have the above definitions.

[0040] In some embodiments, in step (1), the solvent is AcOH.

[0041] In some embodiments, in step (2), the reaction is carried out under the condition of N,N-dimethylformamide dimethyl acetal (DMF-DMA);

[0042] And / or, the reaction solvent is acetone.

[0043] In some embodiments, in step (3), the reaction is carried out under the condition of BBr3;

[0044] And / or, the reaction solvent is dichloromethane.

[0045] In some embodiments, in step (4), the reaction is carried out under the condition of HCHO;

[0046] And / or, the reaction solvent is methanol.

[0047] Among them, the compound of formula SM, boron trifluoride diethyl ether complex BF3·Et2O, DMF-DMAC, BBr3, HCHO, 4-(4-ethyl-1-piperazinyl)aniline are commercially available compounds or can be obtained by those skilled in the art using conventional technical means.

[0048] Third aspect, the present invention provides a pharmaceutical composition, and the pharmaceutical composition includes 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.

[0049] In some embodiments, the pharmaceutical composition optionally comprises at least one additional active ingredient.

[0050] In some embodiments, the additional active ingredients include cholinesterase inhibitors (such as donepezil, rivastigmine, galantamine, huperzine A), N-methyl-D-aspartic acid receptor antagonists (such as memantine), sodium oligomannate capsules (GV-971), and aducanumab.

[0051] In some embodiments, the pharmaceutical composition optionally comprises at least one pharmaceutically acceptable excipient.

[0052] In some embodiments, pharmaceutically acceptable excipients include pharmaceutically acceptable carriers, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, antiadhesives, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickening agents, clathrates, humectants, absorbents, diluents, excipients, flocculants and deflocculants, filter aids, release retardants and other pharmaceutical excipients.

[0053] In some embodiments, the compound represented by the above formula (I), its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs are formulated with pharmaceutically acceptable carriers, diluents or excipients and other pharmaceutical excipients into tablets, capsules, powders, granules, solutions, emulsions, suspensions, etc., which are suitable for oral and parenteral administration.

[0054] In some embodiments, the administration methods include, but are not limited to, oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.

[0055] In some embodiments, the preparation can be administered, but is not limited to, by infusion, bolus injection, transdermal absorption and other routes. The preparation can be prepared by preparation methods known in the art.

[0056] In a fourth aspect, the present invention provides the use of the compound represented by the above formula (I), its stereoisomers, tautomers, isotopically labeled compounds, N-oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs, and the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing Alzheimer's disease.

[0057] Beneficial effects

[0058] The present invention provides a novel compound represented by formula (I), which has activities such as antioxidation and inhibition of Aβ protein deposition, and can achieve multi-targeted treatment of Alzheimer's disease.

[0059] Term Definitions and Explanations Unless otherwise specified, the definitions of groups and terms recorded in the description 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 combined and combined with each other arbitrarily. The defined groups and compound structures after such combination and combination should be understood to be within the scope recorded in the description and / or claims of this application.

[0060] 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 description of substituents, when referring to one, two or more, "more" should refer to an integer ≥ 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0061] Generally speaking, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Further, when the group is substituted by more than 1 of the above-mentioned substituents, the substituents are independent of each other, that is, the more than 1 substituents can be different from each other or the same. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of the group to be substituted. When there is more than one position in the given structural formula that can be substituted by one or more substituents selected from specific groups, the substituents can be the same or different at each position. The substituents can be, but are not limited to, =O, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclic group, heterocyclic alkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, etc.

[0062] In addition, it should be noted that, unless otherwise explicitly specified, the description method "independently selected from" adopted in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independently selected from the same or different specific groups. More specifically, the description method "independently selected from" can either mean that among different groups, the specific options expressed between the same symbols do not affect each other; or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0063] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. Specifically pointed out, the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C" 1-6 alkyl" specifically refers to C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl independently disclosed.

[0064] In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for this group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for this variable lists "alkyl" or "aryl", then it should be understood that this "alkyl" or "aryl" represents a linked alkylene group or arylene group respectively.

[0065] The "hydrogen", "carbon", and "oxygen" in the compounds of the present invention include all their isotopes. Isotopes should be understood to include those atoms with the same atomic number but different mass numbers. For example, the isotopes of hydrogen include protium, tritium, and deuterium, and the isotopes of carbon include 12 C, 13 C, and 14 C, and the isotopes of oxygen include 16 O and 18 O, etc.

[0066] The "halogen" of the present invention refers to fluorine, chlorine, bromine, and iodine. The "halogenated" of the present invention means being substituted by fluorine, chlorine, bromine, or iodine.

[0067] The "C1-6 alkyl" of the present invention refers to a straight-chain or branched-chain group containing 1 to 6 carbon atoms, and further preferably a straight-chain or branched-chain group containing 1 to 3 carbon atoms. 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 can be substituted or unsubstituted. When substituted, the substituent can be at any available connection point.

[0068] The "C1-6 alkoxy" of the present invention refers to -O-C1-6 alkyl. C1-6 alkyl has the above definition.

[0069] The "3- to 10-membered heterocyclic group" of the present invention refers to a group of a 3- to 10-membered non-aromatic ring system having 1 to 4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, provided that the valence is permitted. The heterocyclic group can be saturated or can be partially unsaturated. Each instance of the heterocyclic group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

[0070] The "C6-20 aryl" of the present invention refers to an aromatic system containing 6 to 20 carbon atoms, which can include a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system, and preferably contains 6 to 12 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

[0071] "Stereoisomers" refer to compounds having the same chemical constitution but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, and so on.

[0072] "Tautomers" refer to structural isomers that can be interconverted through a low energy barrier and have different energies. If tautomerization is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions carried out through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions carried out through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-ketone tautomerization. A specific example of phenol-ketone tautomerization is the interconversion between pyridin-4-ol and pyridin-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.

[0073] "Nitrogen oxides" in the present invention refer to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (such as peroxycarboxylic acid) 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), where, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA).

[0074] "Prodrug" represents a compound that is converted in vivo into the compound represented by formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or enzymatic conversion in the blood or tissues into the parent structure. The prodrug compounds of the present invention can be esters. In existing inventions, esters that can serve 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, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl groups on the parent body. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. 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 S.J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0075] As used herein, the term "metabolite" refers to the product obtained by the metabolic action of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by sufficient contact of the compounds of the present invention with a mammal for a period of time.

[0076] Pharmaceutically acceptable salts can be, for example, acid addition salts of the compounds of the present invention having sufficient basicity with a nitrogen atom in the chain or ring, such as acid addition salts formed with the following inorganic acids: for example, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfates, or acid addition salts formed with the following organic acids: for example, 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, digluconic 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, amidosulfonic 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.

[0077] In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention having 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 providing 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, glucamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts formed by the group -COOH with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, 1-amino-2,3,4-butanetriol.

[0078] 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 dipentyl 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 hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate, or meglumine salt, etc. Since the compounds of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salts include not only the salts formed at one salt-forming site of the compounds of the present invention, but also the salts formed at two, three, or all salt-forming sites. For this reason, the molar ratio of the compound of formula (I) to the acid radical ion (anion) or the cation of the base required for salt formation in the pharmaceutically acceptable salt can vary within a wide range, for example, it can be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0079] The "solvate" of the present invention conventionally refers to a complex formed by a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). The solvent refers to a solvent known to those skilled in the art or easily determined. If it is water, the solvate is usually called a hydrate, such as a hemihydrate, monohydrate, dihydrate, trihydrate, or an alternative amount thereof.

[0080] The "ester" of the present invention refers to an in vivo hydrolysable ester formed by a compound containing a hydroxyl group or a carboxyl group. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in a human or animal body to produce the parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolysable ester with an appropriate group, and such groups include, but are not limited to, alkyl, aralkyl, etc.

[0081] The "pharmaceutical composition" of the present invention refers to a mixture comprising any one of the compounds described in the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or their chemically protected forms, 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 treating and / or preventing diseases mediated by one or more kinases.

[0082] The "pharmaceutically acceptable carrier" of the present invention refers to a carrier that does not cause significant irritation to the 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, thickening agents or emulsifying agents, preservatives, solid binders, lubricants, etc. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that can be used as pharmaceutically acceptable carriers include, but are not limited to, saccharides such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, as well as cellulose and cellulose acetate; malt, gelatin, etc.

[0083] The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the compound. Excipients can include calcium carbonate, calcium phosphate, various saccharides and various types of starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol.

[0084] As used herein, the term "treatment" refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of its clinical symptoms); or refers to alleviating or improving at least one body parameter, including those body parameters that may not be distinguishable by the patient; or regulating the disease or disorder physically (e.g., symptoms), physiologically (e.g., body parameters) or both; or preventing or delaying the onset, occurrence and progression of the disease or disorder. Description of the Drawings

[0085] Figure 1 .Determination of Aβ by ThT binding assay 1-42 Graph of the results of the aggregation inhibition test.

[0086] Figure 2 .Graph for evaluating the in vitro anti-inflammatory activity.

[0087] Figure 3 .Graph of the determination results of the DPPH free radical scavenging ability.

[0088] Figure 4 .Graph of the synthetic route of the compound of formula (I). Detailed Description of the Invention

[0089] The technical solution 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 for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0090] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0091] Example 1

[0092] 5,6-Dihydroxy-9-methyl-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S1)

[0093]

[0094] The synthetic route diagram is as Figure 4 shown.

[0095] Step 1:

[0096] Take 10 g of 3,4,5-trimethoxyphenol (54.3 mmol) and 60 mL of glacial acetic acid and add them into a three-necked flask successively. Under nitrogen protection, add 25 mL of BF3·Et2O solution, reflux and stir at 80 °C for 16 h. After the reaction is detected by TLC and cooled to room temperature, quench the reaction with water, extract three times with ethyl acetate / water, combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 8 g of Compound A.

[0097] Step 2:

[0098] 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 and add them into a three-necked flask successively. Under nitrogen protection, reflux and stir at 90 °C for 6 h. After the reaction is detected by TLC and cooled to room temperature, quench the reaction with water, extract three times with ethyl acetate / water, combine the organic phases, wash with saturated brine, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 2.2 g of Compound B.

[0099] Step 3:

[0100] Weigh 4.57 g of Compound B (19.2 mmol) and 65 mL of dichloromethane and add them into a three-necked flask successively. Under nitrogen protection, add 21.6 g of BBr3 (86.63 mmol) under ice bath conditions, stir overnight. After the reaction is detected by TLC and cooled to room temperature, quench the reaction with water, remove the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 2 g of Compound C.

[0101] Step 4:

[0102] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.5 mmol), 0.28 g of 25% aqueous methylamine solution (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir at room temperature overnight. After detecting the end of the reaction by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S1. Add methanol for slurry purification, and filter by suction to obtain 0.30 g of the corresponding pure compound S1, with a yield of 77.9%.

[0103] The structures of compounds A, B, and C are shown as follows:

[0104]

[0105] Example 2

[0106] 9-Ethyl-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S2)

[0107]

[0108] Step 1:

[0109] The same as step 1 of Example 1.

[0110] Step 2:

[0111] The same as step 2 of Example 1.

[0112] Step 3:

[0113] The same as step 3 of Example 1.

[0114] Step 4:

[0115] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.15 g of 70% aqueous ethylamine solution (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir at room temperature overnight. After detecting the end of the reaction by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S2. Add methanol for slurry purification, and filter by suction to obtain 0.20 g of the corresponding pure compound S2, with a yield of 50.2%.

[0116] Example 3

[0117] 5,6-Dihydroxy-9-phenyl-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S3)

[0118]

[0119] Step 1:

[0120] Same as Step 1 of Example 1.

[0121] Step 2:

[0122] Same as Step 2 of Example 1.

[0123] Step 3:

[0124] Same as Step 3 of Example 1.

[0125] Step 4:

[0126] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.20 g of aniline (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir overnight at room temperature. After detecting the end of the reaction by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S3. Add methanol for slurry purification, and filter by suction to obtain 0.38 g of the corresponding pure compound S3, with a yield of 79.2%.

[0127] Example 4

[0128] 9-[4-(4-Ethylpiperazin-1-yl)phenyl]-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S4)

[0129]

[0130] Step 1:

[0131] Same as Step 1 of Example 1.

[0132] Step 2:

[0133] Same as Step 2 of Example 1.

[0134] Step 3:

[0135] Same as Step 3 of Example 1.

[0136] Step 4:

[0137] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.45 g of 4-(4-ethyl-1-piperazinyl)aniline (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir overnight at room temperature. After detecting the end of the reaction by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S4. Add methanol for slurry purification, and filter by suction to obtain 0.41 g of the corresponding pure compound S4, with a yield of 62.6%.

[0138] Example 5

[0139] 9-Benzyl-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S5)

[0140]

[0141] Step 1:

[0142] Same as Step 1 of Example 1

[0143] Step 2:

[0144] Same as Step 2 of Example 1

[0145] Step 3:

[0146] Same as Step 3 of Example 1

[0147] Step 4:

[0148] Weigh 0.3 g of Compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.24 g of benzylamine (2.2 mmol), and add 6 mL of methanol to a pressure-resistant flask in sequence. Start stirring and stir overnight at room temperature. After detecting the end of the reaction by TLC, cool to room temperature and filter by suction to obtain the corresponding crude Compound S5. Add methanol for pulping purification, filter by suction to obtain 0.35 g of the corresponding pure Compound S5, and the yield is 69.6%.

[0149] Example 6

[0150] 9-(4-Fluorophenyl)-5,6-dihydroxy-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S6)

[0151]

[0152] Step 1:

[0153] Same as Step 1 of Example 1

[0154] Step 2:

[0155] Same as Step 2 of Example 1

[0156] Step 3:

[0157] Same as Step 3 of Example 1

[0158] Step 4:

[0159] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.24 g of p-fluoroaniline (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir overnight at room temperature. After the reaction is completed as detected by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S6. Add methanol for slurry purification, and filter by suction to obtain 0.35 g of the corresponding pure compound S6, with a yield of 68.8%.

[0160] Example 7

[0161] 5,6-Dihydroxy-9-(4-hydroxyphenyl)-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S7)

[0162]

[0163] Step 1:

[0164] Same as Step 1 of Example 1.

[0165] Step 2:

[0166] Same as Step 2 of Example 1.

[0167] Step 3:

[0168] Same as Step 3 of Example 1.

[0169] Step 4:

[0170] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.24 g of 4-aminophenol (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir overnight at room temperature. After the reaction is completed as detected by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S7. Add methanol for slurry purification, and filter by suction to obtain 0.35 g of the corresponding pure compound S7, with a yield of 69.2%.

[0171] Example 8

[0172] 5,6-Dihydroxy-9-(4-methoxyphenyl)-4,8,9,10-tetrahydrochromeno[8,7-e][1,3]oxazocine-4-one (Compound S8)

[0173]

[0174] Step 1:

[0175] Same as Step 1 of Example 1.

[0176] Step 2:

[0177] Same as step 2 of Example 1.

[0178] Step 3:

[0179] Same as step 3 of Example 1.

[0180] Step 4:

[0181] Weigh 0.3 g of compound C (1.5 mmol), 0.85 g of 37% aqueous formaldehyde solution (10.4 mmol), 0.27 g of 4-methoxyaniline (2.2 mmol), and add 6 mL of methanol to a pressure-resistant bottle in sequence. Start stirring and stir overnight at room temperature. After the reaction is completed as detected by TLC, cool to room temperature and filter by suction to obtain the corresponding crude compound S8. Add methanol for slurry purification, and filter by suction to obtain 0.38 g of the corresponding pure compound S8, with a yield of 72.1%.

[0182]

[0183]

[0184] Experimental Example 1: Determination of Aβ by ThT binding assay 1-42 Aggregation inhibition assay

[0185] Experimental principle: Thioflavin T (ThT) is a benzothiazole dye and is the most commonly used dye for detecting amyloid aggregation. ThT can specifically recognize the fibrillar structure generated during the aggregation of Aβ and bind to it, showing enhanced fluorescence. The fluorescence intensity 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 compound on Aβ 1-42 self-aggregation can be calculated.

[0186] 1. Experimental materials

[0187] Compounds: Compounds S1, S2, S3, S4, S5, S6, S7, S8 in Examples; Scutellarein in the comparative example

[0188] 2. Experimental method

[0189] All compounds were screened at a concentration of 50 μM, and 3 replicate wells were set up for the experiment, with the experiment being conducted independently 3 times.

[0190] Mix 10 μL of a series of test compounds (50 μM, final concentration) or PBS with 10 μL of Aβ 1-42(25 μM, final concentration) was 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 using a multi-functional microplate reader after gently shaking at low speed for 5 min. (The excitation wavelength was 450 nm and the emission wavelength was 490 nm).

[0191] The percentage inhibition of self-induced aggregation (I Aβ1-42 , %) was calculated using the following formula.

[0192] I Aβ1-42 (%) = 1 - (Fs / F0) × 100%

[0193] Fs: Fluorescence intensity of the sample group after background subtraction; F0: Fluorescence intensity of the blank group after background subtraction.

[0194] 3. Experimental results, see Table 1 and Figure 1 .

[0195] Table 1. Inhibitory effects of different compounds on Aβ 1-42 self-induced aggregation

[0196]

[0197] From the experimental results in Table 1, it can be seen that except for compound S1, the inhibitory rates of the other compounds on self-induced Aβ 1-42 aggregation were all greater than 50% at a concentration of 50 μM. In particular, compound S7 had a stronger inhibitory activity on Aβ 1-42 than the positive control 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 this invention application have great potential in the treatment of Alzheimer's disease.

[0198] Experimental Example 2. Evaluation of in vitro anti-inflammatory activity

[0199] 1 Experimental materials

[0200] Compounds: Compounds S1, S2, S3, S4, S5, S6, S7, S8 of the examples; Scutellarin of the comparative example

[0201] 2 Experimental methods

[0202] In this experiment, the mouse macrophage-like cell line (RAW264.7) was used as a model. First, the cytotoxicity of the compounds to RAW264.7 was tested by the MTT method (the maximum drug concentration was 500 μM) to exclude the interference of the compounds on cell growth activity. The drug concentration was taken when the cell viability > 90%, and the Griess method was used to measure the NO content in the culture medium.

[0203] (1) Detection of the effects of various compounds on the viability of RAW264.7 cells by MTT method

[0204] In each well of a 96-well plate, inoculate 100 μL of RAW264.7 cell suspension (cell density is 5×10 3 cells / well), place it at 37 °C and 5% CO2, and administer the drug after culturing for 24 h. Set the background wells, test groups, and blank group to have 3 replicate wells each. Add 8 different concentrations of the sample solution to the test groups (add DMEM medium to the blank group). After continuing to culture for 24 h, add 20 μL of MTT solution (5 mg / mL) to each well. After incubating in the incubator for 4 h to form crystals, aspirate the supernatant, add 150 μL of DMSO to each well, place it on a shaker and shake at low speed for 15 min to fully dissolve the crystals. Measure the absorbance of each well at 490 nm on an enzyme-linked immunosorbent assay (ELISA) reader, and calculate the cell survival rate according to the following formula.

[0205] Cell survival rate = (OD s - OD r ) / (OD0 - OD r ) × 100%

[0206] OD s : Absorbance of the sample group; OD r : Absorbance of the background group; OD0: Absorbance of the blank group.

[0207] (2) Detection of the effects of various compounds on the release of NO from LPS-induced RAW264.7 cells by Griess method

[0208] In each well of a 96-well plate, inoculate 100 μL of RAW264.7 cell suspension (cell density is 5×10 4 cells / well), place it at 37 °C and 5% CO2 in an incubator. After culturing for 24 h, first add LPS (1 μg / mL) and let it act for 1 h, then administer the drug. After continuing to culture for 24 h, transfer 50 μL of the cell supernatant to another 96-well cell culture plate, add 50 μL of each of Griess A and B reagents, react in the dark for 10 min, and measure the OD value at 540 nm. Calculate the concentration of NO according to the standard curve made with NaNO2.

[0209] Set up a blank group (add DMEM medium, no LPS stimulation), an LPS model group (add DMEM medium, with LPS stimulation), a positive drug group (scutellarin, with LPS stimulation), and a test group (10 μM drug, with LPS stimulation), each with 3 replicate wells.

[0210] 3 Experimental results

[0211] Detection of the effects of various compounds on the viability of RAW264.7 cells by MTT method

[0212] It was obtained through MTT experiments that when the concentration of compounds S1 - S8 was 10 μM, the cell survival rate was greater than 90%. Therefore, under this condition, the determination of the NO expression rate of S1 - S8 was carried out.

[0213] (1) Detection of the effect of each compound on the release of NO from LPS - induced RAW264.7 cells by the Griess method

[0214] Table 2. Effects of different compounds on the release of NO from LPS - induced RAW264.7 cells

[0215]

[0216] The experimental results are shown in Table 2 and Figure 2 , it can be seen from the experimental results that S1, S2, S3, and S4 in the compounds have weak inhibition on NO expression, while S6, S7, and S8 have relatively prominent inhibitory effects on NO, all stronger than the positive control drug scutellarin. Especially compound S7 has an inhibition of NO reaching 50%. The NO experiment confirmed that the scutellarin - modified S - series compounds of this invention application have good anti - inflammatory effects and can effectively counteract the process of Alzheimer's disease through the anti - inflammatory pathway.

[0217] Experimental Example 3 Determination of antioxidant activity - Determination of ABTS free radical scavenging ability

[0218] Experimental principle: 2,2'-azino - bis(3 - ethylbenzothiazoline - 6 - sulfonic acid) diammonium salt (ABTS) is mixed with potassium persulfate solution to form a blue - green ABTS + cationic free radical. In the presence of an antioxidant, the free radical is scavenged, resulting in the fading of the solution. Then, the change in the absorbance value of this reaction solution at 734 nm is measured. The smaller the absorbance of the reaction solution, the stronger the scavenging ability of the free radical scavenger. Using this principle, the antioxidant activity of the compound can be determined.

[0219] 1 Experimental materials

[0220] Compounds: Examples S1, S2, S3, S4, S5, S6, S7, S8; Comparative example scutellarin

[0221] 2 Experimental methods

[0222] All compounds and the positive control drug were prepared into test solutions with concentrations of 400, 200, 100, 50, 25, 12.5, and 6.25 μM by the equal - ratio dilution method using DMSO as the solvent. The experiment was set with 3 replicate wells and independently repeated 3 times.

[0223] Accurately weigh 38.4 mg of ABTS powder, dissolve it in deionized water and make up the volume to 10 ml to obtain a 7 mmol / L ABTS solution for standby. Weigh 13.4 mg of potassium persulfate, dissolve it in deionized water and make up the volume to 10 ml to obtain a 4.96 mmol / L potassium persulfate solution for standby. Mix the ABTS solution and the potassium persulfate solution in a ratio of 1:1, and react in the dark at room temperature for 16 h, then dilute it with deionized water about 23 times. The ABTS solution is prepared and used immediately to make the absorbance value of this solution at 734 nm be 0.7 ± 0.02, and obtain ABTS + working solution.

[0224] Take 20 μL of a series of compounds to be tested or DMSO, mix it evenly with 180 μL of ABTS solution or deionized water, react in the dark at room temperature for 6 min, and then measure the absorbance at 734 nm with an enzyme-labeled instrument.

[0225] Use the following formula to calculate the scavenging rate (I ABTS , %).

[0226] I ABTS (%) = (1 - (A s - A r ) / A0) × 100%

[0227] A0: Absorbance of the blank group; Ar: Absorbance of the reference group; As: Absorbance of the sample group.

[0228] The experimental results are shown in Table 3 and Figure 3 , and it can be seen from the experimental results that all the compounds have stronger DPPH scavenging ability than scutellarin, especially compounds S4 and S7. Oxidation is the initiating core event of Alzheimer's disease and an important inducing factor for its subsequent occurrence and development. Antioxidation has a positive effect on intervening in the process of Alzheimer's disease. The S series of compounds modified from scutellarin in this invention application have very excellent antioxidant effects and can actively combat the occurrence and progression of Alzheimer's disease.

[0229] Table 3. Effects of different compounds on scavenging DPPH radicals

[0230]

[0231] The inventors of the present invention designed and synthesized novel drug molecules targeting multiple targets for Alzheimer's disease, and evaluated their activities of inhibiting Aβ protein deposition, anti-inflammation and anti-oxidation. 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 aggregation, reducing NO expression, and scavenging free radicals, and can counteract the progression of Alzheimer's disease through the above targets. In particular, Compound S7 has better effects of inhibiting amyloid aggregation, reducing NO expression, and scavenging free radicals than the control drug scutellarin, and has great potential for development into a drug for Alzheimer's disease.

[0232] Table 4. Effects of different compounds on Aβ 1-42 self-induced aggregation inhibition, LPS-induced NO release from RAW264.7 cells, and DPPH free radical scavenging

[0233]

[0234]

[0235] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, In formula (I), R1 is selected from -C 1-6 alkyl, -C 1-3 alkyl-C 6-10 aryl, -C 6-10 aryl, -C 6-10 aryl-3- to 10-membered heterocyclic group; wherein C 6-10 aryl, 3- to 10-membered heterocyclic group is optionally substituted by one, two or more R a substituents; R2 is selected from hydroxy; R3 is selected from hydroxy; R4 is selected from H, halogen; R5 is selected from H, halogen; R a Selected from H, hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from -C 1-3 alkyl, -C 1-3 alkyl-C 6-10 aryl, -C 6-10 aryl, -C 6-10 aryl-3- to 6-membered heterocyclic group; wherein C 6-10 aryl, 3- to 6-membered heterocyclic group is optionally substituted by one, two or more R a substituents.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from -C 1-3 alkyl, -C 1-3 alkyl-C6 aryl, -C6 aryl, -C6 aryl-6-membered heterocyclic group; wherein the C6 aryl and 6-membered heterocyclic group are optionally substituted with one, two or more R a substituents.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from methyl, ethyl, propyl, -methylene-phenyl, -methylene-biphenyl, phenyl, biphenyl, -phenyl-piperazinyl, -biphenyl-piperazinyl; wherein the phenyl, biphenyl, and piperazinyl are optionally substituted by one, two or more R a substituents.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, R a selected from H, hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy group.

6. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from methyl, ethyl, phenyl, benzyl, halogen-substituted phenyl, hydroxy-substituted phenyl, methoxy-substituted phenyl, ethylpiperazinyl-substituted phenyl.

7. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from hydroxy; R3 is selected from hydroxy; R4 is selected from H; R5 is selected from H.

8. The compound according to any one of claims 1 - 4, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula (I) is selected from the following compounds:

9. A method for preparing the compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, the preparation method comprising the following steps: (1) Reacting a compound of formula SM with BF3·Et2O to form 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) Reacting the compound of formula C with the compound R1-NH2 to obtain the compound of formula (I); wherein, R1, R2, R3, R4, R5 have the definitions as described in any one of claims 1-8.

10. A pharmaceutical composition, the pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof.

11. Use of the compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating Alzheimer's disease.

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