A vinylpyranone compound and its application

Abstract

This invention provides a vinylpyranone compound, which exhibits excellent antioxidant activity, anti-inflammatory activity, and Aβ inhibition. 1‑42 Aggregation activity and inhibition of cholinesterase activity.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a vinylpyranone compound and its applications. Background Technology

[0002] Alzheimer's disease (AD) is a slowly progressing, ultimately fatal neurodegenerative disease. With increasing life expectancy, the incidence of AD is rising, posing a significant burden on human health, the economy, and society. However, current drug treatments can only moderately improve learning and memory, and cannot slow or stop the progression of AD. Therefore, the development of anti-AD drugs is increasingly urgent. Summary of the Invention

[0003] To address the aforementioned technical problems, the present invention provides a vinylpyranone compound of formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, or prodrugs.

[0004]

[0005] Wherein, R1 is selected from one, two or more R... a Substituted C6-20 aryl, 5-20 heteroaryl;

[0006] R a They may be the same or different, and are independently selected from H, C1-10 alkyl, C1-10 alkoxy, cyano, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, C6-20 aryl, 5-20 heteroaryl, and 3-20 heterocyclic groups;

[0007] R2 and R3 may be the same or different, and are independently selected from H and C1-10 alkyl groups;

[0008] R4 is selected from H, halogens, and C1-10 alkyl groups.

[0009] According to an embodiment of the present invention, R1 is selected from one, two or more R... a The substituted C6-14 aryl or 5-14 heteroaryl group; preferably, R1 is selected from one, two or more R groups. a Substituted C6-10 aryl, 5-10 heteroaryl; more preferably, R1 is selected from one, two or more R... a Substituted phenyl or naphthyl groups.

[0010] According to embodiments of the present invention, R2 and R3 may be the same or different, and are independently selected from H or C1-6 alkyl groups; preferably, R2 and R3 may be the same or different, and are independently selected from H or C1-3 alkyl groups; more preferably, R2 and R3 may be the same or different, and are independently selected from H, methyl, ethyl, or propyl groups; for example, R2 may be selected from methyl and R3 from ethyl.

[0011] According to an embodiment of the present invention, R4 is selected from H, halogen, C1-6 alkyl; preferably, R4 is selected from H, halogen, C1-3 alkyl; more preferably, R4 is selected from H, halogen, methyl, ethyl, propyl.

[0012] According to an embodiment of the present invention, R a They may be the same or different, and are independently selected from H, C1-6 alkyl, C1-6 alkoxy, cyano, halogen, hydroxyl, C6-14 aryl, 5-14 heteroaryl, and 3-10 heterocyclic groups; more preferably, R a The same or different, independently selected from H, C1-3 alkyl, C1-3 alkoxy, cyano, halogen, hydroxyl, C6-10 aryl, 5-10 heteroaryl, 3-6 heterocyclic; for example, R3 is the same or different, independently selected from H, methyl, cyano, methoxy, halogen, hydroxyl, phenyl, naphthyl, piperidinyl, morpholinyl.

[0013] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the compounds represented by formula (II):

[0014]

[0015] Among them, R a It has the above definition;

[0016] m is selected from natural numbers between 0 and 5 (e.g., 0, 1, 2, 3, 4, 5).

[0017] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the compounds represented by formula (III):

[0018]

[0019] Among them, R a It has the above definition.

[0020] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the compounds represented by formula (IV):

[0021]

[0022] Among them, R a It has the above definition;

[0023] n is a natural number selected from 0 to 7 (e.g., 0, 1, 2, 3, 4, 5, 6, 7).

[0024] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the following compounds:

[0025]

[0026]

[0027] The present invention also provides a method for preparing the vinylpyranone compound represented by formula (I) above, wherein the preparation method is selected from method A or method B;

[0028] Method A includes the following steps: the compound shown in formula (IV) reacts with the compound shown in formula (V) under a base and a catalyst to obtain the compound shown in formula (I); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the catalyst is selected from palladium catalysts, such as palladium acetate; preferably, the reaction is carried out in an organic solvent, such as DMF;

[0029] The reaction route is as follows:

[0030]

[0031] R1, R2, and R3 are defined as described above; Y is selected from halogens (e.g., fluorine, chlorine, bromine, iodine).

[0032] Method B includes the following steps: reacting the compound shown in formula (VI) with the compound shown in formula (VII) under a base and a catalyst to obtain the compound shown in formula (I); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the catalyst is selected from coupling catalysts, such as 4-dimethylaminopyridine (4-DMAP); preferably, the reaction is carried out in an organic solvent, such as acetonitrile.

[0033] The reaction route is as follows:

[0034]

[0035] R1, R2, and R3 are defined as described above; X is selected from halogens (e.g., fluorine, chlorine, bromine, iodine).

[0036] According to an embodiment of the present invention, after the reaction is completed, the reaction products can be treated by conventional post-processing methods, such as preparative HPLC, preparative TLC or recrystallization, etc., for separation and purification.

[0037] According to an embodiment of the present invention, the compound shown in formula (IV) is prepared as follows:

[0038] (1) Compound 1 (kojic acid) reacts with a halogenating agent to give the compound shown in formula (II); preferably, the reaction is carried out in an organic solvent, such as tetrahydrofuran; preferably, the halogenating agent is selected from N-bromosuccinimide; preferably, the reaction is carried out in ammonium acetate.

[0039] (2) The compound shown in formula (II) reacts with benzyl bromide under alkaline conditions to obtain the compound shown in formula (III); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the reaction is carried out in an organic solvent, such as acetonitrile.

[0040] (3) The compound shown in formula (III) reacts with the compound shown in formula (VII) under a base and a catalyst to obtain the compound shown in formula (IV); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the catalyst is selected from coupling catalysts, such as 4-dimethylaminopyridine (4-DMAP); preferably, the reaction is carried out in an organic solvent, such as acetonitrile;

[0041] The reaction route is as follows:

[0042]

[0043] R1 is defined as described above; X is selected from halogens (e.g., fluorine, chlorine, bromine, iodine).

[0044] According to an embodiment of the present invention, the compound shown in formula (VI) is prepared as follows:

[0045] (1) Compound 1 (kojic acid) reacts with a halogenating agent to give the compound shown in formula (II); preferably, the reaction is carried out in an organic solvent, such as tetrahydrofuran; preferably, the halogenating agent is selected from N-bromosuccinimide; preferably, the reaction is carried out in ammonium acetate.

[0046] (2) The compound shown in formula (II) reacts with benzyl bromide under alkaline conditions to obtain the compound shown in formula (III); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the reaction is carried out in an organic solvent, such as acetonitrile.

[0047] (3) The compound shown in formula (III) reacts with the compound shown in formula (V) under the presence of a base and a catalyst to obtain the compound shown in formula (IV); preferably, the base is selected from organic or inorganic bases, such as triethylamine, potassium carbonate, etc.; preferably, the catalyst is selected from palladium catalysts, such as palladium acetate; preferably, the reaction is carried out in an organic solvent, such as DMF;

[0048] The reaction route is as follows:

[0049]

[0050] R2 and R3 are defined as described above; X and Y may be the same or different, and are independently selected from halogens (e.g., fluorine, chlorine, bromine, iodine).

[0051] The present invention also provides a pharmaceutical composition comprising one, two or more of the following: a vinylpyranone compound represented by formula (I) above, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, and prodrugs.

[0052] According to embodiments of the present invention, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable excipient. According to embodiments of the present invention, pharmaceutically acceptable excipients include solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, excipients, flocculants and anti-flocculators, filter aids, and release inhibitors.

[0053] According to embodiments of the present invention, the pharmaceutical composition may optionally further comprise at least one additional active ingredient; specifically, the pharmaceutical composition may further comprise one or more active ingredients other than the aforementioned vinylpyranone compounds, their stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, and prodrugs. In the pharmaceutical composition, the dosage of the aforementioned vinylpyranone compounds, their pharmaceutically acceptable salts, solvates, polymorphs, metabolites, stereoisomers, tautomers, isotope-labeled compounds, nitrogen oxides, esters, and prodrugs may be a therapeutically effective amount.

[0054] According to embodiments of the present invention, the pharmaceutical compositions of the present invention can be formulated into dosage forms suitable for administration using methods known in the art. According to embodiments of the present invention, the formulations (or pharmaceutical compositions) include: oral formulations and non-oral formulations. According to embodiments of the present invention, the formulations include: powders, granules, capsules, injections, inhalants, tinctures, oral liquids, tablets, lozenges, or drops.

[0055] The present invention also provides any of the following applications of the vinylpyranone compounds of formula (I) above, their stereoisomers, tautomers, isotope labels, nitrides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs, or pharmaceutical compositions thereof:

[0056] (1) Application in the preparation of antioxidant drugs;

[0057] (2) Application in the preparation of anti-inflammatory drugs;

[0058] (3) Preparation of Aβ 1-42 Applications in aggregation inhibitors, or preparation of Aβ inhibitors 1-42 Application in aggregated drugs;

[0059] (4) Application in the preparation of cholinesterase inhibitors or in the preparation of drugs that inhibit cholinesterase activity;

[0060] (5) Application in the preparation of medicines for the prevention and / or treatment of Alzheimer's disease.

[0061] The present invention also provides a method comprising administering to a therapeutic subject a therapeutically effective amount of a vinylpyranone compound of formula (I) above, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs, or one, two, or more of the above pharmaceutical compositions; the method being used for:

[0062] (i) Antioxidant, or

[0063] (ii) Anti-inflammatory, or

[0064] (iii) Inhibit Aβ 1-42 Gather, or

[0065] (iv) Inhibit cholinesterase activity, or

[0066] (v) Prevention and / or treatment of Alzheimer's disease.

[0067] Beneficial effects

[0068] This invention provides a vinylpyranone compound of formula (I), which exhibits excellent antioxidant activity, anti-inflammatory activity, and Aβ inhibition. 1-42 Aggregation activity and inhibition of cholinesterase activity.

[0069] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0070] The term "halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0071] Generally, the term "substituted" indicates 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 substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted 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 can be substituted at the same or different positions. The substituents mentioned can be, but are not limited to, =O, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, etc.

[0072] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently selected" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can be independently selected from the same or different specific groups. More specifically, the descriptive phrase "...independently selected" can mean either that the specific options expressed by the same symbol in different groups do not affect each other, or that the specific options expressed by the same symbol in the same group do not affect each other.

[0073] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.

[0074] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the 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 "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0075] The term "C1-10 alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 10 carbon atoms. For example, "C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; and in still other embodiments, the alkyl group contains 1-4 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and isopropyl. butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or their isomers.

[0076] The term "3-20 membered heterocyclic group" should be understood to refer to a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane containing 1-5 heteroatoms independently selected from N, O, and S, forming a non-aromatic cyclic group with a total number of ring atoms of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a saturated monovalent monocyclic, bicyclic, or bridged cyclic alkane containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. According to the invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is linked to other groups to form the compounds of the invention, the carbon atom on the 3-20 membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring can be linked to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be linked to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and its para-carbon atom can be linked to other groups.

[0077] Term "C" 6-20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms that is monovalent and partially aromatic, preferably "C". 6-14 "Aromatic". The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0078] The term "5-20-membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems, including aromatic or partially aromatic systems, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, such as "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purinyl, and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylonitrileyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, etc. When the 5-20 membered heteroaryl group is linked with other groups to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked with other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be linked with other groups. When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom linked to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen atom linked to the heteroatom on the heteroaryl ring may be substituted.

[0079] Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may include those in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene groups include thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0080] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereo chemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0081] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0082] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0083] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0084] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0085] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0086] In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0087] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0088] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents 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 using the LWDeady method (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0089] The term "isotope label" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl)-labeled compounds of the present invention. Isotope-labeled compounds of the present invention can be used for the determination of the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3 H and 14 C. Furthermore, in some cases, substitution with a heavier isotope (e.g., deuterium (2H or D)) can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0090] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, etc.

[0091] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0092] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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.

[0093] As used in this invention, the term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0094] Pharmaceutically acceptable salts can be, for example, acid addition salts of compounds of the present invention having sufficient basicity and containing a nitrogen atom in the chain or ring, such as acid addition salts formed with inorganic acids including: 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 including: 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, and diglucose. Gluconic acid, 3-hydroxy-2-naphtholic acid, nicotinic acid, pyruvic acid, pectinic acid, persulfate, 3-phenylpropionic acid, picric acid, pentyl acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric 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, glucohepanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfonic acid or thiocyanate.

[0095] Alternatively, another suitable pharmaceutically acceptable salt of the compounds of the present invention having sufficient acidity is an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium 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 sodium ions, potassium ions, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serine, trihydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts formed by the -COOH group with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serine, trihydroxymethylaminomethane, aminopropylene glycol, and 1-amino-2,3,4-butanetriol.

[0096] In addition, basic nitrogen-containing groups can be quaternized using 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; and aralkyl halides such as benzyl and phenethyl bromides. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, hydrogen sulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates, or meglumine salts.

[0097] Since the compounds of the present invention can have multiple salt-forming sites, the pharmaceutically acceptable salt includes not only the salt formed at one salt-forming site of the compound of the present invention, but also the salt formed at two, three, or all of the salt-forming sites. Therefore, the molar ratio of the compound of formula (I) to the anion of the acid or the cation of the base required for salt formation in the pharmaceutically acceptable salt can vary over a wide range, for example, from 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0098] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0099] In this invention, "ester" refers to an ester that is hydrolyzable in vivo, formed from a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that, upon hydrolysis in a human or animal body, produces a parent alcohol or acid. The compounds of formula (I) of this invention contain a carboxyl group and can form hydrolyzable esters in vivo with suitable groups, including, but not limited to, alkyl, arylalkyl, etc.

[0100] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0101] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound of this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amounts may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the particular compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0102] The pharmaceutical excipients described herein are those widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to ensure that the active ingredient dissolves at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0103] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicates, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0104] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0105] The dosage form of the pharmaceutical product of this invention can be selected according to specific circumstances. Pharmaceutical dosage forms often consist of a drug, excipients, and a container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compounds of this invention to improve or promote the manufacture, stability, administration, and safety of the drug, and to provide a method for obtaining the desired drug release profile. Therefore, the type of excipient added to the drug can be determined by various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. The pharmaceutical compositions of this invention may include one or more physiologically acceptable inactive ingredients that facilitate the processing of the active molecule into a formulation for pharmaceutical use.

[0106] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, administration via mucosa or nose, and oral administration. For oral administration, compounds can be formulated into liquid or solid dosage forms and presented as immediate-release or controlled-release / sustained-release formulations. Suitable dosage forms for individual oral intake include tablets, pills, sugar-coated pills, hard-shell and soft-shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions.

[0107] Solid oral dosage forms can be obtained using excipients, including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, flow aids, anti-adhesion agents, cation exchange resins, humectants, antioxidants, preservatives, colorants, and flavoring agents. These excipients can be synthetic or of natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silica, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth gum, hydrogenated vegetable oils, and waxes. Ethanol and water can be used as granulation aids. In some cases, tablets need to be coated with, for example, a taste-masking film, an acid-resistant film, or a delayed-release film. Natural and synthetic polymers are often combined with colorants, sugars, and organic solvents or water to coat tablets, resulting in sugar-coated pills. When capsules are preferred over tablets, their drug powders, suspensions, or solutions can be delivered in compatible hard-shell or soft-shell capsule forms.

[0108] The effective therapeutic dose can first be estimated using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in cell culture assays. A suitable dose range for humans can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as oral formulations.

[0109] The appropriate formulation, route of administration, dosage, and dosing interval can be selected based on methods known in the art and taking into account the specific circumstances of the individual.

[0110] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0111] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention. Attached Figure Description

[0112] Figure 1 The results are the determination of the antioxidant activity of the compound.

[0113] Figure 2 The results are for determining the half-inhibitory concentration of the compound for nitric oxide using the Griess method.

[0114] Figure 3 Results of the inhibitory effect of the compound on Aβ aggregation determined by the ThT method (administered concentration: 50 μM). Detailed Implementation

[0115] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory 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 covered within the scope of protection intended by the present invention.

[0116] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0117] Example 1: Preparation of the compound

[0118] (1) Starting with kojic acid as the raw material, compound 7c was synthesized through four steps: bromination, hydroxyl protection, acylation and Heck coupling.

[0119] Weigh 71 g of kojic acid (compound 1) (0.5 mol), 133.5 g of N-bromosuccinimide (0.75 mmol, 1.5 eq.), and 38.5 g of ammonium acetate (0.5 mol, 1.0 eq.) into a 1500 mL round-bottom flask. Add 800 mL of tetrahydrofuran. Heat to reflux at 70 °C for 2 hours. Monitor the reaction of the starting material by TLC until complete. Filter to remove ammonium acetate. Then remove tetrahydrofuran by rotary evaporation under reduced pressure to give a brown oily substance. Immediately add ethyl acetate and cool in an ice bath to precipitate a pale yellow solid. Filter and dry to give 59.9 g of pale yellow solid compound 2, yield 47%. 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),6.37(s,1H),5.79(s,1H),4.32(s,2H).

[0120] Weigh 25.0 g of 2-bromo-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 2, 0.11 mol) and 23.5 g of potassium carbonate (0.17 mol, 1.5 eq.) into a round-bottom flask. Add 250 mL of acetonitrile. Stir magnetically until the solid is completely dissolved. After purging with nitrogen three times, add 21.2 g of benzyl bromide (0.12 mol, 1.05 eq.) dropwise. After the addition is complete, heat at 80 °C overnight. Monitor the reaction by TLC until the reactants have reacted completely. Filter to remove potassium carbonate. Remove acetonitrile by rotary evaporation, extract three times with ethyl acetate, wash with brine, concentrate the organic phase to obtain the crude product, and purify by column chromatography (PE:EA = 1:10) to obtain 18.3 g of yellow oily compound 3, yield 52%. 1 HNMR (400MHz, CDCl3) δ7.42-7.47(m,2H),7.31-7.38(m,3H),6.50(t,J=0.8Hz,1H),5.19(s,2H),4.45(d,J=0.6Hz,2H).

[0121] Weigh 3.11 g of 3-(benzyloxy)-2-bromo-6-(hydroxymethyl)-4H-pyran-4-one (compound 3, 10 mmol), 1.51 g of triethylamine (15 mmol, 1.5 eq.), and 0.31 g of 4-dimethylaminopyridine (4-DMAP, 2.5 mmol, 0.25 eq.) into a dry, thick-walled, pressure-resistant flask. After purging with nitrogen three times, add 20 mL of acetonitrile dried with sodium hydride. Then add 1.83 g of N-methyl-N-ethylcarbamoyl chloride (15 mmol, 1.5 eq.). After the addition is complete, purge with nitrogen three more times. Reflux at 70 °C for 24 h. Monitor the reaction by TLC. Rotary evaporation is performed to remove acetonitrile. The residue is extracted three times with saturated brine and ethyl acetate. Combine the organic phases. Column chromatography (stationary phase: silica gel; 300-400 mesh; PE:EA = 3:1) yielded 2.10 g of a pale yellow oily compound 6, with a yield of 53%.

[0122] In a 100 mL double-necked flask equipped with a magnetic stirrer, weigh out 1.0 g of compound 6, 0.57 g of 4-hydroxystyrene (3.5 mmol; 1.25 eq.), and 0.64 g of triethylamine (6.3 mmol, 2.5 eq.). Add 20 mL of N,N-dimethylformamide and stir to dissolve. Purge with nitrogen three times. Weigh out 0.06 g of palladium acetate (0.25 mmol, 0.1 eq.) and add it to the reaction system. Purge with nitrogen three times again. Reflux the reaction at 85 °C for three days, monitoring the reaction until complete by TLC. Filter to remove the black powder. Extract the residue four times with ethyl acetate and saturated brine, and combine the organic phases. Dry the organic phase with anhydrous sodium sulfate. Mix the sample and perform column chromatography (stationary phase: silica gel; 300-400 mesh; EA:PE = 2:1) to obtain 0.51 g of yellow oily substance 7c. The yellow oily substance 7c was recrystallized with PE:EA:Et2O = 7:1:2 to give 0.29 g of pale yellow powdery solid 7c, with a yield of 26%.

[0123] The reaction route is as follows:

[0124]

[0125] The characterization data of compound 7c are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.44-7.42(m,2H),7.35-7.25(m,5H),7.09-7.06(m,1H),6.84-6.83(m,2H),6.83 -6.81(m,1H),6.37(s,1H),5.20(s,2H),4.98(s,2H),3.35(q,J=7.6Hz,2H),2.95(s,3H),1.15(t,J=7.2Hz,3H); 13CNMR(101MHz,D2O)δ177.06,161.74,157.77,143.23,139.41,137.17,131.90,131.55,130.99,130.9 5,128.88,118.57,113.99,75.97,64.21,46.14,45.67,36.57,35.73,15.59,14.98; HRMS(ESI+)calcd for C 25 H 25 NO6[M+H] + 435.1760, found 436.1754; purity 99.806%.

[0126] Following the preparation method of compound 7c described above, compounds 7a, 7b, and 7d were synthesized. The structural formulas and characterization data of compounds 7a-d are shown in Table 1.

[0127] (2) Using kojic acid as the starting material, compound 5a was synthesized through four steps: bromination, hydroxyl protection, Heck coupling and acylation.

[0128] Compound 3 was prepared according to method 1) above.

[0129] In a 100 mL double-necked flask equipped with a magnetic stirrer, weigh out 2.0 g of compound 3, 0.83 g of styrene (8 mmol, 1.25 eq.), and 0.97 g of triethylamine (9.6 mmol, 1.5 eq.). Add 40 mL of N,N-dimethylformamide and stir to dissolve. Purge with nitrogen three times. Weigh out 0.07 g of palladium acetate (0.32 mmol, 0.05 eq.) and add it to the reaction system. Purge with nitrogen three times again. Refrigerate at 85 °C for 24 h and monitor the reaction until complete by TLC. Filter to remove the black powder. Extract the residue three times with ethyl acetate and saturated brine. Combine the organic phases. Dry the organic phase with anhydrous sodium sulfate. Mix the sample and separate by column chromatography (stationary phase: silica gel; 300-400 mesh; PE:EA = 1:1) to obtain a white solid. Recrystallize the white solid with PE:EA = 8:1 to give 1.10 g of compound 4a, yield 51.9%.

[0130] 0.33 g (compound 4a, 10 mmol), 0.15 g triethylamine (15 mmol, 1.5 eq.), and 0.03 g 4-dimethylaminopyridine (4-DMAP, 2.5 mmol, 0.25 eq.) were weighed into a dry, thick-walled, pressure-resistant flask, respectively. After purging with nitrogen three times, 20 mL of acetonitrile dried with sodium hydride was added. Then, 0.18 g N-methyl-N-ethylcarbamoyl chloride (15 mmol, 1.5 eq.) was added. After the addition was complete, the flask was purged with nitrogen three times again. The reaction was refluxed at 70 °C for 24 h. The reaction was monitored by TLC. The acetonitrile was removed by rotary evaporation. The residue was extracted three times with saturated brine and ethyl acetate. The organic phases were combined. Column chromatography (stationary phase: silica gel; 300-400 mesh; PE:EA = 1:1) was used to separate 0.17 g of compound 5a, in 40.5% yield. The reaction route is as follows:

[0131]

[0132] The characterization data of compound 5a are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.46-7.44(m,2H),7.40-7.39(m,2H),7.37-7.29(m,6H),7.19-7.16(m,1H),7 .02-6.99(m,1H),6.39(s,1H),5.25(s,2H),5.00(s,2H),3.42-3.34(m,2H),2.96(s,3H),1.17-1.14(m,3H); 13 C NMR(101MHz,DMSO-d6)δ175.02,162.27,154.82,141.83,137.06,135.53,134.65,129.9 5,129.47,129.44,128.81,127.87,115.39,113.31,73.87,62.00,43.92,33.58,13.40.

[0133] Following the same method used to prepare compound 5a, compounds 5b-5z were synthesized. The structural formulas and characterization data of compounds 5a-5z are shown in Table 1.

[0134] Table 1. Compound structural formulas and characterization data

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] Example 2: Activity test of the compound

[0142] (1) ORAC method for determining the antioxidant activity of compounds

[0143] Experimental Methods: All compounds were screened at a concentration of 2 μM. 120 μL of fluorescein (FL, final concentration 70 nM) and 20 μL of the test compound (final concentration 2 μM) were added to a black 96-well plate. After incubation at 37 °C for 15 min, 60 μL of 2,2'-azobisisobutylamidine dihydrochloride solution (AAPH, final concentration 12 mM) was rapidly added. Fluorescence was recorded once per minute for 120 min. Phosphate-buffered saline (PBS) was used as a blank control instead of the test compounds. (Excitation wavelength: 485 nm; Emission wavelength: 535 nm) ORAC values ​​are expressed as equivalents (eq.) of 6-hydroxy-2,5,7,8-tetramethyltryptane-2-carboxylic acid (Trolox).

[0144] Antioxidant activity test results as follows Figure 1 As shown in Table 2, the results demonstrate that the compounds provided by this invention possess excellent antioxidant activity.

[0145] Table 2. ORAC determination results of the compounds

[0146] compound ORAC value (eq.) 5s 0.65±0.37 5x 0.62±0.07 5y 0.59±0.30 7a 6.45±0.27 7b 3.37±0.30 7c 4.99±0.64 7d 3.51±0.53

[0147] (2) Anti-inflammatory activity test of the compound

[0148] Experimental method (i): MTT assay to determine the effect of the compound on BV-2 cell viability

[0149] 100 μL of BV-2 cell suspension (cell density 5 × 10⁶ cells / well) was seeded into each well of a 96-well plate. 3 Cells were incubated at 37°C with 5% CO2 for 24 hours before drug administration. Three replicates were set up for background wells, test groups, and blank groups. Eight different concentrations of sample solution were added to the test groups (DMEM medium was added to the blank groups). After another 24 hours of incubation, 20 μL of MTT solution (5 mg / mL) was added to each well, and the cells were incubated for 4 hours to allow crystals to form. The supernatant was removed, and 150 μL of DMSO was added to each well. The cells were then shaken at low speed for 15 minutes to fully dissolve the crystals. The absorbance at 490 nm was measured using a microplate reader, and cell viability was calculated using the following formula.

[0150] Cell survival rate = (ODs - OTr) / (OD0 - OTr) × 100%

[0151] ODs: Absorbance of the sample group; ODr: Absorbance of the background group; OD0: Absorbance of the blank group.

[0152] Experimental method (ii): Griess method to determine the effect of compounds on LPS-induced NO release from BV-2 cells

[0153] 100 μL of BV-2 cell suspension (cell density 5 × 10⁶ cells / well) was seeded into each well of a 96-well plate. 4 Cells were cultured in a 37°C, 5% CO2 incubator for 24 h. LPS (1 μg / mL) was added and incubated for 1 h, followed by drug administration. After another 24 h of culture, 50 μL of cell supernatant was transferred to another 96-well cell culture plate. 50 μL each of Griess A and B reagents were added, and the plate was incubated in the dark for 10 min. The OD value was measured at 540 nm. The NO concentration was calculated based on a standard curve prepared using NaNO2.

[0154] The experiment included a blank group (DMEM medium added, no LPS stimulation), an LPS model group (DMEM medium added, LPS stimulation), a positive drug group (dexamethasone, LPS stimulation), and a test group (15 μM drug, LPS stimulation), with 3 replicates for each group.

[0155] Experimental Results: The MTT assay results for the effect of the compound on BV-2 cell viability showed that the compound at a concentration of 20 μM had no effect on the cell cycle of BV-2 cells; the inhibitory effect of the compound on the inflammatory factor nitric oxide at a concentration of 15 μM is shown in Table 3. Figure 2 As shown, the results indicate that the compound provided by the present invention has an inhibitory effect on the inflammatory factor nitric oxide; at the same time, the half-maximal inhibitory concentration of nitric oxide of compound 7c is 8.60±1.33μM.

[0156] Table 3. Inhibitory effects of compounds on the inflammatory factor nitric oxide.

[0157]

[0158]

[0159] (3) The Aβ of the compound was determined by the ThT binding method. 1-42 Aggregation inhibition rate

[0160] Experimental methods: All compounds were screened at a concentration of 50 μM. The experiment was set up with 3 replicates and performed independently 3 times. Resveratrol was used as a positive control. 10 μL of Aβ was added... 1-42Incubate (25 μM, final concentration) ± 10 μL of the compound or PBS (50 μM, final concentration) at 37 °C in the dark for 24 h. After incubation, extract 20 μL of sample into a black 96-well plate, dilute to 200 μL with 180 μL of gly-NaOH buffer (50 mM, pH 8.5) containing 5 μM ThT, vortex at low speed for 5 min, and then measure the fluorescence intensity using a multi-mode microplate reader (excitation wavelength 450 nm, emission wavelength 490 nm). Calculate the percentage of inhibition of self-induced aggregation using the following formula.

[0161] I Aβ1-42 (%) = 1 - (Fs / F0) × 100%

[0162] ThT method for determining the inhibition of Aβ by compounds 1-42 Aggregation results as follows Figure 3 As shown in Table 4, at a dosage concentration of 50 μM, compounds 7a and 7c exhibited Aβ inhibition comparable to resveratrol. 1-42 active.

[0163] Table 4 Compound Aβ 1-42 Aggregation inhibition rate

[0164]

[0165] (4) The inhibitory activity of the compound against cholinesterase was determined using the modified Ellman method.

[0166] Experimental Methods: The experiment was set up with 3 replicates, and each experiment was performed independently 3 times. 40 μL of phosphate-buffered saline (PBS, 0.1 M, pH 8.0), 10 μL of the sample (or PBS), 20 μL of 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB, 10 mM), and 10 μL of eeAChE or eqBuChE (2.5 U / mL) were incubated at 37°C for 10 min. Then, 20 μL of acetylthiocholine chloride (ATC, 75 mM) was added, and the mixture was incubated at 37°C for another 10 min. The absorbance at 412 nm was measured using a microplate reader, and the inhibition rate (IR) and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0167] The results of the inhibitory activities of the compounds determined by the modified Ellman method for eeAChE and eqBuChE are shown in Table 5.

[0168] Table 5. Inhibitory activities of compounds against eeAChE and eqBuChE

[0169]

[0170] In summary, the compounds provided by this invention possess excellent antioxidant activity, anti-inflammatory activity, and Aβ-inhibition activity. 1-42 Aggregation activity and inhibition of cholinesterase activity.

[0171] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A vinyl pyrone compound represented by formula (I) or a pharmaceutically acceptable salt thereof, ###0001### the vinyl pyrone compound is selected from the following compounds: ###0002### ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###020 ​ ​ ​ ​ wherein ​ ​ ​ ​ ​ ​ ​ (2) the preparation of Aβ 1-42 use in the manufacture of a medicament for inhibiting the aggregation of Aβ 1-42 use in the manufacture of a medicament for inhibiting the aggregation of Aβ ​

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