CN109134481B

CN109134481B - Substituted pyrrole chromone compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Info

Publication number: CN109134481B
Application number: CN201810890337.2A
Authority: CN
Inventors: 罗海彬; 吴德燕; 黄雅丹; 陈仪萍; 于艳发
Original assignee: Sun Yat Sen University
Current assignee: Sun Yat Sen University
Priority date: 2018-08-07
Filing date: 2018-08-07
Publication date: 2021-05-14
Anticipated expiration: 2038-08-07
Also published as: CN109134481A

Abstract

The invention discloses a substituted pyrrole chromone compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The structure of the compound or the pharmaceutically acceptable salt thereof is shown as (I). The substituted pyrrole chromone compound or the pharmaceutically acceptable salt thereof has a novel structure, shows excellent inhibition effect on 5-type phosphodiesterase and can be selectively usedThe compound can be used as a type 5 phosphodiesterase inhibitor and can be prepared into medicaments for treating and/or preventing related diseases caused by the type 5 phosphodiesterase, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, tumor resistance reversal and the like.

Description

Substituted pyrrole chromone compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a novel substituted pyrrole chromone compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

Background

Cyclic nucleotide Phosphodiesterases (PDEs) are an important super enzyme family, which effectively control the intracellular concentrations of cAMP and cGMP by hydrolyzing cAMP and cGMP, thereby regulating the biochemical effects conducted by second messengers in vivo. PDEs (PDE1-PDE11) are widely distributed in mammalian tissues, and the diversity of PDEs enables different PDE enzymes to have specific distribution at cellular and subcellular levels, can selectively regulate various cellular functions, and are good drug design and treatment targets.

Phosphodiesterase type 5 (PDE5), a family of PDEs specific for cGMP, was first isolated and identified in mouse platelets and later discovered and purified in mouse lungs. Human PDE5A is mainly distributed in aortic vascular smooth muscle cells, heart, placenta, skeletal muscle cells, pancreas, platelets, and also has a very small distribution in brain, liver, and lung. The level of PDE5 in the corpus cavernosum of the male penis is much higher than in other PDE families.

The most successful of the PDEs inhibitors developed were PDE5A inhibitors. Sildenafil (vildenafil, Viagra), Vardenafil (Levitra), Tadalafil (Tadalafil, Cialis) are drugs for treating erectile dysfunction, and Sildenafil is later proved to have clinical efficacy in treating pulmonary hypertension. In addition, PDE5 inhibitors have been found to be useful in improving memory, in anti-tumor, in treating pulmonary diseases, and in treating cardiac diseases. Nevertheless, the existing PDE5A inhibitors have considerable side effects: such as headache, blurred vision, blush, congestion of nasal mucosa, digestive dysfunction, and muscle pain. On the other hand, the existing medicines can cause more serious adverse reactions to patients with serious liver and kidney insufficiency. The development of a new generation of PDE5 selective inhibitor with strong curative effect and weak side effect is of great significance. At present, substituted pyrrole chromone compounds are mostly used for preparing hypolipidemic drugs, and no research is available on the application of the substituted pyrrole chromone compounds as PDE5 inhibitors.

Disclosure of Invention

The invention aims to provide a novel substituted pyrrole chromone compound. The compound disclosed by the invention is novel in structure, has excellent inhibitory action on type 5 phosphodiesterase, can be used as a type 5 phosphodiesterase inhibitor, and can be further prepared into a medicament for treating and/or preventing related diseases caused by type 5 phosphodiesterase, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, tumor resistance reversal and the like.

The invention also aims to provide a preparation method of the substituted pyrrole chromone compound.

The invention further aims to provide application of the substituted pyrrole chromone compound.

The above object of the present invention is achieved by the following scheme:

a substituted pyrrole chromone compound has a structure shown in formula (I) or a pharmaceutically acceptable salt thereof:

wherein Y is oxygen or sulfur; x is selected from hydrogen, halogen and C_1-5Substituted or unsubstituted cycloalkane, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocycle, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, C_1-5Substituted or unsubstituted carboxylic acid groups, C_1-5Substituted carboxylate-containing groups;

R₁、R₂and R₄Are respectively selected from hydrogen, halogen, hydroxyl and C_1-6Substituted or unsubstituted alkyl, C_1-6Substituted or unsubstituted alkoxy, C_1-6Substituted or unsubstituted alkylamino, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, C_1-5Substituted or unsubstituted carboxylic acid groups, C_1-5Substituted carboxylate-containing groups, nitrogen-containing groups, phosphorus-containing groups, or sulfur-containing groups;

R₃selected from hydrogen, halogen, hydroxy, C_1-6Substituted or unsubstituted alkyl, C_1-6Substituted or unsubstituted alkoxy, C_1-6.Substituted or unsubstituted alkylamino, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, C_1-5Substituted or unsubstituted carboxylic acid groups, C_1-5Substituted carboxylate-containing groups, nitrogen-containing groups, phosphorus-containing groups, or sulfur-containing groups;

R₅selected from hydrogen, halogen, C_1-5Substituted or unsubstituted alkyl, C_1-5Substituted or unsubstituted alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted (3, 4-methylenedioxy) benzyl; substituted or unsubstituted anilino, substituted or unsubstituted benzylamine, C_1-5Substituted or unsubstituted alkoxymethyl, C_1-5Substituted or unsubstituted alkylaminomethyl, substituted or unsubstituted phenoxymethyl, substituted or unsubstituted benzyloxymethyl, substituted or unsubstituted anilinomethyl, substituted or unsubstituted benzylamine methyl, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, C_1-5Substituted or unsubstituted amidomethyl, C_1-5Substituted or unsubstituted carboxylic acid groups, C_1-5Substituted or unsubstituted carboxylic acid methyl, C_1-5Substituted carboxylate radical, nitrogen-containing radical, phosphorus-containing radical, sulfur-containing radical, substituted or unsubstituted benzyl radical, substituted or unsubstituted aromatic radical and amino acid side chain structure.

Preferably, X is selected from hydrogen, halogen, C_1-5Substituted or unsubstituted cycloalkane, substituted or unsubstituted aromatic ring, substituted or unsubstituted aromatic heterocycle;

the R is₁、R₂And R₄Are respectively selected from hydrogen, halogen, hydroxyl and C_1-6Substituted or unsubstituted alkyl, C_1-6Substituted or unsubstituted alkoxy, C_1-6Substituted or unsubstituted alkylamino;

the R is₃Selected from hydrogen, halogen, hydroxy, C_1-6Substituted or unsubstituted alkyl, C_1-6Substituted or unsubstituted alkoxy, C_1-6.Substituted or unsubstituted alkylamino, C_1-5Substituted or unsubstituted acyl, C_1-5Substituted or unsubstituted amide group, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted morpholine;

the R is₅Selected from hydrogen, halogen, C_1-5Substituted or unsubstituted alkyl, C_1-5Substituted or unsubstituted alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxy, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxy, substituted or unsubstituted benzyl

Preferably, X is selected from C_5-6Substituted or unsubstituted aromatic ring, C_5-6Substituted or unsubstituted aromatic heterocyclic ring;

the R is₁、R₂And R₄Are respectively selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy;

the R is₃Wherein the substituent is C_1-4Alkyl radical, C_1-4Alkoxy, piperazine, piperidine or morpholine;

the R is₅Wherein the substituent is a carboxylic acid group, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-5Aliphatic, acyl, or substituted amides.

Preferably, X is selected from 2-thiazole or 2-oxazole;

the R is₃Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy, ethoxy,

-NHCH₃、-NHCH₂CH₂OCH₃、-NHCH₂CH₂N(CH₃)₂、N(CH₃)CH₂CH₂OCH₃or-N (CH)₃)CH₂CH₂N(CH₃)₂；

The R is₅Is selected from-CH₂OC(CH₃)₃、-CH₂COOH、-CH₂COOC(CH₃)₃、CH₂CONHCH₃、

Preferably, the pyrrole chromone compound of formula (I) has a structure of formula (II) or (III):

wherein R is₆One or more selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxy, ethoxy, acetyl, isopropyl, cyano, nitro, amino, N-dimethylamino, benzyloxy, carboxylic acid group, substituted amino, substituted or unsubstituted guanidino, substituted or unsubstituted phosphoric acid group, substituted or unsubstituted phosphoryl group, substituted or unsubstituted sulfonic acid group and substituted or unsubstituted sulfonyl group.

Preferably, said R is₆Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxy, ethoxy, acetyl, isopropyl, cyanogenOne or more of a group, a nitro group, an amino group, an N, N-dimethylamino group, a benzyloxy group, a carboxylic acid group or a substituted amino group.

More preferably, R₆One or more selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, chloromethyl, trifluoromethyl, methoxy, ethoxy, cyano or nitro.

Preferably, the structure of the substituted pyrrole chromone compound or the pharmaceutically acceptable salt thereof is selected from any one of the following:

preferably, the pharmaceutically acceptable salt of the compound is the product of the reaction of the compound of formula (I) with an acid. Thiazole, secondary amine or tertiary amine exists in the compound shown in the formula (I), and the compound can react with acid to generate salt, so that the pharmaceutically acceptable salt with the same biological activity is obtained.

Preferably, the acid includes, but is not limited to, hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid, or glutamic acid.

The invention also provides a preparation method of the substituted pyrrole chromone compound, which comprises the following steps:

s1, mixing a compound 1 with a compound 2 in a solvent with alkaline substances dissolved at-30-25 ℃, and gradually heating to 25-120 ℃ for reaction to obtain a compound 3;

s2, reacting the compound 4 and the compound 3 in a solvent dissolved with an alkaline substance at normal temperature and then at 40-90 ℃ under the action of a condensing agent to obtain a compound 4;

wherein Z is sulfur or oxygen; the R is R in claims 1-3₁～R₄One or more of; r' is R in claims 1-3₅。

Preferably, the condensing agent in step S2 is selected from 2- (7-azobenzotriazol) -N, N '-tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N' -tetramethyluronium Hexafluorophosphate (HBTU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 2- (1H-benzotriazol-L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), N '-Dicyclohexylcarbodiimide (DCC), or N, N' -Carbonyldiimidazole (CDI).

Preferably, the temperature at which compound 1 and compound 2 are mixed in step S1 is 0 ℃.

Preferably, the basic substance in step S1 includes, but is not limited to, one or more of potassium tert-butoxide, sodium hydride, lithium bis-trisilyl amide, sodium bis-trisilyl amide, lithium diisopropylamide.

Preferably, the basic substance in step S2 includes, but is not limited to, one selected from diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, piperidine, sodium bicarbonate, sodium carbonate, potassium carbonate or a mixture thereof.

Preferably, the solvent in step S1 is selected from one or more of tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene, or xylene.

Preferably, the solvent in step S2 is selected from one or more of dimethylformamide, dimethylsulfoxide, pyridine, tetrahydrofuran, 1, 4-dioxane, toluene or xylene.

Preferably, when Z in compound 2 is sulfur, compound 2 is prepared by the following process: reacting thiazole or 2-halogen-thiazole with trimethylhalosilane at-80-10 ℃ under an alkaline condition, and gradually heating to 0-30 ℃ for reaction to obtain an intermediate 1, namely 2- (trimethylsilyl) -thiazole; and then reacting the intermediate 1 with halogenated ethyl formate at 0-30 ℃ to obtain a compound 2. The reaction process is as follows:

wherein R is₆Is hydrogen or halogen.

More preferably, the initial reaction temperature of compound 2 with the trimethylhalosilane is-78 ℃.

Preferably, when R' is

When the compound 4 has the structure

The preparation method comprises the following steps:

s41, mixing the compound 6 with an acidic substance at the temperature of-30-10 ℃, and then gradually heating to 25-100 ℃ for reaction to obtain a compound 7;

s42, mixing the compound 7 with an alkaline substance, gradually adding di-tert-butyl dicarbonate step by step, and reacting at 10-40 ℃ to obtain a compound 8;

s43, mixing the compound 8, dihalogenated methane and an alkaline substance in a solvent, gradually heating to 60-120 ℃, and reacting to obtain a compound 9;

s44, mixing the compound 9 with an alkaline substance in a solvent, and heating to 25-100 ℃ for reaction to obtain a compound 10;

s45, mixing the compound 10 with an acidic substance in a solvent, and stirring at 0-30 ℃ for reaction to obtain a compound 11;

s46, mixing the compound 11 and an alkaline substance in a solvent at the temperature of-20 ℃, then gradually adding chloroformic acid-9-fluorenylmethyl ester (FmocCl) for reaction, and gradually heating to the temperature of 25-40 ℃ for reaction to obtain a target product (namely a compound 12);

wherein R' is C_1-5Alkyl, or benzyl.

Preferably, the initial reaction temperature in step S41 and step S46 is 0 ℃.

Preferably, the acidic substance in step S41 is selected from one or more of thionyl chloride, oxalyl chloride or concentrated sulfuric acid; the reaction is carried out at C_1-5Alkyl alcohol or benzyl alcohol.

Preferably, the basic substance in step S42 is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, triethylamine, diisopropylethylamine, piperidine or pyridine; the reaction is carried out in one or more solvents selected from tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide and water.

Preferably, the dihalomethane in the step S43 is selected from one or a mixture of two of dibromomethane and diiodomethane; the alkaline substance is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide; the reaction is carried out in one or more solvents selected from acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran and 1, 4-dioxane.

Preferably, the basic substance in step S44 is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide; the reaction is carried out in one or more solvents selected from acetone, dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran and 1, 4-dioxane.

Preferably, the acidic substance in step S45 is selected from one or more of trifluoroacetic acid, concentrated hydrochloric acid, hydrogen chloride methanol solution or hydrogen chloride 1, 4-dioxane solution; the reaction is carried out in one or more solvents of dichloromethane, chloroform, toluene, tetrahydrofuran, ethyl acetate or diethyl ether.

Preferably, the basic substance in step S46 is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, pyridine, triethylamine or diisopropylethylamine; the reaction is carried out in one or more solvents selected from tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide and water.

Preferably, after the reaction in step S42 is completed, the reaction solution is extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 8.

Preferably, after the reaction of step S43 is completed, the reaction solution is extracted with ethyl acetate, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, and the residue obtained by concentration is separated by column chromatography to obtain compound 9.

Preferably, after the reaction in step S44 is completed, the reaction solution is concentrated to remove most of the solvent, the system is adjusted to acidity with dilute hydrochloric acid, extraction is performed with ethyl acetate, washing with water and saturated brine respectively, drying with anhydrous sodium sulfate, and concentration is performed to obtain compound 10.

Preferably, after the reaction in step S45 is completed, the reaction solution is diluted with dichloromethane, washed with saturated sodium bicarbonate and water, respectively, dried over anhydrous sodium sulfate, and concentrated to obtain compound 11.

Preferably, after the reaction in step S46 is finished, the reaction solution is diluted with water, washed with diethyl ether, the pH of the water layer is adjusted to 2-4 with hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine respectively, dried with anhydrous sodium sulfate, and concentrated to obtain the target product (i.e., compound 12).

Preferably, after the reaction in step S1 is completed, the reaction solution is introduced into an ice-water mixture, then the reaction solution is adjusted to be acidic, and then extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 3.

Preferably, after the reaction is completed in step S2, the reaction solution is cooled to room temperature, concentrated to remove the solvent, extracted with ethyl acetate, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, and the residue obtained by concentration is separated by column chromatography to obtain compound 5.

The application of the substituted pyrrole chromone compound or the pharmaceutically acceptable salt thereof as a phosphodiesterase type 5 inhibitor is also in the protection scope of the invention.

The invention also protects the application of the substituted pyrrole chromone compound or the pharmaceutically acceptable salt thereof in preparing the medicaments for treating diseases related to 5-type phosphodiesterase.

Preferably, the phosphodiesterase type 5 related disease is male sexual dysfunction, pulmonary arterial hypertension, pulmonary fibrosis or reversal of tumor resistance.

Preferably, the medicament can be prepared into clinically acceptable formulations by adding conventional auxiliary materials according to a conventional process.

More preferably, the medicament is in the form of oral tablets, pills, capsules, injection, powder for injection, and percutaneous or subcutaneous absorption.

Compared with the prior art, the invention has the following beneficial effects:

the substituted pyrrole chromone compound or the pharmaceutically acceptable salt thereof has a novel structure, shows excellent inhibitory action on 5-type phosphodiesterase, can selectively inhibit 5-type phosphodiesterase, has no or very weak inhibitory action on other subtype phosphodiesterases, namely the compound can be used as a 5-type phosphodiesterase inhibitor to prepare medicaments for treating and/or preventing related diseases caused by 5-type phosphodiesterase, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, tumor resistance reversal and the like.

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.

Example 1

In the compound of formula (II), when R is₅Is composed of

The specific synthetic route is as follows:

wherein, the compound 15, the compound 14, the compound 16 and the compound 13 are respectively the compound 1, the compound 2, the compound 3 and the intermediate 1 in the preparation method in the invention;

when X is 2-oxazole, R₅When other substituent groups are adopted, the preparation method is adopted, and the raw materials are replaced to obtain the target compound.

The preparation method comprises the following specific steps:

(1) synthesis of Compound 7

Thionyl chloride (134mL,1.8mol) was slowly added dropwise to a solution of levodopa (compound 6) (59.2g,0.3mol) in 500mL of methanol at 0 ℃ and after addition, the reaction was gradually warmed to room temperature and stirred for 12 hours. After concentration, the product (S) -methyl 2-amino-3- (3, 4-methylenedioxyphenyl) propionate hydrochloride (74.3g) was obtained as compound 7 in the form of a white solid with a yield of 100%.¹H NMR(400MHz,DMSO–d₆)δ8.94(s,1H),8.91(s,1H),8.52(br s,3H),6.68(d,J＝8.0Hz,1H),6.60(d,J＝2.1Hz,1H),6.45(dd,J＝8.0,2.1Hz,1H),4.12(t,J＝6.4Hz,1H),3.70(s,3H),3.00(dd,J＝14.1,5.9Hz,1H),2.92(dd,J＝14.1,6.9Hz,1H).

(2) Synthesis of Compound 8

Sodium bicarbonate (50.4g,0.6mol) was slowly added to a 300mL aqueous solution of (S) -methyl 2-amino-3- (3, 4-methylenedioxyphenyl) propionate hydrochloride (74.3g,0.3mol) at 0 deg.C, and then Boc was slowly added dropwise to the system₂A solution of O (74.3g,0.3mol) in tetrahydrofuran (150mL) was gradually warmed to room temperature after the completion of the dropwise addition, and the reaction was stirred for 16 hours. Concentrating to remove most of the solvent, extracting with ethyl acetate, washing with water and saturated brine, and drying with anhydrous sodium sulfateConcentration gave the product methyl (S) -2- (tert-butoxycarbonylamido) -3- (3, 4-methylenedioxyphenyl) propionate (i.e., compound 8) (89.6g) as a white solid in 96% yield.¹H NMR(400MHz,DMSO–d₆)δ8.69(s,2H),7.12(d,J＝7.9Hz,1H),6.61(dd,J＝9.8,4.9Hz,2H),6.51–6.41(m,1H),4.12–4.00(m,1H),3.60(s,3H),2.79(dd,J＝13.8,5.3Hz,1H),2.68(dd,J＝13.6,9.5Hz,1H),1.35(s,9H).

(3) Synthesis of Compound 9

Potassium carbonate (79.6g,576mmol) was added to a solution of methyl (S) -2-Boc-amino-3- (3, 4-dihydroxyphenyl) propionate (89.6g,288mmol) in 500mL acetonitrile, followed by diiodomethane (46.4mL,576mmol), and the reaction was stirred at reflux for 16 hours. After completion of the reaction, it was cooled to room temperature, concentrated to remove most of the solvent, the residue was diluted with ethyl acetate, insoluble matter was removed by filtration, the filter cake was washed with ethyl acetate, the filtrate was washed three times with water, and then dried over anhydrous sodium sulfate, concentrated, and column-chromatographed (petroleum ether: ethyl acetate ═ 5:1) to obtain the product methyl (S) -2- (tert-butoxycarbonylamido) -3- (3, 4-methylenedioxyphenyl) propionate (i.e., compound 9) (58.7g) as a white solid in 63% yield.¹H NMR(400MHz,CDCl₃)δ6.75(d,J＝7.9Hz,1H),6.63(d,J＝1.5Hz,1H),6.59(dd,J＝7.9,1.6Hz,1H),5.95(d,J＝1.3Hz,2H),5.00(d,J＝6.3Hz,1H),4.54(dd,J＝12.1,5.4Hz,1H),3.74(s,3H),3.02(qd,J＝13.8,5.7Hz,2H),1.45(s,9H).

(4) Synthesis of Compound 10

Sodium hydroxide (7.24g,181mmol) was added to a mixed solvent of methyl (S) -2- (tert-butoxycarbonylamido) -3- (3, 4-methylenedioxyphenyl) propionate (58.7g,181mmol) in methanol/water (3/1 (400mL), and the reaction was stirred at room temperature for 3 hours. After the reaction is completed, water is added for dilution, the methanol is removed by concentration, and then the system is adjusted by 3N hydrochloric acidpH 3.0, extraction with ethyl acetate, water, saturated brine, drying over anhydrous sodium sulfate, and concentration gave the product (S) -2- (tert-butoxycarbonylamido) -3- (3, 4-methylenedioxyphenyl) propionic acid (compound 10) (55.4) as a white solid in 99% yield.¹H NMR(400MHz,CDCl₃)δ6.76(d,J＝7.9Hz,1H),6.69(s,1H),6.65(d,J＝7.9Hz,1H),5.95(d,J＝1.8Hz,2H),5.01(d,J＝7.0Hz,1H),4.57(dd,J＝11.4,5.6Hz,1H),3.20–2.96(m,2H),1.45(s,9H).

(5) Synthesis of Compound 11

Trifluoroacetic acid (40mL) was slowly added to a solution of (S) -2-Boc-amino-3- (3, 4-methylenedioxyphenyl) propionic acid (55.4g,179mmol) in 120mL of dichloromethane, and the reaction was stirred at room temperature for 3 hours. After TLC monitoring of the reaction completion of the starting material, the solvent and trifluoroacetic acid were removed by concentration, and the residue was washed by beating with petroleum ether to precipitate an off-white solid which was filtered and dried to obtain the product (S) -2-amino-3- (3, 4-methylenedioxyphenyl) propionic acid trifluoroacetate salt (i.e., compound 11) (52.1g) in 95% yield.¹HNMR(400MHz,DMSO–d₆)δ8.22(s,2H),6.88(d,J＝7.9Hz,1H),6.84(d,J＝1.5Hz,1H),6.78–6.67(m,1H),6.00(d,J＝1.1Hz,2H),4.20–4.09(m,1H),3.02(ddd,J＝27.4,14.3,6.5Hz,2H).

(6) Synthesis of Compound 4

Sodium carbonate decahydrate (121.6g,425mmol) was slowly added to a solution of (S) -2-amino-3- (3, 4-methylenedioxyphenyl) propionic acid trifluoroacetate (52.1g,170mmol) in 1, 4-dioxane/water (1/1) (400mL) at 0 ℃, then a solution of FmocCl (44.0g,170mol) in 1, 4-dioxane (200mL) was slowly added dropwise thereto, and after completion of the addition, the reaction was continued at 0 ℃ for 1 hour with stirring and then gradually warmed to room temperature for 1 hour. After the reaction is completed, the system is diluted by adding water, and then washed by ethyl etherNext, the aqueous layer was adjusted to pH 3.0 with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the product (S) -2- (9-fluorenylmethoxycarbonylamido) -3- (3, 4-methylenedioxyphenyl) propionic acid (i.e., compound 4) (63.0g) as an off-white solid in 86% yield.¹H NMR(400MHz,CDCl₃)δ7.67(d,J＝7.5Hz,2H),7.39(dd,J＝15.7,7.9Hz,2H),7.35–7.27(m,2H),7.16(dd,J＝12.3,6.9Hz,2H),6.68–6.56(m,2H),6.52(s,1H),6.50–6.39(m,1H),5.71(s,2H),5.63(s,1H),4.47(d,J＝5.0Hz,1H),4.40–4.24(m,1H),4.08–3.99(m,1H),3.04(dd,J＝18.3,8.8Hz,1H),2.88(dd,J＝13.5,7.4Hz,1H).

(7) Synthesis of Compound 13

Under the protection of argon at-78 ℃, slowly dropwise adding 2-bromothiazole (compound 13) (49.2g,300mmol) into 500mL of diethyl ether solution of n-butyllithium (2.5M n-hexane solution, 122mL, 305mmol), after dropwise adding, continuously stirring and reacting for 30 minutes, then slowly adding trimethylchlorosilane (32.6g,300mmol) into the system, continuously reacting for 1 hour, and gradually heating to room temperature for reacting for 1 hour. The reaction was then quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with water and saturated brine, respectively, and the organic layer was dried and distilled under reduced pressure to give the product 2-trimethylsilylthiazole (i.e., compound 13) (38.5g) as a colorless liquid in a yield of 82%.¹H NMR(400MHz,CDCl₃)δ8.13(d,J＝2.9Hz,1H),7.54(d,J＝2.7Hz,1H),0.43(s,9H).

(8) Synthesis of Compound 14

Ethyl chloroformate (24.5mL,257mmol) was slowly added dropwise to a solution of 2-trimethylsilyl thiazole (38.5g,245mmol) in 500mL of toluene, and the reaction was stirred at room temperature for 3 hours. The reaction solution was slowly poured into an aqueous solution of sodium carbonate to quench the reaction, followed by stirring for 30 minutes. Separating organic layer, and using acetic acid for aqueous layerEthyl ester extraction was performed, and organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the product ethyl thiazole-2-carboxylate (i.e., compound 14) (37.7g) in 98% yield.¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝3.1Hz,1H),7.64(d,J＝3.1Hz,1H),4.49(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H).

(9) Synthesis of Compound 16

Dissolving a compound 15 with different substituents in an alkaline solvent at 0 ℃, stirring for reaction for 15 minutes, then slowly adding a compound 14, gradually heating to 25-120 ℃ until the raw materials are completely reacted, then introducing a reaction solution into an ice-water mixture, adjusting the system to be acidic by using dilute hydrochloric acid, then extracting by using ethyl acetate, washing by using water and saturated saline water respectively, drying by using anhydrous sodium sulfate, and concentrating to obtain a compound 16 with different substituents.

(10) Synthesis of target Compound

In a solvent, the compound 12 and the compound 17 are stirred at room temperature for 2 to 5 hours under the action of an alkaline substance and a condensing agent, then the temperature is continuously increased to 40 to 90 ℃ until the raw materials are completely reacted, then the raw materials are cooled to room temperature, most of the solvent is removed by concentration, the raw materials are extracted by ethyl acetate, washed by water and saturated saline respectively, dried by anhydrous sodium sulfate, and the residual liquid obtained by concentration is separated by column chromatography to obtain the target compound, namely the compound 18.

EXAMPLE 2 Synthesis of Compound P1

(1) Synthesis of Compound 16a

Sodium hydride (60% dispersed in mineral oil, 2.0g,50mmol) was slowly added to a solution of 2-fluoro-6-hydroxyacetophenone (1.54g,10mmol) in 50mL of anhydrous toluene at 0 deg.C, the reaction was stirred for 15 minutes, and then thiazole-2-carboxylic acid ethyl ester (2.36g,15mmol) in 20mL of anhydrous toluene was slowly addedThe solution is gradually heated to 60 ℃ for reaction for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched by pouring the reaction mixture into a beaker containing an ice-water mixture, and then adjusted to pH 4.0 with 3M hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, and the residue obtained by concentration was washed with a mixed solvent of petroleum ether/ethyl acetate 5/1 by beating to obtain 1- (2-fluoro-6-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione (i.e., compound 16a) (1.62g) as a yellow solid in 61% yield.¹H NMR(400MHz,DMSO–d₆)δ10.87(s,1H),8.24(d,J＝3.0Hz,1H),8.16(d,J＝2.6Hz,1H),7.83(s,1H),7.38(d,J＝6.8Hz,1H),6.95(s,1H),6.86–6.79(m,1H),6.77(d,J＝3.3Hz,1H).

(2) Synthesis of Compound P1

1- (2-fluoro-6-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione (477mg,1.8mmol) and (S) -2- (9-fluorenylmethoxycarbonylamino) -3- (3, 4-methylenedioxyphenyl) propionic acid (1165mg,2.7mmol) were dissolved in 10mL of pyridine, and then N, N-dicyclohexyldiimine (742mg,3.6mmol) and N, N-lutidine (88mg,0.72mmol) were added, and after stirring at room temperature for 3 hours, the mixture was heated to 50 ℃ and reacted for 6 hours. Cooling, concentrating with rotary evaporator to remove solvent pyridine, diluting with 80mL ethyl acetate, vacuum filtering to remove N, N-dicyclohexylurea, concentrating the filtrate, and separating by column chromatography (petroleum ether: ethyl acetate: 3:1) to obtain 288mg of product P1, i.e. 3- (3, 4-methylenedioxybenzyl) -8-fluoro-1- (thiazol-2-yl) chromone [2, 3-c%]Pyrrolyl-9 (2H) -one as a yellow solid in 38% yield and purity>99％。¹H NMR(400MHz,CDCl₃)δ11.23(br,1H),7.76(d,0.J＝3.1Hz,1H),7.57(td,J＝8.3,5.7Hz,1H),7.39(d,J＝3.2Hz,1H),7.21(d,J＝8.5Hz,1H),7.00(dd,J＝10.9,8.3Hz,1H),6.58(d,J＝7.9Hz,1H),6.50(s,1H),6.43(d,J＝7.9Hz,1H),5.80(s,2H),3.99(s,2H)；¹³C NMR(101MHz,CDCl₃)δ174.19,163.78,161.15,158.25,157.80,147.83,146.33,141.54,133.84,133.73,131.36,121.41,120.91,120.10,114.51,113.51,110.52,110.30,108.46,108.25,101.00,29.52；HRMS(ESI)m/z calcd C₂₂H₁₄FN₂O₄S⁺[M+H]⁺ 421.0653,found 421.0657.

EXAMPLE 3 Synthesis of Compound P2

Compound P1(84mg,0.2mmol) was dissolved in 2mL of toluene, and Lawson's reagent (162mg,0.4mmol) was added under argon and the reaction stirred at reflux for 3 hours. Then cooled to room temperature, concentrated to remove the solvent and isolated by column chromatography to give the product P2(71mg), 3- (3, 4-methylenedioxybenzyl) -8-fluoro-1- (thiazol-2-yl) chromone [2,3-c]Pyrrole-9 (2H) -thione, a reddish-brown solid in 81% yield.¹H NMR(500MHz,DMSO–d₆)δ13.24(br s,1H),8.00(d,J＝3.1Hz,1H),7.83–7.76(m,1H),7.68(d,J＝3.1Hz,1H),7.58–7.50(m,1H),7.39(t,J＝7.6Hz,1H),7.01(d,J＝2.7Hz,1H),7.00(d,J＝2.7Hz,1H),6.97(s,1H),5.95(s,2H),4.16(s,2H).

EXAMPLE 4 Synthesis of Compound P3

1.0mmol of 1- (2-fluoro-6-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione, 1.5mmol of (S) -2- (9-fluorenylmethoxycarbonylamino) -3- (4-fluorophenyl) propionic acid, 2.0mmol of N, N-dicyclohexyldiimine, 0.4mmol of N, N-dimethylpyridine were obtained by the method of example 10 to give 134mg of the product P3, i.e., 3- (4-fluorobenzyl) -8-fluoro-1- (thiazol-2-yl) chromone [2,3-c ] chromone]Pyrrole-9 (2H) -thione, yellow solid, yield 34%.¹H NMR(400MHz,CDCl₃)δ10.80(br s,1H),7.74(d,J＝9.7Hz,1H),7.66–7.49(m,1H),7.38(d,J＝9.7Hz,1H),7.25–7.15(m,1H),7.12–6.98(m,3H),6.92(dt,J＝16.5,8.4Hz,2H),4.08(s,2H).

EXAMPLE 5 Synthesis of Compound P4

1.0mmol of 1- (2-fluoro-6-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione, 1.5mmol of (S) -2- (9-fluorenylmethoxycarbonylamino) -3- (3, 4-difluorophenyl) propionic acid, 2.0mmol of N, N-dicyclohexyldiimine, 0.4mmol of N, N-lutidine, according to the method of example 10, 153mg of the product P4, i.e. 3- (3, 4-difluorobenzyl) -8-fluoro-1- (thiazol-2-yl) chromone [2,3-c ] was obtained]Pyrrole-9 (2H) -thione, yellow solid, 37% yield.¹H NMR(400MHz,CDCl₃)δ11.14(s,1H),7.73(d,J＝3.1Hz,1H),7.62–7.50(m,1H),7.39(d,J＝3.1Hz,1H),7.18(d,J＝8.5Hz,1H),7.04–6.94(m,2H),6.90–6.80(m,1H),6.75(d,J＝8.0Hz,1H),4.03(s,2H).

EXAMPLE 6 Synthesis of Compound P5

(1) Synthesis of Compound 16b

The starting material was replaced with 2-hydroxy-6-methoxyacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) to obtain the product according to the method of step (1) in example 1, which gave 1- (2-hydroxy-6-methoxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 39% yield.¹H NMR(400MHz,CDCl₃)δ12.92(s,1H),8.06(d,J＝3.0Hz,1H),7.74(d,J＝3.0Hz,1H),7.38(t,J＝8.4Hz,1H),6.62(d,J＝8.4Hz,1H),6.34(d,J＝8.3Hz,1H),4.80(s,2H),3.58(s,3H).

(2) Synthesis of Compound P5

The starting material was replaced with 16b and reacted with compound 4 to give the product according to the method of example 2, which gave 3- (3, 4-methylenedioxybenzyl) -8-methoxy-1- (thiazol-2-yl) chromone [2,3-c ]]Pyrrolon-9 (2H) -one as a yellow solid in 21% yield.¹H NMR(400MHz,CDCl₃)δ10.48(br,1H),7.72(d,J＝2.4Hz,1H),7.52(t,J＝8.2Hz,1H),7.32(d,J＝2.3Hz,1H),6.98(d,J＝8.3Hz,1H),6.76(d,J＝8.1Hz,1H),6.65(d,J＝7.9Hz,1H),6.60(s,1H),6.57(d,J＝7.4Hz,1H),5.84(s,2H),4.04(s,3H),4.02(s,2H)；¹³C NMR(101MHz,CDCl₃)δ175.88,161.53,159.35,157.86,147.91,146.38,141.59,141.34,133.94,131.58,121.17,121.14,119.79,113.83,112.92,110.70,110.03,108.74,108.33,105.04,100.98,56.47,29.70；HRMS(ESI)m/z calcd C₂₃H₁₇N₂O₅S⁺[M+H]⁺ 433.0853,found 433.0858.

EXAMPLE 7 Synthesis of Compound P6

(1) Synthesis of Compound 16c

The raw material was replaced with 2-hydroxy-6-tert-butyldimethylsilyloxyacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) to react, and the product was obtained according to the method of example 2, to give 1- (2-hydroxy-6-tert-butyldimethylsilyloxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 71% yield.¹H NMR(400MHz,CDCl₃)δ15.37(br,1H),11.64(s,1H),7.99(d,J＝3.0Hz,1H),7.72(s,1H),7.63(d,J＝3.0Hz,1H),7.25(t,J＝8.2Hz,1H),6.61(dd,J＝8.3,0.8Hz,1H),6.42(dd,J＝8.1,0.8Hz,1H),1.00(s,9H),0.32(s,6H).

(2) Synthesis of Compound P6

Reaction of compound 4 with the starting material substituted 16c gave the product P6, namely 3- (3, 4-methylenedioxybenzyl) -8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 10]Pyrrol-9 (2H) -one, as a yellow solid in 38% yield.¹H NMR(400MHz,CDCl₃)δ12.97(s,1H),11.00(br,1H),7.76(d,J＝2.8Hz,1H),7.49(t,J＝8.3Hz,1H),7.40(d,J＝2.9Hz,1H),6.83(d,J＝8.3Hz,1H),6.74(d,J＝8.2Hz,1H),6.61(d,J＝7.8Hz,1H),6.51(s,1H),6.47(d,J＝7.7Hz,1H),5.77(s,2H),3.99(s,2H)；¹³C NMR(101MHz,CDCl₃)δ180.95,167.82,162.65,157.56,157.45,147.89,146.40,142.22,141.83,135.72,131.27,121.03,120.24,117.91,114.77,110.25,108.55,108.39,106.88,101.04,99.99,29.53；HRMS(ESI)m/z calcd C₂₂H₁₅N₂O₅S⁺[M+H]⁺ 419.0696,found 419.0693.

EXAMPLE 8 Synthesis of Compound P7

(1) Synthesis of Compound 16d

The raw material was replaced with 2-hydroxy-5-fluoroacetophenone to react with thiazole-2-carboxylic acid ethyl ester (compound 14), and the product was obtained according to the method of example 2, yielding 1- (2-hydroxy-5-fluorophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 68% yield.¹H NMR(400MHz,CDCl₃)δ15.13(br,1H),11.65(s,1H),8.07(d,J＝3.1Hz,1H),7.71(d,J＝3.0Hz,1H),7.56(dd,J＝9.1,3.1Hz,1H),7.27(s,1H),7.26–7.21(m,1H),7.00(dd,J＝9.1,4.6Hz,1H).

(2) Synthesis of Compound P7

Reaction of compound 4 with 16d instead of the starting material gave the product P7, 3- (3, 4-methylenedioxybenzyl) -7-fluoro-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrolon-9 (2H) -one as a yellow solid in 37% yield.¹H NMR(400MHz,DMSO–d₆)δ13.12(br,1H),7.93(d,J＝2.9Hz,1H),7.85(d,J＝7.9Hz,1H),7.75(d,J＝2.9Hz,1H),7.70–7.57(m,2H),6.94(s,1H),6.90–6.76(m,2H),5.95(s,2H),4.10(s,2H)；¹³C NMR(101MHz,DMSO–d₆)δ173.79,159.34,157.19,153.11,147.74,146.11,142.86,141.75,133.39,122.77,122.52,121.59,121.04,120.59,120.34,116.48,111.38,111.14,109.22,108.69,101.22,29.37；HRMS(ESI)m/z calcd C₂₂H₁₄FN₂O₄S⁺[M+H]⁺421.0653,found 421.0658.

EXAMPLE 9 Synthesis of Compound P8

(1) Synthesis of Compound 16e

The starting material was replaced with 2-hydroxy-5-chloroacetophenone and reacted with thiazole-2-carboxylic acid ethyl ester (compound 15) to give the product according to the method of example 2, yielding 1- (2-hydroxy-5-chlorophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 71% yield.¹H NMR(400MHz,CDCl₃)δ15.08(br,1H),11.83(s,1H),8.08(d,J＝3.1Hz,1H),7.86(d,J＝2.5Hz,1H),7.72(d,J＝3.0Hz,1H),7.45(dd,J＝8.9,2.5Hz,1H),7.30(s,1H),6.99(d,J＝8.9Hz,1H).

(2) Synthesis of Compound P8

Reaction of compound 4 with the starting material replaced with 16e gave the product P8, 3- (3, 4-methylenedioxybenzyl) -7-chloro-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrolon-9 (2H) -one as a yellow solid in 41% yield.¹H NMR(400MHz,DMSO–d₆)δ13.13(br,1H),8.09(d,J＝2.7Hz,1H),7.94(d,J＝3.2Hz,1H),7.81–7.73(m,2H),7.58(d,J＝8.9Hz,1H),6.94(s,1H),6.86–6.78(m,2H),5.94(s,2H),4.10(s,2H)；¹³C NMR(101MHz,DMSO–d₆)δ173.40,157.12,155.33,147.74,146.12,142.87,141.55,134.56,133.33,127.89,125.61,123.39,121.61,121.13,120.65,120.63,116.64,109.23,108.68,108.65,101.22,29.36；HRMS(ESI)m/z calcd C₂₂H₁₄ClN₂O₄S⁺[M+H]⁺437.0357,found 437.0364.

EXAMPLE 10 Synthesis of Compound P9

(1) Synthesis of compound 16 f:

the starting material was replaced with 2-hydroxy-5-bromoacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) and the product was obtained according to the method of example 2, yielding 1- (2-hydroxy-5-bromophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 67% yield.¹H NMR(400MHz,CDCl₃)δ15.06(br,1H),11.83(s,1H),8.06(d,J＝3.0Hz,1H),7.97(d,J＝2.3Hz,1H),7.70(d,J＝3.0Hz,1H),7.56(dd,J＝8.9,2.3Hz,1H),7.27(s,1H),6.91(d,J＝8.9Hz,1H).

(2) Synthesis of Compound P9

Reaction of compound 4 with the starting material substituted 16f gave the product P9, 3- (3, 4-methylenedioxybenzyl) -7-bromo-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrolon-9 (2H) -one as a yellow solid in 37% yield.¹H NMR(400MHz,DMSO–d₆)δ13.15(br,1H),8.23(d,J＝1.2Hz,1H),7.94(d,J＝1.7Hz,1H),7.88(d,J＝7.9Hz,1H),7.76(d,J＝1.9Hz,1H),7.53(d,J＝8.8Hz,1H),6.94(s,1H),6.84–6.79(m,2H),5.95(s,2H),4.09(s,2H)；¹³C NMR(101MHz,DMSO–d₆)δ173.32,157.14,155.77,147.76,146.14,142.91,141.52,137.32,133.34,128.74,123.86,121.63,121.18,120.94,120.71,116.69,115.62,109.25,108.71,108.67,101.24,29.37；HRMS(ESI)m/z calcd C₂₂H₁₄BrN₂O₄S⁺[M+H]⁺ 480.9852,found 480.9852.

EXAMPLE 11 Synthesis of Compound P10

(1) Synthesis of Compound 16g

The starting material was replaced with 2-hydroxy-5-methoxyacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) to give the product according to the method of example 2, which gave 1- (2-hydroxy-5-methoxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 38% yield.¹H NMR(400MHz,CDCl₃)δ15.33(br,1H),11.51(s,1H),8.06(d,J＝3.0Hz,1H),7.69(d,J＝3.1Hz,1H),7.31(s,1H),7.30(d,J＝3.1Hz,1H),7.15(d,J＝3.0Hz,1H),6.98(d,J＝9.1Hz,1H),3.86(s,3H).

(2) Synthesis of Compound P10

The starting material was replaced with 16g and reacted with Compound 4 to give the product P10, 3- (3, 4-methylenedioxybenzyl) -7-methoxy-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 10]Pyrrolon-9 (2H) -one as a yellow solid in 34% yield.¹H NMR(400MHz,CDCl₃)δ11.53(br,1H),7.79(d,J＝3.0Hz,1H),7.73(d,J＝3.1Hz,1H),7.36(d,J＝3.1Hz,1H),7.33(d,J＝9.1Hz,1H),7.26–7.22(m,1H),6.52(d,J＝7.9Hz,1H),6.42(s,1H),6.35(d,J＝7.7Hz,1H),5.67(s,2H),3.95(s,2H),3.92(s,3H)；¹³C NMR(101MHz,CDCl₃)δ175.39,158.27,155.38,151.74,147.67,146.16,142.69,141.44,131.61,123.68,122.62,120.88,120.60,119.72,118.91,114.81,109.36,108.43,108.21,106.45,100.90,55.88,29.52；HRMS(ESI)m/z calcd C₂₃H₁₇N₂O₅S⁺[M+H]⁺ 433.0853,found 433.0857.

EXAMPLE 12 Synthesis of Compound P11

(1) Synthesis of Compound 16h

The raw material was replaced with 2-hydroxy-5-methylacetophenone to react with thiazole-2-carboxylic acid ethyl ester (compound 14) and the product was obtained according to the method of example 2 to give 1- (2-hydroxy-5-methylphenyl) -3- (thiazol-2-yl) propane-1, 3-dione, yellow solid, yield 74%.¹H NMR(400MHz,CDCl₃)δ15.24(br,1H),11.70(s,1H),8.06(d,J＝2.9Hz,1H),7.68(d,J＝2.9Hz,1H),7.66(s,1H),7.36–7.30(m,2H),6.93(d,J＝8.5Hz,1H),2.34(s,3H).

(2) Synthesis of Compound P111

Reaction of the starting material with compound 4 instead of 16h gave the product P11, 3- (3, 4-methylenedioxybenzyl) -7-methyl-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrolon-9 (2H) -one as a yellow solid in 38% yield.¹H NMR(400MHz,CDCl₃)δ11.36(br,1H),8.18(s,1H),7.75(d,J＝3.2Hz,1H),7.47(dd,J＝8.5,1.9Hz,1H),7.38(d,J＝3.2Hz,1H),7.31(d,J＝8.5Hz,1H),6.56(d,J＝7.9Hz,1H),6.48(s,1H),6.41(d,J＝7.8Hz,1H),5.72(s,2H),3.99(s,2H),2.48(s,3H)；¹³C NMR(101MHz,CDCl₃)δ175.61,158.20,155.23,147.72,146.21,142.56,141.43,135.11,132.62,131.60,126.29,122.08,120.91,120.85,119.74,117.35,114.76,109.72,108.47,108.21,100.90,29.56,20.78；HRMS(ESI)m/z calcd C₂₃H₁₇N₂O₄S⁺[M+H]⁺ 417.0904,found 417.0902.

EXAMPLE 13 Synthesis of Compound P12

(1) Synthesis of Compound 16i

The starting material was replaced with 2-hydroxy-4-methoxyacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) to give the product according to the method of example 2, which gave 1- (2-hydroxy-4-methoxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 46% yield.¹H NMR(400MHz,CDCl₃)δ15.04(br,1H),12.41(s,1H),8.03(d,J＝3.0Hz,1H),7.80(d,J＝9.0Hz,1H),7.66(d,J＝2.9Hz,1H),7.24(s,1H),6.53–6.45(m,2H),3.88(s,3H).

(2) Synthesis of Compound P12

Reaction of compound 4 with the starting material replaced with 16i gave the product P12, 3- (3, 4-methylenedioxybenzyl) -6-methoxy-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrol-9 (2H) -one as a yellow solid in 35% yield.¹H NMR(400MHz,CDCl₃)δ10.29(br,1H),8.30(d,J＝8.9Hz,1H),7.77(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),6.91(dd,J＝8.9,2.3Hz,1H),6.85(d,J＝2.3Hz,1H),6.71(d,J＝7.8Hz,1H),6.67(s,1H),6.64(d,J＝7.9Hz,1H),5.88(s,2H),4.09(s,2H),3.95(s,3H)；¹³C NMR(101MHz,CDCl₃)δ175.02,167.81,164.55,158.93,157.78,148.02,146.49,142.50,141.77,131.48,128.28,121.23,120.96,119.78,116.40,114.43,111.87,108.78,108.43,101.03,100.45,55.75,29.76；HRMS(ESI)m/z calcd C₂₃H₁₇N₂O₅S⁺[M+H]⁺ 433.0853,found 433.0858.

EXAMPLE 14 Synthesis of Compound P13

(1) Synthesis of Compound 16j

The raw material was replaced with 2-hydroxy-4-fluoroacetophenone to react with thiazole-2-carboxylic acid ethyl ester (compound 14), and the product was obtained according to the method of example 2, yielding 1- (2-hydroxy-4-fluorophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 67% yield.¹H NMR(400MHz,CDCl₃)δ14.93(br,1H),12.26(s,1H),8.11–7.92(m,1H),7.92–7.78(m,1H),7.70–7.52(m,1H),7.20(s,1H),6.74–6.53(m,2H).

(2) Synthesis of Compound P13

Reaction of compound 4 with 16j instead of the starting material gave the product P13, 3- (3, 4-methylenedioxybenzyl) -6-fluoro-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrol-9 (2H) -one as a yellow solid in 36% yield.¹H NMR(400MHz,CDCl₃)δ10.42(br,1H),8.40(dd,J＝8.7,6.6Hz,1H),7.78(d,J＝3.2Hz,1H),7.40(d,J＝3.1Hz,1H),7.15–7.02(m,2H),6.71(d,J＝7.8Hz,1H),6.65(s,1H),6.64(d,J＝7.9Hz,1H),5.88(s,2H),4.09(s,2H)；¹³C NMR(101MHz,CDCl₃)δ174.49,167.32,164.78,157.90,147.78,146.29,141.56,131.35,129.16,121.16,120.94,119.98,119.39,115.02,111.69,111.46,108.46,108.25,104.43,104.18,100.94,29.53；HRMS(ESI)m/z calcd C₂₂H₁₄FN₂O₄S⁺[M+H]⁺ 421.0653,found 421.0647.

EXAMPLE 15 Synthesis of Compound P14

(1) Synthesis of Compound 16k

The starting material was replaced with 2-hydroxy-4-chloroacetophenone and reacted with thiazole-2-carboxylic acid ethyl ester (compound 14) to give the product according to the method of example 2, yielding 1- (2-hydroxy-4-chlorophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 61% yield.¹H NMR(400MHz,CDCl₃)δ15.01(br,1H),12.07(s,1H),8.03(d,J＝3.0Hz,1H),7.80(d,J＝8.7Hz,1H),7.68(d,J＝3.1Hz,1H),7.28(s,1H),7.03(d,J＝2.0Hz,1H),6.92(dd,J＝8.7,2.0Hz,1H).

(2) Synthesis of Compound P14

Reaction of the starting material instead of 16k with Compound 4 gave the product P14, 3- (3, 4-methylenedioxy) according to example 2Benzyl) -6-chloro-1- (thiazol-2-yl) chromone [2,3-c]Pyrrolon-9 (2H) -one as a yellow solid in 39% yield.¹H NMR(400MHz,CDCl₃)δ11.22(br,1H),8.32(d,J＝8.5Hz,1H),7.76(d,J＝3.2Hz,1H),7.44(d,J＝1.8Hz,1H),7.40(d,J＝3.2Hz,1H),7.31(dd,J＝8.5,1.9Hz,1H),6.59(d,J＝7.9Hz,1H),6.51(s,1H),6.46(d,J＝7.9Hz,1H),5.78(s,2H),4.00(s,2H)；¹³C NMR(101MHz,CDCl₃)δ174.57,157.78,157.17,147.82,146.34,142.17,141.63,139.88,131.30,128.12,123.83,121.21,121.11,120.99,120.01,117.69,115.09,109.38,108.50,108.29,100.97,29.58；HRMS(ESI)m/z calcd C₂₂H₁₄ClN₂O₄S⁺[M+H]⁺ 437.0357,found 437.0358.

EXAMPLE 16 Synthesis of Compound P15

(1) Synthesis of Compound 16l

The starting material was replaced with 2-hydroxy-4-bromoacetophenone and thiazole-2-carboxylic acid ethyl ester (compound 14) to give the product according to the method of example 9, which gave 1- (2-hydroxy-4-bromophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 65% yield.¹H NMR(400MHz,CDCl₃)δ15.00(br,1H),12.01(s,1H),8.03(d,J＝3.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.68(d,J＝3.0Hz,1H),7.28(s,1H),7.21(d,J＝1.7Hz,1H),7.07(dd,J＝8.6,1.7Hz,1H).

(2) Synthesis of Compound P15

The starting material was replaced with 16l and reacted with compound 4 to give the product P15, 3- (3, 4-methylenedioxybenzyl) -6-bromo-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrol-9 (2H) -one as a yellow solid in 36% yield.¹H NMR(400MHz,CDCl₃)δ11.19(br,1H),8.24(d,J＝8.5Hz,1H),7.77(d,J＝3.2Hz,1H),7.62(d,J＝1.5Hz,1H),7.46(dd,J＝8.5,1.5Hz,1H),7.40(d,J＝3.2Hz,1H),6.59(d,J＝7.9Hz,1H),6.50(s,1H),6.45(d,J＝7.9Hz,1H),5.77(s,2H),3.99(s,2H)；¹³C NMR(101MHz,CDCl₃)δ174.69,157.76,157.11,147.85,146.37,142.10,141.66,131.28,128.20×2,126.67,121.49,121.25,120.99,120.75,120.04,115.09,109.39,108.50,108.31,100.99,29.58；HRMS(ESI)m/z calcd C₂₂H₁₄BrN₂O₄S⁺[M+H]⁺ 480.9852,found 480.9848.

EXAMPLE 17 Synthesis of Compound P16

Compound P15(241mg,0.5mmol) was dissolved in 5.0mL of dimethyl sulfoxide, and morpholine (131mg,1.5mmol), BINAP (62mg,0.1mmol), Pd (dppf) were added thereto₂Cl₂(41mg,0.05mmol) and sodium tert-butoxide (96mg,1.0mmol), under argon, the temperature is raised to 120 ℃ for reaction for 6 hours. After completion of the reaction, it was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, and the residue obtained by concentration was separated by column chromatography to give the product P16(76mg), i.e., 3- (3, 4-methylenedioxybenzyl) -6-morpholinyl-1- (thiazol-2-yl) chromone [2,3-c ]]Pyrrol-9 (2H) -one as a yellow solid in 31% yield.¹H NMR(400MHz,CDCl₃)δ11.28(s,1H),8.22(d,J＝9.0Hz,1H),7.71(d,J＝3.2Hz,1H),7.34(d,J＝3.2Hz,1H),6.86(dd,J＝9.0,2.3Hz,1H),6.68(d,J＝2.3Hz,1H),6.53(d,J＝7.9Hz,1H),6.45(s,1H),6.38(d,J＝7.9Hz,1H),5.72(s,2H),3.93(s,2H),3.91–3.80(m,4H),3.43–3.29(m,4H)；¹³C NMR(101MHz,CDCl₃)δ174.85,158.94,158.40,155.27,147.70,146.18,142.61,141.37,131.74,127.91,120.87,120.67,119.69,114.70,114.55,110.55,109.85,108.45,108.20,100.95,100.23,66.56×2,47.59×2,29.53；HRMS(ESI)m/z calcd C₂₆H₂₂N₃O₅S⁺[M+H]⁺ 488.1275,found 488.1263.

EXAMPLE 18 Synthesis of Compound P17

Reaction of N-methylpiperazine with Compound P15 instead of the starting Material gave the product P17, i.e. 3- (3, 4-methylenedioxybenzyl) -6- (4-methylpiperazin-1-yl) -1- (thiazol-2-yl) chromone [2,3-c, according to the method of example 17]Pyrrolyl-9 (2H) -one as a tan solid in 33% yield.¹H NMR(400MHz,CDCl₃)δ10.92(s,1H),8.22(d,J＝9.0Hz,1H),7.73(d,J＝3.2Hz,1H),7.35(d,J＝3.2Hz,1H),6.89(dd,J＝9.1,2.3Hz,1H),6.71(d,J＝2.2Hz,1H),6.60(d,J＝7.9Hz,1H),6.54(d,J＝1.3Hz,1H),6.48(d,J＝7.9Hz,1H),5.79(s,2H),3.99(s,2H),3.52–3.35(m,4H),2.63–2.50(m,4H),2.38(s,3H)；¹³C NMR(101MHz,CDCl₃)δ174.87,159.03,158.35,155.14,147.76,146.22,142.59,141.41,131.76,127.84,120.95,120.63,119.65,114.59,114.09,110.83,109.91,108.54,108.25,100.96,100.22,54.71,47.32,46.12,29.58；HRMS(ESI)m/z calcd C₂₇H₂₅N₄O₄S⁺[M+H]⁺501.1591,found 501.1584.

EXAMPLE 19 Synthesis of Compound P18

Reaction of 2- (4-methylpiperazin-1-yl) ethylamine with the starting material substituted by the compound P15 gave the product P18, 3- (3, 4-methylenedioxybenzyl) -6- (2- (4-methylpiperazin-1-yl) ethylamino) -1- (thiazol-2-yl) chromone [2,3-c, according to the procedure of example 17]Pyrrolyl-9 (2H) -one as a tan solid in 46% yield.¹H NMR(400MHz,CD₃OD–d₄)δ7.95(d,J＝8.8Hz,1H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,1H),6.82(s,1H),6.79(d,J＝8.1Hz,1H),6.75(d,J＝8.0Hz,1H),6.66(d,J＝8.9Hz,1H),6.50(s,1H),5.90(s,2H),4.59(s,1H),4.13(s,2H),3.40(t,J＝6.2Hz,2H),3.37(br s,4H),3.15(br s,4H),2.79(t,J＝6.5Hz,2H),2.77(s,3H).

EXAMPLE 20 Synthesis of Compound P19

Reaction of 2-methoxyethylamine with the starting material substituted for compound P15 followed by the procedure of example 17 gave the product P29, 3- (3, 4-methylenedioxybenzyl) -6- (2-methoxyethylamino) -1- (thiazol-2-yl) chromone [2, 3-c-]And pyrrol-9 (2H) -one as a tan solid in 48% yield.¹H NMR(400MHz,CDCl₃)δ10.29(s,2H),8.15(d,J＝8.7Hz,1H),7.74(d,J＝3.2Hz,1H),7.34(d,J＝3.2Hz,1H),6.70(d,J＝7.9Hz,1H),6.65(s,1H),6.62(d,J＝7.9Hz,1H),6.58(dd,J＝8.8,2.2Hz,1H),6.45(d,J＝2.1Hz,1H),5.87(s,2H),4.70(t,J＝5.3Hz,1H),4.06(s,2H),3.68(t,J＝5.2Hz,2H),3.44(s,3H),3.44–3.39(m,2H)；¹³C NMR(101MHz,CDCl₃)δ174.86,159.51,158.32,153.21,147.82,146.28,142.50,141.46,131.77,128.05,121.05,120.57,119.61,114.42,113.48,110.67,109.91,108.64,108.30,100.97,97.02,70.51,58.87,42.93,29.65；HRMS(ESI)m/z calcd C₂₅H₂₂N₃O₅S⁺[M+H]⁺ 476.1275,found 476.1263.

EXAMPLE 21 Synthesis of Compound P20

The starting material was replaced by the reaction of compound P15 with 2-dimethylaminoethylamine and the procedure of example 17 was followed to give the product P20, 3- (3, 4-methylenedioxybenzyl) -6- (2-dimethylaminoethylamino) -1- (thiazol-2-yl) chromone [2,3-c ] chromone]Pyrrolyl-9 (2H) -one, a tan solid, 3- (3, 4-methylenedioxybenzyl) -6- (2-dimethylaminoethylamino) -1- (thiazol-2-yl) chromone [2,3-c ]]Pyrrolon-9 (2H) -one, 44% yield.¹H NMR(400MHz,DMSO–d₆)δ12.69(s,1H),7.88(d,J＝3.2Hz,1H),7.84(d,J＝8.8Hz,1H),7.68(d,J＝3.2Hz,1H),6.93(s,1H),6.83(d,J＝7.9Hz,1H),6.79(d,J＝8.0Hz,1H),6.71–6.61(m,2H),6.43(d,J＝1.8Hz,1H),5.95(s,2H),4.06(s,2H),3.24(dd,J＝11.9,6.3Hz,2H),2.50–2.47(m,2H),2.22(s,6H)；¹³C NMR(101MHz,CDCl₃)δ178.48,164.15,162.51,159.23,152.46,150.80,147.26,146.48,138.49,132.25,126.27,125.39,124.49,120.74,119.86,116.47,114.26,113.94,113.43,105.96,99.96,62.71,50.41×2,45.67,34.17.

EXAMPLE 22 Synthesis of Compound P21

Reaction of 2- (pyrrol-1-yl) ethylamine with the starting material substituted for compound P15 gave, according to the procedure of example 17, the product P21, 3- (3, 4-methylenedioxybenzyl) -6- (2- (pyrrol-1-yl) ethylamino) -1- (thiazol-2-yl) chromone [2,3-c]Pyrrolyl-9 (2H) -one as a tan solid in 46% yield.¹H NMR(400MHz,CDCl₃)δ10.46(s,1H),8.14(d,J＝8.7Hz,1H),7.73(d,J＝3.2Hz,1H),7.34(d,J＝3.2Hz,1H),6.67(d,J＝7.9Hz,1H),6.62(s,1H),6.61–6.55(m,2H),6.43(d,J＝1.8Hz,1H),5.85(s,2H),5.18(s,1H),4.04(s,2H),3.33(dd,J＝11.1,5.3Hz,2H),2.84(t,J＝5.9Hz,2H),2.64(s,4H),1.85(s,4H)；¹³C NMR(101MHz,CDCl₃)δ174.85,159.58,158.22,153.40,147.87,146.32,142.46,141.51,131.77,127.96,121.13,120.55,119.55,114.31,113.16,110.60,109.95,108.72,108.32,100.97,96.78,54.26,53.88×2,41.55,29.72,23.49×2.

EXAMPLE 23 Synthesis of Compound P22

The starting material was replaced by compound P15 and (2-dimethylamino) ethylmethylamine and the procedure was followed as in example 17 to give product P22, 3- (3, 4-methylenedioxybenzyl) -6- ((2-dimethylamino) ethylmethylamino) -1- (thiazol-2-yl) chromone [2,3-c]Pyrrolyl-9 (2H) -one as a tan solid in 41% yield.¹H NMR(400MHz,CDCl₃)δ10.78(s,1H),8.19(d,J＝9.0Hz,1H),7.72(d,J＝3.2Hz,1H),7.34(d,J＝3.2Hz,1H),6.69(dd,J＝9.1,2.2Hz,1H),6.63(d,J＝7.9Hz,1H),6.57(s,1H),6.52(d,J＝7.9Hz,1H),6.48(d,J＝2.2Hz,1H),5.81(s,2H),4.02(s,2H),3.63–3.54(m,2H),3.11(s,3H),2.60–2.53(m,2H),2.35(s,6H)；¹³C NMR(126MHz,CDCl₃)δ174.84,159.30,158.42,153.50,147.77,146.22,142.58,141.38,131.84,128.04,121.00,120.54,119.55,114.44,112.37,109.98,108.60,108.41,108.25,100.96,97.05,56.04,50.85,45.87×2,38.85,29.60.

EXAMPLE 24 Synthesis of Compound P23

The starting material was replaced by compound P15 and (2-methoxy) ethylmethylamine and the procedure was followed as in example 17 to give product P23, 3- (3, 4-methylenedioxybenzyl) -6- ((2-methoxy) ethylmethylamino) -1- (thiazol-2-yl) chromone [2,3-c]Pyrrolyl-9 (2H) -one as a tan solid in 43% yield.¹H NMR(400MHz,CDCl₃)δ10.66(s,1H),8.20(d,J＝9.0Hz,1H),7.73(d,J＝3.2Hz,1H),7.34(d,J＝3.2Hz,1H),6.72(dd,J＝9.1,2.4Hz,1H),6.64(d,J＝7.9Hz,1H),6.59(d,J＝1.3Hz,1H),6.54(d,J＝7.9Hz,1H),6.51(d,J＝2.3Hz,1H),5.83(s,2H),4.03(s,2H),3.70–3.60(m,4H),3.40(s,3H),3.14(s,3H)；¹³C NMR(126MHz,CDCl₃)δ174.87,159.27,158.35,153.64,147.79,146.24,142.57,141.42,131.80,127.97,121.02,120.55,119.56,114.37,112.41,109.98,108.62,108.55,108.27,100.96,97.21,70.14,59.16,52.17,39.31,29.61.

EXAMPLE 25 Synthesis of Compound P24

(1) Synthesis of Compound 16m

The starting material was replaced with 2-hydroxy-3-chloroacetophenone and reacted with thiazole-2-carboxylic acid ethyl ester (compound 14) to give the product according to the method of example 2, yielding 1- (2-hydroxy-3-chlorophenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 54% yield.¹H NMR(400MHz,CDCl₃)δ14.93(br,1H),12.46(s,1H),8.04(d,J＝3.0Hz,1H),7.81(d,J＝8.1Hz,1H),7.69(d,J＝3.0Hz,1H),7.59(d,J＝7.8Hz,1H),7.35(s,1H),6.90(t,J＝8.0Hz,1H).

(2) Synthesis of Compound P24

Reaction of 17m instead of the starting material with Compound 4 gave the product P24, 3- (3, 4-methylenedioxybenzyl) -5-chloro-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrol-9 (2H) -one as a yellow solid in 35% yield.¹H NMR(400MHz,DMSO–d₆)δ13.16(br,1H),8.12(d,J＝7.9Hz,1H),7.94(d,J＝3.1Hz,1H),7.90(d,J＝7.7Hz,1H),7.75(d,J＝3.1Hz,1H),7.35(t,J＝7.9Hz,1H),7.00(s,1H),6.87(d,J＝7.8Hz,1H),6.83(d,J＝7.9Hz,1H),5.94(s,2H),4.10(s,2H)；¹³C NMR(101MHz,DMSO–d₆)δ173.81,157.11,152.04,147.74,146.17,142.88,141.03,134.80,133.15,125.71,123.92,123.77,121.79,121.75,121.13,120.54,117.10,109.37,108.72,108.56,101.23,29.71；HRMS(ESI)m/z calcd C₂₂H₁₄ClN₂O₄S⁺[M+H]⁺ 437.0357,found 437.0354.

EXAMPLE 26 Synthesis of Compound P25

(1) Synthesis of Compound 16n

The raw material was replaced with 2-fluoro-4-bromo-6-hydroxyacetophenone to react with thiazole-2-carboxylic acid ethyl ester (compound 14), and the product was obtained according to the method of example 2, to give 1- (2-fluoro-4-bromo-6-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione as a yellow solid in 68% yield.¹H NMR(400MHz,CDCl₃)δ15.10(br s,1H),12.39(s,1H),8.05(d,J＝2.9Hz,1H),7.68(d,J＝3.0Hz,1H),7.44(s,1H),7.02(s,1H),6.86(d,J＝11.6Hz,1H).

(2) Synthesis of Compound P25

Reaction of compound 4 with 17n instead of the starting material gave the product P25, 3- (3, 4-methylenedioxybenzyl) -6-bromo-8-fluoro-1- (thiazol-2-yl) chromone [2,3-c ], according to the procedure of example 2]Pyrrolon-9 (2H) -one as a yellow solid in 56% yield.¹H NMR(400MHz,DMSO–d₆)δ13.16(s,1H),7.94(d,J＝2.0Hz,1H),7.78(d,J＝1.9Hz,1H),7.17(s,1H),6.93(s,1H),6.90(s,1H),6.86–6.74(m,2H),5.94(s,2H),4.04(s,2H)；¹³C NMR(101MHz,DMSO–d₆)δ180.22,162.74,157.37,156.73,147.76,146.17,143.11,141.13,133.14,129.29,121.70×2,120.96,116.77,113.42,110.84,109.29,108.73,107.63,107.40,101.26,29.26；HRMS(ESI)m/z calcd C₂₂H₁₃BrFN₂O₄S⁺[M+H]⁺ 498.9758,found 498.9745.

EXAMPLE 27 Synthesis of Compound P26

Reaction of 2-methoxyethylamine with the starting material substituted Compound P25 following the procedure of example 17 gave the product P26, 3- (3, 4-methylenedioxybenzyl) -6- (2-methoxyethylamino) -8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c]Pyrrolon-9 (2H) -one as a yellow solid in 37% yield.¹HNMR(500M,Acetone–d₆)δ13.25(s,1H),7.82(d,J＝3.1Hz,1H),7.59(d,J＝3.1Hz,1H),6.89(s,1H),6.83(d,J＝8.0Hz,1H),6.76(d,J＝7.9Hz,1H),6.17(s,1H),6.01(s,1H),5.94(s,2H),4.18(s,2H),3.60(t,J＝5.3Hz,2H),3.43(dd,J＝10.2,5.1Hz,2H),3.35(s,3H)；¹³C NMR(101MHz,DMSO–d₆)δ178.23,163.32,159.06,157.56,155.90,147.73,146.11,141.75,141.50,133.35,121.56,121.20,119.26,116.83,109.20,108.70,108.10,101.26,99.81,93.76,89.75,70.80,58.52,42.49,29.32；HRMS(ESI)m/z calcd C₂₅H₂₂N₃O₆S⁺[M+H]⁺ 492.1224,found 492.1223.

EXAMPLE 28 Synthesis of Compound P27

Reaction of starting Material instead of Compound P25 with methylamine hydrochloride gave the product P27, 3- (3, 4-methylenedioxybenzyl) -6-methylamino-8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c ] according to the procedure of example 17]Pyrrolon-9 (2H) -one as a yellow solid in 32% yield.¹H NMR(500MHz,DMSO–d₆)δ13.20(s,1H),12.86(s,1H),7.91(d,J＝3.2Hz,1H),7.73(d,J＝3.2Hz,1H),6.91(d,J＝1.5Hz,1H),6.84(d,J＝8.0Hz,1H),6.77(dd,J＝8.0,1.6Hz,1H),6.00(d,J＝2.0Hz,1H),5.95(s,2H),5.86(d,J＝2.0Hz,1H),4.03(s,2H),2.77(s,3H)；¹³C NMR(101MHz,DMSO–d₆)178.49,163.41,159.09,157.37,156.64,147.73,146.09,142.73,141.33,133.54,121.53,121.12,119.95,116.11,109.19,108.70,107.74,101.24,99.75,93.39,89.46,29.60,29.31；HRMS(ESI)m/z calcd C₂₃H₁₈N₃O₅S⁺[M+H]⁺ 448.0962,found 448.0960.

EXAMPLE 29 Synthesis of Compound P28

Reaction of starting material substituted compound P25 with morpholine followed by example 17 gave the product P28, 3- (3, 4-methylenedioxybenzyl) -6-morpholinyl-8-hydroxy-1- (thiazol-2-yl) chromone [2, 3-c-]Pyrrolon-9 (2H) -one as a brown solid in 31% yield.¹H NMR(400MHz,CDCl₃)δ13.05(s,1H),10.74(s,1H),7.73(d,J＝3.1Hz,1H),7.36(d,J＝3.1Hz,1H),6.62(d,J＝7.8Hz,1H),6.53(s,1H),6.48(d,J＝7.7Hz,1H),6.25(d,J＝1.9Hz,1H),6.21(s,1H),5.81(s,2H),3.96(s,2H),3.91–3.76(m,4H),3.44–3.26(m,4H)；¹³C NMR(101MHz,CDCl₃)δ179.13,163.65,159.04,157.78,156.14,147.89,146.38,142.22,141.71,131.44,121.02,120.01,114.53,108.57,108.37×2,102.04,101.08,100.00,95.41,91.69,66.51×2,47.13×2,29.55；HRMS(ESI)m/z calcd C₂₆H₂₂N₃O₆S⁺[M+H]⁺ 504.1224,found 504.1223.

EXAMPLE 30 Synthesis of Compound P29

Reaction of N-methylpiperazine with the starting material replaced by the compound P25 gave the product P29, i.e. 3- (3, 4-methylenedioxybenzyl) -6- (4-methylpiperazin-1-yl) -8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c, according to the procedure of example 17]Pyrrolon-9 (2H) -one as a brown solid in 33% yield.¹H NMR(400MHz,CDCl₃)δ13.05(s,1H),7.71(d,J＝2.9Hz,1H),7.35(d,J＝2.9Hz,1H),6.56(d,J＝7.6Hz,1H),6.46(s,1H),6.41(s,1H),6.23(d,J＝1.9Hz,1H),6.20(s,1H),5.76(s,2H),3.91(s,2H),3.53–3.31(m,4H),2.60–2.44(m,4H),2.35(s,3H)；¹³C NMR(101MHz,CDCl₃)δ178.99,163.62,159.07,158.06,155.86,147.78,146.28,145.48,142.28,141.54,131.56,120.89,120.52,119.92,114.65,108.46,108.28,101.69,101.04,95.51,91.76,54.63×2,46.86×2,46.07,29.71；HRMS(ESI)m/z calcd C₂₇H₂₅N₄O₅S⁺[M+H]⁺ 517.1540,found 517.1535.

EXAMPLE 31 Synthesis of Compound P30

Reaction of 2- (morpholin-1-yl) ethylamine with the starting material substituted for compound P25 gave, according to the method of example 17, the product P30, 3- (3, 4-methylenedioxybenzyl) -6- (2- (morpholin-1-yl) ethylamino) -8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c]Pyrrolon-9 (2H) -one as a brown solid in 34% yield.¹HNMR(500M,Acetone–d₆)δ13.25(s,1H),7.80(s,1H),7.58(s,1H),6.88(s,1H),6.82(d,J＝6.9Hz,1H),6.75(d,J＝7.6Hz,1H),6.14(s,1H),5.96(s,1H),5.93(s,2H),4.17(s,2H),3.70(s,4H),3.40(s,2H),2.75(s,2H),2.60(s,4H)；¹³C NMR(101MHz,Acetone–d₆)δ178.74,159.30,157.21,156.68,155.36,147.85,146.22,142.26,141.70,133.06,129.68,121.24,120.40,120.00,115.31,108.74,108.06,100.99,100.33,93.47,89.69,66.10×2,56.67,53.26×3,29.27；HRMS(ESI)m/z calcd C₂₈H₂₇N₄O₆S⁺[M+H]⁺ 547.1646,found 547.1644.

EXAMPLE 32 Synthesis of Compound P31

Reaction of the starting material instead of the compound P25 with 2- (4-methylpiperazin-1-yl) ethylamine gave the product P31, 3- (3, 4-methylenedioxybenzyl) -6- (2- (4-methylpiperazin-1-yl) ethylamino) -8-hydroxy-1- (thiazol-2-yl) chromone [2,3-c, according to the procedure of example 17]Pyrrolon-9 (2H) -one as a brown solid in 36% yield.¹H NMR(400MHz,CDCl₃)δ13.19(s,1H),7.75(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),6.70(d,J＝7.9Hz,1H),6.65(s,1H),6.62(d,J＝7.9Hz,1H),6.02(d,J＝2.0Hz,1H),5.96(d,J＝2.0Hz,1H),5.89(s,2H),5.07(s,1H),4.03(s,2H),3.27(dd,J＝10.3,5.4Hz,2H),2.75–2.68(m,2H),2.60(s,6H),2.38(s,3H),2.13(s,4H)；¹³C NMR(101MHz,CDCl₃)δ175.26,163.93,159.30,154.50,151.25,147.90,144.86,141.67,134.19,131.58,130.34,121.11,119.90,114.47,108.67,108.37,101.32,101.06,99.99,94.09,90.14,55.84,54.73×2,52.12×2,45.58,39.27,29.61；HRMS(ESI)m/z calcd C₂₉H₃₀N₅O₅S⁺[M+H]⁺ 560.1962,found 560.1957.

EXAMPLE 33 Synthesis of Compound P31 hydrochloride

Compound P31(280mg,0.5mmol) was dissolved in 20mL dichloromethaneTo the alkane, 4M HCl in 1, 4-dioxane (1.5mL,6.0mmol) was added, the reaction was stirred at room temperature for 1 hour, the precipitated solid was filtered and washed with dichloromethane to obtain the product, which was reacted with 2- (4-methylpiperazin-1-yl) ethylamine instead of compound P25 to obtain the product P31 hydrochloride (286mg) as a brown solid in 96% yield according to the method of example 17.¹H NMR(400MHz,CDCl₃)δ13.21(s,1H),7.76(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),6.71(d,J＝7.9Hz,1H),6.67(s,1H),6.64(d,J＝7.9Hz,1H),6.03(d,J＝2.0Hz,1H),5.97(d,J＝2.0Hz,1H),5.89(s,2H),5.08(s,1H),4.05(s,2H),3.28(dd,J＝10.3,5.4Hz,2H),2.75–2.68(m,2H),2.60(s,6H),2.38(s,3H),2.14(s,4H).

EXAMPLE 34 Synthesis of Compound 32

The starting material was replaced with 1- (2-fluoro-4-bromophenyl) -3- (oxazol-2-yl) propane-1, 3-dione and (S) -2- (9-fluorenylmethoxycarbonylamido) -3- (4-fluorophenyl) propionic acid and the procedure of example 2 was followed to give the product P32, i.e. 3- (4-fluorobenzyl) -6-bromo-1- (oxazol-2-yl) chromone [2,3-c]Pyrrolon-9 (2H) -one as a yellow solid in 37% yield.¹H NMR(400MHz,CDCl₃)δ11.29(brs,1H),8.26(d,J＝8.5Hz,1H),7.84(s,1H),7.63(d,J＝1.6Hz,1H),7.47(dd,J＝8.5,1.6Hz,1H),7.10(s,1H),7.04(dd,J＝8.4,5.4Hz,2H),6.89(t,J＝8.6Hz,2H),4.11(s,2H).

EXAMPLE 35 Synthesis of Compound P33

The starting material was replaced by reacting compound P32 with 2- (4-methylpiperazin-1-yl) ethylamine and the product P33, i.e. 3- (4-fluorobenzyl) -6- (2- (4-methylpiperazin-1-yl) ethylamino) -8-hydroxy-1- (oxazol-2-yl) chromone [2,3-c, was obtained according to the method of example 17]Pyrrolon-9 (2H) -one as a brown solid in 33% yield.¹H NMR(500MHz,DMSO–d₆)δ12.85(br s,1H),8.21(s,1H),7.81(d,J＝8.8Hz,1H),7.40(s,1H),7.34(dd,J＝8.6,5.6Hz,2H),7.13(dd,J＝12.3,5.5Hz,2H),6.66(t,J＝5.2Hz,1H),6.63(dd,J＝8.8,2.1Hz,1H),6.41(d,J＝1.9Hz,1H),4.13(s,2H),3.24(dd,J＝12.2,6.4Hz,4H),3.17(s,3H),2.53(d,J＝6.7Hz,2H),2.46(s,2H),2.37(s,4H).

EXAMPLE 36 Synthesis of Compound P34

The starting material was replaced with 1- (2-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione and reacted with FMOC-O-tert-butyl-L-serine to give the product P34, 3-tert-butoxymethyl-1- (thiazol-2-yl) chromone [2,3-c ] according to the procedure of example 2]Pyrrol-9 (2H) -one as a yellow solid in 35% yield.¹H NMR(400MHz,CDCl₃)δ10.34(s,1H),8.35(dd,J＝7.9,1.6Hz,1H),7.84(d,J＝3.2Hz,1H),7.63(ddd,J＝8.7,7.1,1.7Hz,1H),7.42–7.36(m,2H),7.31(t,J＝7.5Hz,1H),4.69(s,2H),1.33(s,9H).

EXAMPLE 37 Synthesis of Compound P35

The starting material was replaced with 1- (2-hydroxyphenyl) -3- (thiazol-2-yl) propane-1, 3-dione and Fmoc-L-aspartic acid-4-tert-butyl ester and the procedure of example 2 was followed to give the product P35, 2- [ 9-oxo-1- (thiazol-2-yl) -2, 9-dihydrochromone [2,3-c ] as]Pyrrolon-3-yl]Tert-butyl acetate, yellow solid, 39% yield.¹H NMR(500MHz,CDCl₃)δ10.71(br s,1H),8.35(dd,J＝7.9,1.6Hz,1H),7.84(d,J＝3.2Hz,1H),7.68–7.60(m,1H),7.42–7.36(m,2H),7.31(t,J＝7.5Hz,1H),3.86(s,2H),1.52(s,9H).

EXAMPLE 38 Synthesis of Compound P36

Compound P35(382mg,1.0mmol) was dissolved in 3.0mL of dichloromethane, and then 1.0mL of trifluoroacetic acid was slowly added to the system, and the reaction was stirred at room temperature for 1 hour. Concentrating to remove most of the solvent, diluting with ethyl acetate, washing with water and saturated sodium bicarbonate solution, drying over anhydrous sodium sulfate, and concentrating to obtain product P36(320mg), i.e. 2- [ 9-oxo-1- (thiazol-2-yl) -2, 9-dihydrochromone [2,3-c ]]Pyrrolon-3-yl]Acetic acid, yellow solid, yield 98%.¹H NMR(400MHz,DMSO–d₆)δ13.00(s,1H),12.68(br s,1H),8.21(dd,J＝7.9,1.7Hz,1H),7.95(d,J＝3.2Hz,1H),7.83–7.73(m,2H),7.54(d,J＝8.3Hz,1H),7.40(t,J＝7.4Hz,1H),3.87(s,2H).

EXAMPLE 39 Synthesis of Compound P37

Compound P36(81mg,0.25mmol) was dissolved in 2.0mL of dichloromethane, and methylamine hydrochloride (24mg,0.35mmol), triethylamine (70. mu.L, 0.5mmol) and HATU (143mg,0.38mmol) were added to the system, and the reaction was stirred at room temperature for 4 hours. After the reaction is completed, the product P37(57mg), namely N-methyl-2- [ 9-oxo-1- (thiazole-2-yl) -2, 9-dihydrochromone [2,3-c ] is obtained by column chromatography separation]Pyrrolon-3-yl]Acetamide, yellow solid, yield 67%.¹H NMR(400MHz,DMSO–d₆)δ12.86(s,1H),8.21(dd,J＝7.9,1.6Hz,1H),7.94(d,J＝3.2Hz,1H),7.87(d,J＝4.5Hz,1H),7.82–7.70(m,2H),7.52(d,J＝8.1Hz,1H),7.39(dd,J＝11.0,4.0Hz,1H),3.72(s,2H),2.62(d,J＝4.6Hz,3H).

EXAMPLE 40 test of the inhibitory Activity of Compounds on the PDE5 enzyme

The test molecule is conjugated with a peptide containing recombinant PDE5A1 protein (see Bioorganic for preparation of the recombinant protein: Bioorganic)&Medicinal Chemistry Letters, 2012, volume 22, page number: 3261-3264), 20mM Tris-HCl, pH 7.5,2mM dithiothreitol (dithiothreitol), 10mM MgCl₂And 20,000-³H-cGMP was incubated for 15 min at room temperature and then separately incubated with 0.2M ZnSO₄And Ba (OH)₂The reaction was stopped and then measured using a PerkinElmer 2910 meterThe counter measures unreacted in the supernatant³H-cGMP, measured at least three times per molecule. IC for inhibition of PDE5A1 protein activity₅₀Values were calculated by concentration testing and non-linear regression. The expression and purification of other subtypes of PDEs is similar to that of PDE 5.

The data of the test for the inhibitory activity of the compounds of the invention on the PDE5 enzyme are shown in Table 1 (under equivalent conditions, the inhibitory activity IC of the positive control Sildenafil on the PDE5 enzyme₅₀At 5.1 nM).

Results of the PDE5 enzyme inhibition Activity test with the Compounds of Table 1

As can be seen from Table 1, most of the compounds showed inhibitory effects on the PDE5 enzyme, and the inhibitory effects of the other compounds on the PDE5 enzyme were superior to that of the positive control sildenafil except for the compounds P2, P3, P4, P8, P32 and P33-P37; and the compounds P16, P19, P20, P23, P26, P27, P28, P30 and P31 have better inhibition effect on PDE5 enzyme, and the IC of the compounds is₅₀All values were less than 1nM, and the best for PDE5 enzyme inhibition was compound P26.

The selectivity index of the activity-optimized compound P26 to the PDEs family was determined and the results are shown in table 2.

Table 2 results of selectivity index test of representative compound P26 on PDEs family

The results show that the substituted pyrrole chromone compound has good inhibitory activity on phosphodiesterase type 5 and is superior to the positive drug sildenafil; the compound has good selectivity on other subtypes of phosphodiesterase family, has subtype selectivity similar to sildenafil, and shows excellent inhibition on type 5 phosphodiesterase, but has no inhibition or very weak inhibition on other subtypes of phosphodiesterase. Therefore, the substituted pyrrole chromone compound has wide application space as a phosphodiesterase type 5 inhibitor.

It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A substituted pyrrole chromone compound is characterized by having a structure shown as a formula (I) or a pharmaceutically acceptable salt thereof:

wherein Y is oxygen; x is 2-thiazole;

R₁、R₂and R₄Each independently selected from hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy;

the R is₃Is selected from

The R is₅Is selected from

2. The substituted pyrrole chromone compound of claim 1, wherein the pharmaceutically acceptable salt of the compound is a product obtained by reacting a compound of formula (I) with an acid; the acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, malic acid, or glutamic acid.

3. The method for preparing the substituted pyrrole chromone compound of claim 1, comprising the following steps:

s2, reacting the compound 3 and the compound 4 in a solvent dissolved with an alkaline substance at normal temperature and then at 40-90 ℃ under the action of a condensing agent to obtain a compound 5;

wherein Z is sulfur; the R is₁～R₅Is as defined in claim 1.

4. The method for preparing a substituted pyrrole chromone compound according to claim 3, wherein the condensing agent in step S2 is 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, N, N '-dicyclohexylcarbodiimide, or N, N' -carbonyldiimidazole;

the alkaline substance in the step S1 is selected from one or more of potassium tert-butoxide, sodium hydride, lithium bis-trisilyl amide, sodium bis-trisilyl amide and lithium diisopropylamide;

the basic substance in step S2 is selected from one or a mixture of diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, piperidine, sodium bicarbonate, sodium carbonate, and potassium carbonate.

5. The method for preparing substituted pyrrole chromone compounds of claim 3, wherein the structure of compound 4 is

The preparation method comprises the following steps:

s46, mixing the compound 11 and an alkaline substance in a solvent at the temperature of-20 ℃, then gradually adding chloroformic acid-9-fluorenylmethyl ester for reaction, and gradually heating to the temperature of 25-40 ℃ for reaction to obtain a target product;

wherein R' is C1-5 alkyl or benzyl.

6. Use of a substituted pyrrole chromone compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of a phosphodiesterase type 5 inhibitor.

7. Use of a substituted pyrrole chromone compound of any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a phosphodiesterase type 5 related disease.