Chromone compounds preparable from natural active products and use thereof

Abstract

The application discloses a chromone compound prepared from a natural active product and application thereof, and the chromone compound is a thiazolidinedione derivative, and the thiazolidinedione derivative has the following structure: wherein R represents a substituted or unsubstituted aromatic hydrocarbon group, and the substitution is optional substitution. The application designs and synthesizes a series of thiazolidinedione compounds by taking thiazolidinedione as a mother nucleus, and the thiazolidinedione compounds have good alpha-glucosidase inhibiting effect and can be used as alpha-glucosidase inhibitors to treat or prevent diabetes.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a chromone compound that can be prepared from natural active products and its applications. Background Technology

[0002] Diabetes mellitus is a disease characterized by the body's loss of control over blood sugar. With the development of human society and changes in lifestyle, diabetes has become one of the world's leading chronic non-communicable diseases, significantly impacting people's health and lives. Currently, clinically used hypoglycemic drugs mainly include sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and non-sulfonylurea insulin secretagogues. Among them, alpha-glucosidase inhibitors are oral hypoglycemic drugs that treat diabetes by reducing the rate of carbohydrate digestion and inhibiting postprandial hyperglycemia. Their mechanism of action is as follows: alpha-glucosidase inhibitors interfere with enzymatic activity in the brush border of the small intestine, slowing the release of D-glucose from oligosaccharides and disaccharides, thereby leading to a decrease in postprandial plasma glucose levels and delayed glucose absorption. Alpha-glucosidase is a family of enzymes located on the brush border surface of small intestinal cells; it is a carbohydrate hydrolase that specifically hydrolyzes 1,4-alpha-glucosidic bonds to release alpha-D-glucose. Alpha-glucosidase plays an important role in the systemic circulation of mammals; therefore, its inhibitors hold a crucial position in the treatment of diabetes.

[0003] Natural bioactive products are an important source of drug discovery. Due to their unique and diverse activities and structures, good biocompatibility with the human body and environment, and ability to bind to various enzymes or proteins, they possess numerous advantages, including high efficacy and low toxicity. Extensive research has shown that active components in natural products, such as polyphenols, ketones, glycosides, and alkaloids, all exhibit good inhibitory effects on α-glucosidase. my country is rich in natural product resources, and early researchers focused on extracting hypoglycemic agents from these products. However, natural products often have poor solubility, complex structures, and unstable chemical properties, thus requiring structural modification before they can be used as clinical drugs. Synthesizing derivatives from natural products to prepare α-glucosidase inhibitors is a low-cost, abundant, challenging, and valuable research direction that has become a major focus for researchers worldwide in recent years.

[0004] Thiazolidinedione derivatives are an important class of chromone compounds. Related studies have shown that many thiazolidinedione derivatives have α-glucosidase inhibitory effects. However, existing diabetes drugs have different limitations and cannot fully meet clinical needs. Therefore, the development of new thiazolidinedione derivatives with α-glucosidase inhibitory effects is still of great significance. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention proposes a chromone compound that can be prepared from a natural active product, specifically a thiazolidinedione derivative, which has good α-glucosidase inhibitory activity.

[0006] The present invention also proposes a method for preparing the above-mentioned derivatives.

[0007] The present invention also proposes applications of the above-mentioned derivatives.

[0008] According to one aspect of the present invention, a thiazolidinedione derivative is provided, said thiazolidinedione derivative having the structure shown in the following formula:

[0009]

[0010] In the formula, R represents a substituted or unsubstituted aromatic group, and the substitution is optional.

[0011] According to a preferred embodiment of the present invention, at least the following beneficial effects are achieved: The present invention uses thiazolidinediones as the parent nucleus to design and synthesize a series of thiazolidinedione compounds, wherein these compounds have good α-glucosidase inhibitory activity, are highly efficient and low in toxicity, and can be used as α-glucosidase inhibitors for the treatment or prevention of diabetes.

[0012] In some embodiments of the present invention, the substitution is at least one of halogenation, halogenated alkyl substitution, or halogenated alkoxy substitution.

[0013] In some preferred embodiments of the present invention, the number of carbon atoms in the haloalkyl or haloalkoxy group is 4 or less.

[0014] In some preferred embodiments of the present invention, the halogenation in the haloalkyl or haloalkoxy group is fluorination.

[0015] In some more preferred embodiments of the present invention, the R is selected from the following groups:

[0016]

[0017] According to another aspect of the present invention, a method for preparing the above-mentioned derivative is provided, comprising the following steps:

[0018] S1. Compound 1 was prepared from 2,4-dihydroxyacetophenone; Compound 2 was prepared from Compound 1; Compound 3 was prepared from 2,4-thiazolidinedione.

[0019] S2. React compounds 2 and 3 to obtain the derivative;

[0020] The structural formulas of compounds 1, 2, and 3 are as follows:

[0021]

[0022] The preparation method according to the preferred embodiment of the present invention has at least the following beneficial effects: The present invention uses the natural product 2,4-dihydroxyacetophenone as a raw material to prepare chromone compounds—thiazolidinedione derivatives, and can prepare a series of derivatives with thiazolidinedione structure as the parent core. The preparation method is efficient and convenient and has good prospects for industrial application.

[0023] In some embodiments of the present invention, the preparation process of compound 1 in step S1 includes the following steps:

[0024] S11. POCl3 was added to a solution of 2,4-dihydroxyacetophenone at low temperature. After the reaction, compound 1 was obtained.

[0025] In some embodiments of the present invention, the reaction in step S11 is carried out at 15–40°C.

[0026] In some embodiments of the present invention, the low temperature in step S11 refers to -2 to 4°C; preferably 0°C.

[0027] In some embodiments of the present invention, the 2,4-dihydroxyacetophenone solution refers to a DMF solution of 2,4-dihydroxyacetophenone.

[0028] In some embodiments of the present invention, the preparation process of compound 2 in step S1 includes the following steps:

[0029] S12, containing compound 1 and A base was added to the mixture, and after the reaction, compound 2 was obtained.

[0030] In some embodiments of the present invention, the preparation process of compound 2 in step S1 includes the following steps:

[0031] S13. Add a base to a mixture containing thiazolidinedione and p-bromomethylbenzoic acid, and after reaction, obtain compound 3.

[0032] According to some embodiments of the present invention, the alkali is an inorganic alkali; preferably, the alkali is at least one selected from K2CO3, Na2CO3 and Cs2CO3; more preferably, the alkali is K2CO3.

[0033] According to another aspect of the present invention, the use of the above-mentioned thiazolidinedione derivatives in the preparation of α-glucosidase inhibitors is proposed.

[0034] According to another aspect of the present invention, the use of the above-mentioned thiazolidinedione derivatives in the preparation of products for the prevention and / or treatment of diabetes is proposed.

[0035] The application of the preferred embodiments of the present invention has at least the following beneficial effects: The present invention uses computer-aided drug design methods, combined with in vitro pharmacological activity evaluation experiments, to conduct in-depth research on the related biological activities and structure-activity relationships of α-glucosidase as the target protein, providing a solid theoretical basis for finding and discovering lead compounds of highly effective and low-toxicity α-glucosidase inhibitors.

[0036] In some embodiments of the present invention, the product includes a drug.

[0037] According to another aspect of the invention, a medicament is provided comprising the above-described thiazolidinedione derivatives and / or their pharmaceutically acceptable salts.

[0038] In some embodiments of the present invention, the dosage form of the drug is a tablet, capsule, oral liquid, or injection.

[0039] According to another aspect of the invention, a pharmaceutical composition is provided comprising the above-described thiazolidinedione derivatives and / or their pharmaceutically acceptable salts.

[0040] As used herein, “optional substitution” means that a group may or may not be further substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, aryl, halogen, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxyl, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, heteroaryl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclic, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, phenylamino, diphenylamino, benzylamino, dibenzylamino, hydrazyl, acyl, acylamino, diacylamino, acyloxy, heterocyclic, heterocyclic oxy, heterocyclic amino, haloheterocyclic, carboxyl ester, carboxyl, carboxylamide, mercapto, alkylthio, benzylthio, acylthio, and phosphorus-containing groups.

[0041] As used herein, the term "heteroaryl" refers to an aromatic group containing one to four heteroatomic groups selected from O, N, and S. Heteroaryl groups within this definition include, but are not limited to: acridinel, carbazolyl, cenolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrroleyl, and tetrahydroquinoline.

[0042] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0043] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0044] Figure 1 This is a graph showing the half-maximal inhibitory concentration (IC50) of thiazolidinedione derivative H31 as an α-glucosidase inhibitor in vitro in Example 1 of the present invention.

[0045] Figure 2 The diagram shows the in vitro enzyme kinetics of α-glucosidase by the thiazolidinedione derivative H31 as an α-glucosidase inhibitor in Example 1 of this invention.

[0046] Figure 3 This is a substrate kinetic diagram of thiazolidinedione derivative H31 as an α-glucosidase inhibitor in vitro in Example 1 of the present invention. Detailed Implementation

[0047] The following will clearly and completely describe the concept and technical effects of the present invention in conjunction with embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available. Unless otherwise specified, the same parameter value is the same in all embodiments. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0048] In the description of this invention, the following terms are to be understood as including the stated number. Where 1, 2, 3, etc., are used for the purpose of distinguishing technical features, and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.

[0049] In the description of this invention, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the 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.

[0050] Example 1

[0051] This embodiment prepared a series of thiazolidinedione derivatives, and the preparation route is as follows:

[0052]

[0053] The specific steps are as follows:

[0054] At 0 °C, POCl3 (6 mmol) was added to a 1.2 mL LMF solution containing 2,4-dihydroxyacetophenone (1 mmol), and the mixture was stirred at room temperature (25 °C) and monitored by TLC until the reaction was complete. The reaction system was poured into ice water, stirred for 4 h, and then filtered to give compound 1. Compound 1 (1 mmol) and benzyl bromide with different substituents were then reacted... Add 1.5 mmol of Na₂CO₃ to 1.5 mmol of dichloromethane, and then add 4 mL of DMF. Wash the dichloromethane layer with saturated NaHCO₃ and brine, dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain compound 2. Add 2 mmol of K₂CO₃ to 1 mmol of thiazolidinedione and 2 mmol of p-bromomethylbenzoic acid, add 10 mL of acetone, stir at 56 °C and detect by thin-layer chromatography (TLC) until the reaction is complete, wash the ethyl acetate layer with water, dry with anhydrous sodium sulfate, and concentrate to obtain compound 3. Add 5 mL of anhydrous ethanol, 3 drops of piperidine, and 3 drops of glacial acetic acid to 1 mmol of compound 2 and 1 mmol of compound 3, stir at 56 °C and detect by TLC until the reaction is complete, then filter to prepare product 4 (named H1). H33):

[0055] In the formula, H1 R1 in H33 is shown in Table 1 below:

[0056] Table 1. Structural formulas of the R1 group

[0057]

[0058]

[0059] The numbers in the table indicate the substitution positions of group R1 on the benzene ring. Taking 2-F as an example, and others in the same way, 2-F represents that the F substituent substitutes at position 2 on the benzene ring. That is, in the structural formula of thiazolidinedione derivatives, the substituent R is...

[0060] H1 was characterized by NMR, MS, and melting point. The structure of H33 is shown below, along with the properties, yields, NMR and mass spectrometry results of each compound:

[0061] (Z)-4-((5-((7-(benzyloxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid(H1-1)Molecular formula: C 28 H 19 NO7S; Appearance: white solid; Yield: 67%; Melting point: 328.6-329.2℃; 1H NMR (500MHz, DMSO) δ 8.87 (s, 1H), 8.04 (d, J = 8.9Hz, 1H), 7.92 (d, J = 8.2Hz, 2H), 7.72 (s, 1H), 7.49 (d, J = 7.1Hz, 2H), 7.45–7.35 (m, 5H), 7.34 (d, J = 2.4Hz, 1H), 7.21 (dd, J = 9.0, 2.4Hz, 1H), 5.28 (s, 2H), 4.88 (s, 2H). 13C NMR (126MHz, DMSO) δ174.56,169.42,167.47,166.41,163.97,162.30,157.64,140.86,136.37,130.73,130.16,129.05,12 8.73,128.50,127.97,127.59,127.34,122.85,118.14,117.25,116.58,102.52,70.75,44.60.HRMS(ESI)[M+H]+calcd.for C 28 H 19 N7OS:512.0814, found:512.0805.

[0062] (Z)-4-((5-((7-((2-fluorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-2) Molecular formula: C 28 H 18 FNO7S; Appearance: white solid; Yield: 65%; Melting point: 300.0–301.2℃; ¹H NMR (500MHz, DMSO) δ 12.91 (s, ¹H), 8.89 (s, ¹H), 8.05 (d, J = 8.9Hz, ¹H), 7.92 (d, J = 8.1Hz, 2H), 7.73 (s, ¹H), 7.62 (td, J = 7.6, 1.8Hz, ¹H), 7.47 (q, J = 6.5Hz, ¹H), 7.41 (d, J = 2.4Hz, 1H), 7.38 (d, J = 8.2Hz, 2H), 7.31–7.25 (m, 2H), 7.21 (dd, J = 8.9, 2.4Hz, 1H), 5.32 (s, 2H), 4.88 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.58,169.42,166.42,163.77,162.35,162.01,160.05,157.65,131.60,131.57,131.47,131.40,130.16,127.95,127.65 ,127.32,125.17,125.14,123.25,123.14,122.89,118.17,117.41,116.44,116.11,115.95,102.48,65.17,44.61.HRMS(ESI)[M+H]+calcd.for C 28 H 18 FNO7S:530.0721,found:530.0711.

[0063] (Z)-4-((5-((7-((3-fluorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-3) Molecular formula: C 28 H 18FNO7S; Appearance: white solid; Yield: 56%; Melting point: 304.9–305.3 °C; ¹H NMR (500 MHz, DMSO) δ 8.86 (s, ¹H), 8.04 (d, J = 8.9 Hz, ¹H), 7.91 (d, J = 8.0 Hz, 2H), 7.72 (s, ¹H), 7.46 (q, J = 7.4 Hz, ¹H), 7.36–7.29 (m, 5H), 7.23–7.17 (m, 2H), 5.30 (s, 2H), 4.85 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.58,169.40,166.41,163.73,161.70,157.62,131.17,131.10,130.08,127.73,127.28,124.34 ,122.90,118.17,117.39,116.53,115.58,115.41,115.14,114.97,102.61,69.82,44.65.HRMS(ESI)[M+H]+calcd.for C 28 H 18 FNO7S:530.0722,found:530.0711.

[0064] (Z)-4-((5-((7-((4-fluorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-4) Molecular formula: C 28 H 18 FNO7S; Properties: White solid; Yield: 43%; Melting point: 287.2–287.9℃; 1H NMR (500MHz, DMSO) δ 8.88 (s, 1H), 8.05 (d, J = 8.9Hz, 1H), 7.92 (d, J = 8.1Hz, 2H), 7.73 (s, 1H), 7.62–7.49 (m, 2H), 7.38 (d, J = 8.1Hz, 2H), 7.35 (d, J = 2.3Hz, 1H), 7.26 (d, J = 8.9Hz, 2H), 7.24–7.19 (m, 1H), 5.27 (s, 2H), 4.88 (s, 2H). HRMS (ESI) [M+H]+calcd.for C 28 H 18 FNO7S:530.0721,found:530.0711.

[0065] (Z)-4-((5-((7-((2-chlorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-5) Molecular formula: C 28 H 18 ClNO7S; Appearance: white solid; Yield: 27%; Melting point: 284.4–284.7 °C; ¹H NMR (500 MHz, DMSO) δ 12.97 (s, ¹H), 8.89 (s, ¹H), 8.06 (d, J = 8.9 Hz, ¹H), 7.92 (d, J = 8.0 Hz, 2H), 7.73 (s, ¹H), 7.66 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.47–7.37 (m, 5H), 7.23 (d, J = 9.1 Hz, 1H), 5.34 (s, 2H), 4.88 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.59,169.42,167.47,166.42,163.80,162.37,157.65,133.69,133.57,131.27,130.92,130.16,13 0.05,128.00,127.96,127.70,127.33,122.90,118.18,117.47,116.40,102.56,68.49,44.61.HRMS(ESI)[M+H]+calcd.for C 28 H 18 ClNO7S:546.0427,found:546.0415.

[0066] (Z)-4-((5-((7-((3-chlorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-6) Molecular formula: C 28 H 18ClNO7S; Appearance: white solid; Yield: 31%; Melting point: 239.5–239.6 °C; ¹H NMR (500 MHz, DMSO) δ 8.88 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.91 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 3.7 Hz, 1H), 7.58 (s, ¹H), 7.44 (dt, J = 10.0, 5.6 Hz, 4H), 7.37–7.31 (m, 3H), 7.23 (dd, J = 9.0, 2.3 Hz, 1H), 5.30 (s, 2H), 4.86 (s, 2H). ¹³C NMR (126 MHz) z,DMSO)δ174.58,169.41,163.72,162.32,157.62,138.96,133.68,131.01,130.12,128.65,128.13,127.85,127.67 ,127.30,127.00,122.90,118.17,117.41,116.52,102.62,69.74,44.63,44.20,22.85.HRMS(ESI)[M+H]+calcd.for C 28 H 18 ClNO7S:550.0652,found:550.0692.

[0067] (Z)-4-((5-((7-((4-chlorobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-7) Molecular formula: C 28 H 18ClNO7S; Appearance: white solid; Yield: 33%; Melting point: 307.0–307.4 °C; ¹H NMR (500 MHz, DMSO) δ 12.98 (s, ¹H), 8.88 (s, ¹H), 7.92 (d, J = 8.0 Hz, 2H), 7.73 (s, ¹H), 7.54–7.46 (m, 5H), 7.39 (d, J = 7.8 Hz, 2H), 7.34 (s, ¹H), 7.21 (d, J = 8.8 Hz, 1H), 5.29 (s, 2H), 4.88 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.57,163.78,162.34,157.63,135.44,133.32,130.34,130.16,129.08,127.95 ,127.64,127.32,122.89,118.16,117.35,116.56,102.60,69.85,44.61.HRMS(ESI)[M+H]+calcd.forC 28 H 18 ClNO7S:550.0790,found:550.0692.

[0068] (Z)-4-((5-((7-((2-bromobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-8) Molecular formula: C 28 H 18BrNO7S; Appearance: white solid; Yield: 37%; Melting point: 275.3–276.1 °C; ¹H NMR (500 MHz, DMSO) δ 8.89 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.92 (d, J = 8.1 Hz, 2H), 7.73 (s, ¹H), 7.62 (td, J = 7.6, 1.8 Hz, ¹H), 7.47 (q, J = 6.5 Hz, ¹H), 7.41–7.37 (m, 3H), 7.31–7.24 (m, 2H), 7.21 (dd, J = 8.9, 2.4 Hz, 1H), 5.32 (s, 2H), 4.88 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.58,169.42,166.42,163.77,162.35,162.01,160. 05,157.65,140.79,131.60,131.57,131.47,131.40,130.16,127.95,127.6 5,127.32,125.17,125.14,123.25,123.14,122.89,118.17,117.41,116.44 ,116.11,115.95,102.48,65.17,44.61,21.55.HRMS(ESI)[M+H]+calcd.for C 28 H 18 BrNO7S:589.9922,found:589.9910.

[0069] (Z)-4-((5-((7-((3-bromobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-9) Molecular formula: C 28 H 18BrNO7S; Appearance: white solid; Yield: 26%; Melting point: 233.8–234.2 °C; ¹H NMR (500 MHz, DMSO) δ 8.87 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.91 (d, J = 8.0 Hz, ³H), 7.72 (d, J = 3.2 Hz, ²H), 7.57 (dt, J = 7.9, 1.4 Hz, ¹H), 7.50 (d, J = 7.7 Hz, ¹H), 7.39 (t, J = 7.8 Hz, ¹H), 7.33 (d, J = 7.5 Hz, ³H), 7.22 (dd, J = 8.9, 2.4 Hz, ¹H), 5.29 (s, ²H), 4.86 (s, ²H). ¹³C NMR (126MHz, DMSO) δ174.56,169.39,166.41,163.70,162.29,157.60,139.19,131.55,131.28,131.01,130.05,127.6 5,127.38,127.26,122.90,122.25,118.17,117.40,116.50,102.61,69.68,44.66,23.01.HRMS(ESI)[M+H]+calcd.for C 28 H 18 BrNO7S:589.9926,found:589.9910.

[0070] (Z)-4-((5-((7-((4-bromobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-10) Molecular formula: C 28 H 18 BrNO7S; Appearance: white solid; Yield: 21%; Melting point: 280.0–281.0 °C; ¹H NMR (500 MHz, DMSO) δ 8.87 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.90 (d, J = 8.1 Hz, ³H), 7.72 (s, ¹H), 7.62 (d, J = 8.1 Hz, ²H), 7.46 (d, J = 8.0 Hz, ²H), 7.37–7.32 (m, ³H), 7.21 (dd, J = 9.0, 2.4 Hz, ¹H), 5.27 (s, ²H), 4.86 (s, ²H). HRMS (ESI) [M+H]+calcd.for C 28 H 18 BrNO7S:589.9926,found:589.9910.

[0071] (Z)-4-((5-((7-((2-methylbenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-11) Molecular formula: C 29 H 21 NO7S; Appearance: white solid; Yield: 24%; Melting point: 298.1–298.8 °C; ¹H NMR (500 MHz, DMSO) δ 8.89 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.94–7.90 (m, 2H), 7.73 (s, ¹H), 7.45 (d, J = 7.4 Hz, ¹H), 7.41–7.36 (m, 3H), 7.31–7.25 (m, 2H), 7.23 (ddd, J = 11.3, 6.4, 3.4 Hz, 2H), 5.27 (s, 2H), 4.88 (s, 2H), 2.34 (s, 3H).¹³C NMR (126MHz, DMSO) δ174.58,169.43,167.62,166.42,164.09,162.33,157.68,140.65,137.38,134.32,130.76,130.14,129.34,128.98,127. 91,127.60,127.35,126.38,122.86,118.15,117.28,116.50,102.52,69.53,44.61,44.13,22.81,22.24,18.97.HRMS(ESI)[M+H]+calcd.for C 29 H 21 NO7S:526.0972, found:526.0962.

[0072] (Z)-4-((5-((7-((3-methylbenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-12) Molecular formula: C 29 H 21NO7S; Appearance: white solid; Yield: 26%; Melting point: 286.9–289.3℃; 1H NMR (500MHz, DMSO) δ 8.87 (s, 1H), 8.04 (d, J = 8.9Hz, 1H), 7.94–7.90 (m, 2H), 7.72 (s, 1H), 7.38 (d, J = 8.1Hz, 2H), 7.35–7.25 (m, 4H), 7.19 (ddd, J = 11.5, 8.6, 2.1Hz, 2H), 5.23 (s, 2H), 4.87 (s, 2H), 2.32 (s, 3H). HRMS (ESI) [M+H]+calcd.for C 29 H 21 NO7S:526.0970, found:526.0962.

[0073] (Z)-4-((5-((7-((4-methylbenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-13) Molecular formula: C 29 H 21 NO7S; Appearance: white solid; Yield: 29%; Melting point: 276.5–277.2 °C; ¹H NMR (500 MHz, DMSO) δ 12.97 (s, ¹H), 8.87 (s, ¹H), 8.03 (d, J = 8.9 Hz, ¹H), 7.92 (d, J = 8.0 Hz, 2H), 7.72 (s, ¹H), 7.42–7.35 (m, 3H), 7.32 (d, J = 2.3 Hz, 1H), 7.24–7.16 (m, 3H), 5.23 (s, 2H), 4.88 (s, 2H), 2.31 (s, 3H). ¹³C NMR (126MHz, DMSO) δ174.57,169.42,167.51,166.41,164.01,162.30,157.65,140.87,138.06,133.32,130.16,130.04,129.60,128.62,1 28.06,127.97,127.56,127.36,122.85,118.14,117.20,116.63,102.50,70.68,44.60,44.50,44.22,21.27.HRMS(ESI)[M+H]+calcd.forC 29 H 21 NO7S:526.0974, found:526.0962.

[0074] (Z)-4-((5-((7-((2-nitrobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-14) Molecular formula: C 28 H 18 N₂O₉S; Properties: White solid; Yield: 25%; Melting point: 274.1–280.0℃; 1H NMR (500MHz, DMSO) δ8.88(s,1H),8.19–8.15(m,1H),8.07(d,J=8.9Hz,1H),7.93–7.89(m,2H),7.83–7.77(m,2H),7.72(s,1H),7.66(ddd,J=8.5, 6.5,2.3Hz,1H),7.38(d,J=2.4Hz,1H),7.33(d,J=8.0Hz,2H),7.23(dd,J=8.9,2.4Hz,1H),5.65(s,2H),4.86(s,2H).HRMS(ESI)[M+H]+calcd.for C 28 H 18 N2O9S:557.0668,found:557.0656.

[0075] (Z)-4-((5-((7-((3-nitrobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-15) Molecular formula: C 28 H 18 N₂O₉S; Properties: White solid; Yield: 28%; Melting point: 263.5–264.4℃; 1H NMR(500MHz,DMSO)δ8.87(s,1H),8.19–8.14(m,1H),8.07(d,J=8.9Hz,1H), 7.91(d,J=8.2Hz,2H),7.80(dd,J=6.6,1.5Hz,3H),7.72(s,1H),7.66(ddd,J =8.5,6.4,2.4Hz,1H),7.38(d,J=2.4Hz,1H),7.35(d,J=8.1Hz,2H),7.23(dd,J=8.9,2.4Hz,1H),5.65(s,3H),4.86(s,2H).HRMS(ESI)[M+H]+calcd.forC 28 H 18N2O9S:557.0668,found:557.0656.

[0076] (Z)-4-((5-((7-((4-nitrobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-16) Molecular formula: C28H18N2O9S; Appearance: White solid; Yield: 65%; Melting point: 280.6–281.2℃; 1H NMR (500MHz, DMSO) δ8.88(s,1H),8.29(d,J=8.4Hz,2H),8.07(d,J=8.9Hz,1H),7.90(d,J=7.9Hz,2H),7.76(d,J=8.4Hz,2H),7 .72(s,1H),7.35(dd,J=12.0,5.0Hz,3H),7.25(dd,J=9.0,2.4Hz,1H),5.47(s,2H),4.86(s,2H).HRMS(ESI)[M+H]+calcd.for C28H18N2O9S:557.0668,found:557.0656.

[0077] (Z)-4-((5-((7-((2-cyanobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-17) Molecular formula: C29H18N2O7S; Appearance: White solid; Yield: 37%; Melting point: 280.1–281.2℃; 1H NMR (500MHz, DMSO) δ8.90(s,1H),8.08(d,J=9.0Hz,1H),7.96(d,J=7.7Hz,1H),7.92(d,J=8.0Hz,2H),7.81–7.78(m,2H),7.74(s,1H),7. 13C NMR (126MHz, DMSO) δ174.59,169.40,166.41,163.59,162.37,157.61,139.29,134.07,133.97,130.54,130.12,130.03,12 7.85,127.76,127.28,122.94,118.20,117.65,117.61,116.37,112.09,102.66,69.01,44.63.HRMS(ESI)[M+H]+calcd.for C29H18N2O7S:560.0626,found:560.0656.

[0078] (Z)-4-((5-((7-(((3-cyanobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-18) Molecular formula: C29H18N2O7S; Appearance: White solid; Yield: 35%; Melting point: 290.5–291.2℃; 1H NMR (500MHz, DMSO) δ8.88(s,1H),8.06(d,J=9.0Hz,1H),7.98(d,J=1.8Hz,1H),7.91(d,J=8.1Hz,2H),7.85(dd,J=9.5,4.0Hz,2 H),7.72(s,1H),7.64(t,J=7.8Hz,1H),7.36(dd,J=5.4,2.9Hz,3H),7.24(dd,J=9.0,2.4Hz,1H),5.35(s,2H),4.87(s,2H).13C NMR (126MHz, DMSO) δ174.58,169.41,166.41,163.61,162.35,157.60,138.13,133.20,132.52,131.84,130.36,130.15,127.9 4,127.69,127.30,122.90,119.08,118.17,117.48,116.49,112.04,102.66,69.48,44.61,21.55.HRMS(ESI)[M+H]+calcd.for C29H18N2O7S:537.0770,found:537.0758.

[0079] (Z)-4-((5-((7-((4-cyanobenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-19) Molecular formula: C29H18N2O7S; Appearance: White solid; Yield: 32%; Melting point: 249.1–249.5℃; 1H NMR(500MHz,DMSO)δ8.88(s,1H),8.06(d,J=8.9Hz,1H),7.94–7.88(m,4H),7.72(s,1H),7.69(d,J=8 .0Hz,2H),7.38(d,J=8.0Hz,2H),7.35(d,J=2.3Hz,1H),7.24(dd,J=9.0,2.4Hz,1H),5.41(s,2H),4.8 7(s,2H).13CNMR(126MHz,DMSO)δ169.39,166.41,163.58,162.33,157.60,142.15,133.04,130.10,1 28.83,127.82,127.27,122.93,118.19,117.50,116.49,102.69,69.67.HRMS(ESI)[M+H]+calcd.for C29H18N2O7S:560.0617,found:560.0656.

[0080] (Z)-4-((5-((7-((2-(methoxycarbonyl)benzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-diox othiazolidin-3-yl)methyl)benzoic acid (H1-20) Molecular formula: C 30 H 21NO9S; Appearance: white solid; Yield: 22%; Melting point: 248.2–249.2 °C; ¹H NMR (500 MHz, DMSO) δ 8.87 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.93 (dd, J = 12.9, 7.9 Hz, 3H), 7.72 (s, ¹H), 7.66 (d, J = 7.2 Hz, 2H), 7.54–7.49 (m, ¹H), 7.36 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 5.57 (s, 2H), 4.87 (s, 2H), 3.80 (s, 3H). ¹³C NMR (126MHz, DMSO) δ174.58,169.41,167.30,166.41,163.92,162.32,157.65,137.22,133.06,130.87,130.11,130.01,129.42,129.3 0,128.90,127.83,127.72,127.32,122.88,118.16,117.38,116.33,102.51,69.12,52.73,44.62,21.58.HRMS(ESI)[M+H]+calcd.for C 30 H 21 NO9S:593.0736, found:593.0758.

[0081] (Z)-4-((5-((7-((3-(methoxycarbonyl)benzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-diox othiazolidin-3-yl)methyl)benzoic acid (H1-21) Molecular formula: C 30 H 21NO9S; Appearance: white solid; Yield: 25%; Melting point: 251.6–252.1 °C; ¹H NMR (500 MHz, DMSO) δ 12.97 (s, ¹H), 8.87 (s, ¹H), 8.09 (d, J = 1.8 Hz, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.95 (dt, J = 7.8, 1.5 Hz, ¹H), 7.92 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.72 (s,1H),7.58(t,J=7.7Hz,1H),7.39(d,J=8.2Hz,2H),7.35(d,J=2.4Hz,1H),7.23(dd, J=8.9,2.4Hz,1H),5.38(s,2H),4.88(s,2H),3.87(s,3H).HRMS(ESI)[M+H]+calcd.for C 30 H 21 NO9S:570.0874, found:570.0861.

[0082] (Z)-4-((5-((7-([1,1'-biphenyl]-2-ylmethoxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothia zolidin-3-yl)methyl)benzoic acid (H1-22) Molecular formula: C 34 H 23 NO7S; Appearance: white solid; Yield: 24%; Melting point: 238.5–238.8℃; 1H NMR(500MHz,DMSO)δ8.84(s,1H),8.00(d,J=8.9Hz,1H),7.90(d,J=7.9Hz,2H) ,7.71(s,1H),7.64(dd,J=7.5,1.7Hz,1H),7.52–7.43(m,2H),7.41(d,J=4.3H z,4H),7.38–7.34(m,2H),7.31(d,J=8.0Hz,2H),7.17(d,J=2.3Hz,1H),7.09( dd,J=9.0,2.4Hz,1H),5.10(s,2H),4.85(s,2H).HRMS(ESI)[M+H]+calcd.for C 34 H 23 NO7S:588.1137, found:588.1121.

[0083] (Z)-4-((5-((7-([1,1'-biphenyl]-3-ylmethoxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothia zolidin-3-yl)methyl)benzoic acid (H1-23) Molecular formula: C 34 H 23 NO7S; Appearance: white solid; Yield: 60%; Melting point: 244.4–245.5℃; 1H NMR (500MHz, DMSO) δ 8.87 (s, 1H), 8.05 (d, J = 8.9Hz, 1H), 7.91 (d, J = 8.3Hz, 2H), 7.80 (d, J = 2.2Hz, 1H), 7.72 (s, 1H), 7.70–7.65 (m, 3H), 7.54–7.45 (m, 5H), 7.41–7.32 (m, 4H), 7.24 (dd, J = 8.9, 2.4Hz, 1H), 5.36 (s, 2H), 4.87 (s, 2H). 13C NMR (126MHz, DMSO) δ174.58,169.42,166.41,163.98,162.31,157.65,140.94,140.26,137.12,130.13,129.73,129.48,128.13,127.90,12 7.62,127.53,127.33,127.22,127.06,126.85,122.86,118.15,117.29,116.60,102.58,70.69,44.61,21.56.HRMS(ESI)[M+H]+calcd.for C 34 H 23 NO7S:588.1137, found:588.1121.

[0084] (Z)-4-((5-((7-([1,1'-biphenyl]-4-ylmethoxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothia zolidin-3-yl)methyl)benzoic acid (H1-24) Molecular formula: C 34 H 23NO7S; Appearance: white solid; Yield: 68%; Melting point: 268.1–2692 °C; ¹H NMR (500 MHz, DMSO) δ 12.99 (s, ¹H), 8.87 (s, ¹H), 8.05 (d, J = 8.9 Hz, ¹H), 7.92 (d, J = 8.1 Hz, 2H), 7.74–7.65 (m, 5H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.42–7.34 (m, 4H), 7.23 (dd, J = 8.9, 2.4 Hz, 1H), 5.33 (s, 2H), 4.88 (s, 2H). ¹³C NMR (126MHz, DMSO) δ174.57,169.42,167.50,166.41,163.96,162.31,157.65,140.86,140.56,140.15,135.54,130.16,129.45,12 9.12,128.08,127.97,127.62,127.35,127.18,122.86,118.15,117.28,116.61,102.56,70.43,44.59.HRMS(ESI)[M+H]+calcd.for C 34 H 23 NO7S:627.0784, found:627.0758.

[0085] (Z)-4-((5-((7-((4-(methoxycarbonyl)benzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-diox othiazolidin-3-yl)methyl)benzoic acid (H1-25) Molecular formula: C 30 H 21NO9S; Appearance: white solid; Yield: 57%; Melting point: 271.9–272.3 °C; ¹H NMR (500 MHz, DMSO) δ 12.94 (s, ¹H), 8.87 (s, ¹H), 8.06 (d, J = 8.7 Hz, ¹H), 8.00 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.72 (s, ¹H), 7.63 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.35 (s, ¹H), 7.23 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 4.88 (s, 2H), 3.86 (s, 3H).¹³C NMR (126MHz, DMSO) δ174.57,169.41,167.43,166.42,163.72,162.33,157.61,141.88,140.91,130.62,130.17,129.91,129.7 7,128.27,127.98,127.68,127.31,122.90,118.17,117.43,116.52,102.65,69.97,52.68,44.62.HRMS(ESI)[M+H]+calcd.for C 30 H 21 NO9S:570.0875, found:570.0861.

[0086] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((2-(trifluoromethyl)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-26) Molecular formula: C 29 H 18F3NO7S; Appearance: white solid; Yield: 24%; Melting point: 278.3–279.0 °C; 1H NMR (500 MHz, DMSO) δ 12.97 (s, 1H), 8.89 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.82 (dd, J = 10.4, 7.7 Hz, 2H), 7.78–7.72 (m, 2H), 7.64 (t, J = 7.7 Hz, 1H), 7.42–7.37 (m, 3H), 7.21 (dd, J = 8.9, 2.4 Hz, 1H), 5.40 (s, 2H), 4.88 (s, 2H). 13C NMR (126MHz, DMSO) δ174.59,169.41,167.45,166.41,163.59,162.38,157.64,140.92,134.07,133.47,131.77,130.63,130.17,129.81 ,127.98,127.75,127.32,126.89,126.84,123.63,122.91,118.19,117.55,116.35,102.53,67.91,44.60.HRMS(ESI)[M+H]+calcd.for C 29 H 18 F3NO7S:580.0693,found:580.0679.

[0087] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-27) Molecular formula: C 29 H 18F3NO7S; Appearance: white solid; Yield: 43%; Melting point: 276.4–277.7 °C; 1H NMR (500 MHz, DMSO) δ 8.88 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.93–7.86 (m, 3H), 7.81 (d, J = 7.7 Hz, 1H), 7.77–7.70 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 13.3, 5.1 Hz, 3H), 7.24 (dd, J = 8.9, 2.4 Hz, 1H), 5.39 (s, 2H), 4.86 (s, 2H). 13C NMR (126MHz, DMSO) δ174.58,169.41,166.41,163.71,162.35,157.62,137.92,132.50,130.23,130.14,129.62,127.90,12 7.69,127.30,125.46,124.93,124.90,122.90,118.17,117.44,116.50,102.62,69.78,44.62.HRMS(ESI)[M+H]+calcd.for C 29 H 18 F3NO7S:580.0693,found:580.0679.

[0088] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((4-(trifluoromethyl)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-28) Molecular formula: C 29 H 18F3NO7S; Appearance: white solid; Yield: 46%; Melting point: 274.9–275.6 °C; 1H NMR (500 MHz, DMSO-H6) δ 8.88 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.2 Hz, 3H), 7.41–7.35 (m, 3H), 7.24 (dd, J = 8.9, 2.4 Hz, 1H), 5.42 (s, 2H), 4.88 (s, 2H). 13C NMR (126MHz, DMSO) δ174.57,169.40,166.41,163.66,162.33,157.62,141.27,130.14,128.79,127.91,127.71,127.29,125.98,125.95 ,125.92,122.91,118.17,117.46,116.52,102.65,69.73,46.22,44.61,44.21,26.68,25.35,24.69,22.73.HRMS(ESI)[M+H]+calcd.for C 29 H 18 F3NO7S:580.0693,found:580.0679.

[0089] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((2-(trifluoromethoxy)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-29) Molecular formula: C 29 H 18F3NO3S; Properties: White solid; Yield: 37%; Melting point: 262.8–263.3℃; 1H NMR (500MHz, DMSO) δ 8.89 (s, 1H), 8.06 (d, J = 9.0Hz, 1H), 7.93–7.90 (m, 2H), 7.73 (s, 1H), 7.56 (td, J = 7.7, 1.8Hz, 1H), 7.49–7.44 (m, 2H), 7.41–7.35 (m, 3H), 7.20 (dd, J = 9.0, 2.4Hz, 1H), 5.32 (s, 2H), 4.87 (s, 2H). 13C NMR (126MHz, DMSO) δ174.58,169.41,166.41,163.68,162.35,157.65,131.78,131.24,130.14,128.67,128.18,12 7.90,127.69,127.31,122.90,121.18,118.18,117.48,116.38,102.46,65.80,44.61.HRMS(ESI)[M+H]+calcd.for C 29 H 18 F3NO3S:596.0644,found:596.0628.

[0090] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((3-(trifluoromethoxy)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-30) Molecular formula: C 29 H 18F3NO3S; Appearance: white solid; Yield: 26%; Melting point: 267.4–268.8℃; 1H NMR (500MHz, DMSO) δ 8.87 (s, 1H), 8.05 (d, J = 9.0Hz, 1H), 7.91 (d, J = 7.9Hz, 2H), 7.72 (s, 1H), 7.60–7.50 (m, 3H), 7.40–7.32 (m, 4H), 7.23 (dd, J = 8.9, 2.4Hz, 1H), 5.34 (s, 2H), 4.86 (s, 2H). 13C NMR (126MHz, DMSO) δ174.57,169.40,166.41,163.69,162.32,157.61,148.94,140.40,139.22,131.14,130.12,130.00,127.85,127.66 ,127.41,127.28,122.90,121.56,121.18,120.75,119.52,118.17,117.42,116.51,102.62,69.67,44.62.HRMS(ESI)[M+H]+calcd.forC 29 H 18 F3NO3S:596.0643,found:596.0628.

[0091] (Z)-4-((2,4-dioxo-5-((4-oxo-7-((4-(trifluoromethoxy)benzyl)oxy)-4H-chromen-3-yl)methylene)thiazolidin-3-yl)methyl)benzoic acid (H1-31) Molecular formula: C 29 H 18F3NO3S; Properties: White solid; Yield: 55%; Melting point: 286.7–287.8℃; 1H NMR (500MHz, DMSO) δ 8.88 (s, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.94–7.88 (m, 2H), 7.72 (s, 1H), 7.66–7.61 (m, 2H), 7.40 (dd, J = 17.9, 8.1 Hz, 4H), 7.35 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.9, 2.4 Hz, 1H), 5.32 (s, 2H), 4.88 (s, 2H). 13C NMR (126MHz, DMSO) δ174.57,169.41,167.60,166.41,163.77,162.32,157.63,148.60,140.76,135.92,130.43,130.15,127.94 ,127.66,127.31,122.89,121.67,121.55,119.52,118.17,117.38,116.51,102.57,69.75,44.61.HRMS(ESI)[M+H]+calcd.for C29H18F3NO3S:596.0646,found:596.0628.

[0092] (Z)-4-((5-((7-((3-methoxybenzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-32) Molecular formula: C 29 H 18F3NO8S; Appearance: white solid; Yield: 33%; Melting point: 256.9–257.8 °C; 1H NMR (500 MHz, DMSO) δ 8.87 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.35–7.30 (m, 2H), 7.21 (dd, J = 9.0, 2.4 Hz, 1H), 7.07–7.03 (m, 2H), 6.94–6.90 (m, 1H), 5.26 (s, 2H), 4.87 (s, 2H), 3.76 (s, 3H). 13C NMR (126MHz, DMSO) δ174.57,169.41,166.41,163.93,162.30,159.86,157.64,137.92,130.20,130.13,130.05,127.89,127.5 9,127.33,122.87,120.48,118.15,117.27,116.60,114.11,113.94,102.54,70.57,55.57,44.61.HRMS(ESI)[M+H]+calcd.for C 29 H 18 F3NO8S:542.0927,found:542.0911.

[0093] (Z)-4-((5-((7-((4-(tert-butyl)benzyl)oxy)-4-oxo-4H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)benzoic acid (H1-33) Molecular formula: C 32 H 27NO7S; Appearance: white solid; Yield: 35%; Melting point: 257.1–258.6 °C; ¹H NMR (500 MHz, DMSO) δ 8.86 (s, ¹H), 8.03 (d, J = 8.9 Hz, ¹H), 7.90 (d, J = 8.1 Hz, 2H), 7.71 (s, ¹H), 7.45–7.39 (m, 4H), 7.34–7.29 (m, 3H), 7.18 (dd, J = 8.9, 2.4 Hz, ¹H), 5.23 (s, 2H), 4.85 (s, 2H), 1.28 (s, 9H). ¹³C NMR (126 MHz, DMSO) δ 174.57, 1 69.42,166.42,164.05,162.29,157.67,151.25,133.36,130.11,128.45,128.15,127.82,127.58,127.33,125.81, 125.69,122.86,118.14,117.20,116.60,102.45,70.58,44.62,34.82,31.59,31.57.HRMS(ESI)[M+H]+calcd.forC 32 H 27 NO7S:568.1447, found:568.1433.

[0094] The results above show that a series of derivatives with thiazolidinedione structures as the parent core can be successfully prepared by the above synthetic route, and the preparation method has the advantages of high yield and simple operation.

[0095] Example 2

[0096] This embodiment provides the application of thiazolidinedione derivatives in the preparation of α-glucosidase activity inhibitors or diabetes prevention and treatment products. The thiazolidinedione derivatives obtained in Example 1 were used as α-glucosidase inhibitors, and their α-glucosinolate activity was tested in vitro to verify their efficacy as α-glucosidase inhibitors and diabetes prevention and treatment products.

[0097] 1. Preparation of reagents and standard solutions

[0098] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0099] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare a working concentration of 0.05U / mL, and then dispense and freeze.

[0100] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, prepare a substrate working solution with a concentration of 0.25mM, vortex mix well, and prepare fresh before each experiment.

[0101] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0102] 2. Experimental steps (1) Add 10 μL of α-glucosidase with a working concentration of 0.05 U / mL, 130 μL of phosphate buffer (pH 6.8) with a concentration of 100 mM, and 10 μL of compounds of different concentrations (thiazolidinedione derivatives H1 to H12 prepared in Example 1) to a 96-well plate in sequence. Replace 10 μL of the compound with 10 μL of DMSO with a content of 5% in the blank control group. Use acarbose as a positive control. Set up 4 replicates for each group. Incubate the enzyme reaction system on a microplate reader at 37°C for 10 min.

[0103] (2) Subsequently, 50 μL of substrate PNPG was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation, the time was evenly distributed 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0104] (3) The α-glucosidase inhibitory activity of the test compound is calculated according to the following formula:

[0105] Inhibition rate (%) = [(OD3-OD)-(OD1-OD)] / OD3-OD × 100%

[0106] Where OD represents the absorbance value of the blank control group. Data processing: Data were analyzed and processed using MS Excel, and the half-maximal inhibitory concentration (IC50) was calculated using Origin 9.1. 50 IC 50 This represents the concentration of the test compound required to inhibit α-glucosidase activity by 50% under the experimental conditions stated.

[0107] 3. Results Analysis

[0108] The α-glucosidase inhibitory activity of the synthesized compounds was evaluated using in vitro enzymatic experiments, and the results are shown in Table 2.

[0109] Table 2. Evaluation of the in vitro inhibitory activity of compounds H1–H33 against α-glucosidase

[0110]

[0111]

[0112] a The inhibition rate of the tested compounds was less than 50% at 100 μM;

[0113] b The value is the mean ± S of the results of three independent experiments.

[0114] The positive control drug, acarbose, had an IC50 value of [missing information]. 50 The concentration was 569.43 μM. As shown in Table 2, among H1–H33, derivative H31 exhibited the strongest inhibitory activity against α-glucosidase, with an inhibition rate of 2.09 μM, 225 times that of acarbose. These results indicate that these small molecule compounds demonstrate strong binding affinity to α-glucosidase. Therefore, it can be inferred that the thiazolidinedione skeleton plays a crucial role in the good α-glucosidase inhibitory activity of this type of compound, and compounds H1–33 can all serve as α-glucosidase inhibitors for the treatment or prevention of diabetes.

[0115] Experimental Example 1: Enzyme Kinetics Experiment

[0116] The α-glucosidase inhibitory activity of the synthesized active compound H31 was evaluated using in vitro enzyme kinetic experiments.

[0117] 1. Preparation of reagents and standard solutions

[0118] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0119] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare working concentrations of 0.0375U / mL, 0.05U / mL, 0.0625U / mL and 0.075U / mL, and then dispense and freeze.

[0120] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, prepare a substrate working solution with a concentration of 0.25mM, vortex mix well, and prepare fresh before each experiment.

[0121] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0122] 2. Experimental steps (1) Add 10 μL of α-glucosidase with concentrations of 0.0375 U / mL, 0.05 U / mL, 0.0625 U / mL and 0.075 U / mL respectively, 130 μL of 100 mM phosphate buffer (pH 6.8), and 10 μL of different concentrations of the compound (the compound prepared in Example 1) to the 96-well plate. Replace 10 μL of the compound with 10 μL of DMSO with 5% DMSO for the blank control group. Use acarbose as a positive control. Set up 4 replicates for each group. Incubate the enzyme reaction system at 37°C for 10 min on a microplate reader.

[0123] (2) Subsequently, 50 μL of substrate PNPG with a concentration of 0.25 mM was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation process, the time was evenly divided into 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0124] (3) Data processing: MS Excel was used to analyze and process the data. The reaction rate of the enzyme reaction system was ΔOD / min.

[0125] 3. Results Analysis

[0126] The results of the enzyme kinetic inhibition type evaluation experiment of thiazolidinedione derivative H31 are as follows: Figure 2 As shown. By Figure 2 It can be seen that the inhibitor binds to the enzyme via non-covalent bonds, repressing its activity; this is a reversible inhibitory effect. Results for other compounds are similar; to avoid redundancy, they are not all shown.

[0127] Experiment Example 2: Substrate Dynamics Experiment

[0128] The α-glucosidase inhibitory activity of the synthesized active compounds was evaluated using in vitro substrate kinetic experiments.

[0129] 1. Preparation of reagents and standard solutions

[0130] (1) 100mM phosphate buffer (PBS, pH 6.8): Weigh a certain amount of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them in ultrapure water, and use them to dissolve and dilute the reagent.

[0131] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100mM PBS to the enzyme with an activity of 100U to prepare a working concentration of 0.05U / mL, and then dispense and freeze.

[0132] (3) Substrate preparation: Accurately weigh an appropriate amount of 4-nitrophenyl-D-pyranoside (PNPG), add 100mM PBS solution to dissolve, and prepare substrate working solutions with concentrations of (0.25mM, 0.5mM, 0.75mM, 1mM). Vortex mix well and prepare fresh before each experiment.

[0133] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it in DMSO to prepare a 10 mM stock solution, and store it at -20℃ protected from light. Before the experiment, dilute with DMSO to different required concentrations (0–200 μM), with the DMSO content equal to 5%.

[0134] 2. Experimental steps (1) Add 10 μL of 0.5 U / mL α-glucosidase, 130 μL of 100 mM phosphate buffer (pH 6.8), and 10 μL of different concentrations of compound (the compound prepared in Example 1) to a 96-well plate in sequence. Replace 10 μL of compound with 10 μL of 5% DMSO for the blank control group. Use acarbose as a positive control. Set up 4 replicates for each group. Incubate the enzyme reaction system at 37°C for 10 min on a microplate reader.

[0135] (2) Subsequently, 50 μL of substrate PNPG of different concentrations was added to the enzyme reaction system to start the enzyme reaction. The microplate was placed on the microplate reader and incubated at 37°C for 15 min. During the incubation, the time was evenly distributed 3 times, and the reading was taken once at a wavelength of 405 nm for each time period. The readings were recorded as OD1, OD2, and OD3.

[0136] (3) Data processing: MS Excel was used to analyze and process the data. The reaction rate of the enzyme reaction system was ΔOD / min.

[0137] 3. Results Analysis

[0138] The experimental results for evaluating the substrate kinetic inhibition type of thiazolidinedione derivative H31 are as follows: Figure 3 As shown, Figure 3 The in vitro substrate kinetics of α-glucosidase corresponding to different concentrations of the thiazolidinedione derivative H31 are shown. Figure 3 This is a dynamical diagram of the substrate produced using the double reciprocal plotting method. (From...) Figure 3 As can be seen, the screened inhibitors are mixed inhibitors. This indicates that they can bind not only to α-glucosidase but also to the α-glucosidase-substrate complex. Results for other compounds were similar; to avoid redundancy, they are not shown individually.

[0139] In summary, this invention prepared a series of thiazolidinedione derivatives H1–H33 and determined their activities against α-glucosidase. The results showed that all synthesized derivatives exhibited significant inhibitory activity against α-glucosidase, with compound H31 exhibiting the strongest inhibitory effect (IC50, 1000 mmol / L). 50 The values ​​were 2.53 μM, which is 225 times that of acarbose, and it can be used as an α-glucosidase inhibitor for the treatment or prevention of diabetes.

[0140] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A thiazolidinedione derivative, characterized in that: The thiazolidinedione derivatives have the structure shown in the following formula: The R is selected from the following groups: 。 2. A method for preparing a thiazolidinedione derivative as described in claim 1, characterized in that: Includes the following steps: S1. Compound 1 was prepared from 2,4-dihydroxyacetophenone; Compound 2 was prepared from Compound 1; Compound 3 was prepared from 2,4-thiazolidinedione. S2. React compounds 2 and 3 to obtain the derivative; The structural formulas of compounds 1, 2, and 3 are as follows: 。 3. The use of the thiazolidinedione derivatives as described in claim 1 in the preparation of α-glucosidase inhibitors.

4. The use of the thiazolidinedione derivatives as described in claim 1 in the preparation of medicaments for the prevention and / or treatment of diabetes.

5. A drug, characterized in that: It includes thiazolidinedione derivatives as described in claim 1 and / or their pharmaceutically acceptable salts.

6. The drug according to claim 5, characterized in that: The dosage form of the drug is tablets, capsules, oral liquid, or injection.

7. A pharmaceutical composition, characterized in that: It includes thiazolidinedione derivatives as described in claim 1 and / or their pharmaceutically acceptable salts.

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