Thiazolidinedione ethyl ester compounds containing a chromone structure, and preparation methods, pharmaceutical compositions, and applications thereof

Abstract

The application discloses a thiazolidinedione ethyl ester compound containing a chromone structure and a preparation method, a pharmaceutical composition and an application thereof. 6～12 The application designs and synthesizes a series of thiazolidinedione ethyl ester compounds containing a chromone structure, and the compounds exhibit strong PTP1B inhibition and can be used as PTP1B enzyme inhibitors for treating or preventing diabetes.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a thiazolidinedione ethyl ester compound containing a chromone structure, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Diabetes mellitus is a serious metabolic disease characterized by elevated blood sugar levels, which can lead to chronic damage to various tissues. For example, increased blood sugar levels can cause many microvascular and macrovascular complications. Microvascular complications include retinopathy, cataracts, nephropathy, and neuropathy, while macrovascular complications include stroke, cardiovascular disease, coronary artery disease, cerebrovascular disease, and diabetic foot, which can lead to amputation in severe cases. Currently, the main hypoglycemic drugs used clinically include sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and non-sulfonylurea insulin secretagogues.

[0003] Among the PTP family members, protein tyrosine phosphatase 1B (PTP1B) plays a negative regulatory role in the insulin and leptin signaling systems and has been shown to be an important molecular target for the potential treatment of type 2 diabetes. Numerous studies in human and animal models have demonstrated that insulin resistance in type 2 diabetes is achieved through increased PTP activity and expression levels of PTP family members. Insulin binding to the insulin receptor (IR) induces a conformational change, thereby activating the receptor tyrosine kinase structure and triggering intracytoplasmic insulin signaling transduction. Activated receptors at multiple tyrosine residues undergo autophosphorylation, resulting in insulin receptor substrate 1 (IRS1), which in turn activates the PI3K and Akt pathways. Subsequently, glucose transporter type 4 (GLUT4) is transported to the cell surface and takes up cellular glucose. PTP1B catalyzes the dephosphorylation of phosphorylated IR and IRS1 by tyrosine residues (pY1162 / pY1163), thereby inactivating and terminating IR signaling. According to Johnson's research, leptin binding to its receptor leads to phosphorylation of Janus kinase 2 (JAK2), thereby activating the JAK2 signal transducer and transcription 3 (STAT3). STAT3 induces gene regulation to reduce the transcription of acetyl-CoA carboxylase and malonyl-CoA and fatty acid synthesis, while increasing fatty acid oxidation. Therefore, protein tyrosine phosphatase 1B (PTP1B) is considered an important target for the treatment of diabetes and obesity, and could potentially serve as a target for drug therapy.

[0004] Therefore, it is necessary to develop a compound that acts on protein tyrosine phosphatase 1B to treat diabetes. 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 first aspect of the present invention provides a thiazolidinedione ethyl ester compound containing a chromone structure. The thiazolidinedione ethyl ester compound provided by the present invention has PTP1B inhibitory activity and can treat and / or prevent diabetes by inhibiting PTP1B.

[0006] A second aspect of the present invention also provides a method for preparing thiazolidinedione ethyl ester compounds containing a chromone structure.

[0007] A third aspect of the present invention also provides a pharmaceutical composition.

[0008] A fourth aspect of the present invention also provides a protein tyrosine phosphatase 1B inhibitor.

[0009] The fifth aspect of the present invention also provides the application of thiazolidinedione ethyl ester compounds containing a chromone structure.

[0010] According to a first aspect of the present invention, a thiazolidinedione ethyl ester compound containing a chromone structure or a pharmaceutically acceptable salt thereof is provided, said thiazolidinedione ethyl ester compound having a compound as shown in formula (I):

[0011] ;

[0012] Wherein, R is selected from substituted or unsubstituted C. 6~12 Aryl groups.

[0013] The thiazolidinedione ethyl esters containing a chromone structure, or pharmaceutically acceptable salts thereof, according to embodiments of the present invention, have at least the following beneficial effects:

[0014] This invention designs and synthesizes a series of thiazolidinedione ethyl ester compounds containing chromone structures. These compounds exhibit strong PTP1B inhibitory activity and can be used as PTP1B enzyme inhibitors for the treatment or prevention of diabetes.

[0015] According to some embodiments of the present invention, R is selected from substituted or unsubstituted phenyl groups, the substitution is monosubstituted or polysubstituted, and the substituted group is selected from halogens, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl, C 1~6 The halogenated alkoxy, nitro, cyano or phenyl groups.

[0016] According to some embodiments of the present invention, the R is selected from the following groups:

[0017] .

[0018] According to a second aspect of the present invention, a method for preparing the thiazolidinedione ethyl ester compound containing a chromone structure as described above is provided, comprising the following steps:

[0019] Compound 4, A copper catalyst and a reducing agent undergo a cycloaddition reaction to yield thiazolidinedione ethyl esters containing a chromone structure;

[0020] The structural formulas of compound 4 and the thiazolidinedione ethyl ester compounds containing chromone structures are as follows:

[0021] .

[0022] According to some embodiments of the present invention, the reaction temperature of the cycloaddition reaction is 40~80°C.

[0023] According to some embodiments of the present invention, the reaction time of the cycloaddition reaction is 4 to 8 hours.

[0024] According to some embodiments of the present invention, the reducing agent includes at least one of sodium ascorbate or metallic copper.

[0025] According to some embodiments of the present invention, the copper catalyst is at least one of copper sulfate pentahydrate, copper iodide, or copper bromide.

[0026] According to some embodiments of the present invention, compound 4 is prepared by the following method:

[0027] The compound 3 and propargyl alcohol were esterified to obtain the product.

[0028] The structural formula of compound 3 is as follows:

[0029] .

[0030] According to some embodiments of the present invention, compound 3 is prepared by the following method:

[0031] Compound 2 was hydrolyzed under acidic conditions to obtain compound 3;

[0032] The structural formula of compound 2 is as follows:

[0033] .

[0034] According to some embodiments of the present invention, the acidic conditions refer to the presence of at least one of hydrochloric acid, nitric acid, sulfuric acid, or acetic acid in the reaction solution.

[0035] According to some embodiments of the present invention, compound 2 is prepared by the following method:

[0036] Compound 1, chromone-3-carboxaldehyde, sodium acetate, and acetic acid were mixed and reacted to obtain compound 2;

[0037] The structural formula of compound 1 is as follows:

[0038] .

[0039] According to some embodiments of the present invention, compound 1 is prepared by the following method:

[0040] The substituted compound 1 was obtained by nucleophilic substitution reaction of 2,4-thiazolyldione with ethyl bromoacetate.

[0041] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described thiazolidinedione ethyl ester compound containing a chromone structure or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable excipients.

[0042] A fourth aspect of the present invention provides a protein tyrosine phosphatase 1B inhibitor, comprising the thiazolidinedione ethyl ester compound containing a chromone structure as described above, or a pharmaceutically acceptable salt thereof.

[0043] The fifth aspect of this invention provides the use of the thiazolidinedione ethyl ester compounds with the chromone structure described above in the preparation of products for the treatment and / or prevention of diabetes.

[0044] According to some embodiments of the present invention, the product is a pharmaceutical product.

[0045] Definitions and general terms

[0046] "C replaced or not replaced" 6~12 "Aryl" indicates an all-carbon monocyclic or fused polycyclic group with a fully conjugated π-electron system; and the total number of carbon atoms is 6 to 12. In addition, at least one H in the aryl group may be replaced by the corresponding group defined herein.

[0047] “C 1~6 "alkyl" indicates an alkyl group with a total number of 1-6 carbon atoms, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups and C 3-6 The cycloalkyl group can be, for example, a straight-chain alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched-chain alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkyl group with a total number of carbon atoms of 3, 4, 5 or 6, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc.

[0048] “C 1~6"Alkoxy" refers to alkoxy groups with a total number of carbon atoms of 1-6, including C1-6 straight-chain alkoxy groups, C1-6 branched-chain alkoxy groups, and C2-6 cycloalkoxy groups. For example, it can be a straight-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6; a branched-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, or 6; or a cycloalkoxy group with a total number of carbon atoms of 2, 3, 4, 5, or 6, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0049] “C 1~6 "Halogenated alkyl" refers to an alkyl group with a total number of carbon atoms of 1 to 6, preferably an alkyl group as defined above, which is substituted by one or more identical or different halogen atoms, for example... CH2Cl, CF3 CCl3, CH2CF3, CH2CCl3, etc.

[0050] “C 1~6 "Haloalkoxy" refers to an alkoxy group with a total number of carbon atoms of 1 to 6, preferably an alkoxy group as defined above, which is substituted by one or more identical or different halogen atoms.

[0051] The structural formula in this invention appears as " "" indicates the linking site of a functional group.

[0052] The term "pharmaceutically acceptable" as used in this invention refers to a substance that is acceptable from a toxicological point of view for pharmaceutical use and will not adversely interact with the active ingredient.

[0053] The pharmaceutically acceptable excipients used in this invention include any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, flow aid or lubricant, etc., suitable for the specific target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the content of this literature shows that different excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional excipients that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0054] Substances that are pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0055] The pharmaceutical composition of the compounds of this invention can be administered in unit dose form. The dosage form can be a liquid or a solid. Liquid dosage forms can be true solutions, colloids, microparticles, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0056] Oral tablets and capsules may contain excipients such as binders, like syrup, gum arabic, sorbitol, astragalus gum, or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets may be coated using pharmaceutically known methods.

[0057] Oral liquids can be formulated as suspensions, solutions, emulsions, syrups, or elixirs of hydrated oils, or as dry products to be replenished with water or other suitable media before use. These liquid formulations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelling agents, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils, emulsifiers such as lecithin, sorbitan monooleate, and gum arabic; or non-aqueous carriers (which may contain edible oils such as almond oil), oils such as glycerin, ethylene glycol, or ethanol; preservatives such as methylparaben or propylparaben, and sorbic acid. Flavorings or colorings may be added if desired.

[0058] 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

[0059] 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:

[0060] Figure 1 The half-maximal inhibitory concentration (IC50) of PTP1B in vitro is shown in Examples 28 and 29 of this invention as an inhibitor of PTP1B.

[0061] Figure 2 The above is a diagram showing the in vitro enzyme kinetics of thiazolidinedione ethyl ester compounds containing chromone structures as PTP1B enzyme inhibitors in Example 28 of this invention.

[0062] Figure 3 This is a kinetic diagram of the substrate of PTP1B enzyme in vitro, showing that the thiazolidinedione ethyl ester compound containing a chromone structure, as a PTP1B inhibitor, is used in Example 28 of this invention. Detailed Implementation

[0063] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0064] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0065] This invention provides a general method for preparing thiazolidinedione ethyl ester compounds containing a chromone structure. The general reaction equation and preparation method are as follows:

[0066]

[0067] S1. Thiazolidinedione (3 mmol, 351.4 mg) and potassium carbonate (6 mmol, 829.2 mg) were added to acetone (3 mL). Ethyl bromoacetate (3 mmol, 335 μL) was added to the mixture. After reflux for 2 hours, K2CO3 was removed by filtration and the mixture was thoroughly washed with a large amount of ethyl acetate. Finally, the solvent was evaporated under reduced pressure to give a yellow oily product, compound 1.

[0068] S2. Compound 1 (2 mmol, 406.5 mg), chromone-3-carboxaldehyde (2 mmol, 348.3 mg), and sodium acetate (2 mmol, 165.6 mg) were refluxed in 2 mL of glacial acetic acid solution and stirred for 5 h. After the reaction was complete, the reaction system was cooled to room temperature. The solid was then filtered and washed with as little ethyl acetate as possible. Finally, the resulting mixture was dried at room temperature to give compound 2.

[0069] S3. Compound 2 (1 mmol, 400.7 mg) was added to a mixture of 12N HCl (1 mL) and glacial acetic acid (4 mL). The reaction solution was stirred at 100 °C. After the reaction was complete, the solid was filtered. Finally, the white solid was washed three times with water (3 × 100 mL) and dried in a vacuum oven (40 °C) for 24 h to obtain compound 3.

[0070] S4. Compound 3 (660.6 mg, 2.0 mmol), 1-hydroxybenzotriazole (81.1 mg, 0.6 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (421.7 mg, 2.2 mmol) were dissolved in anhydrous dimethylformamide (6 mL). Then, N,N-diisopropylethylamine (520.0 μL, 3.0 mmol) and propargyl alcohol (175.0 μL, 3.0 mmol) were added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted 3–4 times with water and saturated brine, respectively. The organic phase was collected and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain a reddish-brown solid compound 4.

[0071] S5. Add compound 4 (150.0 mg, 0.41 mmol) to a 15 mL reaction tube. Copper sulfate pentahydrate (0.82 mmol), sodium ascorbate (10.2 mg, 0.041 mmol), and sodium ascorbate (16.1 mg, 0.082 mmol) were added to a mixed solution of tert-butanol / water (2:1, 4 mL) as a solvent, and stirred at 60 °C in the dark for 4 h. After the reaction was complete, the solid was filtered off and recrystallized from DMF to obtain a series of thiazolidinedione ethyl esters with different R-groups containing chromone structures.

[0072] Examples 1-30

[0073] Examples 1-30 provide a series of thiazolidinedione ethyl ester compounds containing chromone structures. These compounds were prepared using the general preparation method described above. The general structural formulas of these thiazolidinedione ethyl ester compounds containing chromone structures are as follows: The R substituents are shown in Table 1 below:

[0074] ;

[0075] Table 1 R Substituents

[0076]

[0077] The structures of compounds I-1 to I-30 prepared in Examples 1-30 were characterized by NMR, MS, and melting point. The following are the characterization results of each compound, including its properties, yield, NMR, and mass spectrometry:

[0078]

[0079] ( Ⅰ -1,C 25 H 18 N 4O 6 S) . White sold; Yield 75%; m.p. 207.3 – 209.8 °C; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =7.9, 1.7 Hz, 1H), 8.19 (d, J =0.8 Hz, 1H), 7.78(s, 1H), 7.75 (ddd, J =8.7, 7.1, 1.7 Hz, 1H), 7.56 – 7.46 (m, 3H), 7.42 – 7.32(m, 3H), 7.28 (dd, J =7.9, 1.8 Hz, 2H), 5.53 (s, 2H), 5.30 (s, 2H), 4.46 (s,2H). 13 C NMR (126 MHz, CDCl3) δ 175.37, 168.12, 166.44, 165.62, 158.61, 155.98,142.52, 134.89, 134.42, 129.34, 129.01, 128.29, 126.64, 126.53, 126.26,124.04, 123.79, 123.78, 119.27, 118.41, 59.18, 54.42, 42.10. HRMS (ESI) [M+H] + calcd. for C 25 H 18 N4O6S: 503.1019; found: 503.1017.

[0080]

[0081] ( Ⅰ -2,C 25 H 17 FN 4 O 6 S) . White sold; Yield 67%; m.p. 202.1℃~205.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.28 (dd, J=8.1, 1.7 Hz, 1H), 8.20 (s, 1H), 7.75 (ddd, J =8.6, 7.1, 1.7 Hz, 2H), 7.56 – 7.46 (m, 3H), 7.28 (dd, J =8.3, 5.0 Hz, 2H), 7.12– 7.03 (m, 2H), 5.50 (s, 2H), 5.31 (s, 2H), 4.47 (s, 2H). 13 C NMR (126 MHz,CDCl3) δ 175.37, 168.16, 166.46, 165.62, 164.04, 162.06, 158.65, 155.98,134.89, 130.33, 130.22, 130.16, 126.64, 126.54, 126.31, 123.78, 119.25,118.42, 116.45, 116.27, 59.16, 53.68, 42.10. HRMS (ESI) [M+H] + calcd. forC 25 H 18 N4O6S: 521.0926; found: 521.0927.

[0082]

[0083] ( Ⅰ -3,C 25 H 17 FN 4 O 6 S) . White sold; Yield 71%; m.p. 203.3℃~205.9℃; 1 H NMR(500 MHz, CDCl3) δ 8.28 (dd, J =8.0, 1.7 Hz, 1H), 8.20 (s, 1H), 7.79 (s, 1H),7.75 (ddd, J =8.6, 7.1, 1.7 Hz, 1H), 7.57 (s, 1H), 7.54 (s, 2H), 7.36 (td, J =8.0, 5.8 Hz, 1H), 7.06 (dd, J=7.6, 3.7 Hz, 2H), 6.98 (dt, J =9.3, 2.1 Hz, 1H),5.53 (s, 2H), 5.33 (s, 2H), 4.48 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.38,168.15, 166.48, 165.63, 164.14, 158.63, 155.99, 142.74, 136.78, 134.90,131.07, 131.00, 126.65, 126.55, 126.32, 124.16, 123.79, 119.27, 118.42,116.16, 116.00, 115.34, 115.16, 59.12, 53.78, 42.11. HRMS (ESI) [M+H] + calcd.for C 25 H 18 N4O6S: 521.0926; found: 521.0925.

[0084]

[0085] ( Ⅰ -4,C 25 H 17 FN 4 O 6 S) . White sold; Yield 72%; m.p. 216.4℃~218.7℃; 1 H NMR(500 MHz, CDCl3) δ 8.28 (dd, J =8.0, 1.7 Hz, 1H), 8.20 (s, 1H), 7.79 (s, 1H),7.75 (ddd, J =8.6, 7.1, 1.7 Hz, 1H), 7.57 (s, 1H), 7.54 (s, 2H), 7.36 (td, J =8.0, 5.8 Hz, 1H), 7.06 (dd, J =7.6, 3.7 Hz, 2H), 6.98 (dt, J =9.3, 2.1 Hz, 1H),5.53 (s, 2H), 5.33 (s, 2H), 4.48 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.38,168.15, 166.48, 165.63, 164.14, 158.63, 155.99, 142.74, 136.78, 134.90,131.07, 131.00, 126.65, 126.55, 126.32, 124.16, 123.79, 119.27, 118.42,116.16, 116.00, 115.34, 115.16, 59.12, 53.78, 42.11. HRMS (ESI) [M+H] + calcd.for C 25 H 18 N4O6S: 521.0926; found: 521.0927.

[0086]

[0087] ( Ⅰ -5,C 25 H 17 ClN 4 O 6 S). White sold; Yield 66%; m.p. 203.4℃~205.6℃; 1 H NMR(500 MHz, CDCl3) δ 8.28 (dd, J =8.0, 1.7 Hz, 1H), 8.20 (s, 1H), 7.78 (s, 1H),7.75 (s, 1H), 7.55 (s, 1H), 7.53 (d, J =8.5 Hz, 1H), 7.51 – 7.47 (m, 1H), 7.39– 7.33 (m, 2H), 7.25 – 7.19 (m, 2H), 5.50 (s, 2H), 5.31 (s, 2H), 4.47 (s,2H). 13C NMR (126 MHz, DMSO) δ 174.97, 168.39, 166.68, 165.38, 162.60, 155.38,141.44, 135.24, 134.92, 132.91, 129.93, 128.79, 127.42, 126.57, 125.58,125.38, 123.03, 122.04, 118.66, 117.65, 58.51, 52.03, 41.94. HRMS (ESI) [M+H] + calcd. for C 25 H 17 ClN4O6S: 536.0557; found: 536.0564.

[0088]

[0089] ( Ⅰ -6,C 25 H 17 ClN 4 O 6 S). White sold; Yield 74%; m.p. 218.3℃~220.1℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.29 (s, 1H), 8.14 (dd, J =8.0, 1.7 Hz, 1H),7.93 – 7.86 (m, 1H), 7.75 (t, J =4.2 Hz, 2H), 7.61 – 7.55 (m, 1H), 7.45 – 7.37(m, 3H), 7.30 – 7.24 (m, 1H), 5.64 (s, 2H), 5.25 (s, 2H), 4.50 (s, 2H). 13C NMR(126 MHz, DMSO) δ 175.01, 168.41, 166.72, 165.41, 162.59, 155.42, 141.52,138.29, 135.28, 133.33, 130.78, 128.24, 127.95, 127.43, 126.76, 126.61,125.61, 125.52, 123.05, 122.10, 118.70, 117.69, 58.53, 52.09, 41.96. HRMS(ESI) [M+H] + calcd. for C 25 H 17 ClN4O6S: 536.0557; found: 536.0566.

[0090]

[0091] ( Ⅰ -7,C 25 H 17 ClN 4 O 6 S). White sold; Yield 68%; m.p. 198.8℃~200.2℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.1, 1.7 Hz, 1H), 8.19 (d, J =0.8 Hz, 1H), 7.78(d, J =0.8 Hz, 1H), 7.77 – 7.72 (m, 1H), 7.64 (s, 1H), 7.55 – 7.46 (m, 2H),7.43 (dd, J =7.6, 1.7 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.19 (dd, J =7.4, 2.0 Hz,1H), 5.67 (s, 2H), 5.32 (s, 2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ175.35, 168.11, 166.42, 165.60, 158.62, 155.96, 142.39, 134.87, 133.67,132.29, 130.52, 130.49, 130.11, 127.81, 126.62, 126.52, 126.25, 124.40,123.78, 123.76, 119.25, 118.41, 59.15, 51.68, 42.09. HRMS (ESI) [M+H] + calcd.for C 25 H 17 ClN4O6S: 536.0557; found: 536.0562.

[0092]

[0093] ( Ⅰ -8,C 25 H 17 BrN 4 O 6 S). White sold; Yield 72%; m.p. 203.3℃~205.9℃;FL-5-4Br: 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J =7.9 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J =13.4 Hz, 2H), 7.51 (ddd, J =14.8, 12.4, 7.0 Hz, 5H), 7.15 (d, J =8.1 Hz, 2H),5.49 (s, 2H), 5.31 (s, 2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.37,168.16, 166.46, 165.62, 158.66, 155.98, 142.76, 134.90, 133.47, 132.51,129.87, 126.65, 126.54, 126.32, 124.06, 123.78, 123.18, 119.25, 118.42,59.14, 53.71, 42.10. HRMS (ESI) [M+H] + calcd. for C 25 H 17 BrN4O6S: 583.0104;found: 583.0101.

[0094]

[0095] ( Ⅰ -9,C 25 H 17 BrN 4 O 6 S). White sold; Yield 74%; m.p. 227.1℃~229.3℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.30 (s, 1H), 8.14 (dd, J =8.0, 1.7 Hz, 1H),7.93 – 7.85 (m, 1H), 7.75 (t, J =4.2 Hz, 2H), 7.61 – 7.51 (m, 3H), 7.38 – 7.28(m, 2H), 5.63 (s, 2H), 5.25 (s, 2H), 4.50 (s, 2H). 13 C NMR (126 MHz, DMSO) δ174.96, 168.38, 166.69, 165.38, 162.58, 155.38, 141.47, 138.52, 135.23,131.10, 131.01, 130.81, 127.41, 127.12, 126.57, 125.58, 125.48, 123.03,122.05, 121.86, 118.67, 117.66, 58.51, 51.99, 41.93. HRMS (ESI) [M+H]+ calcd.for C 25 H 17 BrN4O6S: 583.0104; found: 583.0100.

[0096]

[0097] ( Ⅰ -10,C 25 H 17 BrN 4 O 6 S). White sold; Yield 67%; m.p. 192.3℃~193.4℃;FL-5-2Br: 1 H NMR (500 MHz, CDCl3) δ 8.28 (dd, J =7.9, 1.7 Hz, 1H), 8.19 (s, 1H), 7.79(s, 1H), 7.75 (ddd, J =8.7, 7.1, 1.7 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.55 – 7.46(m, 2H), 7.33 (t, J =7.5 Hz, 1H), 7.23 (td, J =7.7, 1.7 Hz, 1H), 7.17 (dd, J =7.6,1.7 Hz, 1H), 5.67 (s, 2H), 5.32 (s, 2H), 4.48 (s, 2H). 13 C NMR (126 MHz, CDCl3)δ 175.36, 168.11, 166.43, 165.62, 158.60, 155.97, 142.40, 134.88, 133.99,133.41, 130.66, 130.55, 128.45, 126.65, 126.53, 126.26, 124.44, 123.80,123.78, 123.66, 119.27, 118.41, 59.17, 54.09, 42.11. HRMS (ESI) [M+H] + calcd.for C 25 H 17 BrN4O6S: 583.0104; found: 583.0103.

[0098]

[0099] ( Ⅰ -11,C 26 H 20 N 4 O 6 S) . White sold; Yield 70%; m.p. 213.4℃~215.7℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.7 Hz, 1H), 8.19 (s, 1H), 7.80 – 7.71 (m,2H), 7.58 – 7.46 (m, 3H), 7.18 (s, 4H), 5.48 (s, 2H), 5.30 (s, 2H), 4.47 (s,2H), 2.35 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 175.35, 168.12, 166.42, 165.61,158.63, 155.96, 138.96, 134.87, 131.36, 129.97, 128.36, 126.62, 126.51,126.25, 123.79, 123.76, 119.25, 118.41, 59.14, 54.38, 42.09, 21.30. HRMS(ESI) [M+H] + calcd. for C 26 H 20 N4O6S: 517.1176; found: 517.1174.

[0100]

[0101] ( Ⅰ -12,C 26 H 20 N 4 O 6 S) . White sold; Yield 75%; m.p. 210.2℃~213.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J=8.0, 1.7 Hz, 1H), 8.19 (s, 1H), 7.80 – 7.71 (m,2H), 7.57 – 7.46 (m, 3H), 7.26 (d, J =2.7 Hz, 1H), 7.16 (d, J =7.6 Hz, 1H), 7.08(d, J =11.2 Hz, 2H), 5.49 (s, 2H), 5.30 (s, 2H), 4.47 (s, 2H), 2.34 (s, 3H). 13 CNMR (126 MHz, CDCl3) δ 175.35, 168.12, 166.44, 165.61, 158.62, 155.96,139.18, 134.88, 134.31, 129.75, 129.19, 129.01, 126.62, 126.52, 126.26,125.36, 123.79, 123.76, 119.25, 118.41, 59.19, 54.44, 42.09, 21.47. HRMS(ESI) [M+H] + calcd. for C 26 H 20 N4O6S: 517.1176; found: 517.1177.

[0102]

[0103] ( Ⅰ -13,C 26 H 20 N 4 O 6 S) . White sold; Yield 73%; m.p. 218.2℃~219.8℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.6 Hz, 1H), 8.19 (s, 1H), 7.78 (s, 1H),7.75 (ddd, J=8.6, 7.2, 1.7 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.42 (s, 1H), 7.31 –7.27 (m, 1H), 7.25 – 7.20 (m, 2H), 7.16 (d, J =8.0 Hz, 1H), 5.54 (s, 2H), 5.29(s, 2H), 4.46 (s, 2H), 2.28 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 175.34, 168.08,166.40, 165.59, 158.59, 155.96, 142.28, 137.05, 134.87, 132.31, 131.22,129.62, 129.38, 126.88, 126.62, 126.51, 126.23, 123.85, 123.77, 119.25,118.41, 59.17, 52.58, 42.09, 19.13. HRMS (ESI) [M+H] + calcd. for C 26 H 20 N4O6S:517.1176; found: 517.1175.

[0104]

[0105] ( Ⅰ -14,C 26 H 20 N 4 O 7 S). White sold; Yield 78%; m.p. 208.2℃~212.1℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =7.9, 1.7 Hz, 1H), 8.20 (s, 1H), 7.79 – 7.71 (m,2H), 7.55 – 7.46 (m, 2H), 7.23 (d, J =8.3 Hz, 2H), 6.90 (d, J =8.2 Hz, 2H), 5.46(s, 2H), 5.30 (s, 2H), 4.47 (s, 2H), 3.80 (s, 3H).13 C NMR (126 MHz, CDCl3) δ175.25, 168.04, 166.33, 165.51, 160.02, 158.60, 155.85, 134.77, 129.85,126.50, 126.41, 126.26, 126.18, 123.67, 123.65, 119.12, 118.30, 114.55,59.07, 55.37, 54.23, 42.00. HRMS (ESI) [M+H] + calcd. for C 26 H 20 N4O7S: 532.1053;found: 532.1060.

[0106]

[0107] ( Ⅰ -15,C 26 H 20 N 4 O 7 S). White sold; Yield 74%; m.p. 192.7℃~193.9℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =7.9, 1.6 Hz, 1H), 8.19 (s, 1H), 7.77 (s, 1H),7.75 (ddd, J =8.7, 7.2, 1.7 Hz, 1H), 7.54 – 7.51 (m, 1H), 7.51 – 7.46 (m, 1H),7.29 (t, J =7.9 Hz, 1H), 7.26 (s, 1H), 6.90 – 6.84 (m, 2H), 6.79 (t, J =2.0 Hz,1H), 5.49 (s, 2H), 5.30 (s, 2H), 4.47 (s, 2H), 3.78 (s, 3H). 13C NMR (126 MHz,CDCl3) δ 175.35, 168.12, 166.43, 165.61, 160.24, 158.66, 155.96, 135.81,134.87, 130.41, 126.61, 126.51, 126.27, 123.77, 120.48, 119.24, 118.40,114.56, 113.78, 59.19, 55.47, 54.44, 42.09. HRMS (ESI) [M+H] + calcd. forC 26 H 20 N4O7S: 532.1053; found: 532.1058.

[0108]

[0109] ( Ⅰ -16,C 26 H 17 F 3 N 4 O 6 S). White sold; Yield 67%; m.p. 206.7℃~207.3℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.7 Hz, 1H), 8.19 (s, 1H), 7.77 (s, 1H),7.77 – 7.71 (m, 1H), 7.65 (d, J =7.9 Hz, 2H), 7.60 (s, 1H), 7.55 – 7.46 (m,2H), 7.38 (d, J=8.0 Hz, 2H), 5.60 (s, 2H), 5.32 (s, 2H), 4.47 (s, 2H). 13C NMR(126 MHz, DMSO) δ 174.98, 168.39, 166.69, 165.39, 162.61, 155.40, 141.52,140.60, 135.25, 128.67, 127.43, 126.58, 125.74, 125.71, 125.68, 125.65,125.58, 123.03, 122.06, 118.68, 117.66, 58.49, 52.16, 41.95. HRMS (ESI) [M+H] + calcd. for C 26 H 17 F3N4O6S: 571.0894; found: 571.0889.

[0110]

[0111] ( Ⅰ -17,C 26 H 17 F 3 N 4 O 6 S). White sold; Yield 63%; m.p. 199.6℃~202.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.6 Hz, 1H), 8.19 (s, 1H), 7.78 (s, 1H),7.75 (ddd, J =8.7, 7.2, 1.7 Hz, 1H), 7.62 (d, J =7.9 Hz, 1H), 7.60 (s, 1H), 7.56(s, 1H), 7.55 – 7.47 (m, 3H), 7.44 (d, J =7.7 Hz, 1H), 5.60 (s, 2H), 5.32 (s,2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.37, 168.15, 166.49, 165.62,158.63, 155.98, 142.91, 135.50, 134.90, 131.49, 130.00, 126.64, 126.55,126.32, 125.91, 124.94, 124.17, 123.77, 119.25, 118.42, 59.12, 53.77, 42.10.HRMS (ESI) [M+H] + calcd. for C 26 H 17 F3N4O6S: 571.0894; found: 571.0890.

[0112]

[0113] ( Ⅰ -18,C 26 H 17 F 3 N 4 O 6 S). White sold; Yield 65%; m.p. 193.6℃~195.3℃; 1 H NMR(500 MHz, CDCl3) δ 8.29 (dd, J =8.1, 1.7 Hz, 1H), 8.22 (s, 1H), 7.80 (s, 1H),7.79 – 7.72 (m, 2H), 7.62 (s, 1H), 7.58 (t, J =7.6 Hz, 1H), 7.56 – 7.47 (m,3H), 7.21 (d, J =7.7 Hz, 1H), 5.78 (s, 2H), 5.35 (s, 2H), 4.50 (s, 2H). 13C NMR(126 MHz, CDCl3) δ 175.35, 168.11, 166.41, 165.61, 158.64, 155.96, 134.88,132.96, 130.23, 128.98, 128.21, 127.97, 126.62, 126.52, 126.42, 126.37,126.27, 125.29, 124.56, 123.76, 123.11, 119.23, 118.41, 59.08, 50.42, 50.39,42.08. HRMS (ESI) [M+H] + calcd. for C 26 H 17 F3N4O6S: 571.0894; found: 571.0890.

[0114]

[0115] ( Ⅰ -19,C 26 H 17 F 3 N 4 O 7 S). White sold; Yield 67%; m.p. 205.8℃~208.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.6 Hz, 1H), 8.20 (d, J =0.8 Hz, 1H), 7.78(s, 1H), 7.77 – 7.72 (m, 1H), 7.57 (s, 1H), 7.52 (dd, J =8.6, 1.0 Hz, 1H), 7.51– 7.47 (m, 1H), 7.32 (d, J =8.7 Hz, 2H), 7.23 (d, J =8.3 Hz, 2H), 5.54 (s, 2H),5.32 (s, 2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.37, 168.17, 166.48,165.62, 158.66, 155.97, 149.61, 142.79, 134.90, 133.17, 129.74, 126.62,126.54, 126.33, 124.11, 123.76, 121.74, 121.51, 119.46, 119.23, 118.41,59.12, 53.51, 42.10. HRMS (ESI) [M+H] + calcd. for C 26 H 17 F3N4O7S: 587.0843; found:587.0839.

[0116]

[0117] ( Ⅰ -20,C 26 H 17 F 3 N 4 O 7 S). White sold; Yield 70%; m.p. 189.3℃~192.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.0, 1.7 Hz, 1H), 8.20 (d, J =0.8 Hz, 1H), 7.78(d, J =0.8 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.60 (s, 1H), 7.56 – 7.46 (m, 2H),7.42 (t, J =8.0 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.19 (dd, J =7.6, 1.4 Hz, 1H), 7.14(s, 1H), 5.56 (s, 2H), 5.33 (s, 2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ175.37, 168.15, 166.48, 165.61, 158.65, 155.97, 136.67, 134.90, 130.89,126.62, 126.54, 126.39, 126.32, 124.22, 123.76, 121.35, 120.70, 119.24,118.42, 59.08, 53.67, 42.09. HRMS (ESI) [M+H] + calcd. for C 26 H 17 F3N4O7S:587.0843; found: 587.0840.

[0118]

[0119] ( Ⅰ -21,C 26 H 17 F 3 N 4 O 7 S). White sold; Yield 68%; m.p. 191.5℃~193.5℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.1, 1.7 Hz, 1H), 8.19 (s, 1H), 7.78 (s, 1H),7.77 – 7.72 (m, 1H), 7.60 (s, 1H), 7.52 (dd, J =8.5, 1.0 Hz, 1H), 7.51 – 7.47(m, 1H), 7.41 (td, J =7.8, 1.4 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.23 (dd, J =7.9,1.7 Hz, 1H), 5.62 (s, 2H), 5.32 (s, 2H), 4.47 (s, 2H). 13C NMR (126 MHz, CDCl3)δ 175.36, 168.11, 166.43, 165.61, 158.62, 155.97, 147.04, 142.56, 134.88,130.65, 130.51, 127.70, 127.18, 126.63, 126.52, 126.25, 124.42, 123.79,123.77, 121.63, 120.80, 119.57, 119.26, 118.41, 59.13, 48.65, 42.09. HRMS(ESI) [M+H] + calcd. for C 26 H 17 F3N4O7S: 587.0843; found: 587.0838.

[0120]

[0121] ( Ⅰ -22,C 25 H 17 N 5 O 8 S). White sold; Yield 62%; m.p. 206.2℃~207.9℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.33 (s, 1H), 8.29 – 8.21 (m, 2H), 8.14 (dd, J =8.0, 1.7 Hz, 1H), 7.93 – 7.86 (m, 1H), 7.75 (t, J =4.2 Hz, 2H), 7.58 (t, J =7.5Hz, 1H), 7.53 (d, J =8.6 Hz, 2H), 5.81 (s, 2H), 5.27 (s, 2H), 4.50 (s, 2H). 13CNMR (126 MHz, DMSO) δ 195.04, 165.86, 163.09, 155.86, 143.80, 135.71, 129.50,127.90, 127.04, 126.25, 126.04, 124.41, 119.14, 118.11, 58.94, 52.39, 42.41.HRMS (ESI) [M+H] + calcd. for C 25 H 17 N5O8S: 547.0798; found: 547.0803.

[0122]

[0123] ( Ⅰ -23,C 25 H 17 N 5 O 8 S). White sold; Yield 65%; m.p. 221.3℃~222.9℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.30 (d, J =45.5 Hz, 2H), 8.17 (dd, J =30.5, 8.1Hz, 2H), 7.89 (t, J =7.9 Hz, 1H), 7.75 (d, J =6.9 Hz, 3H), 7.69 (t, J =8.0 Hz, 1H),7.58 (t, J =7.6 Hz, 1H), 5.80 (s, 2H), 5.26 (s, 2H), 4.49 (s, 2H). 13C NMR (126MHz, DMSO) δ 174.97, 168.39, 166.69, 165.38, 162.59, 155.38, 147.88, 141.55,137.97, 135.24, 134.79, 130.47, 127.41, 126.57, 125.62, 125.58, 123.21,123.03, 122.94, 122.05, 118.67, 117.65, 58.49, 51.79, 41.93. HRMS (ESI) [M+H] + calcd. for C 25 H 17 N5O8S: 547.0798; found: 547.0804.

[0124]

[0125] ( Ⅰ -24,C 25 H 17 N 5 O 8 S). White sold; Yield 61%; m.p. 216.2℃~218.1℃; 1 H NMR(500 MHz, DMSO) δ 8.98 (s, 1H), 8.26 (s, 1H), 8.17 – 8.11 (m, 2H), 7.93 –7.86 (m, 1H), 7.67 – 7.55 (m, 2H), 7.02 (dd, J =7.8, 1.4 Hz, 1H), 5.99 (s, 2H),5.28 (s, 2H), 4.51 (s, 2H). 13 C NMR (126 MHz, CDCl3) δ 175.38, 168.15, 166.44,165.65, 158.68, 155.98, 147.51, 142.72, 134.90, 134.72, 130.51, 129.92,126.64, 126.54, 126.35, 125.61, 125.21, 123.78, 123.76, 119.25, 118.42,59.10, 51.16, 42.12. HRMS (ESI) [M+H] +calcd. for C 25 H 17 N5O8S: 547.0798; found:547.0802.

[0126]

[0127] ( Ⅰ -25,C 26 H 17 N 5 O 6 S). White sold; Yield 59%; m.p. 192.3℃~193.8℃; 1 H NMR(500 MHz, DMSO) δ 8.98 (s, 1H), 8.31 (s, 1H), 8.17 – 8.12 (m, 1H), 7.87 (dd, J =12.8, 7.9 Hz, 3H), 7.75 (t, J =4.2 Hz, 2H), 7.58 (t, J =7.5 Hz, 1H), 7.45 (d, J =8.0 Hz, 2H), 5.75 (s, 2H), 5.26 (s, 2H), 4.50 (s, 2H). 13 C NMR (126 MHz, DMSO)δ 174.97, 168.39, 166.69, 165.39, 162.61, 155.38, 141.54, 141.38, 135.23,132.76, 128.70, 127.43, 126.56, 125.74, 125.58, 123.02, 122.04, 118.66,118.54, 117.64, 110.97, 58.48, 52.20, 41.94. HRMS (ESI) [M+H] + calcd. forC 26 H 17 N5O6S: 528.0972; found: 528.0970.

[0128]

[0129] ( Ⅰ -26,C 26 H17 N 5 O 6 S). White sold; Yield 57%; m.p. 228.3℃~230.5℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.14 (dd, J =8.0, 1.7 Hz, 1H), 7.93 – 7.86 (m,1H), 7.85 – 7.80 (m, 2H), 7.76 – 7.73 (m, 2H), 7.67 – 7.55 (m, 3H), 5.70 (s,2H), 5.25 (s, 2H), 4.50 (s, 2H). 13 C NMR (126 MHz, DMSO) δ 174.97, 168.38,166.69, 165.38, 162.59, 155.38, 141.54, 137.43, 135.23, 133.00, 132.07,131.75, 130.13, 127.42, 126.56, 125.57, 123.03, 122.05, 118.67, 118.43,117.65, 111.72, 58.48, 51.88, 41.94. HRMS (ESI) [M+H] + calcd. for C 26 H 17 N5O6S:528.0972; found: 528.0970.

[0130]

[0131] ( Ⅰ -27,C 26 H 17 N 5 O 6 S). White sold; Yield 67%; m.p. 205.8℃~207.2℃; 1 H NMR(500 MHz, DMSO) δ 8.97 (s, 1H), 8.31 (s, 1H), 8.14 (dd, J =8.0, 1.7 Hz, 1H),7.94 – 7.85 (m, 2H), 7.74 (dt, J=7.7, 5.0 Hz, 3H), 7.61 – 7.53 (m, 2H), 7.35(d, J =7.8 Hz, 1H), 5.84 (s, 2H), 5.27 (s, 2H), 4.50 (s, 2H). 13 C NMR (126 MHz,DMSO) δ 174.97, 168.36, 166.67, 165.37, 162.58, 155.39, 141.44, 138.70,135.24, 133.87, 133.39, 129.35, 129.25, 127.41, 126.57, 125.81, 125.58,123.03, 122.05, 118.67, 117.66, 116.97, 111.22, 58.44, 51.03, 41.94. HRMS(ESI) [M+H] + calcd. for C 26 H 17 N5O6S: 528.0972; found: 528.0970.

[0132]

[0133] ( Ⅰ -28,C 31 H 22 N 4 O 6 S). White sold; Yield 73%; m.p. 212.8℃~214.3℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =8.2, 1.7 Hz, 1H), 8.15 (s, 1H), 7.77 (s, 1H),7.76 – 7.72 (m, 1H), 7.61 (d, J =8.3 Hz, 2H), 7.59 – 7.55 (m, 3H), 7.54 – 7.47(m, 2H), 7.43 (t, J =7.6 Hz, 2H), 7.36 (d, J=7.7 Hz, 3H), 5.58 (s, 2H), 5.32 (s,2H), 4.47 (s, 2H). 13C NMR (126 MHz, DMSO) δ 174.98, 168.39, 166.69, 165.39,162.60, 155.39, 141.43, 140.08, 139.57, 135.24, 135.07, 128.96, 128.63,127.63, 127.42, 127.10, 126.71, 126.57, 125.58, 125.34, 123.03, 122.06,118.68, 117.65, 58.55, 52.52, 41.95. HRMS (ESI) [M+H] + calcd. for C 31 H 22 N4O6S:579.1333; found: 579.1329.

[0134]

[0135] ( Ⅰ -29,C 31 H 22 N 4 O 6 S). White sold; Yield 78%; m.p. 158.3℃~160.4℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (dd, J =7.9, 1.6 Hz, 1H), 8.16 (s, 1H), 7.76 (s, 1H),7.59 (d, J =2.0 Hz, 2H), 7.56 – 7.53 (m, 2H), 7.53 – 7.48 (m, 3H), 7.46 (d, J =7.6 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.38 – 7.33 (m, 1H), 7.26 (s, 2H), 5.59 (s,2H), 5.31 (s, 2H), 4.46 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 175.34, 168.12,166.44, 165.60, 158.62, 155.95, 142.59, 142.39, 140.34, 134.97, 134.86,129.80, 129.01, 128.99, 127.86, 127.80, 127.31, 127.29, 127.10, 127.06,126.62, 126.51, 126.27, 124.07, 123.76, 119.22, 118.40, 59.20, 54.46, 42.09.HRMS (ESI) [M+H] + calcd. for C 31 H 22 N4O6S: 579.1333; found: 579.1329.

[0136]

[0137] ( Ⅰ -30,C 31 H 22 N 4 O 6 S). White sold; Yield 74%; m.p. 155.4℃~157.6℃; 1 H NMR(500 MHz, CDCl3) δ 8.27 (d, J =8.0 Hz, 1H), 8.19 (s, 1H), 7.76 (d, J =11.9 Hz,2H), 7.50 (dd, J =18.8, 8.6 Hz, 2H), 7.42 (dq, J =15.3, 7.4 Hz, 5H), 7.32 (d, J =7.0 Hz, 1H), 7.27 – 7.17 (m, 4H), 5.50 (s, 2H), 5.26 (s, 2H), 4.46 (s, 2H). 13CNMR (126 MHz, CDCl3) δ 175.35, 168.11, 166.38, 165.60, 158.66, 155.95,142.17, 141.98, 139.87, 134.87, 131.82, 130.64, 129.39, 129.13, 128.91,128.81, 128.79, 128.77, 128.40, 127.93, 126.61, 126.51, 126.27, 124.27,123.78, 123.75, 119.23, 118.40, 59.22, 52.10, 42.09. HRMS (ESI) [M+H] + calcd.for C 31 H 22 N4O6S: 579.1333; found: 579.1329.

[0138] Performance testing

[0139] PTP1B enzyme inhibitory activity assay of thiazolidinedione ethyl esters containing chromone structures

[0140] Experimental steps

[0141] The test solutions were dissolved in dimethyl sulfoxide (DMSO) to prepare 10 gradient concentrations: 32 μM, 16 μM, 8 μM, 4 μM, 2 μM, 1 μM, 0.5 μM, 0.25 μM, 0.125 μM, and 0.625 μM. In each well of a 384-well black-based plate, 20 μL of a mixture containing enzyme (0.29 μg / mL PTP1B) and buffer (50 mM MOPS, 2 mM DTT, and 1 mM EDTA: pH=6.5) was added. Then, 10 μL of the pre-prepared stock solution was added to each well (four replicates per group). After adding the stock solution, the 384-well plate was incubated at 37 °C for 15 min. Then, 20 μL of substrate (DiFMUP, 20 mM) was added to each well. Finally, the fluorescence intensity (RFU) was measured using a microplate reader.

[0142] Inhibition rate calculation formula:

[0143]

[0144] RFU 样品 RFU values ​​measured after adding the compound to a 384-well plate, reacting it with the protein, and then adding the substrate DiMUP.

[0145] RFU空白 The RFU value was measured by adding DMSO and protein to a 384-well plate, followed by the addition of the substrate DiMUP.

[0146] 3. Results Analysis

[0147] The PTP1B enzyme inhibitory activity of the synthesized compounds was evaluated using in vitro enzymatic experiments, and the results are shown in Table 2.

[0148] Table 2. Evaluation of the in vitro inhibitory activity of the screened compounds against PTP1B enzyme.

[0149]

[0150] a The value is the mean ± S of the results of three independent experiments.

[0151] Table 2 shows that the IC50 of the positive control drug oleanolic acid is... 50 The concentration was 5.33 μM. Two compounds (I-28 and I-29) with good PTP1B enzyme inhibitory activity were screened. Figure 1 It can be seen that, Figure 1 (a) in the figure is the half-maximal inhibitory concentration plot for I-28; Figure 1 (b) shows the half-maximal inhibitory concentration (IC50) of I-29; the inhibition rates of I-28 and I-29 were 2.06 μM and 2.17 μM, respectively, which were 2.5 times that of acarbose. These results indicate that these small molecule compounds exhibit strong binding affinity when interacting with PTP1B enzymes. Therefore, it can be inferred that the chromone and thiazolyl dione skeletons play a crucial role in the good PTP1B enzyme inhibitory activity of this type of compound, and compounds I-28 and I-29 could be used as PTP1B enzyme inhibitors for the treatment or prevention of diabetes.

[0152] Enzyme kinetics experiment

[0153] The inhibitory activity of the synthesized active compound against PTP1B enzyme was evaluated using in vitro enzyme kinetic experiments.

[0154] 1. Experimental Procedure

[0155] Enzyme kinetics experiments require several different concentrations of PTP1B enzyme. Therefore, five different concentrations of PTP1B protein (final concentrations of 0.29, 0.58, 0.87, and 1.16 μg / mL) were used for subsequent experiments on compound I-28, which exhibited the best activity. First, 20 μL of a mixture containing the enzyme (0.29, 0.58, 0.87, and 1.16 μg / mL PTP1B) and buffer (50 mM MOPS, 2 mM DTT, and 1 mM EDTA, pH=6.5) was added to each well of a 384-well black-based plate. Then, 10 μL of the prepared stock solution of the compound was added to each well (four replicates per group). The 384-well plate was then incubated at 37 °C with shaking for 15 min. Immediately after incubation, 20 μL of substrate (DiFMUP, 20 μM) was added. Finally, the fluorescence intensity (RFU) was detected using a microplate reader. The fluorescence intensity of different concentrations of the compound against PTP1B (0.29, 0.58, 0.87, 1.16 μg / mL) was measured, and a graph was plotted based on the different enzyme concentrations and the rate of change of fluorescence intensity.

[0156] 2. Results Analysis

[0157] The results of the enzyme kinetic inhibition type evaluation experiment 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 to inhibit the enzyme's activity, which is a reversible inhibitory effect.

[0158] Substrate dynamics experiment

[0159] The inhibitory activity of the synthesized active compound against PTP1B enzyme was evaluated using in vitro substrate kinetic experiments.

[0160] 1. Experimental Procedure

[0161] Subsequent experiments were conducted using five different concentrations of DiMUP substrate (final concentrations of 20, 40, 60, and 80 μM) to detect the best-activity compound, I-28. First, 20 μL of a mixture containing enzyme (0.29 μg / mL PTP1B) and buffer (50 mM MOPS, 2 mM DTT, and 1 mM EDTA: pH 6.5) was added to each well of a 384-well black plate. Then, 10 μL of a pre-prepared stock solution of the compound was added to each well (four wells per group). After adding the stock solution, the 384-well plate was incubated at 37 °C with shaking for 15 min. Immediately after incubation, 20 μL of DiMUP substrate (20, 40, 60, and 80 μM) was added. Finally, the fluorescence intensity (RFU) was detected using a microplate reader. The changes in fluorescence intensity at different concentrations of the compound were measured, and Lineweaver-Burk double reciprocal plots were generated based on the different substrate concentrations and their rates of change in fluorescence intensity.

[0162] 2. Results Analysis

[0163] The experimental results for evaluating the type of substrate kinetic inhibition are as follows: Figure 3 As shown, Figure 3 The in vitro substrate kinetics of thiazolidinedione ethyl ester compound I-28, corresponding to a chromone structure, against PTP1B enzyme is plotted using a double reciprocal plot method. Figure 3 It can be seen that the inhibitors obtained through screening are non-competitive inhibitors.

[0164] The present invention has been described in detail above with reference to the embodiments of the present invention. However, 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 ethyl ester compound containing a chromone structure, or a pharmaceutically acceptable salt thereof, characterized in that, The thiazolidinedione ethyl ester compounds containing a chromone structure have compounds as shown in formula (I): ； Wherein, R is selected from substituted or unsubstituted phenyl groups, the substitution being monosubstituted or polysubstituted, and the substituted group being selected from halogens, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl, C 1~6 The halogenated alkoxy, nitro, cyano or phenyl groups.

2. The thiazolidinedione ethyl ester compound containing a chromone structure according to claim 1, or a pharmaceutically acceptable salt thereof, is characterized in that, The R is selected from the following groups: 。 3. The method for preparing thiazolidinedione ethyl ester compounds containing a chromone structure according to claim 1, characterized in that, Includes the following steps: Compound 4, A cycloaddition reaction occurs when a copper catalyst and a reducing agent are mixed to give thiazolidinedione ethyl esters containing a chromone structure. The structural formulas of compound 4 and the thiazolidinedione ethyl ester compounds containing chromone structures are as follows: ； The definition of R is the same as that of R in claim 1.

4. The preparation method according to claim 3, characterized in that, The copper catalyst is at least one of copper sulfate pentahydrate, copper iodide, or copper bromide.

5. The preparation method according to claim 3, characterized in that, Compound 4 was prepared by the following method: The compound 3 and propargyl alcohol were esterified to obtain the product. The structural formula of compound 3 is as follows: 。 6. A pharmaceutical composition, characterized in that, Includes thiazolidinedione ethyl esters of compounds with a chromone structure as described in claim 1 or 2, or pharmaceutically acceptable salts thereof; and pharmaceutically acceptable excipients.

7. A protein tyrosine phosphatase 1B inhibitor, characterized in that, This includes thiazolidinedione ethyl esters of compounds with a chromone structure as described in claim 1 or 2, or pharmaceutically acceptable salts thereof.

8. The use of the thiazolidinedione ethyl ester compound containing a chromone structure according to claim 1 or 2 in the preparation of products for the treatment and / or prevention of diabetes; said product being a pharmaceutical product.

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