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CN114409626B - Preparation and Antiviral Application of Baicalein Derivatives - Google Patents

Preparation and Antiviral Application of Baicalein Derivatives Download PDF

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CN114409626B
CN114409626B CN202210219016.6A CN202210219016A CN114409626B CN 114409626 B CN114409626 B CN 114409626B CN 202210219016 A CN202210219016 A CN 202210219016A CN 114409626 B CN114409626 B CN 114409626B
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刘旭
高磊
童浩文
甘志军
王立升
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Abstract

本发明公开了黄芩素类衍生物的制备和抗病毒应用。黄芩素类衍生物以黄芩素(5,6,7‑三羟基黄酮)为原料，经亲电取代反应制得。反应溶剂为干燥脱水后的无水丙酮，反应过程是在冰浴(0℃)条件下反应1小时后，反应液加入冰水淬灭反应，而后过滤，得淡黄色或米白色粗产物。黄芩素类衍生物对流感病毒的神经氨酸酶NA，新型冠状病毒的主蛋白酶Mpro的半数抑制浓度均小于100μM，且衍生物的合成方法简便易行，黄芩素C6‑OH、C7‑OH的两个羟基在反应过程中被各种磺酰氯化合物所取代。The invention discloses the preparation and antiviral application of baicalein derivatives. The baicalein derivatives are prepared from baicalein (5,6,7-trihydroxyflavone) through electrophilic substitution reaction. The reaction solvent is anhydrous acetone after drying and dehydration. The reaction process is to react in an ice bath (0° C.) for 1 hour, then add ice water to the reaction solution to quench the reaction, and then filter to obtain a light yellow or off-white crude product. The half inhibitory concentration of baicalein derivatives to neuraminidase NA of influenza virus and main protease M pro of new coronavirus is less than 100 μ M, and the synthesis method of derivatives is simple and easy, and baicalein C6‑OH, C7‑OH The two hydroxyl groups of are replaced by various sulfonyl chloride compounds during the reaction.

Description

黄芩素类衍生物的制备和抗病毒应用Preparation and antiviral application of baicalin derivatives

技术领域Technical Field

本发明涉及黄芩素类衍生物，具体是黄芩素类衍生物的制备和抗病毒应用。The invention relates to baicalein derivatives, in particular to the preparation and antiviral application of baicalein derivatives.

背景技术Background Art

黄芩素(5,6,7-三羟基黄酮)，又名黄芩苷元，最初从传统中药材黄芩(Scutellaria baicalensis Georgi)中分离得到。黄芩素资源丰富，来源广泛，价廉易得，毒副作用小，且已被证明具有许多良好的生物活性，包括抗癌、抗炎、抗肿瘤、抗过敏、抗氧化等。是新药开发研究中一个值得重视的资源，有较好的开发利用前景。然而，黄芩素结构中存在三个相邻酚羟基(5-OH、6-OH、7-OH)，易于形成分子内氢键，造成其亲脂性、亲水性均较差、口服生物利用度低，而这极大地限制了其临床应用。近几年，如何提高黄芩素类药物的溶解性与生物利用度，增加在人体内的吸收，成为国内外研究热点。此外，许多其他研究表明，在黄芩素类衍生物中，C-5位羟基保持不变，C-6或C-7位羟基经过修饰后具有很强活性。因此，在此基础上，本研究以黄芩素为先导化合物，利用化学反应对其进行结构修饰，引入官能团，设计合成一系列黄芩素类衍生物，同时该方法也是一种药物创新的有效途径。Baicalein (5,6,7-trihydroxyflavone), also known as baicalein, was originally isolated from the traditional Chinese medicine Scutellaria baicalensis Georgi. Baicalein is rich in resources, widely available, cheap and easy to obtain, with little toxicity and side effects, and has been proven to have many good biological activities, including anti-cancer, anti-inflammatory, anti-tumor, anti-allergic, and antioxidant. It is a resource worthy of attention in new drug development research and has good development and utilization prospects. However, there are three adjacent phenolic hydroxyl groups (5-OH, 6-OH, 7-OH) in the structure of baicalein, which are easy to form intramolecular hydrogen bonds, resulting in poor lipophilicity and hydrophilicity, and low oral bioavailability, which greatly limits its clinical application. In recent years, how to improve the solubility and bioavailability of baicalein drugs and increase their absorption in the human body has become a research hotspot at home and abroad. In addition, many other studies have shown that in baicalein derivatives, the C-5 hydroxyl group remains unchanged, and the C-6 or C-7 hydroxyl group has strong activity after modification. Therefore, on this basis, this study uses baicalein as the lead compound, uses chemical reactions to modify its structure, introduces functional groups, and designs and synthesizes a series of baicalein derivatives. At the same time, this method is also an effective way to innovate drugs.

发明内容Summary of the invention

本发明需要解决的技术问题是合成一类提高黄芩素类化合物生物利用度且合成方法简便，后处理简易，成本低廉的一种方法。本发明解决的另一技术问题是提供上述黄芩素类衍生物的制备方法和在制药中的应用。The technical problem to be solved by the present invention is to synthesize a class of baicalin compounds with improved bioavailability, and the synthesis method is simple, the post-treatment is simple, and the cost is low. Another technical problem solved by the present invention is to provide a preparation method of the above baicalin derivatives and their application in pharmaceutical manufacturing.

为实现上述目的，本发明采用了以下的技术手段：To achieve the above purpose, the present invention adopts the following technical means:

一种黄芩素类衍生物，具有为以下通式的化合物：A baicalein derivative having the following general formula:

Figure GDA0004160328140000011
Figure GDA0004160328140000011

通式中，R分别为：In the general formula, R is:

Figure GDA0004160328140000012
Figure GDA0004160328140000012

Figure GDA0004160328140000021
Figure GDA0004160328140000021

所述的黄芩素类衍生物为以下结构式的化合物：The baicalein derivatives are compounds of the following structural formula:

Figure GDA0004160328140000031
Figure GDA0004160328140000031

Figure GDA0004160328140000041
Figure GDA0004160328140000041

Figure GDA0004160328140000051
Figure GDA0004160328140000051

Figure GDA0004160328140000061
Figure GDA0004160328140000061

Figure GDA0004160328140000071
Figure GDA0004160328140000071

Figure GDA0004160328140000081
Figure GDA0004160328140000081

名称为：GL31。The name is: GL31.

所述的黄芩素类衍生物的制备方法，以黄芩素为原料，经亲电取代反应使得C-6和C-7的羟基都被磺酰氧取代，反应的方程式如下：The preparation method of the baicalein derivatives is to use baicalein as a raw material, and to replace the hydroxyl groups of C-6 and C-7 with sulfonyloxy through an electrophilic substitution reaction. The reaction equation is as follows:

Figure GDA0004160328140000082
Figure GDA0004160328140000082

所述的亲电取代反应的反应溶剂为干燥后的无水丙酮。The reaction solvent of the electrophilic substitution reaction is dried anhydrous acetone.

所述的亲电取代反应的条件是反应过程是在冰浴条件下反应1小时后，反应液加入冰水淬灭反应，而后过滤。The condition of the electrophilic substitution reaction is that after the reaction is carried out in an ice bath for 1 hour, ice water is added to the reaction solution to quench the reaction, and then the reaction solution is filtered.

所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂上中的应用。The application of the baicalin derivatives in the preparation of influenza virus neuraminidase NA inhibitors.

所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂上中的应用，所述化合物为：GL09、GL15、GL25、GL31。The application of the baicalein derivatives in the preparation of influenza virus neuraminidase NA inhibitors, the compounds are: GL09, GL15, GL25, GL31.

所述的黄芩素类衍生物在制备新型冠状病毒主蛋白酶Mpro抑制剂中的应用。The use of the baicalin derivatives in the preparation of novel coronavirus main protease M protease inhibitors.

所述的黄芩素类衍生物在制备新型冠状病毒主蛋白酶Mpro抑制剂中的应用，所述化合物为：GL08、GL10、GL29。The use of the baicalin derivatives in the preparation of novel coronavirus main protease M protease inhibitors, the compounds are: GL08, GL10, GL29.

所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂及制备新型冠状病毒主蛋白酶Mpro抑制剂的应用。The baicalein derivatives are used in the preparation of influenza virus neuraminidase NA inhibitors and the preparation of novel coronavirus main protease M protease inhibitors.

本发明获得的有益效果是：The beneficial effects obtained by the present invention are:

1、提供了黄芩素类衍生物GL01-GL31。1. Provided are baicalein derivatives GL01-GL31.

2、提供了黄芩素类衍生物GL01-GL31的制备方法。2. A preparation method of baicalin derivatives GL01-GL31 is provided.

3、制备出的黄芩素类衍生物GL01-GL31表现出较好的酶抑制活性。3. The prepared baicalin derivatives GL01-GL31 showed good enzyme inhibitory activity.

4、黄芩素类衍生物GL01-GL31的制备方法简单易行。4. The preparation method of baicalin derivatives GL01-GL31 is simple and easy.

具体实施方式DETAILED DESCRIPTION

黄芩素的结构和原子序号如下：The structure and atomic number of baicalin are as follows:

Figure GDA0004160328140000091
Figure GDA0004160328140000091

黄芩素类衍生物GL01-GL31的制备以黄芩素(5,6,7-三羟基黄酮)为原料，经亲电取代反应制得，其结构分别如下：The preparation of baicalin derivatives GL01-GL31 is prepared from baicalin (5,6,7-trihydroxyflavone) as raw material through electrophilic substitution reaction, and their structures are as follows:

Figure GDA0004160328140000092
Figure GDA0004160328140000092

Figure GDA0004160328140000101
Figure GDA0004160328140000101

Figure GDA0004160328140000111
Figure GDA0004160328140000111

Figure GDA0004160328140000121
Figure GDA0004160328140000121

Figure GDA0004160328140000131
Figure GDA0004160328140000131

Figure GDA0004160328140000141
Figure GDA0004160328140000141

反应溶剂为干燥后的无水丙酮，反应过程是在冰浴(0℃)条件下反应1小时后，反应液加入冰水淬灭反应，而后过滤，得淡黄色或米白色粗产物。The reaction solvent is dried anhydrous acetone. The reaction process is to react in an ice bath (0° C.) for 1 hour, then add ice water to the reaction solution to quench the reaction, and then filter to obtain a light yellow or off-white crude product.

制备本发明的黄芩素类衍生物的反应如下反应式所示：The reaction for preparing the baicalein derivatives of the present invention is shown in the following reaction formula:

Figure GDA0004160328140000142
Figure GDA0004160328140000142

实施例1GL01的制备Example 1 Preparation of GL01

制备GL01Preparation of GL01

准确称量纯度为98％黄芩素0.2206g,0.8mmol和纯度为98％以上的4-吗啉碳酰氯0.3053g,2mmol置于50ml圆底烧瓶中，加入10ml无水丙酮使其溶解，随后加入2ml吡啶。将上述反应液置于冰浴(0℃)条件下，搅拌1h。整个反应过程氮气保护。经薄层色谱(TLC)监测反应完成后，向反应液中加入20ml冰水，静置片刻，待固体沉淀析出后，抽滤，滤饼用20ml 0℃的乙醇清洗。残余物上硅胶柱层析(流动相：DCM)，重结晶纯化，得到金黄色粉末状固体，收率为79％。Accurately weigh 0.2206g, 0.8mmol of baicalein with a purity of 98% and 0.3053g, 2mmol of 4-morpholinecarbonyl chloride with a purity of more than 98% and place them in a 50ml round-bottom flask, add 10ml of anhydrous acetone to dissolve it, and then add 2ml of pyridine. The above reaction solution is placed in an ice bath (0℃) and stirred for 1h. The whole reaction process is protected by nitrogen. After the reaction is completed by thin layer chromatography (TLC), 20ml of ice water is added to the reaction solution, and it is allowed to stand for a while. After the solid precipitates, it is filtered and the filter cake is washed with 20ml of 0℃ ethanol. The residue is chromatographed on a silica gel column (mobile phase: DCM) and purified by recrystallization to obtain a golden yellow powder solid with a yield of 79%.

实施例2GL02的制备Example 2 Preparation of GL02

制备GL02Preparation of GL02

准确称量黄芩素(纯度：98％)(0.2206g,0.8mmol)和4-氯-3-硝基苯磺酰氯(纯度：98％+)(0.5226g,2mmol)置于50ml圆底烧瓶中，加入无水丙酮(10ml)使其溶解，随后加入吡啶(2ml)。将上述反应液置于冰浴(0℃)条件下，搅拌1h。整个反应过程需氮气保护。经薄层色谱(TLC)监测反应完成后，向反应液中加入20ml冰水，静置片刻，待固体沉淀析出后，抽滤，滤饼用20ml 0℃的乙醇清洗。残余物上硅胶柱层析(流动相：DCM)，重结晶纯化，得到灰白色粉末状固体,收率为84％。Accurately weigh baicalein (purity: 98%) (0.2206g, 0.8mmol) and 4-chloro-3-nitrobenzenesulfonyl chloride (purity: 98%+) (0.5226g, 2mmol) and place them in a 50ml round-bottom flask, add anhydrous acetone (10ml) to dissolve them, and then add pyridine (2ml). Place the above reaction solution in an ice bath (0℃) and stir for 1h. The entire reaction process requires nitrogen protection. After the reaction is completed by thin layer chromatography (TLC), add 20ml of ice water to the reaction solution, let it stand for a while, wait for the solid to precipitate, filter it, and wash the filter cake with 20ml of 0℃ ethanol. The residue is chromatographed on a silica gel column (mobile phase: DCM), and recrystallized and purified to obtain an off-white powder solid with a yield of 84%.

GL03-GL31的制备方法参考GL01和GL02。The preparation method of GL03-GL31 refers to GL01 and GL02.

黄芩素类衍生物结构鉴定数据如下：The structural identification data of baicalin derivatives are as follows:

GL01收率79％；mp:239.6-239.6；金黄色粉末；1HNMR(500MHz,Chloroform-d)δ12.86(s,1H),7.82(t,J＝1.4Hz,1H),7.81(d,J＝1.7Hz,1H),7.53–7.49(m,1H),7.48(d,J＝1.7Hz,1H),7.46(d,J＝6.8Hz,1H),6.99(s,1H),6.66(s,1H),3.70(dt,J＝7.2,4.0Hz,8H),3.63–3.58(m,4H),3.53(t,J＝4.9Hz,4H).13C NMR(126MHz,Chloroform-d)δ182.95,164.97,153.50,153.28,152.33,151.60,149.44,132.22,130.93,129.18,126.95,126.42,109.21,105.69,101.50,66.59,66.47,45.34,45.15,44.60,44.41.HRMS(m/z):cacld forC25H24N2O9[M-H]-495.14090,found 495.14001.GL01 yield 79%; mp: 239.6-239.6; golden yellow powder; 1 H NMR (500MHz, Chloroform-d) δ12.86 (s, 1H), 7.82 (t, J = 1.4 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.53-7.49 (m, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 3.70 (dt, J = 7.2, 4.0 Hz, 8H), 3.63-3.58 (m, 4H), 3.53 (t, J = 4.9 Hz, 4H). 13 C NMR(126MHz,Chloroform-d)δ182.95,164.97,153.50,153.28,152.33,151.60,149.44,132.22,130.93,129.18,126.95,126.42,109.21,105.69,101.50,6 6.59,66.47,45.34,45.15,44.60,44.41.HRMS(m/z):cacld forC 25 H 24 N 2 O 9 [MH] - 495.14090,found 495.14001.

GL02收率84％；mp:215.5-215.5；灰白色粉末；1H NMR(500MHz,DMSO-d6)δ13.26(d,J＝9.8Hz,1H),8.61(d,J＝2.3Hz,1H),8.59(d,J＝2.1Hz,1H),8.21(dd,J＝8.6,2.3Hz,1H),8.19(t,J＝1.4Hz,1H),8.18(d,J＝1.5Hz,1H),8.16(dd,J＝8.6,2.2Hz,1H),8.13(d,J＝8.6Hz,1H),8.11(d,J＝8.6Hz,1H),7.71–7.66(m,1H),7.65–7.57(m,2H),7.52(s,1H),7.29(s,1H).13CNMR(126MHz,DMSO-d6)δ183.00,165.63,154.40,154.32,148.32,148.19,146.08,135.64,134.26,134.07,133.97,133.35,133.29,133.17,132.61,130.42,129.73,127.40,126.14,125.93,124.75,110.91,106.27,103.83,55.37.HRMS(m/z):cacld forC27H14Cl2N2O13S2[M-H]-707.92416,found 706.92236.GL02 yield 84%; mp: 215.5-215.5; off-white powder; 1 H NMR (500MHz, DMSO-d 6 )δ13.26(d,J＝9.8Hz,1H),8.61(d,J＝2.3Hz,1H),8.59(d,J＝2.1Hz,1H),8.21(dd,J＝8.6,2.3Hz,1H),8.19(t,J＝1.4Hz,1H),8.18(d,J＝1.5Hz,1H),8.16(dd,J ＝8.6,2.2Hz,1H),8.13(d,J＝8.6Hz,1H),8.11(d,J＝8.6Hz,1H),7.71–7.66(m,1H),7.65–7.57(m,2H),7.52(s,1H),7.29(s,1H). 13 CNMR(126MHz,DMSO-d 6 )δ183.00,165.63,154.40,154.32,148.32,148.19,146.08,135.64,134.26,134.07,133.97,133.35,133.29,133.17,132.61,130.42,129.73,1 27.40,126.14,125.93,124.75,110.91,106.27,103.83,55.37.HRMS(m/z):cacld forC 27 H 14 Cl 2 N 2 O 13 S 2 [MH] - 707.92416,found 706.92236.

GL03收率86％；mp:255.4-255.4；米白色粉末；1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),8.19(d,J＝1.9Hz,2H),8.18(d,J＝1.7Hz,2H),8.17(d,J＝1.9Hz,1H),8.16(d,J＝2.0Hz,1H),8.08(d,J＝2.0Hz,1H),8.07(d,J＝2.0Hz,1H),8.02(d,J＝1.9Hz,1H),8.00(d,J＝1.9Hz,1H),7.71–7.64(m,1H),7.62(dd,J＝8.3,6.7Hz,2H),7.47(s,1H),7.28(s,1H).13C NMR(126MHz,DMSO-d6)δ183.06,165.61,154.43,154.23,146.12,139.62,138.00,134.48,134.26,133.32,130.43,129.72,129.57,129.39,127.41,124.67,118.36,117.85,117.79,117.65,110.72,106.22,103.64.HRMS(m/z):cacld for C29H16N2O9S2[M-H]-599.02002,found 599.02244.GL03 yield 86%; mp: 255.4-255.4; off-white powder; 1 H NMR (500MHz, DMSO-d 6 )δ13.26(s,1H),8.19(d,J＝1.9Hz,2H),8.18(d,J＝1.7Hz,2H),8.17(d,J＝1.9Hz,1H),8.16(d,J＝2.0Hz,1H),8.08(d,J＝2.0Hz,1H),8.07(d,J＝2.0Hz,1H), 8.02(d,J＝1.9Hz,1H),8.00(d,J＝1.9Hz,1H),7.71–7.64(m,1H),7.62(dd,J＝8.3,6.7Hz,2H),7.47(s,1H),7.28(s,1H). 13 C NMR (126MHz, DMSO-d 6 )δ183.06,165.61,154.43,154.23,146.12,139.62,138.00,134.48,134.26,133.32,130.43,129.72,129.57,129.39,127.41,124.67,118.36,1 17.85,117.79,117.65,110.72,106.22,103.64.HRMS(m/z): cacld for C 29 H 16 N 2 O 9 S 2 [MH] - 599.02002, found 599.02244.

GL04收率82％；mp:182.9-183.1；米白色粉末；1H NMR(500MHz,Chloroform-d)δ13.04(s,1H),8.01–7.96(m,2H),7.94–7.88(m,4H),7.64–7.59(m,1H),7.59–7.53(m,2H),7.25(d,J＝5.9Hz,2H),7.23–7.17(m,3H),6.76(s,1H).13C NMR(126MHz,Chloroform-d)δ182.63,167.53,167.24,165.64,165.47,165.19,154.82,153.83,147.36,132.72,132.45,132.42,131.78,131.70,131.54,131.46,130.79,130.77,130.35,129.35,126.56,125.32,116.83,116.65,116.52,116.34,110.15,105.90,102.29.HRMS(m/z):cacld forC27H16F2O9S2[M-H]-585.01310,found 585.01044.GL04 yield 82%; mp: 182.9-183.1; off-white powder; 1 H NMR (500 MHz, Chloroform-d) δ 13.04 (s, 1H), 8.01–7.96 (m, 2H), 7.94–7.88 (m, 4H), 7.64–7.59 (m, 1H), 7.59–7.53 (m, 2H), 7.25 (d, J = 5.9 Hz, 2H), 7.23–7.17 (m, 3H), 6.76 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.63,167.53,167.24,165.64,165.47,165.19,154.82,153.83,147.36,132.72,132.45,132.42,131.78,131.70,131.54,131.46,130.79,130.77,130.35,129.35,126.56,125.32,116.83,116.65,116.52,116.34,110.15,105.90,102.29.HRMS(m/z):cacld forC 27 H 16 F 2 O 9 S 2 [MH] - 585.01310, found 585.01044.

GL05收率73％；mp:126.9-128.1；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.79(s,1H),8.07(dd,J＝8.0,1.7Hz,1H),7.90(ddd,J＝10.4,7.5,1.7Hz,3H),7.77(ddd,J＝8.8,7.7,1.7Hz,1H),7.72–7.64(m,1H),7.63–7.52(m,3H),7.51–7.44(m,2H),7.41(dt,J＝8.4,1.6Hz,1H),7.35(t,J＝7.7Hz,1H),7.23(s,1H),6.73(s,1H).13C NMR(126MHz,Chloroform-d)δ182.60,165.59,154.62,153.76,147.44,147.01,136.63,135.76,132.67,131.82,131.14,130.39,129.61,129.32,127.83,126.64,126.55,126.15,125.55,121.17,121.09,120.81,120.80,120.36,120.34,119.10,119.01,109.97,105.88,102.18.HRMS(m/z):cacld for C29H16F6O11S2[M-H]-716.99655,found 716.99426.GL05 yield 73%; mp: 126.9-128.1; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.79 (s, 1H), 8.07 (dd, J = 8.0, 1.7 Hz, 1H), 7.90 (ddd, J = 10.4, 7.5, 1.7 Hz, 3H), 7.77 (ddd, J = 8.8, 7.7, 1.7 Hz, 1H), 7.72–7.64 (m, 1H), 7.63–7.52 (m, 3H), 7.51–7.44 (m, 2H), 7.41 (dt, J = 8.4, 1.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.23 (s, 1H), 6.73 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.60,165.59,154.62,153.76,147.44,147.01,136.63,135.76,132.67,131.82,131.14,130.39,129.61,129.32,127.83,1 26.64,126.55,126.15,125.55,121.17,121.09,120.81,120.80,120.36,120.34,119.10,119.01,109.97,105.88,102.18.HRMS(m/z): cacld for C 29 H 16F 6 O 11 S 2 [MH] - 716.99655, found 716.99426.

GL06收率82％；mp:235.2-235.2；柠檬黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.76(s,1H),8.57(ddt,J＝18.4,8.6,1.1Hz,2H),8.28(dt,J＝8.6,0.9Hz,1H),8.14–8.06(m,3H),7.89–7.80(m,2H),7.59–7.56(m,1H),7.56(s,1H),7.55(dd,J＝2.8,1.4Hz,1H),7.52(d,J＝7.0Hz,1H),7.46(dd,J＝8.7,7.6Hz,1H),7.40(ddd,J＝8.5,7.4,6.2Hz,2H),7.19(ddd,J＝8.8,7.7,1.0Hz,2H),7.13(s,1H),6.68(s,1H),2.89(d,J＝6.9Hz,12H).13CNMR(126MHz,Chloroform-d)δ182.52,165.31,155.09,153.72,151.63,147.98,133.06,132.57,132.52,131.73,130.95,130.78,130.53,130.26,129.85,129.76,129.72,129.26,129.23,128.50,126.51,125.36,122.80,122.73,119.88,119.50,115.80,115.31,109.67,105.89,100.75,45.46.HRMS(m/z):cacld for C39H32N2O9S2[M-H]-735.14765,found735.14508.GL06 yield 82%; mp: 235.2-235.2; lemon yellow powder; 1 H NMR (500MHz, Chloroform-d) δ12.76 (s, 1H), 8.57 (ddt, J = 18.4, 8.6, 1.1 Hz, 2H), 8.28 (dt, J = 8.6, 0.9 Hz, 1H), 8.14–8.06 (m, 3H), 7.89–7.80 (m, 2H), 7.59–7.56 (m, 1H), 7.56 (s, 1H), 7.55 (dd, J＝2.8,1.4Hz,1H),7.52(d,J＝7.0Hz,1H),7.46(dd,J＝8.7,7.6Hz,1H),7.40(ddd,J＝8.5,7.4,6.2Hz,2H),7.19(ddd,J＝8.8,7.7,1.0Hz,2H),7.13(s,1H),6. 68(s,1H),2.89(d,J＝6.9Hz,12H). 13 CNMR(126MHz,Chloroform-d)δ182.52,165.31,155.09,153.72,151.63,147.98,133.06,132.57,132.52,131.73,130.95,130.78,130.53,130.26,129.85,1 29.76,129.72,129.26,129.23,128.50,126.51,125.36,122.80,122.73,119.88,119.50,115.80,115.31,109.67,105.89,100.75,45.46.HRMS(m /z):cacld for C 39 H 32 N 2 O 9 S 2 [MH] - 735.14765,found735.14508.

GL07收率66％；mp:189.5-190.2；淡粉红色粉末；1H NMR(500MHz,Chloroform-d)δ13.03(s,1H),8.03–7.97(m,1H),7.94–7.85(m,3H),7.65–7.60(m,1H),7.57(dd,J＝8.3,6.6Hz,2H),7.25(s,1H),7.17(t,J＝8.6Hz,1H),7.12(t,J＝8.6Hz,1H),6.77(s,1H).13CNMR(126MHz,Chloroform-d)δ182.57,165.87,163.77,163.20,161.67,161.12,159.92,157.82,154.59,153.97,146.88,132.84,132.67,132.15,130.24,129.38,126.60,125.12,110.36,107.81,107.61,107.40,107.31,107.11,106.90,105.99,102.72.HRMS(m/z):cacld for C27H12Cl2F4O9S2[M-H]-688.91631,found 688.91412.GL07 yield 66%; mp: 189.5-190.2; light pink powder; 1 H NMR (500MHz, Chloroform-d) δ13.03 (s, 1H), 8.03–7.97 (m, 1H), 7.94–7.85 (m, 3H), 7.65–7.60 (m, 1H), 7.57 (dd, J = 8.3, 6.6 Hz, 2H), 7.25 (s, 1H), 7.17 (t, J = 8.6 Hz, 1H), 7.12 (t, J = 8.6 Hz, 1H), 6.77 (s, 1H). 13 CNMR(126MHz,Chloroform-d)δ182.57,165.87,163.77,163.20,161.67,161.12,159.92,157.82,154.59,153.97,146.88,132.84,132.67,132.15,130.24, 129.38,126.60,125.12,110.36,107.81,107.61,107.40,107.31,107.11,106.90,105.99,102.72.HRMS(m/z): cacld for C 27 H 12 Cl 2 F 4 O 9 S 2 [MH] - 688.91631, found 688.91412.

GL08收率74％；mp:222.5-223.0；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.88(s,1H),8.07(dd,J＝8.0,1.6Hz,1H),7.94(dd,J＝8.0,1.6Hz,1H),7.91–7.85(m,2H),7.67–7.57(m,3H),7.57–7.49(m,3H),7.49–7.43(m,2H),7.34(ddd,J＝7.9,7.2,1.4Hz,1H),7.20(s,1H),6.72(s,1H).13C NMR(126MHz,Chloroform-d)δ182.56,165.54,154.92,153.75,147.38,135.61,135.56,134.77,133.81,133.72,133.53,132.65,132.50,132.00,131.90,131.20,130.40,129.31,127.18,126.70,126.54,125.47,109.92,105.92,101.72.HRMS(m/z):cacld for C27H16Cl2O9S2[M-H]-616.95400,found 619.95190.GL08 yield 74%; mp: 222.5-223.0; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.88 (s, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.91–7.85 (m, 2H), 7.67–7.57 (m, 3H), 7.57–7.49 (m, 3H), 7.49–7.43 (m, 2H), 7.34 (ddd, J = 7.9, 7.2, 1.4 Hz, 1H), 7.20 (s, 1H), 6.72 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.56,165.54,154.92,153.75,147.38,135.61,135.56,134.77,133.81,133.72,133.53,132.65,132.50,132.00,131.90,1 31.20,130.40,129.31,127.18,126.70,126.54,125.47,109.92,105.92,101.72.HRMS(m/z):cacld for C 27 H 16 Cl 2 O 9 S 2 [MH] - 616.95400,found 619.95190 .

GL09收率75％；mp:225.8-225.9；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.90(s,1H),7.90–7.85(m,2H),7.62–7.51(m,3H),7.18(s,1H),6.91(d,J＝62.2Hz,4H),6.72(s,1H),2.54(d,J＝30.3Hz,12H),2.33(d,J＝30.1Hz,6H).13C NMR(126MHz,Chloroform-d)δ182.67,165.32,155.14,153.57,147.80,143.23,140.69,139.74,132.71,132.50,131.89,131.39,130.62,130.56,129.26,126.50,125.58,109.63,105.85,101.43,22.83,22.69,21.22,21.15.HRMS(m/z):cacld for C33H30O9S2[M-H]-633.12585,found633.12323.GL09 yield 75%; mp: 225.8-225.9; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.90 (s, 1H), 7.90–7.85 (m, 2H), 7.62–7.51 (m, 3H), 7.18 (s, 1H), 6.91 (d, J = 62.2 Hz, 4H), 6.72 (s, 1H), 2.54 (d, J = 30.3 Hz, 12H), 2.33 (d, J = 30.1 Hz, 6H). 13 C NMR(126MHz,Chloroform-d)δ182.67,165.32,155.14,153.57,147.80,143.23,140.69,139.74,132.71,132.50,131.89,131.39,130.62,130.56,129.26,1 26.50,125.58,109.63,105.85,101.43,22.83,22.69,21.22,21.15.HRMS(m/z):cacld for C 33 H 30 O 9 S 2 [MH] - 633.12585,found633.12323.

GL10收率85％；mp:199.4-199.5；淡粉色粉末；1H NMR(500MHz,Chloroform-d)δ13.15(s,1H),8.36(d,J＝2.2Hz,1H),8.29(d,J＝2.2Hz,1H),8.08(dt,J＝8.5,2.1Hz,2H),7.94–7.89(m,2H),7.73(dd,J＝8.4,4.0Hz,2H),7.66–7.54(m,3H),7.29(s,1H),6.78(s,1H).13C NMR(126MHz,Chloroform-d)δ182.59,165.90,154.64,154.01,146.97,140.06,139.38,135.50,133.98,132.87,132.80,132.69,132.61,132.44,130.22,129.40,128.48,128.44,128.03,127.99,126.61,125.04,122.88,122.81,110.40,105.98,102.57.HRMS(m/z):cacld for C29H14Cl2F6O9S2[M-H]-752.92877,found 752.92645.GL10 yield 85%; mp: 199.4-199.5; light pink powder; 1 H NMR (500MHz, Chloroform-d) δ13.15 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.08 (dt, J = 8.5, 2.1 Hz, 2H), 7.94-7.89 (m, 2H), 7.73 (dd, J = 8.4, 4.0 Hz, 2H), 7.66-7.54 (m, 3H), 7.29 (s, 1H), 6.78 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.59,165.90,154.64,154.01,146.97,140.06,139.38,135.50,133.98,132.87,132.80,132.69,132.61,132.44,130.22,1 29.40,128.48,128.44,128.03,127.99,126.61,125.04,122.88,122.81,110.40,105.98,102.57.HRMS(m/z): cacld for C 29 H 14 Cl 2 F 6 O 9 S 2 [MH] - 752.92877, found 752.92645.

GL11收率70％；mp:189.7-189.9；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.91(s,1H),8.27(d,J＝8.3Hz,1H),8.12–8.06(m,2H),7.97(d,J＝1.7Hz,1H),7.91–7.86(m,2H),7.79(dd,J＝8.4,1.8Hz,1H),7.67(dd,J＝8.5,1.8Hz,1H),7.64–7.52(m,3H),7.19(s,1H),6.75(s,1H).13C NMR(126MHz,Chloroform-d)δ182.49,165.77,154.70,153.88,147.08,140.96,139.17,137.10,136.83,136.36,136.09,133.16,133.13,132.81,132.68,132.47,132.44,131.85,130.24,129.37,126.57,125.30,124.83,124.80,124.36,124.33,122.35,122.00,110.15,105.98,102.14.HRMS(m/z):cacld for C29H14Br2F6O9S2[M-H]-842.82569,found 842.82245.GL11 yield 70%; mp: 189.7-189.9; light yellow powder; 1 H NMR (500MHz, Chloroform-d) δ12.91 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.12-8.06 (m, 2H), 7.97 (d, J = 1.7 Hz, 1H), 7.91-7.86 (m, 2H), 7.79 (dd, J = 8.4, 1.8 Hz, 1H), 7.67 (dd, J = 8.5, 1.8 Hz, 1H), 7.64-7.52 (m, 3H), 7.19 (s, 1H), 6.75 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.49,165.77,154.70,153.88,147.08,140.96,139.17,137.10,136.83,136.36,136.09,133.16,133.13,132.81,132.68,1 32.47,132.44,131.85,130.24,129.37,126.57,125.30,124.83,124.80,124.36,124.33,122.35,122.00,110.15,105.98,102.14.HRMS(m/z):cacld for C 29 H 14 Br 2 F 6 O 9 S 2 [MH] - 842.82569, found 842.82245.

GL12收率79％；mp:213.9-214.4；金黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.90(s,1H),8.12(dd,J＝8.9,5.6Hz,1H),7.95(dd,J＝8.9,5.7Hz,1H),7.91–7.86(m,2H),7.64–7.51(m,3H),7.37(dd,J＝8.2,2.5Hz,1H),7.26–7.23(m,1H),7.22(s,1H),7.18(ddd,J＝9.0,7.4,2.5Hz,1H),7.05(ddd,J＝8.8,7.4,2.5Hz,1H),6.74(s,1H).13C NMR(126MHz,Chloroform-d)δ182.56,166.88,166.32,165.66,164.80,164.25,154.78,153.82,147.30,136.16,136.07,135.75,135.66,134.34,134.26,133.48,133.40,132.72,131.94,131.92,130.34,130.05,130.02,129.34,126.56,125.37,120.31,120.11,119.69,119.48,114.81,114.64,114.24,114.06,110.00,105.94,101.96.HRMS(m/z):cacld forC27H14Cl2F2O9S2[M-H]-652.93516,found 652.93280.GL12 yield 79%; mp: 213.9-214.4; golden yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.90 (s, 1H), 8.12 (dd, J = 8.9, 5.6 Hz, 1H), 7.95 (dd, J = 8.9, 5.7 Hz, 1H), 7.91–7.86 (m, 2H), 7.64–7.51 (m, 3H), 7.37 (dd, J = 8.2, 2.5 Hz, 1H), 7.26–7.23 (m, 1H), 7.22 (s, 1H), 7.18 (ddd, J = 9.0, 7.4, 2.5 Hz, 1H), 7.05 (ddd, J = 8.8, 7.4, 2.5 Hz, 1H), 6.74 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.56,166.88,166.32,165.66,164.80,164.25,154.78,153.82,147.30,136.16,136.07,135.75,135.66,134.34,134.26,1 33.48,133.40,132.7 2,131.94,131.92,130.34,130.05,130.02,129.34,126.56,125.37,120.31,120.11,119.69,119.48,114.81,114.64,114.24,114.06,110.00, 105.94,101.96.HRMS(m/z): cacld forC 27 H 14 Cl 2 F 2 O 9 S 2 [MH] - 652.93516, found 652.93280.

GL13收率73％；mp:215.9-215.9；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.09(s,1H),8.04–7.99(m,2H),7.92–7.85(m,4H),7.72–7.64(m,4H),7.62–7.58(m,3H),7.57–7.54(m,4H),7.51–7.39(m,6H),7.29(s,1H),6.76(s,1H).13C NMR(126MHz,Chloroform-d)δ182.69,165.54,155.09,153.80,147.73,147.50,147.23,138.98,138.68,134.94,133.27,132.65,130.46,129.33,129.17,129.14,129.07,128.95,128.81,127.73,127.56,127.43,127.41,126.57,125.46,110.14,105.91,102.34.HRMS(m/z):cacld forC39H26O9S2[M-H]-701.09455,found701.09235.GL13 yield 73%; mp: 215.9-215.9; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 13.09 (s, 1H), 8.04–7.99 (m, 2H), 7.92–7.85 (m, 4H), 7.72–7.64 (m, 4H), 7.62–7.58 (m, 3H), 7.57–7.54 (m, 4H), 7.51–7.39 (m, 6H), 7.29 (s, 1H), 6.76 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.69,165.54,155.09,153.80,147.73,147.50,147.23,138.98,138.68,134.94,133.27,132.65,130.46,129.33,129.17,1 29.14,129.07,128.95,128.81,127.73,127.56,127.43,127.41,126.57,125.46,110.14,105.91,102.34.HRMS(m/z):cacld forC 39 H 26 O 9 S 2 [MH] - 701.09455, found701.09235.

GL14收率55％；mp:141.2-141.3；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.00(s,1H),7.92–7.89(m,2H),7.88–7.84(m,2H),7.68–7.63(m,2H),7.61–7.58(m,1H),7.57–7.53(m,2H),7.36(d,J＝1.8Hz,1H),7.35(d,J＝2.0Hz,1H),7.27(d,J＝1.7Hz,1H),7.25(s,1H),7.24(s,1H),6.74(s,1H),2.72(dd,J＝8.4,6.8Hz,2H),2.68–2.62(m,2H),1.73–1.62(m,4H),0.98(t,J＝7.3Hz,3H),0.93(t,J＝7.3Hz,3H).13C NMR(126MHz,Chloroform-d)δ182.70,165.47,154.98,153.70,150.74,150.14,147.62,133.65,132.61,131.88,130.48,129.31,129.23,129.07,128.68,128.67,126.55,125.54,110.04,105.86,102.32,38.06,38.00,24.21,24.03,13.71,13.64.HRMS(m/z):cacld for C33H30O9S2[M-H]-633.12585,found 633.12323.GL14 yield 55%; mp: 141.2-141.3; light yellow powder; 1 H NMR (500MHz, Chloroform-d) δ13.00 (s, 1H), 7.92–7.89 (m, 2H), 7.88–7.84 (m, 2H), 7.68–7.63 (m, 2H), 7.61–7.58 (m, 1H), 7.57–7.53 (m, 2H), 7.36 (d, J=1.8 Hz, 1H), 7.35 (d, J=2.0 Hz ,1H),7.27(d,J＝1.7Hz,1H),7.25(s,1H),7.24(s,1H),6.74(s,1H),2.72(dd,J＝8.4,6.8Hz,2H),2.68–2.62(m,2H),1.73–1.62(m,4H),0.98(t,J＝7. 3Hz, 3H), 0.93 (t, J = 7.3Hz, 3H). 13 C NMR(126MHz,Chloroform-d)δ182.70,165.47,154.98,153.70,150.74,150.14,147.62,133.65,132.61,131.88,130.48,129.31,129.23,129.07,128.68,128.67,126.55,125.54,110.04,105.86,102.32,38.06,38.00,24.21,24.03,13.71,13.64.HRMS(m/z):cacld for C 33 H 30 O 9 S 2 [MH] - 633.12585,found 633.12323.

GL15收率67％；mp:191.9-192.1；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.02(s,1H),7.93–7.85(m,4H),7.70–7.66(m,2H),7.63–7.58(m,1H),7.57–7.51(m,2H),7.44–7.39(m,2H),7.34–7.29(m,2H),7.24(s,1H),6.74(s,1H),3.01(dp,J＝31.6,6.9Hz,2H),1.32(d,J＝6.9Hz,6H),1.26(d,J＝6.9Hz,6H).13C NMR(126MHz,Chloroform-d)δ182.69,165.45,156.68,156.16,154.99,153.69,147.63,133.70,132.60,132.01,130.48,129.30,128.79,127.30,127.13,126.53,125.49,110.03,105.85,102.29,34.39,34.32,23.65,23.52.HRMS(m/z):cacld for C33H30O9S2[M-H]-633.12585,found 633.12317.GL15 yield 67%; mp: 191.9-192.1; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 13.02 (s, 1H), 7.93–7.85 (m, 4H), 7.70–7.66 (m, 2H), 7.63–7.58 (m, 1H), 7.57–7.51 (m, 2H), 7.44–7.39 (m, 2H), 7.34–7.29 (m, 2H), 7.24 (s, 1H), 6.74 (s, 1H), 3.01 (dp, J = 31.6, 6.9 Hz, 2H), 1.32 (d, J = 6.9 Hz, 6H), 1.26 (d, J = 6.9 Hz, 6H). 13 C NMR(126MHz,Chloroform-d)δ182.69,165.45,156.68,156.16,154.99,153.69,147.63,133.70,132.60,132.01,130.48,129.30,128.79,127.30,127.13,1 26.53,125.49,110.03,105.85,102.29,34.39,34.32,23.65,23.52.HRMS(m/z): cacld for C 33 H 30 O 9 S 2 [MH] - 633.12585,found 633.12317.

GL16收率69％；mp:190.4-190.4；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.20(s,1H),8.53–8.49(m,2H),8.43–8.39(m,2H),8.22(d,J＝20.4Hz,2H),7.95–7.90(m,2H),7.66–7.61(m,1H),7.58(dd,J＝8.3,6.6Hz,2H),7.31(s,1H),6.79(s,1H).13C NMR(126MHz,Chloroform-d)δ182.54,166.03,154.56,154.14,146.75,138.96,137.63,133.79,133.52,133.24,133.17,132.95,132.89,132.61,130.16,129.43,129.30,128.92,128.64,128.01,126.64,124.84,123.32,123.25,121.15,121.08,110.54,106.04,102.76.HRMS(m/z):cacld for C31H14F12O9S2[M-H]-820.98148,found 820.97913.GL16 yield 69%; mp: 190.4-190.4; light yellow powder; 1 H NMR (500MHz, Chloroform-d) δ13.20 (s, 1H), 8.53–8.49 (m, 2H), 8.43–8.39 (m, 2H), 8.22 (d, J＝20.4Hz, 2H), 7.95–7.90 (m, 2H), 7.66–7.61 (m, 1H), 7.58 (dd, J＝8.3, 6.6Hz, 2H), 7.31 (s, 1H), 6.79 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.54,166.03,154.56,154.14,146.75,138.96,137.63,133.79,133.52,133.24,133.17,132.95,132.89,132.61,130.16,1 29.43,129.30,128.92,128.64,128.01,126.64,124.84,123.32,123.25,121.15,121.08,110.54,106.04,102.76.HRMS(m/z): cacld for C 31 H 14 F 12 O 9 S 2 [MH] - 820.98148, found 820.97913.

GL17收率77％；mp:181.8-183.1；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.91(s,1H),8.24(dd,J＝8.3,0.9Hz,1H),8.06(dd,J＝8.3,0.9Hz,1H),7.93–7.86(m,3H),7.78(d,J＝1.7Hz,1H),7.73(ddd,J＝8.3,1.8,0.8Hz,1H),7.64–7.58(m,2H),7.57–7.53(m,2H),7.21(s,1H),6.74(s,1H).13C NMR(126MHz,Chloroform-d)δ182.50,165.80,154.63,153.88,147.08,138.98,137.39,137.21,137.12,136.64,136.37,134.91,134.45,132.82,132.53,131.72,130.24,129.71,129.68,129.37,129.01,128.98,126.58,125.32,124.20,124.17,123.75,123.72,123.32,121.22,110.18,105.97,102.32.HRMS(m/z):cacld for C29H14Cl2F6O9S2[M-H]-752.92877,found 752.92651.GL17 yield 77%; mp: 181.8-183.1; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.91 (s, 1H), 8.24 (dd, J = 8.3, 0.9 Hz, 1H), 8.06 (dd, J = 8.3, 0.9 Hz, 1H), 7.93–7.86 (m, 3H), 7.78 (d, J = 1.7 Hz, 1H), 7.73 (ddd, J = 8.3, 1.8, 0.8 Hz, 1H), 7.64–7.58 (m, 2H), 7.57–7.53 (m, 2H), 7.21 (s, 1H), 6.74 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.50,165.80,154.63,153.88,147.08,138.98,137.39,137.21,137.12,136.64,136.37,134.91,134.45,132.82,132.53,1 31.7 2,130.24,129.71,129.68,129.37,129.01,128.98,126.58,125.32,124.20,124.17,123.75,123.72,123.32,121.22,110.18,105.97,102.32. HRMS(m/z): cacld for C 29 H 14 Cl 2 F 6 O 9 S 2 [MH] - 752.92877, found 752.92651.

GL18收率60％；mp:191.9-191.9；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.22–8.14(m,2H),7.77–7.72(m,2H),7.70–7.64(m,3H),7.61(dd,J＝8.3,6.7Hz,2H),7.46(dd,J＝8.3,2.8Hz,4H),7.38(s,1H),7.24(s,1H),2.44(d,J＝6.3Hz,6H).13C NMR(126MHz,Chloroform-d)δ182.68,165.48,154.93,153.70,147.59,146.15,145.50,133.52,132.61,131.72,130.47,129.81,129.62,129.31,128.67,128.61,126.54,125.49,110.01,105.85,102.19,21.82,21.81.HRMS(m/z):cacld for C29H22O9S2[M-H]-577.06325,found 577.06116.GL18 yield 60%; mp: 191.9-191.9; light yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.22 (s, 1H), 8.22–8.14 (m, 2H), 7.77–7.72 (m, 2H), 7.70–7.64 (m, 3H), 7.61 (dd, J=8.3, 6.7 Hz, 2H), 7.46 (dd, J=8.3, 2.8 Hz, 4H), 7.38 (s, 1H), 7.24 (s, 1H), 2.44 (d, J=6.3 Hz, 6H). 13 C NMR(126MHz,Chloroform-d)δ182.68,165.48,154.93,153.70,147.59,146.15,145.50,133.52,132.61,131.72,130.47,129.81,129.62,129.31,128.67,1 28.61,126.54,125.49,110.01,105.85,102.19,21.82,21.81.HRMS(m/z):cacld for C 29 H 22 O 9 S 2 [MH] - 577.06325,found 577.06116.

GL19收率69％；mp:244.1-244.1；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.28(s,1H),8.21(dd,J＝3.8,1.7Hz,1H),8.19–8.14(m,2H),7.99(dd,J＝4.5,1.9Hz,1H),7.94–7.87(m,2H),7.81(d,J＝8.5Hz,1H),7.76(dt,J＝8.6,1.6Hz,1H),7.69–7.64(m,1H),7.63–7.58(m,2H),7.35(d,J＝3.0Hz,1H),7.24(d,J＝4.5Hz,1H).13C NMR(126MHz,DMSO-d6)δ183.05,165.62,154.51,154.10,146.35,135.59,134.95,134.09,133.71,133.49,133.28,132.80,132.08,131.99,131.48,130.92,130.44,129.85,129.66,127.44,125.08,110.44,106.18,102.86.HRMS(m/z):cacld for C27H14Br2Cl2O9S2[M-H]-774.77298,found774.77075.GL19 yield 69%; mp: 244.1-244.1; light yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.28 (s, 1H), 8.21 (dd, J = 3.8, 1.7 Hz, 1H), 8.19–8.14 (m, 2H), 7.99 (dd, J = 4.5, 1.9 Hz, 1H), 7.94–7.87 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 (dt, J = 8.6, 1.6 Hz, 1H), 7.69–7.64 (m, 1H), 7.63–7.58 (m, 2H), 7.35 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 4.5 Hz, 1H). 13 C NMR (126MHz, DMSO-d 6 ) δ183.05,165.62,154.51,154.10,146.35,135.59,134.95,134.09,133.71,133.49,133.28,132.80,132.08,131.99,131.48, 130.92,130.44,129.85,129.66,127.44,125.08,110.44,106.18,102.86.HRMS(m/z):cacld for C 27 H 14 Br 2 Cl 2 O 9 S 2 [MH] - 774.77298,found774.77075.

GL20收率66％；mp:199.6-199.6；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.30(s,1H),8.22–8.17(m,2H),8.11(ddd,J＝16.0,6.6,2.4Hz,2H),7.95(ddd,J＝8.8,4.4,2.4Hz,1H),7.87(ddd,J＝8.7,4.3,2.4Hz,1H),7.74(td,J＝8.8,3.0Hz,2H),7.70–7.66(m,1H),7.62(dd,J＝8.3,6.6Hz,2H),7.49(s,1H),7.28(s,1H).13C NMR(126MHz,Chloroform-d)δ182.61,165.79,163.16,162.81,161.08,160.75,154.77,153.95,147.06,133.30,133.27,132.81,131.90,131.70,131.67,131.59,130.28,129.47,129.39(d,J＝2.1Hz),129.26,129.19,126.60,125.14,123.11,122.96,122.72,122.57,117.74,117.56,117.52,117.34,110.32,105.97,102.46.HRMS(m/z):cacld for C27H14Cl2F2O9S2[M-H]-652.93516,found652.93292.GL20 yield 66%; mp: 199.6-199.6; light yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.30 (s, 1H), 8.22–8.17 (m, 2H), 8.11 (ddd, J = 16.0, 6.6, 2.4 Hz, 2H), 7.95 (ddd, J = 8.8, 4.4, 2.4 Hz, 1H), 7.87 (ddd, J = 8.7, 4.3, 2.4 Hz, 1H), 7.74 (td, J = 8.8, 3.0 Hz, 2H), 7.70–7.66 (m, 1H), 7.62 (dd, J = 8.3, 6.6 Hz, 2H), 7.49 (s, 1H), 7.28 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.61,165.79,163.16,162.81,161.08,160.75,154.77,153.95,147.06,133.30,133.27,132.81,131.90,131.70,131.67,1 31.59,130.28, 129.47,129.39(d,J＝2.1Hz),129.26,129.19,126.60,125.14,123.11,122.96,122.72,122.57,117.74,117.56,117.52,117.34,110.32,105.97 ,102.46.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [MH] - 652.93516,found652.93292.

GL21收率72％；mp:215.5-215.6；金黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),8.19–8.15(m,2H),8.10(dd,J＝9.0,5.6Hz,1H),7.99–7.93(m,2H),7.77(dd,J＝8.7,2.6Hz,1H),7.69–7.64(m,1H),7.60(dd,J＝8.3,6.8Hz,2H),7.55(ddd,J＝8.9,7.9,2.6Hz,1H),7.41(ddd,J＝9.0,7.9,2.6Hz,1H),7.33(s,1H),7.25(s,1H).13C NMR(126MHz,DMSO-d6)δ182.48,166.49,165.93,165.03,163.88,153.96,153.50,145.92,134.56,134.47,134.30,134.20,133.57,132.69,130.84,129.87,129.09,128.80,126.86,124.50,120.63,120.42,120.03,119.82,115.76,115.58,115.15,114.97,109.77,105.60,102.03.HRMS(m/z):cacld for C27H14Cl2F2O9S2[M-H]-652.93516,found 652.93292.GL21 yield 72%; mp: 215.5-215.6; golden yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 8.19–8.15 (m, 2H), 8.10 (dd, J = 9.0, 5.6 Hz, 1H), 7.99–7.93 (m, 2H), 7.77 (dd, J = 8.7, 2.6 Hz, 1H), 7.69–7.64 (m, 1H), 7.60 (dd, J = 8.3, 6.8 Hz, 2H), 7.55 (ddd, J = 8.9, 7.9, 2.6 Hz, 1H), 7.41 (ddd, J = 9.0, 7.9, 2.6 Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H). 13 C NMR (126MHz, DMSO-d 6 ) δ182.48,166.49,165.93,165.03,163.88,153.96,153.50,145.92,134.56,134.47,134.30,134.20,133.57,132.69,130.84,12 9.87,129.09,128.80,126.86,124.50,120.63,120.42,120.03,119.82,115.76,115.58,115.15,114.97,109.77,105.60,102.03.HRMS(m/z): cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [MH] - 652.93516, found 652.93292.

GL22收率75％；mp:230.9-231.2；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.31(s,1H),8.53(t,J＝1.2Hz,1H),8.43(d,J＝2.1Hz,1H),8.21–8.16(m,2H),8.10–8.05(m,3H),7.98(dd,J＝8.6,2.1Hz,1H),7.70–7.65(m,1H),7.64–7.58(m,2H),7.45(s,1H),7.29(s,1H).13C NMR(126MHz,DMSO-d6)δ183.00,165.72,154.38,154.35,148.63,148.57,146.18,142.56,141.77,133.95,133.46,133.35,133.26,130.38,129.70,127.44,127.18,126.32,125.73,125.58,125.14,110.78,106.27,103.51.HRMS(m/z):cacld for C27H14Cl2N2O13S2[M-H]-706.92416,found 706.92218.GL22 yield 75%; mp: 230.9-231.2; light yellow powder; 1 H NMR (500MHz, DMSO-d 6 )δ13.31(s, 1H), 8.53(t, J＝1.2Hz, 1H), 8.43(d, J＝2.1Hz, 1H), 8.21–8.16(m, 2H), 8.10–8.05(m, 3H), 7.98(dd, J＝8.6, 2.1Hz, 1H), 7.70–7.65(m, 1H), 7.64–7.58(m, 2H), 7.45(s, 1H), 7.29(s, 1H). 13 C NMR (126MHz, DMSO-d 6 )δ183.00,165.72,154.38,154.35,148.63,148.57,146.18,142.56,141.77,133.95,133.46,133.35,133.26,130.38,129.70,127.44,127.18,1 26.32,125.73,125.58,125.14,110.78,106.27,103.51.HRMS(m/z): cacld for C 27 H 14 Cl 2 N 2 O 13 S 2 [MH] - 706.92416,found 706.92218.

GL23收率64％；mp:198.3-198.4；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.07(s,1H),8.06–7.94(m,4H),7.93–7.88(m,2H),7.65–7.59(m,1H),7.59–7.53(m,2H),7.40–7.33(m,4H),7.25(s,1H),6.77(s,1H).13C NMR(126MHz,Chloroform-d)δ182.63,165.71,154.82,153.88,153.48,147.26,134.56,132.94,132.76,131.10,130.85,130.32,129.36,126.57,125.23,121.24,121.18,120.77,120.66,119.17,119.11,110.23,105.93,102.42.HRMS(m/z):cacld for C29H16F6O9S2[M-H]-685.00672,found 685.00421.GL23 yield 64%; mp: 198.3-198.4; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 13.07 (s, 1H), 8.06–7.94 (m, 4H), 7.93–7.88 (m, 2H), 7.65–7.59 (m, 1H), 7.59–7.53 (m, 2H), 7.40–7.33 (m, 4H), 7.25 (s, 1H), 6.77 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.63,165.71,154.82,153.88,153.48,147.26,134.56,132.94,132.76,131.10,130.85,130.32,129.36,126.57,125.23,1 21.24,121.18,120.77,120.66,119.17,119.11,110.23,105.93,102.42.HRMS(m/z): cacld for C 29 H 16 F 6 O 9 S 2 [MH] - 685.00672, found 685.00421.

GL24收率63％；mp:213.7-213.7；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.27(s,1H),8.20–8.14(m,2H),8.06(dd,J＝9.9,1.8Hz,1H),7.95(dd,J＝9.8,1.8Hz,1H),7.77(dd,J＝8.5,7.1Hz,1H),7.74–7.69(m,2H),7.69–7.64(m,2H),7.60(dd,J＝8.3,6.7Hz,2H),7.45(s,1H),7.25(s,1H).13C NMR(126MHz,DMSO-d6)δ183.04,165.65,160.10,159.93,158.01,157.84,154.35,154.13,146.28,133.29,132.53,132.12,132.04,131.97,131.13,131.05,130.43,129.67,129.46,129.02,127.42,124.88,123.75,123.64,122.32,122.13,121.97,121.86,121.84,121.65,110.53,106.22,103.35.HRMS(m/z):cacld forC27H14Br2F2O9S2[M-H]-742.83208,found 742.82941.GL24 yield 63%; mp: 213.7-213.7; light yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.27 (s, 1H), 8.20–8.14 (m, 2H), 8.06 (dd, J = 9.9, 1.8 Hz, 1H), 7.95 (dd, J = 9.8, 1.8 Hz, 1H), 7.77 (dd, J = 8.5, 7.1 Hz, 1H), 7.74–7.69 (m, 2H), 7.69–7.64 (m, 2H), 7.60 (dd, J = 8.3, 6.7 Hz, 2H), 7.45 (s, 1H), 7.25 (s, 1H). 13 C NMR (126 MHz, DMSO-d 6 )δ183.04,165.65,160.10,159.93,158.01,157.84,154.35,154.13,146.28,133.29,132.53,132.12,132.04,131.97,131.13,131.05,130.43,1 29.67,129.46,129.02,127.42,124.88,123.75,123.64,122.32,122.13,121.97,121.86,121.84,121.65,110.53,106.22,103.35.HRMS(m/z): cacld forC 27 H 14 Br 2 F 2 O 9 S 2 [MH] - 742.83208, found 742.82941.

GL25收率70％；mp:170.1-170.3；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.06(s,1H),8.22(dt,J＝10.5,1.8Hz,2H),8.17(dt,J＝7.9,1.4Hz,1H),8.11(dt,J＝8.2,1.4Hz,1H),7.97(td,J＝8.3,7.7,1.4Hz,2H),7.93–7.89(m,2H),7.72(t,J＝7.9Hz,2H),7.65–7.60(m,1H),7.59–7.54(m,2H),7.28(s,1H),6.77(s,1H).13C NMR(126MHz,Chloroform-d)δ182.60,165.79,154.77,153.95,147.07,137.61,136.07,132.80,132.27,132.00,131.97,131.92,131.70,131.66,131.63,131.05,131.03,130.29,130.17,129.89,129.38,126.60,126.02,125.99,125.73,125.70,125.15,124.07,123.94,121.90,121.77,110.33,105.97,102.50.HRMS(m/z):cacld for C29H16F6O9S2[M-H]-685.00672,found685.00421.GL25 yield 70%; mp: 170.1-170.3; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ13.06 (s, 1H), 8.22 (dt, J = 10.5, 1.8 Hz, 2H), 8.17 (dt, J = 7.9, 1.4 Hz, 1H), 8.11 (dt, J = 8.2, 1.4 Hz, 1H), 7.97 (td, J = 8.3, 7.7, 1.4 Hz, 2H), 7.93-7.89 (m, 2H), 7.72 (t, J = 7.9 Hz, 2H), 7.65-7.60 (m, 1H), 7.59-7.54 (m, 2H), 7.28 (s, 1H), 6.77 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.60,165.79,154.77,153.95,147.07,137.61,136.07,132.80,132.27,132.00,131.97,131.92,131.70,131.66,131.63,1 31.05,13 1.03,130.29,130.17,129.89,129.38,126.60,126.02,125.99,125.73,125.70,125.15,124.07,123.94,121.90,121.77,110.33,105.97,102. 50.HRMS(m/z): cacld for C 29 H 16 F 6 O 9 S 2 [MH] - 685.00672,found685.00421.

GL26收率71％；mp:186.8-187.1；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.11(s,1H),8.14(t,J＝1.8Hz,1H),8.03(t,J＝1.9Hz,1H),7.94(td,J＝7.0,1.6Hz,3H),7.85(dddd,J＝7.5,4.3,1.9,1.0Hz,2H),7.78(ddd,J＝7.9,1.8,1.0Hz,1H),7.67–7.61(m,1H),7.61–7.55(m,2H),7.48(t,J＝8.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.28(d,J＝7.5Hz,1H),6.79(s,1H).13CNMR(126MHz,Chloroform-d)δ182.62,165.70,154.92,153.88,147.04,138.10,138.08,137.48,136.44,132.74,131.47,131.33,130.67,130.55,130.35,129.35,127.14,127.07,126.59,125.22,123.20,122.92,110.30,105.96,102.49.HRMS(m/z):cacld for C27H16Br2O9S2[M-H]-706.85093,found 706.84937.GL26 yield 71%; mp: 186.8-187.1; light yellow powder; 1 H NMR(500MHz,Chloroform-d)δ13.11(s,1H),8.14(t,J＝1.8Hz,1H),8.03(t,J＝1.9Hz,1H),7.94(td,J＝7.0,1.6Hz,3H),7.85(dddd,J＝7.5,4.3,1.9,1.0Hz,2H),7.78(ddd,J＝7.9,1.8,1.0Hz,1H),7.67–7.61(m,1H),7.61–7.55(m,2H),7.48(t,J＝8.0Hz,1H),7.43(t,J＝8.0Hz,1H),7.28(d,J＝7.5Hz,1H),6.79(s,1H). 13 CNMR(126MHz,Chloroform-d)δ182.62,165.70,154.92,153.88,147.04,138.10,138.08,137.48,136.44,132.74,131.47,131.33,130.67,130.55,130.35, 129.35,127.14,127.07,126.59,125.22,123.20,122.92,110.30,105.96,102.49.HRMS(m/z): cacld for C 27 H 16 Br 2 O 9 S 2 [MH] - 706.85093, found 706.84937.

GL27收率74％；mp:170.5-170.6；橙黄色粉末；1H NMR(500MHz,Chloroform-d)δ13.14(s,1H),7.94–7.90(m,2H),7.65–7.60(m,1H),7.57(dd,J＝8.3,6.6Hz,2H),7.53(ddd,J＝5.2,2.3,1.0Hz,2H),7.48(ddd,J＝4.9,2.3,1.1Hz,2H),7.25(s,1H),7.18(dddd,J＝8.3,6.0,4.7,2.4Hz,2H),6.78(s,1H).13C NMR(126MHz,Chloroform-d)δ182.58,165.84,163.74,163.64,163.55,161.70,161.61,161.52,154.83,153.99,146.84,139.33,139.26,139.19,137.72,137.65,137.58,132.83,130.26,129.38,126.61,124.96,112.61,112.55,112.44,112.37,112.30,112.19,112.13,111.04,110.85,110.65,110.40,110.22,110.02,106.01,102.43.HRMS(m/z):cacld for C27H14F4O9S2[M-H]-620.99426,found620.99109.GL27 yield 74%; mp: 170.5-170.6; orange-yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 13.14 (s, 1H), 7.94–7.90 (m, 2H), 7.65–7.60 (m, 1H), 7.57 (dd, J = 8.3, 6.6 Hz, 2H), 7.53 (ddd, J = 5.2, 2.3, 1.0 Hz, 2H), 7.48 (ddd, J = 4.9, 2.3, 1.1 Hz, 2H), 7.25 (s, 1H), 7.18 (dddd, J = 8.3, 6.0, 4.7, 2.4 Hz, 2H), 6.78 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.58,165.84,163.74,163.64,163.55,161.70,161.61,161.52,154.83,153.99,146.84,139.33,139.26,139.19,137.72,1 37.65,137.58,132.8 3,130.26,129.38,126.61,124.96,112.61,112.55,112.44,112.37,112.30,112.19,112.13,111.04,110.85,110.65,110.40,110.22,110.02, 106.01,102.43.HRMS(m/z):cacld for C 27 H 14 F 4 O 9 S 2 [MH] - 620.99426,found620.99109.

GL28收率67％；mp:174.0-174.0；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.96(s,1H),7.96–7.88(m,3H),7.83(ddd,J＝9.5,7.7,5.9Hz,1H),7.63–7.59(m,1H),7.56(dd,J＝8.4,6.6Hz,2H),7.24(s,1H),7.05(tdd,J＝10.4,5.1,2.6Hz,2H),6.99(ddt,J＝10.7,7.8,2.6Hz,2H),6.74(s,1H).13C NMR(126MHz,Chloroform-d)δ182.59,168.51,168.42,167.99,167.91,166.43,166.34,165.93,165.84,165.71,162.00,161.92,161.89,161.81,159.89,159.82,159.79,159.72,154.68,153.84,147.09,133.22,133.13,132.76,132.64,132.56,130.29,129.35,126.56,125.32,121.67,121.64,121.56,121.53,119.85,119.81,119.74,119.71,112.52,112.49,112.34,112.31,111.93,111.91,111.76,111.73,110.19,106.69,106.49,106.48,106.29,106.18,105.98,105.91,105.78,102.54.HRMS(m/z):cacld for C27H14F4O9S2[M-H]-620.99426,found 620.99146.GL29收率77％；mp:199.7-199.8；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.27(s,1H),8.18–8.14(m,3H),8.08(ddd,J＝8.3,6.7,1.7Hz,1H),7.78(ddt,J＝8.1,6.1,2.0Hz,2H),7.69–7.64(m,1H),7.61(dd,J＝8.3,6.7Hz,2H),7.52–7.42(m,3H),7.25(s,1H).13C NMR(126MHz,DMSO-d6)δ177.73,160.77,150.23,148.94,142.41,132.56,131.25,130.81,130.66,129.94,127.47,126.59,125.53,124.51,123.07,122.55,121.75,120.64,116.64,116.41,105.10,101.11,96.64.HRMS(m/z):cacld for C27H14Cl2F2O9S2[M-H]-652.93516,found 652.93280.GL28 yield 67%; mp: 174.0-174.0; light yellow powder; 1 H NMR (500 MHz, Chloroform-d) δ 12.96 (s, 1H), 7.96–7.88 (m, 3H), 7.83 (ddd, J = 9.5, 7.7, 5.9 Hz, 1H), 7.63–7.59 (m, 1H), 7.56 (dd, J = 8.4, 6.6 Hz, 2H), 7.24 (s, 1H), 7.05 (tdd, J = 10.4, 5.1, 2.6 Hz, 2H), 6.99 (ddt, J = 10.7, 7.8, 2.6 Hz, 2H), 6.74 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.59,168.51,168.42,167.99,167.91,166.43,166.34,165.93,165.84,165.71,162.00,161.92,161.89,161.81,159.89,1 59.82,159.79,159.72,154.68,153.84,147.09,133.22,133.13,132.76,132.64,132.56,130.29,12 9.35,126.56,125.32,121.67,121.64,121.56,121.53,119.85,119.81,119.74,119.71,112.52,112.49,112.34,112.31,111.93,111.91,111. 76,111.73,110.19,106.69,106.49,106.48,106.29,106.18,105.98,105.91,105.78,102.54.HRMS(m/z):cacld for C 27 H 14 F 4 O 9 S 2 [MH] - 620.99426, found 620.99146.GL29 yield 77%; mp: 199.7-199.8; light yellow powder; 1 H NMR (500MHz, DMSO-d 6 )δ13.27(s,1H),8.18–8.14(m,3H),8.08(ddd,J＝8.3,6.7,1.7Hz,1H),7.78(ddt,J＝8.1,6.1,2.0Hz,2H),7.69–7.64(m,1H),7.61(dd,J＝8.3,6.7Hz,2H),7.52–7.42(m,3H),7.25(s,1H). 13 C NMR (126MHz, DMSO-d 6 ) δ177.73,160.77,150.23,148.94,142.41,132.56,131.25,130.81,130.66,129.94,127.47,126.59,125.53,124.51,123.07, 122.55,121.75,120.64,116.64,116.41,105.10,101.11,96.64.HRMS(m/z):cacld for C 27 H 14 Cl 2 F 2 O 9 S 2 [MH] - 652.93516,found 652.93280.

GL30收率57％；mp:183.9-184.3；淡黄色粉末；1H NMR(500MHz,Chloroform-d)δ12.89(s,1H),8.14–8.09(m,1H),7.99–7.95(m,1H),7.90–7.86(m,2H),7.84–7.80(m,1H),7.70–7.65(m,1H),7.62–7.58(m,1H),7.57–7.49(m,4H),7.44–7.34(m,2H),7.19(s,1H),6.72(s,1H).13C NMR(126MHz,Chloroform-d)δ182.54,165.50,154.98,153.74,147.32,137.47,136.02,135.61,135.46,135.42,134.62,132.63,132.27,131.41,130.39,129.30,127.77,127.27,126.53,125.44,121.53,121.29,109.88,105.91,101.53.HRMS(m/z):cacld for C27H16Br2O9S2[M-H]-706.85093,found 706.84827.GL30 yield 57%; mp: 183.9-184.3; light yellow powder; 1 H NMR (500MHz, Chloroform-d) δ12.89 (s, 1H), 8.14–8.09 (m, 1H), 7.99–7.95 (m, 1H), 7.90–7.86 (m, 2H), 7.84–7.80 (m, 1H), 7.70–7.65 (m, 1H), 7.62–7.58 (m, 1H), 7.57–7.49 (m, 4H), 7.44–7.34 (m, 2H), 7.19 (s, 1H), 6.72 (s, 1H). 13 C NMR(126MHz,Chloroform-d)δ182.54,165.50,154.98,153.74,147.32,137.47,136.02,135.61,135.46,135.42,134.62,132.63,132.27,131.41,130.39,1 29.30,127.77,127.27,126.53,125.44,121.53,121.29,109.88,105.91,101.53.HRMS(m/z):cacld for C 27 H 16 Br 2 O 9 S 2 [MH] - 706.85093,found 706.84827.

GL31收率59％；mp:168.5-168.9；淡黄色粉末；1H NMR(500MHz,DMSO-d6)δ13.48(s,1H),8.22–8.17(m,2H),7.70–7.64(m,1H),7.61(dd,J＝8.3,6.7Hz,2H),7.52(s,1H),7.26(s,1H),3.74(dq,J＝25.0,7.3Hz,4H),1.47(dt,J＝8.5,7.3Hz,6H).13C NMR(126MHz,Chloroform-d)δ182.84,165.69,154.14,153.74,147.67,132.69,130.37,129.33,126.57,125.49,109.89,105.78,102.11,48.33,47.63,8.39,8.12.HRMS(m/z):cacld forC19H18O9S2[M-H]-453.03195,found 453.03012.GL31 yield 59%; mp: 168.5-168.9; light yellow powder; 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.48 (s, 1H), 8.22–8.17 (m, 2H), 7.70–7.64 (m, 1H), 7.61 (dd, J=8.3, 6.7 Hz, 2H), 7.52 (s, 1H), 7.26 (s, 1H), 3.74 (dq, J=25.0, 7.3 Hz, 4H), 1.47 (dt, J=8.5, 7.3 Hz, 6H). 13 C NMR(126MHz,Chloroform-d)δ182.84,165.69,154.14,153.74,147.67,132.69,130.37,129.33,126.57,125.49,109.89,105.78,102.11,48.33,47.63,8.3 9,8.12.HRMS(m/z): cacld forC 19 H 18 O 9 S 2 [MH] - 453.03195, found 453.03012.

药理实验Pharmacological experiments

实验材料Experimental Materials

生物活性测定实验中使用的仪器有:Perkin Elmer多功能酶标仪；ZW-A型微振荡器；-20℃青岛海尔冰箱(型号:BC/BD-429HEM)；Thermo Fisher移液枪(规格:2-2μl、1-10μl、10-100μl、100-1000μl)；WHB 96孔全黑细胞培养板；神经氨酸酶抑制剂筛选试剂盒(上海碧云天生物科技有限公司P0309)，包括神经氨酸酶检测缓冲液10ml，神经氨酸酶1ml，神经氨酸酶荧光底物1ml，纯化水1.2ml；新型冠状病毒Mpro/3CLpro抑制剂筛选试剂盒(增强型)(上海碧云天生物科技有限公司P0315S)，包括Assay Buffer 30ml,2019-nCoV Mpro/3CLpro100μl，底物200μl,Ebselen(10mM)20μl。The instruments used in the biological activity assay experiment are: Perkin Elmer multifunctional microplate reader; ZW-A micro-oscillator; -20℃ Qingdao Haier refrigerator (model: BC/BD-429HEM); Thermo Fisher pipette (specifications: 2-2μl, 1-10μl, 10-100μl, 100-1000μl); WHB 96-well all-black cell culture plate; neuraminidase inhibitor screening kit (Shanghai Biyuntian Biotechnology Co., Ltd. P0309), including neuraminidase detection buffer 10ml, neuraminidase 1ml, neuraminidase fluorescent substrate 1ml, purified water 1.2ml; Novel coronavirus Mpro/3CLpro inhibitor screening kit (enhanced) (Shanghai Biyuntian Biotechnology Co., Ltd. P0315S), including Assay Buffer 30ml, 2019-nCoV Mpro/3CLpro 100μl, substrate 200μl, Ebselen (10mM) 20μl.

实验方法Experimental methods

1.神经氨酸酶潜在抑制剂的筛选1. Screening of potential neuraminidase inhibitors

a.样品的准备：a. Sample preparation:

以2％DMSO为溶剂，将待测样品分别制备为10μM、20μM、30μM和40μM。放入4℃冰箱保存备用。Using 2% DMSO as solvent, the samples to be tested were prepared at 10 μM, 20 μM, 30 μM and 40 μM, respectively, and stored in a 4°C refrigerator for later use.

b.样品的测定：b. Sample determination:

根据神经氨酸酶试剂盒的操作说明，分步进行：在每个样品孔加入70μl缓冲液，随后加入神经氨酸酶、待测样品和超纯水的总积为20μl，使得每孔总积为90μl。摇匀搅拌约1分钟。37℃孵育2分钟，使化合物与神经氨酸酶充分相互作用。每个样品孔加入10μl神经氨酸氨酸酶荧光底物。摇匀搅拌约1分钟。37℃孵育30min后，进行荧光测定。激发波长为322nm，发射波长为450nm。检测系统设置如表2所示。According to the operating instructions of the neuraminidase kit, proceed step by step: add 70μl of buffer to each sample well, then add neuraminidase, the sample to be tested and ultrapure water with a total volume of 20μl, so that the total volume of each well is 90μl. Shake and stir for about 1 minute. Incubate at 37℃ for 2 minutes to allow the compound to fully interact with neuraminidase. Add 10μl of neuraminidase fluorescent substrate to each sample well. Shake and stir for about 1 minute. After incubation at 37℃ for 30min, perform fluorescence measurement. The excitation wavelength is 322nm and the emission wavelength is 450nm. The detection system settings are shown in Table 2.

表2神经氨酸酶抑制剂检测系统Table 2 Neuraminidase inhibitor detection system

Figure GDA0004160328140000221
Figure GDA0004160328140000221

每个样品的抑制率可以计算如下:The inhibition rate for each sample can be calculated as follows:

抑制率(100％)＝[1-(RFU样品组-RFU空白组)/(RFU酶值组-RFU空白组)]×100％Inhibition rate (100%) = [1-(RFU sample group -RFU blank group )/(RFU enzyme value group -RFU blank group )] × 100%

2.新型冠状病毒Mpro蛋白酶潜在抑制剂的筛选2. Screening of potential inhibitors of 2019-nCoV M protease

a.样品的准备:a. Sample preparation:

以2％DMSO为溶剂，将待测样品分别制备为10μM、20μM、30μM和40μM。放入4℃冰箱冷藏保存，留存备用。Using 2% DMSO as solvent, the samples to be tested were prepared at 10 μM, 20 μM, 30 μM and 40 μM, respectively, and stored in a 4°C refrigerator for later use.

b.阳性对照的准备:b. Preparation of positive control:

将试剂盒中提供的阳性对照抑制剂Ebselen按10mM(提供初始浓度)的浓度稀释至10μM、20μM、30μM和40μM。The positive control inhibitor Ebselen provided in the kit was diluted at a concentration of 10 mM (provided initial concentration) to 10 μM, 20 μM, 30 μM and 40 μM.

c.样品的测定:c. Sample determination:

按照新型冠状病毒Mpro蛋白酶抑制剂筛选试剂盒说明书的操作步骤:参照表S-2，配制适量的检测试剂。检测系统设置如表3所示。According to the operating steps of the novel coronavirus M protease inhibitor screening kit instructions: refer to Table S-2 to prepare an appropriate amount of detection reagent. The detection system settings are shown in Table 3.

表3检测试剂的制备方法Table 3 Preparation method of detection reagents

Figure GDA0004160328140000222
Figure GDA0004160328140000222

在96孔板中，空白对照孔加93μl缓冲溶剂，除空白对照孔外的其余每孔加93μl检测试剂。阳性对照药Ebselen、样品溶剂和待测样品按操作要求分别滴加5μl。摇匀搅拌1分钟。然后快速在每孔中加入2μl底物。再摇匀约1分钟。37℃黑暗孵育5min，使被测化合物与Mpro蛋白酶充分相互作用，随后进行荧光测定。激发波长为325nm，发射波长为393nm。检测系统设置如表4所示。In a 96-well plate, add 93 μl of buffer solvent to the blank control well, and add 93 μl of detection reagent to each well except the blank control well. Add 5 μl of positive control drug Ebselen, sample solvent and sample to be tested according to the operating requirements. Shake and stir for 1 minute. Then quickly add 2 μl of substrate to each well. Shake and stir for about 1 minute. Incubate in the dark at 37°C for 5 minutes to allow the test compound to fully interact with the M protease, and then perform fluorescence measurement. The excitation wavelength is 325 nm and the emission wavelength is 393 nm. The detection system settings are shown in Table 4.

表4新型冠状病毒Mpro蛋白酶抑制剂检测系统Table 4 Detection system of novel coronavirus M protease inhibitor

Figure GDA0004160328140000223
Figure GDA0004160328140000223

每个样品的抑制率可以计算如下:The inhibition rate for each sample can be calculated as follows:

抑制率(100％)＝(RFU100％酶活对照-RFU样品组)/(RFU100％酶活对照-RFU空白对照)×100％Inhibition rate (100%) = (RFU 100% enzyme activity control - RFU sample group ) / (RFU 100% enzyme activity control - RFU blank control ) × 100%

实验结果Experimental Results

通过上述药理实验操作，分别对神经氨酸酶NA和新型冠状病毒主蛋白酶Mpro进行活性测定，得到实验结果。并计算IC50值，其中大多数化合物显示出较好的酶抑制活性。实验结果汇总如表5所示。Through the above pharmacological experimental operation, the activity of neuraminidase NA and the main protease M protease of the new coronavirus was measured respectively to obtain the experimental results. The IC 50 value was calculated, and most of the compounds showed good enzyme inhibitory activity. The experimental results are summarized in Table 5.

表5酶活性测定结果Table 5 Enzyme activity determination results

Figure GDA0004160328140000231
Figure GDA0004160328140000231

由表5可知，在关于NA抑制剂的筛选过程中，化合物GL03、GL08、GL09、GL15、GL25、GL31的IC50值均低于黄芩素，即这些化合物均有一定抑制作用，其中GL31(IC50＝25.53μM)的抑制作用最佳，具有成为神经氨酸酶抑制剂的潜力。As shown in Table 5, in the screening process of NA inhibitors, the IC 50 values of compounds GL03, GL08, GL09, GL15, GL25, and GL31 were all lower than that of baicalein, that is, these compounds all had certain inhibitory effects, among which GL31 (IC 50 = 25.53 μM) had the best inhibitory effect and had the potential to become a neuraminidase inhibitor.

对比Mpro抑制剂的筛选结果可以发现，化合物GL08、GL10、GL23、GL29的IC50值均低于黄芩素，且化合物GL10的IC50值最低(IC50＝28.35μM)。即，化合物GL10具有最好的抑制新冠病毒Mpro蛋白酶的作用，有望成为新冠病毒Mpro蛋白酶的潜在抑制剂。Comparing the screening results of M pro inhibitors, it can be found that the IC 50 values of compounds GL08, GL10, GL23, and GL29 are all lower than that of baicalin, and the IC 50 value of compound GL10 is the lowest (IC 50 = 28.35 μM). That is, compound GL10 has the best inhibitory effect on the M protease of the new coronavirus and is expected to become a potential inhibitor of the M protease of the new coronavirus.

Claims (10)

1.一种黄芩素类衍生物，其特征在于，具有为以下通式的化合物：1. A baicalein derivative, characterized in that, has the compound of the following general formula:
Figure FDA0004160328120000011
Figure FDA0004160328120000011
 通式中，R分别为：In the general formula, R are respectively:
Figure FDA0004160328120000012
Figure FDA0004160328120000012
Figure FDA0004160328120000021
Figure FDA0004160328120000021
 2.根据权利要求1所述的黄芩素类衍生物，其特征在于，所述的黄芩素类衍生物为以下结构式的化合物：2. baicalein derivatives according to claim 1, characterized in that, described baicalein derivatives are compounds of the following structural formula:
Figure FDA0004160328120000022
Figure FDA0004160328120000022
Figure FDA0004160328120000031
Figure FDA0004160328120000031
Figure FDA0004160328120000041
Figure FDA0004160328120000041
Figure FDA0004160328120000051
Figure FDA0004160328120000051
Figure FDA0004160328120000061
Figure FDA0004160328120000061
Figure FDA0004160328120000071
Figure FDA0004160328120000071
 3.根据权利要求1所述的黄芩素类衍生物的制备方法，其特征在于，以黄芩素为原料，经亲电取代反应使得C6-OH、C7-OH的两个羟基被磺酰氧取代，反应的方程式如下：3. the preparation method of baicalein derivatives according to claim 1 is characterized in that, with baicalein as raw material, two hydroxyl groups of C6-OH, C7-OH are substituted by sulfonyl oxygen through electrophilic substitution reaction , the reaction equation is as follows:
Figure FDA0004160328120000072
Figure FDA0004160328120000072
 4.根据权利要求3所述的黄芩素类衍生物的制备方法，其特征在于，所述的亲电取代反应的反应溶剂为干燥脱水后的无水丙酮。4. The preparation method of baicalein derivatives according to claim 3, characterized in that, the reaction solvent of the electrophilic substitution reaction is anhydrous acetone after drying and dehydration. 5.根据权利要求3所述的黄芩素类衍生物的制备方法，其特征在于，所述的亲电取代反应的条件是反应过程是在冰浴条件下反应1小时后，反应液加入冰水淬灭反应，而后过滤。5. the preparation method of baicalein derivatives according to claim 3 is characterized in that, the condition of described electrophilic substitution reaction is that reaction process is after reacting 1 hour under ice-bath condition, and reaction solution adds ice water The reaction was quenched, then filtered. 6.根据权利要求1或2所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂中的应用。6. The application of the baicalein derivatives according to claim 1 or 2 in the preparation of influenza virus neuraminidase NA inhibitors. 7.根据权利要求6所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂中的应用，其特征在于，所述化合物为：GL09、GL15、GL25、GL31。7. The application of the baicalein derivatives according to claim 6 in the preparation of influenza virus neuraminidase NA inhibitors, characterized in that the compounds are: GL09, GL15, GL25, GL31. 8.根据权利要求1或2所述的黄芩素类衍生物在制备新型冠状病毒主蛋白酶Mpro抑制剂中的应用。8. the application of baicalein derivatives according to claim 1 and 2 in the preparation of novel coronavirus main protease M pro inhibitor. 9.根据权利要求8所述的黄芩素类衍生物在制备新型冠状病毒主蛋白酶Mpro抑制剂中的的应用，其特征在于，所述化合物为：GL08、GL10、GL29。9. The application of the baicalein derivatives according to claim 8 in the preparation of the novel coronavirus main protease M pro inhibitor, characterized in that the compounds are: GL08, GL10, GL29. 10.根据权利要求1所述的黄芩素类衍生物在制备流感病毒神经氨酸酶NA抑制剂及制备新型冠状病毒主蛋白酶Mpro抑制剂的应用。10. the application of baicalein derivatives according to claim 1 in the preparation of influenza virus neuraminidase NA inhibitor and the preparation of novel coronavirus main protease M pro inhibitor.
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CN105566306A (en) * 2014-10-14 2016-05-11 四川农业大学 Preparation of flavone derivative and application to neuraminidase inhibition
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