Sulfonylated amino acid spliced isoflavone derivative and application thereof in preparation of antitumor drugs

Abstract

The invention discloses an isoflavone derivative spliced by sulfonylated amino acids and application of the isoflavone derivative in preparation of anti-tumor drugs. The isoflavone derivative has obvious anti-tumor activity on human cervical cancer cells, human breast cancer cells, human non-small cell lung cancer cells and human triple negative breast cancer cells. The compound is relatively high in safety and suitable for preparing water-soluble prodrugs. The product synthesis is mild and simple, and is suitable for process amplification.

Description

Technical Field

[0001] The present invention relates to an anti-tumor compound, and specifically relates to a class of compounds that can inhibit human cervical cancer cells, human breast cancer cells, human non-small cell lung cancer cells, and human triple-negative breast cancer cells, as well as their uses. Background Art

[0002] Cancer is a major disease threatening human health and is the second leading cause of death in developing countries after cardiovascular diseases. Therefore, the research and development of anti-tumor drugs has become a hot field in global drug research and development. It is statistically shown that 40% of the R & D expenses of the pharmaceutical industry are invested in anti-tumor drugs. Among the cancer incidences in China, lung cancer has the highest incidence, while the incidences of breast cancer and cervical cancer rank among the top two in female malignant tumors.

[0003] Currently, the main marketed drugs for treating lung cancer include erlotinib, gefitinib, and osimertinib targeting EGFR, and lorlatinib targeting ALK, etc. The main marketed drugs for treating breast cancer include trastuzumab, pertuzumab, and lapatinib targeting HER2, PARP inhibitors such as olaparib and talazoparib, and tamoxifen targeting hormone receptor ER and endocrine therapy, etc. The main marketed drugs for treating cervical cancer include bevacizumab targeting VEGF, pembrolizumab targeting PD-1, and entrectinib targeting NTRK gene fusion, etc. However, in the past three decades, new targeted drugs and treatment methods have emerged in an endless stream internationally, and the treatment costs have been rising steadily, but there has not been much improvement in cancer treatment. For example, the overall five-year survival rate of lung cancer patients is about 15%, with only a slight increase. On the other hand, the toxic and side effects of anti-tumor drugs are relatively large. Therefore, designing and synthesizing anti-tumor drugs with advantages such as high bioavailability, obvious anti-cancer activity, and low toxicity is still a hot topic in current research.

[0004] Isoflavones and amino acids are both natural compounds existing in nature, with small toxic and side effects, and are suitable for developing new low-toxic anti-tumor drugs. Research shows that natural isoflavones such as calycosin and daidzein have good preventive and therapeutic effects on various tumors such as breast cancer, prostate cancer, lung cancer, and rectal cancer. However, there is no literature report on the application of isoflavone derivatives spliced with sulfonylated amino acids in the preparation of anti-tumor drugs. Summary of the Invention

[0005] The object of the present invention is to provide a novel isoflavone derivative spliced with sulfonylated amino acids and its use. This isoflavone derivative has a certain inhibitory effect on human cervical cancer cells, human non-small cell lung cancer cells, and human breast cancer cells. Isoflavones and amino acids are both natural compounds existing in nature, with small toxic and side effects, and the synthesis method is simple, which is suitable for industrial production.

[0006] The technical solution of the present invention includes:

[0007] A sulfonylated amino acid spliced isoflavone derivative, which is a compound having the structure shown in general formula I, its optical isomer, solvate or pharmaceutically acceptable salt thereof;

[0008]

[0009] In formula I, R1 is single or multiple H, alkyl, alkoxy, nitro, trifluoromethyl or halogen;

[0010] R2 is phenyl or C1-C4 alkyl.

[0011] In the present invention, through the structural modification and optimization of natural isoflavones with anti-tumor activity, a new type of sulfonylated amino acid spliced isoflavone derivative is obtained. The results show that it has obvious activity in inhibiting the proliferation of tumor cells against human cervical cancer Hela cells, human breast cancer MCF-7 cells, non-small cell lung cancer H460 cells and human triple-negative breast cancer MDA-MB231 cells, and can be applied to the preparation of related anti-tumor drugs.

[0012] The R1 is single or multiple H, C1-C5 alkyl, C1-C5 alkoxy, nitro, trifluoromethyl, fluorine or chlorine;

[0013] R2 is phenyl or isobutyl.

[0014] Preferably, the R1 is single or multiple H, methyl, methoxy, nitro, trifluoromethyl, fluorine or chlorine.

[0015] Preferably, the sulfonylated amino acid spliced isoflavone derivative is the following compound, its optical isomer, solvate or pharmaceutically acceptable salt thereof;

[0016]

[0017] The sulfonylated amino acid spliced isoflavone derivative of general formula I is obtained by two-step reactions of condensation and hydrolysis of sulfonylated D-(-)-α-phenylglycine or D-leucine with 3-(4-aminophenyl)-7-(methoxymethoxy)-4H-chromen-4-one. The synthetic route is as follows:

[0018]

[0019] The present invention also provides an application of the sulfonylated amino acid spliced isoflavone derivative in the preparation of anti-tumor drugs, and the active ingredient of the anti-tumor drug is the sulfonylated amino acid spliced isoflavone derivative alone or in combination of multiple compounds.

[0020] Preferably, the anti-tumor drug is used for the treatment of cervical cancer, non-small cell lung cancer or breast cancer.

[0021] Preferably, the anti-tumor drug is used to inhibit the proliferation or migration of tumor cells, and the tumor cells are any one of human cervical cancer cells, human breast cancer cells, human non-small cell lung cancer cells, and human triple-negative breast cancer cells.

[0022] In the present invention, in the anti-tumor drug, the active ingredient is a mixture of a single or multiple compounds of isoflavone derivatives spliced with sulfonylated amino acids of general formula I.

[0023] The present invention also provides a pharmaceutical composition, which comprises one or more compounds of formula (I) and one or more pharmaceutically acceptable carriers. Preferably, the one or more pharmaceutically acceptable carriers are inert non-toxic carriers, and the inert non-toxic carriers can be selected according to the knowledge already possessed by those skilled in the art, including diluents, binders, disintegrants, lubricants, and glidants used in pharmacy, such as starch, gelatin, crospovidone, magnesium stearate, and colloidal silicon dioxide, etc.

[0024] The beneficial effects of the technical solution of the present invention are as follows:

[0025] The target compound is composed of sulfonylated amino acids and isoflavones spliced together, and the toxicity of this natural hybrid molecule is relatively low. At the same time, the target compound of the present invention can be prepared into a prodrug of monosodium phosphate diester by a method similar to tedizolid phosphate, so as to improve its water solubility and bioavailability. The product synthesis is simple and suitable for industrial production. The target compound has obvious anti-tumor activity against human cervical cancer cells, human breast cancer cells, human non-small cell lung cancer cells, and human triple-negative breast cancer cells. Description of the Drawings

[0026] Figure 1 1H NMR spectrum of the best compound T18;

[0027] Figure 2 13C NMR spectrum of the best compound T18;

[0028] Figure 3 High-resolution mass spectrum of the best compound T18. Detailed Embodiments

[0029] The specific embodiments of the present invention are described with reference to the following examples. These examples are used to illustrate the present invention and do not limit the present invention in any way.

[0030] All reagents were purchased from Shanghai Titan Scientific Co., Ltd. The starting materials A1 - A24 were prepared according to the references "European Journal of Medicinal Chemistry" 2017, 135: 349 - 369 and "Journal of Medicinal Chemistry" 1989, 32(1): 145 - 151. The starting material B was prepared according to the reference "ACS Chemical Neuroscience" 2015, 6(4): 542 - 550.

[0031] Instruments for compound structure characterization: Agilent 1290Ⅱ + 6545 mass spectrometer; Bruker Avance Neo 600 MHz nuclear magnetic resonance spectrometer (using DMSO as the solvent and TMS as the internal standard).

[0032] Synthesis of intermediates T1M - T24M in Example 1

[0033]

[0034] Weigh sulfonyl amino acid A (1 mmol), 3-(4-aminophenyl)-7-(methoxymethoxy)-4H-chromen-4-one B (1 mmol), EDCI (1.2 mmol), and HOBt (1.2 mmol), stir and dissolve them in dichloromethane (15 mL). At room temperature, add triethylamine (3 mmol) dropwise. After the addition is complete, stir at room temperature for 30 hours. Monitor the reaction by TLC until it is complete (the developing agent is toluene: ethyl acetate 2:1). Wash the reaction solution with water 3 times, dry it with anhydrous sodium sulfate, filter by suction, concentrate by rotary evaporation, and separate and purify by column chromatography (the eluent is toluene: ethyl acetate 2:1) to obtain the products T1M - T24M.

[0035] T1M:

[0036]

[0037] Yellow solid, yield 71%. 1 H NMR (600 MHz, DMSO-d6) δ 10.36 (brs, 1H), 8.81 (d, J = 9.6 Hz, 1H), 8.43 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.76 - 7.78 (m, 2H), 7.39 - 7.52 (m, 9H), 7.22 - 7.29 (m, 4H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 5.37 (s, 2H), 5.22 (d, J = 9.6 Hz, 1H), 3.42 (s, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 175.0, 168.0, 161.5, 157.5, 154.4, 141.4, 138.4, 137.6, 132.7, 129.7, 129.2, 128.8, 128.3, 127.63, 127.59, 127.5, 127.0, 123.7, 119.5, 118.8, 116.0, 103.6, 94.6, 60.6, 56.5. HRMS, m / z calcd. for C 31 H 27 N2O7S [M+H] + : 571.1533; found: 571.1538.

[0038] T2M:

[0039]

[0040] Pale yellow solid, yield 74%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.29 (brs, 1H), 8.67 (d, J = 9.6 Hz, 1H), 8.42 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.65 - 7.67 (m, 2H), 7.50 - 7.52 (m, 2H), 7.41 - 7.44 (m, 4H), 7.28 - 7.31 (m, 2H), 7.24 - 7.27 (m, 1H), 7.21 - 7.23 (m, 3H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.18 (d, J = 9.6 Hz, 1H), 3.43 (s, 3H), 2.25 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 168.1, 161.5, 157.5, 154.3, 143.0, 138.5, 138.4, 137.7, 129.63, 129.58, 128.8, 128.3, 127.6, 127.5, 127.1, 123.7, 119.5, 118.8, 116.0, 103.6, 94.6, 60.6, 56.5, 21.3. HRMS, m / z calcd. for C 32 H 29 N2O7S [M+H] + : 585.1690; found: 585.1692.

[0041] T3M:

[0042]

[0043] Pale yellow solid, yield 69%. 1 H NMR(600MHz,DMSO-d6)δ10.30(brs,1H),8.57(d,J=9.7Hz,1H),8.42(s,1H),8.07(d,J=8.9Hz,1H),7.68-7.71(m,2H),7.50-7.52(m,2H),7.40-7.45(m,4H),7.22-7.31(m,4H),7.17(dd,J=8.9,2.3Hz,1H),6.91-6.94(m,2H),5.37(s,2H),5.16(d,J=9.7Hz,1H),3.69(s,3H),3.43(s,3H). 13 C NMR(150MHz,DMSO-d6)δ175.0,168.1,162.5,161.5,157.5,154.3,138.5,137.6,133.0,129.6,129.2,128.8,128.3,127.6,127.5,123.7,119.5,118.8,116.0,114.4,103.6,94.6,60.6,56.5,56.0.HRMS,m / z calcd.for C 32 H 29 N2O8S[M+H] + :601.1639;found:601.1643.

[0044] T4M:

[0045]

[0046] Pale yellow solid, yield 77%. 1 H NMR(600MHz,DMSO-d6)δ10.37(brs,1H),8.85(d,J=9.6Hz,1H),8.43(s,1H),8.06(d,J=8.9Hz,1H),7.78-7.81(m,2H),7.45-7.53(m,4H),7.37-7.40(m,2H),7.22-7.29(m,6H),7.17(dd,J=8.9,2.3Hz,1H),5.37(s,2H),5.22(d,J=9.6Hz,1H),3.43(s,3H). 1313C NMR (150 MHz, DMSO-d6) δ 175.0, 167.9, 164.4 (J = 249.0 Hz), 161.5, 157.5, 154.4, 138.4, 137.8 (J = 3.0 Hz), 137.3, 130.0 (J = 10.5 Hz), 129.7, 128.8, 128.3, 127.7, 127.59, 127.56, 123.7, 119.4, 118.8, 116.3 (J = 22.5 Hz), 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 31 H 26 FN2O7S [M+H] + : 589.1439; found: 589.1444.

[0047] T5M:

[0048]

[0049] White solid, yield 73%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.36 (brs, 1H), 9.00 (d, J = 9.6 Hz, 1H), 8.44 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.80 (dt, J = 7.7, 1.8 Hz, 1H), 7.56 - 7.60 (m, 1H), 7.44 - 7.52 (m, 6H), 7.25 - 7.33 (m, 5H), 7.23 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 8.8, 2.3 Hz, 1H), 5.37 (s, 2H), 5.32 (d, J = 9.6 Hz, 1H), 3.42 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 168.0, 161.5, 158.7 (J = 253.5 Hz), 157.5, 154.4, 138.5, 137.6, 135.7 (J = 9.0 Hz), 123.0, 129.7, 129.2 (J = 13.5 Hz), 128.9, 128.4, 127.62, 127.58, 125.0 (J = 3.0 Hz), 123.7, 119.4, 118.8, 117.4 (J = 21.0 Hz), 116.0, 103.6, 94.6, 60.6, 56.5. HRMS, m / z calcd. for C 31 H 26 FN2O7S [M+H] + : 589.1439; found: 589.1441.

[0050] T6M:

[0051]

[0052] Yellow solid, yield 65%. 1 H NMR(600MHz, DMSO-d6) δ 10.40(brs, 1H), 8.98(d, J = 9.6Hz, 1H), 8.44(s, 1H), 8.06(d, J = 8.9Hz, 1H), 7.59(ddd, J = 7.8, 1.7, 0.9Hz, 1H), 7.46 - 7.52(m, 6H), 7.39 - 7.40(m, 2H), 7.33 - 7.36(m, 1H), 7.22 - 7.29(m, 4H), 7.17(dd, J = 8.8, 2.3Hz, 1H), 5.37(s, 2H), 5.25(d, J = 9.6Hz, 1H), 3.42(s, 3H). 13 C NMR(150MHz, DMSO-d6) δ 175.0, 167.8, 161.9(J = 246.0Hz), 161.5, 157.5, 154.4, 143.5(J = 6.0Hz), 138.3, 137.2, 131.6(J = 7.5Hz), 129.7, 128.8, 128.4, 127.7, 127.59, 127.54, 123.7, 123.2(J = 3.0Hz), 119.8(J = 21.0Hz), 119.4, 118.8, 116.0, 114.1(J = 24.0Hz), 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 31 H 26 FN2O7S[M + H] + : 589.1439; found: 589.1441.

[0053] T7M:

[0054]

[0055] Light yellow solid, yield 72%. 11H NMR (600 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.93 (d, J = 9.6 Hz, 1H), 8.43 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.73 - 7.75 (m, 2H), 7.48 - 7.53 (m, 4H), 7.44 - 7.46 (m, 2H), 7.39 - 7.41 (m, 2H), 7.22 - 7.30 (m, 4H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.22 (d, J = 9.6 Hz, 1H), 3.43 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 167.8, 161.5, 157.5, 154.4, 140.2, 138.3, 137.6, 137.2, 129.7, 129.3, 129.0, 128.8, 128.4, 127.7, 127.59, 127.57, 123.7, 119.5, 118.8, 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 31 H 26 ClN2O7S [M + H] + : 605.1144; found: 605.1147.

[0056] T8M:

[0057]

[0058] Yellow solid, yield 75%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.42 (brs, 1H), 9.01 (d, J = 9.6 Hz, 1H), 8.44 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.69 - 7.73 (m, 2H), 7.51 - 7.56 (m, 3H), 7.44 - 7.47 (m, 3H), 7.39 - 7.41 (m, 2H), 7.22 - 7.30 (m, 4H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.26 (d, J = 9.6 Hz, 1H), 3.43 (s, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 175.0, 167.8, 161.5, 157.5, 154.4, 143.2, 138.3, 137.1, 133.9, 132.6, 131.2, 129.7, 128.8, 128.5, 127.7, 127.6, 127.5, 126.8, 125.6, 123.7, 119.5, 118.8, 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 31 H 26 ClN2O7S [M+H] + : 605.1144; found: 605.1149.

[0059] T9M:

[0060]

[0061] Pale yellow solid, yield 64%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.40 (brs, 1H), 9.09 (d, J = 9.7 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.49 - 7.51 (m, 2H), 7.41 - 7.43 (m, 2H), 7.37 - 7.39 (m, 2H), 7.21 - 7.26 (m, 4H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.26 (d, J = 9.7 Hz, 1H), 3.43 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 167.6, 161.5, 157.5, 154.3, 145.1, 138.2, 137.0, 132.4 (J = 32.0 Hz), 129.6, 128.8, 128.4, 128.0, 127.8, 127.6, 126.3 (J = 3.5 Hz), 123.6, 123.9 (J = 271.0 Hz), 119.5, 118.8, 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 32 H 26 F3N2O7S [M+H] + : 639.1407; found: 639.1411.

[0062] T10M:

[0063]

[0064] Yellow solid, yield 66%. 1 H NMR(600MHz, DMSO-d6) δ 10.38(brs, 1H), 9.02(d, J = 9.3Hz, 1H), 8.43(s, 1H), 8.10 - 8.12(m, 1H), 8.06(d, J = 8.9Hz, 1H), 7.87 - 7.90(m, 1H), 7.72 - 7.75(m, 2H), 7.50 - 7.55(m, 4H), 7.45 - 7.46(m, 2H), 7.27 - 7.34(m, 3H), 7.23(d, J = 2.3Hz, 1H), 7.17(dd, J = 8.9, 2.3Hz, 1H), 5.37(s, 2H), 5.29(d, J = 9.3Hz, 1H), 3.43(s, 3H). 13 C NMR(150MHz, DMSO-d6) δ 175.0, 168.0, 161.5, 157.5, 154.4, 140.3, 138.4, 137.3, 133.3, 130.8, 129.8, 128.9, 128.6, 128.5(J = 6.0Hz), 127.73, 127.69, 127.6, 126.4(J = 32.0Hz), 123.7, 123.3(J = 271.0Hz), 119.4, 118.8, 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 32 H 26 F3N2O7S[M + H] + : 639.1407; found: 639.1409.

[0065] T11M:

[0066]

[0067] Yellow solid, yield 62%. 11H NMR (600 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.09 (d, J = 9.3 Hz, 1H), 8.43 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.94 (dd, J = 7.9, 1.3 Hz, 1H), 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.74 (dt, J = 7.7, 1.4 Hz, 1H), 7.69 (dt, J = 7.7, 1.2 Hz, 1H), 7.52 (s, 4H), 7.45 (dd, J = 7.2, 1.8 Hz, 2H), 7.25 - 7.32 (m, 3H), 7.22 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.30 (d, J = 9.3 Hz, 1H), 3.42 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 167.7, 161.5, 157.5, 154.4, 147.7, 138.4, 137.1, 134.4, 133.5, 132.7, 130.1, 129.7, 128.9, 128.6, 127.8, 127.7, 127.6, 124.6, 123.7, 119.5, 118.8, 116.0, 103.6, 94.6, 60.8, 56.5. HRMS, m / z calcd. for C 31 H 26 N3O9S [M + H] + : 616.1384; found: 616.1388.

[0068] T12M:

[0069]

[0070] Pale yellow solid, yield 59%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.24 (d, J = 9.6 Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.49 - 7.55 (m, 5H), 7.43 - 7.47 (m, 3H), 7.31 - 7.37 (m, 3H), 7.27 - 7.30 (m, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 5.34 (d, J = 9.6 Hz, 1H), 3.43 (s, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 175.0, 167.8, 161.5, 157.6, 157.5 (J = 243.0, 3.0 Hz), 154.9 (J = 249.0, 1.5 Hz), 154.4, 138.4, 137.2, 130.4 (J = 16.5, 6.0 Hz), 129.7, 128.9, 128.5, 127.7, 127.61, 127.58, 123.7, 122.1 (J = 24.0, 9.0 Hz), 119.5 (J = 24.8, 12.0 Hz), 119.4, 118.8, 116.5 (J = 27.0 Hz), 116.0, 103.6, 94.6, 60.7, 56.5. HRMS, m / z calcd. for C 31 H 25 F2N2O7S [M+H] + : 607.1345; found: 607.1349.

[0071] T13M:

[0072]

[0073] Pale yellow solid, yield 63%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.45 (s, 1H), 8.14 (d, J = 8.9 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.80 - 7.82 (m, 2H), 7.47 - 7.55 (m, 5H), 7.44 - 7.45 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 3.95 (dt, J = 9.0, 5.8 Hz, 1H), 3.43 (s, 3H), 1.57 - 1.62 (m, 1H), 1.37 - 1.47 (m, 2H), 0.85 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.4, 161.5, 157.5, 154.4, 141.5, 138.6, 132.7, 129.5, 129.3, 127.6, 127.4, 126.9, 123.8, 119.6, 118.8, 116.0, 103.6, 94.6, 56.6, 55.9, 42.0, 24.4, 23.2, 21.9. HRMS, m / z calcd. for C 29 H 31N2O7S[M+H] + : 551.1846; found: 551.1851.

[0074] T14M:

[0075]

[0076] White solid, yield 78%. 1 H NMR(600MHz, DMSO-d6) δ 9.95(s, 1H), 8.44(s, 1H), 8.08(d, J = 8.8Hz, 1H), 7.99(d, J = 9.1Hz, 1H), 7.66 - 7.68(m, 2H), 7.49 - 7.51(m, 2H), 7.40 - 7.41(m, 2H), 7.23 - 7.25(m, 3H), 7.18(dd, J = 8.8, 2.3Hz, 1H), 5.38(s, 2H), 3.91(dt, J = 9.1, 5.8Hz, 1H), 3.43(s, 3H), 1.59 - 1.64(m, 1H), 1.43 - 1.48(m, 1H), 1.36 - 1.41(m, 1H), 0.87(d, J = 6.7Hz, 3H), 0.79(d, J = 6.6Hz, 3H). 13 C NMR(150MHz, DMSO-d6) δ 175.0, 170.3, 161.5, 157.5, 154.3, 142.9, 138.6, 138.6, 129.7, 129.4, 127.6, 127.3, 127.0, 123.8, 119.6, 118.8, 116.0, 103.6, 94.6, 56.6, 55.93, 42.0, 24.4, 23.2, 21.9, 21.3. HRMS, m / z calcd. for C 30 H 33 N2O7S[M+H] + : 565.2003; found: 565.2005.

[0077] T15M:

[0078]

[0079] Light yellow solid, yield 67%. 11H NMR (600 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.43 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.71 - 7.73 (m, 2H), 7.50 - 7.51 (m, 2H), 7.43 - 7.44 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 6.94 - 6.96 (m, 2H), 5.38 (s, 2H), 3.90 (dt, J = 9.2, 5.8 Hz, 1H), 3.68 (s, 3H), 3.43 (s, 3H), 1.60 - 1.66 (m, 1H), 1.43 - 1.48 (m, 1H), 1.36 - 1.41 (m, 1H), 0.87 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.4, 162.5, 161.5, 157.48, 154.3, 138.7, 133.1, 129.4, 129.2, 127.6, 127.3, 123.8, 119.6, 118.8, 116.0, 114.4, 103.6, 94.6, 56.5, 56.0, 55.9, 42.0, 24.4, 23.3, 21.9. HRMS, m / z calcd. for C 30 H 33 N2O8S [M + H] + : 581.1952; found: 581.1955.

[0080] T16M:

[0081]

[0082] Pale yellow solid, yield 73%. 11H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.44 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.84 - 7.86 (m, 2H), 7.50 - 7.52 (m, 2H), 7.43 - 7.44 (m, 2H), 7.30 - 7.33 (m, 2H), 7.24 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 3.94 (dt, J = 9.1, 5.7 Hz, 1H), 3.43 (s, 3H), 1.59 - 1.64 (m, 1H), 1.44 - 1.49 (m, 1H), 1.38 - 1.42 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.2, 164.4 (J = 252.0 Hz), 161.5, 157.5, 154.4, 138.5, 137.9 (J = 3.0 Hz), 130.0 (J = 9.0 Hz), 129.5, 127.6, 127.4, 123.7, 119.6, 118.8, 116.3 (J = 22.5 Hz), 116.0, 103.6, 94.6, 56.6, 55.9, 41.9, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 29 H 30 FN2O7S [M + H] + : 569.1752; found: 569.1755.

[0083] T17M:

[0084]

[0085] Pale yellow solid, yield 70%. 11H NMR(600 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.45 (d, J = 0.7 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.80 (dt, J = 7.6, 1.7 Hz, 1H), 7.59 (ddt, J = 7.4, 4.8, 1.7 Hz, 1H), 7.49 - 7.50 (m, 2H), 7.43 - 7.44 (m, 2H), 7.32 - 7.35 (m, 1H), 7.26 - 7.29 (m, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 3.99 - 4.04 (m, 1H), 3.43 (s, 3H), 1.65 - 1.71 (m, 1H), 1.54 - 1.59 (m, 1H), 1.38 - 1.43 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H). 13 13C NMR(150 MHz, DMSO-d6) δ 175.0, 170.3, 161.5, 158.9 (J = 253.5 Hz), 157.5, 154.4, 138.6, 135.6 (J = 9.0 Hz), 130.0, 129.5, 129.1 (J = 13.5 Hz), 127.6, 127.3, 124.9 (J = 3.0 Hz), 123.8, 119.5, 118.8, 117.4 (J = 21.0 Hz), 116.0, 103.6, 94.6, 56.6, 56.0, 41.7, 24.4, 23.4, 21.6. HRMS, m / z calcd. for C 29 H 30 FN2O7S [M + H] + : 569.1752; found: 569.1756. T18M:

[0086]

[0087] Pale yellow solid, yield 73%. 11H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.45 (d, J = 0.7 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.64 - 7.65 (m, 1H), 7.59 (dt, J = 8.6, 2.2 Hz, 1H), 7.51 - 7.56 (m, 3H), 7.44 - 7.45 (m, 2H), 7.39 (dt, J = 8.6, 2.7 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 3.99 (dt, J = 9.1, 5.7 Hz, 1H), 3.44 (s, 3H), 1.59 - 1.64 (m, 1H), 1.46 - 1.51 (m, 1H), 1.39 - 1.44 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.1, 162.0 (J = 246.0 Hz), 161.5, 157.5, 154.4, 143.6 (J = 6.0 Hz), 138.5, 131.7 (J = 7.5 Hz), 129.5, 127.6, 127.4, 123.8, 123.1 (J = 3.0 Hz), 119.8 (J = 21.0 Hz), 119.5, 118.8, 116.0, 114.1 (J = 25.5 Hz), 103.6, 94.6, 56.5, 55.9, 41.9, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 29 H 30 FN2O7S [M + H] + : 569.1752; found: 569.1756.

[0088] T19M:

[0089]

[0090] Pale yellow solid, yield 68%. 11H NMR (600 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.43 (s, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.77 - 7.80 (m, 2H), 7.50 - 7.55 (m, 4H), 7.40 - 7.42 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.9, 2.3 Hz, 1H), 5.38 (s, 2H), 3.95 (dt, J = 9.0, 5.7 Hz, 1H), 3.43 (s, 3H), 1.59 - 1.66 (m, 1H), 1.46 - 1.50 (m, 1H), 1.39 - 1.43 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.1, 161.5, 157.5, 154.3, 140.3, 138.5, 137.6, 129.5, 129.4, 128.9, 127.6, 127.4, 123.8, 119.6, 118.8, 116.0, 103.6, 94.6, 56.6, 55.9, 41.9, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 29 H 30 ClN2O7S [M + H] + : 585.1457; found: 585.1460.

[0091] T20M:

[0092]

[0093] White solid, yield 76%. 11H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.45 (s, 1H), 8.36 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.82 (t, J = 1.9 Hz, 1H), 7.74 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.57 - 7.59 (m, 1H), 7.49 - 7.52 (m, 3H), 7.43 - 7.45 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 4.00 (dt, J = 9.1, 5.7 Hz, 1H), 3.44 (s, 3H), 1.59 - 1.66 (m, 1H), 1.46 - 1.51 (m, 1H), 1.40 - 1.44 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.0, 161.5, 157.5, 154.4, 143.4, 138.5, 134.0, 132.6, 131.3, 129.5, 127.6, 127.5, 126.8, 125.5, 123.8, 119.6, 118.8, 116.0, 103.6, 94.6, 56.5, 55.9, 41.9, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 29 H 30 ClN2O7S [M + H] + : 585.1457; found: 585.1459.

[0094] T21M:

[0095]

[0096] Pale yellow solid, yield 61%. 11H NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.46 (d, J = 9.1 Hz, 1H), 8.40 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.47 - 7.49 (m, 2H), 7.34 - 7.36 (m, 2H), 7.24 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 3.99 (dt, J = 9.2, 5.7 Hz, 1H), 3.43 (s, 3H), 1.60 - 1.65 (m, 1H), 1.47 - 1.52 (m, 1H), 1.39 - 1.44 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 169.8, 161.5, 157.5, 154.3, 145.3, 138.3, 132.4 (J = 31.5 Hz), 129.4, 128.0, 127.6, 127.5, 126.4 (J = 3.5 Hz), 123.9 (J = 271.5 Hz), 123.7, 119.6, 118.8, 116.0, 103.6, 94.6, 56.5, 56.0, 41.7, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 30 H 30 F3N2O7S [M + H] + : 619.1720; found: 619.1722.

[0097] T22M:

[0098]

[0099] Pale yellow solid, yield 65%. 11H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.45 (s, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.19 (dd, J = 8.0, 1.3 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 7.8, 1.3 Hz, 1H), 7.78 (dt, J = 7.7, 1.4 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.49 - 7.51 (m, 2H), 7.43 - 7.45 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.3 Hz, 1H), 5.38 (s, 2H), 4.01 - 4.06 (m, 1H), 3.43 (s, 3H), 1.66 - 1.71 (m, 1H), 1.59 - 1.64 (m, 1H), 1.41 - 1.45 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.3, 161.5, 157.5, 154.4, 140.1, 138.5, 133.3, 133.2, 131.0, 129.6, 128.5 (J = 6.0 Hz), 127.6, 127.4, 126.4 (J = 32.0 Hz), 123.8, 123.4 (J = 272.0 Hz), 119.5, 118.8, 116.0, 103.6, 94.6, 56.5, 56.1, 41.8, 24.4, 23.3, 21.6. HRMS, m / z calcd. for C 30 H 30 F3N2O7S [M + H] + : 619.1720; found: 619.1722.

[0100] T23M:

[0101]

[0102] Pale yellow solid, yield 64%. 11H NMR (600 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.44 (s, 1H), 8.05 - 8.08 (m, 2H), 7.90 - 7.92 (m, 1H), 7.75 - 7.79 (m, 2H), 7.49 - 7.51 (m, 2H), 7.44 - 7.46 (m, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.17 (dd, J = 8.9, 2.3 Hz, 1H), 5.37 (s, 2H), 4.09 (dt, J = 9.4, 5.3 Hz, 1H), 3.43 (s, 3H), 1.68 - 1.74 (m, 1H), 1.59 - 1.64 (m, 1H), 1.45 - 1.50 (m, 1H), 0.90 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 167.0, 161.5, 157.5, 154.4, 147.7, 138.5, 134.4, 133.6, 132.8, 130.2, 129.6, 127.6, 127.5, 124.7, 123.8, 119.6, 118.8, 116.0, 103.6, 94.6, 56.6, 56.3, 41.8, 24.5, 23.3, 21.7. HRMS, m / z calcd. for C 29 H 30 N3O9S [M + H] + : 596.1697; found: 596.1700.

[0103] T24M:

[0104]

[0105] Pale yellow solid, yield 74%. 11H NMR (600 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.59 (d, J = 9.1 Hz, 1H), 8.45 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.54 - 7.57 (m, 1H), 7.49 - 7.52 (m, 2H), 7.38 - 7.46 (m, 4H), 7.23 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.8, 2.4 Hz, 1H), 5.37 (s, 2H), 4.04 (dt, J = 9.6, 6.1 Hz, 1H), 3.43 (s, 3H), 1.65 - 1.72 (m, 1H), 1.56 - 1.61 (m, 1H), 1.40 - 1.45 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 175.0, 170.1, 161.5, 157.49, 157.47 (J = 243.0, 1.5 Hz), 155.0 (J = 249.0, 1.5 Hz), 154.4, 138.5, 130.3 (J = 17.3, 6.8 Hz), 129.5, 127.6, 127.4, 123.8, 122.0 (J = 23.3, 8.3 Hz), 119.5, 119.4 (J = 23.3, 8.3 Hz), 118.8, 116.6 (J = 27.0 Hz), 116.0, 103.6, 94.6, 56.6, 56.0, 41.6, 24.4, 23.3, 21.6. HRMS, m / z calcd. for C 29 H 27 F2N2O7S [M - H] - : 585.1513; found: 585.1530.

[0106] Synthesis of Target Compounds T1 - T24 in Example 2

[0107]

[0108] Weigh the MOM - protected intermediates T1M - T24M (0.5 mmol), chloroform (5 mL), methanol (5 mL), concentrated hydrochloric acid (0.5 mL), and react at 60 °C for 3 hours. Monitor the reaction by TLC until it is complete (the developing solvent is toluene:ethyl acetate = 2:3). Cool to room temperature, add 20 mL of water, and a large amount of precipitate will form. Wash it three times with water and once with a small amount of ice ethanol. Dry the product under vacuum at 50 °C for 10 hours.

[0109] T1:

[0110]

[0111] White solid, yield 97%. 1 H NMR (600 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.58 (s, 1H), 8.84 (d, J = 8.6 Hz, 1H), 8.35 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 7.3, 1.8 Hz, 2H), 7.41 - 7.50 (m, 9H), 7.22 - 7.28 (m, 3H), 6.98 (dd, J = 8.8, 2.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 5.28 (s, 1H). 13 C NMR (150 MHz, DMSO-d6) δ 173.8, 167.0, 162.2, 156.8, 152.9, 140.3, 137.3, 136.6, 131.6, 128.5, 128.1, 127.7, 127.2, 126.7, 126.6, 126.5, 125.9, 122.4, 118.3, 115.9, 114.7, 101.6, 59.6. HRMS, m / z calcd. for C 29 H 21 N2O6S [M-H] - : 525.1126; found: 525.1132.

[0112] T2:

[0113]

[0114] White solid, yield 97%. 1 H NMR (600 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.66 - 7.67 (m, 2H), 7.48 - 7.49 (m, 2H), 7.42 - 7.45 (m, 4H), 7.20 - 7.30 (m, 5H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.21 (s, 1H), 2.23 (s, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 173.8, 167.0, 162.6, 156.9, 152.8, 141.9, 137.4, 137.3, 136.7, 128.5, 128.4, 127.7, 127.1, 126.7, 126.6, 126.5, 126.0, 122.4, 118.3, 115.7, 114.9, 101.5, 59.6, 20.3. HRMS, m / z calcd. for C 30 H 23 N2O6S [M-H] - : 539.1282; found: 539.1286.

[0115] T3:

[0116]

[0117] White solid, yield 91%. 1 1H NMR (600 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.57 (s, 1H), 8.64 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.71 - 7.73 (m, 2H), 7.45 - 7.47 (m, 6H), 7.23 - 7.30 (m, 3H), 6.89 - 6.99 (m, 4H), 5.23 (s, 1H), 3.67 (s, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 173.8, 167.1, 162.4, 161.4, 156.8, 152.8, 137.4, 136.7, 131.8, 128.4, 128.2, 127.7, 127.1, 126.7, 126.5, 126.5, 122.4, 118.3, 115.8, 114.8, 113.3, 101.5, 59.6, 54.9. HRMS, m / z calcd. for C 30 H 23 N2O7S [M-H] - : 555.1231; found: 555.1235.

[0118] T4:

[0119]

[0120] Pale yellow solid, yield 95%. 11H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.90 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.80 - 7.82 (m, 2H), 7.49 (s, 4H), 7.42 - 7.44 (m, 2H), 7.22 - 7.28 (m, 5H), 6.97 (dd, J = 8.8, 2.2 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 5.28 (s, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 173.8, 166.9, 163.3 (J = 246.0 Hz), 162.5, 156.8, 152.8, 137.3, 136.7 (J = 3.0 Hz), 136.4, 129.0 (J = 9.0 Hz), 128.5, 127.7, 127.2, 126.8, 126.54, 126.52, 122.3, 118.3, 115.7, 115.2 (J = 22.5 Hz), 114.8, 101.5, 59.6 1. HRMS, m / z calcd. for C 29 H 20 FN2O6S [M-H] - : 543.1032; found: 543.1036.

[0121] T5:

[0122]

[0123] White solid, yield 96%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.4 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 7.96 (dd, J = 8.8, 1.2 Hz, 1H), 7.80 (tt, J = 7.3, 2.0 Hz, 1H), 7.58 (tdd, J = 7.5, 4.9, 1.7 Hz, 1H), 7.46 - 7.50 (m, 6H), 7.25 - 7.32 (m, 5H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.34 (s, 1H). 1313C NMR (150 MHz, DMSO-d6) δ 173.8, 167.0, 162.5, 157.6 (J = 253.5 Hz), 156.9, 152.8, 137.3, 136.6, 134.6 (J = 7.5 Hz), 128.9, 128.6, 128.2 (J = 13.5 Hz), 127.8, 127.3, 126.8, 126.6, 126.5, 123.9 (J = 4.5 Hz), 122.4, 118.3, 116.4 (J = 19.5 Hz), 115.8, 114.8, 101.5, 59.6. HRMS, m / z calcd. for C 29 H 20 FN2O6S [M-H] - : 543.1032; found: 543.1036.

[0124] T6:

[0125]

[0126] Yellow solid, yield 97%. 1 1H NMR (600 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.60 (s, 1H), 9.03 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.59 - 7.61 (m, 1H), 7.43 - 7.53 (m, 8H), 7.32 - 7.36 (m, 1H), 7.22 - 7.29 (m, 3H), 6.97 (dd, J = 8.8, 2.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 5.31 (s, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 173.8, 166.8, 162.4, 160.8 (J = 246.0 Hz), 156.8, 152.9, 142.4 (J = 7.5 Hz), 137.2, 136.3, 130.5 (J = 9.0 Hz), 128.5, 127.7, 127.3, 126.8, 126.6, 126.5, 122.3, 122.1 (J = 3.0 Hz), 118.7 (J = 21.0 Hz), 118.3, 115.8, 114.8, 113.1 (J = 25.5 Hz), 101.5, 59.6. HRMS, m / z calcd. for C 29 H 20 FN2O6S [M-H] - : 543.1032; found: 543.1036.

[0127] T7:

[0128]

[0129] White solid, yield 96%. 1 H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.93 (brs, 1H), 8.34 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.73 - 7.74 (m, 2H), 7.48 - 7.51 (m, 4H), 7.45 (d, J = 8.5 Hz, 2H), 7.40 - 7.42 (m, 2H), 7.23 - 7.29 (m, 3H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.24 (s, 1H). 13 C NMR (150 MHz, DMSO-d6) δ 174.9, 167.8, 163.2, 157.9, 153.9, 140.2, 138.2, 137.6, 137.3, 129.6, 129.3, 129.0, 128.8, 128.3, 127.9, 127.7, 127.6, 123.4, 119.5, 117.0, 115.8, 102.6, 60.7. HRMS, m / z calcd. for C 29 H 20 ClN2O6S [M - H] - : 559.0736; found: 559.0743.

[0130] T8:

[0131]

[0132] Yellow solid, yield 93%. 1 H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.55 (s, 1H), 9.03 (s, 1H), 8.35 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 - 7.74 (m, 2H), 7.41 - 7.55 (m, 8H), 7.22 - 7.29 (m, 3H), 6.97 (dd, J = 8.8, 2.3 Hz, 1H), 6.91 (t, J = 1.8 Hz, 1H), 5.29 (s, 1H). 1313C NMR (150 MHz, DMSO-d6) δ 173.8, 166.7, 162.2, 156.8, 152.9, 142.1, 137.2, 136.2, 132.8, 131.5, 130.1, 128.5, 127.7, 127.3, 126.8, 126.6, 126.5, 125.8, 124.5, 122.3, 118.3, 115.9, 114.7, 101.6, 59.6. HRMS, m / z calcd. for C 29 H 20 ClN2O6S [M-H] - : 559.0736; found: 559.0739.

[0133] T9:

[0134]

[0135] White solid, yield 95%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.54 (s, 1H), 9.10 (d, J = 9.7 Hz, 1H), 8.32 (s, 1H), 7.95 (dd, J = 17.8, 8.5 Hz, 3H), 7.77 (d, J = 8.3 Hz, 2H), 7.47 - 7.49 (m, 2H), 7.39 - 7.44 (m, 4H), 7.21 - 7.26 (m, 3H), 6.97 (dd, J = 8.8, 2.2 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 5.30 (d, J = 9.7 Hz, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 167.7, 163.2, 157.9, 153.9, 145.1, 138.2, 137.1, 132.4 (J = 32.0 Hz), 129.6, 128.8, 128.3, 128.0, 127.9, 127.7, 127.6, 126.3 (J = 3.0 Hz), 123.9 (J = 271.5 Hz), 123.4, 119.4, 117.0, 115.8, 102.6, 60.7. HRMS, m / z calcd. for C 30 H 20 F3N2O6S [M-H] - : 593.1000; found: 593.1005.

[0136] T10:

[0137]

[0138] Yellow solid, yield 92%. 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.49(s,1H),9.05(s,1H),8.35(s,1H),8.12-8.14(m,1H),7.96(d,J=8.8Hz,1H),7.87-7.89(m,1H),7.71-7.75(m,2H),7.46-7.54(m,6H),7.26-7.33(m,3H),6.96(dd,J=8.8,2.3Hz,1H),6.90-6.93(m,1H),5.32(s,1H). 13 C NMR(150MHz,DMSO-d6)δ173.8,167.0,162.3,156.8,152.9,139.3,137.2,136.4,132.22,132.15,129.8,128.6,127.8,127.4,127.3(J=6.5Hz),126.9,126.63,126.60,125.3(J=32.0Hz),122.4,122.3(J=272.0Hz),118.3,115.8,114.8,101.6,59.6.HRMS,m / z calcd.for C 30 H 20 F3N2O6S[M-H] - :593.1000;found:593.1003.

[0139] T11:

[0140]

[0141] Yellow solid, yield 98%. 1 H NMR(600MHz,DMSO-d6)δ10.87(s,1H),10.48(s,1H),9.10(d,J=9.2Hz,1H),8.35(s,1H),7.93-7.97(m,2H),7.88(dd,J=7.9,1.2Hz,1H),7.74(td,J=7.7,1.4Hz,1H),7.68(td,J=7.7,1.3Hz,1H),7.49-7.53(m,4H),7.45-7.46(m,2H),7.24-7.31(m,3H),6.96(ddd,J=8.8,2.2,0.9Hz,1H),6.89(t,J=1.7Hz,1H),5.31(d,J=9.0Hz,1H). 1313C NMR (150 MHz, DMSO-d6) δ 173.8, 166.6, 162.1, 156.8, 152.9, 146.6, 137.2, 136.1, 133.3, 132.4, 131.6, 129.0, 128.7, 127.8, 127.5, 126.9, 126.7, 126.6, 123.5, 122.4, 118.3, 116.9, 114.7, 101.6, 59.7. HRMS, m / z calcd. for C 29 H 20 N3O8S [M-H] - : 570.0977; found: 570.0979.

[0142] T12:

[0143]

[0144] Pale yellow solid, yield 94%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.25 (s, 1H), 8.36 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.48 - 7.55 (m, 7H), 7.42 - 7.46 (m, 1H), 7.30 - 7.36 (m, 3H), 7.26 - 7.28 (m, 1H), 6.98 (dd, J = 8.8, 2.2 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 5.37 (s, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 167.9, 163.3, 157.9, 157.4 (J = 242.3, 2.3 Hz), 154.8 (J = 249.0, 1.5 Hz), 153.9, 138.4, 137.4, 130.4 (J = 16.5, 6.0 Hz), 129.7, 128.8, 128.5, 127.9, 127.7, 127.6, 123.4, 122.1 (J = 24.8, 9.8 Hz), 119.5 (J = 7.5 Hz), 119.3, 117.0, 116.6 (J = 27.0 Hz), 115.8, 102.6, 60.7. HRMS, m / z calcd. for C 29 H 19 F2N2O6S [M-H] - : 561.0937; found: 561.0942.

[0145] T13:

[0146]

[0147] Pale yellow solid, yield 96%. 1 H NMR(600MHz,DMSO-d6)δ11.01(s,1H),10.17(s,1H),8.36(s,1H),8.24(d,J=9.0Hz,1H),7.97(d,J=8.8Hz,1H),7.81-7.82(m,2H),7.44-7.53(m,7H),6.98(dt,J=8.7,1.6Hz,1H),6.94(t,J=1.8Hz,1H),3.95(dt,J=8.9,5.6Hz,1H),1.58-1.63(m,1H),1.45-1.50(m,1H),1.38-1.43(m,1H),0.86(d,J=6.7Hz,3H),0.77(d,J=6.6Hz,3H). 13 CNMR(150MHz,DMSO-d6)δ173.9,169.3,162.2,156.8,152.8,140.4,137.5,131.6,128.4,128.2,126.6,126.5,125.9,122.5,118.5,115.9,114.7,101.6,55.1,40.9,23.4,22.2,20.8.HRMS,m / z calcd.for C 27 H 25 N2O6S[M-H] - :505.1439;found:505.1446.

[0148] T14:

[0149]

[0150] White solid, yield 95%. 11H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.31 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.40 - 7.47 (m, 4H), 7.21 (d, J = 8.1 Hz, 2H), 6.94 (dd, J = 8.8, 2.2 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 3.90 (dd, J = 9.4, 5.7 Hz, 1H), 2.21 (s, 3H), 1.60 - 1.67 (m, 1H), 1.48 - 1.53 (m, 1H), 1.39 - 1.43 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 170.2, 164.9, 158.1, 153.6, 142.9, 138.52, 138.48, 129.6, 129.3, 127.6, 127.4, 127.0, 123.5, 119.5, 116.4, 116.2, 102.5, 56.5, 42.0, 24.5, 23.2, 21.9, 21.3. HRMS, m / z calcd. for C 28 H 27 N2O6S [M - H] - : 519.1595; found: 519.1601.

[0151] T15:

[0152]

[0153] Pale yellow solid, yield 93%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.32 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.70 - 7.72 (m, 2H), 7.42 - 7.48 (m, 4H), 6.91 - 6.95 (m, 3H), 6.87 (d, J = 2.3 Hz, 1H), 3.89 (dd, J = 8.9, 5.9 Hz, 1H), 3.66 (s, 3H), 1.61 - 1.67 (m, 1H), 1.46 - 1.51 (m, 1H), 1.38 - 1.42 (m, 1H), 0.87 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.5 Hz, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 174.9, 170.3, 164.4, 162.4, 158.0, 153.6, 138.6, 133.0, 129.3, 129.2, 127.6, 127.5, 123.5, 119.5, 116.4, 116.2, 114.4, 102.6, 56.3, 55.9, 42.0, 24.5, 23.3, 21.9. HRMS, m / z calcd. for C 28 H 27 N2O7S [M-H] - : 535.1544; found: 535.1551. T16:

[0154]

[0155] Pale yellow solid, yield 94%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.29 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.84 - 7.87 (m, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.28 - 7.31 (m, 2H), 6.89 (dd, J = 8.8, 2.2 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 3.94 (dd, J = 9.4, 5.7 Hz, 1H), 1.59 - 1.66 (m, 1H), 1.46 - 1.51 (m, 1H), 1.39 - 1.43 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.8, 170.2, 164.4 (J = 247.5 Hz), 158.3, 153.5, 148.1, 138.4, 137.9 (J = 3.0 Hz), 130.0 (J = 10.5 Hz), 129.4, 127.9, 127.4, 123.3, 119.5, 116.8, 116.3 (J = 22.5 Hz), 115.7, 102.5, 56.1, 42.0, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 27 H 24 FN2O6S [M-H] - : 523.1345; found: 523.1352. T17:

[0156]

[0157] Pale yellow solid, yield 95%. 1 H NMR(600MHz,DMSO-d6)δ10.08(s,1H),8.29(s,1H),7.91(d,J=8.8Hz,1H),7.79(dt,J=7.6,1.7Hz,1H),7.58(ddt,J=8.6,6.0,1.7Hz,1H),7.47(d,J=8.5Hz,2H),7.42(d,J=8.7Hz,2H),7.32(dd,J=10.4,8.3Hz,1H),7.27(t,J=7.6Hz,1H),6.88(dd,J=8.8,2.2Hz,1H),6.77(d,J=2.4Hz,1H),4.00(dd,J=10.0,5.1Hz,1H),1.65-1.72(m,1H),1.54-1.59(m,1H),1.39-1.43(m,1H),0.88(d,J=6.7Hz,3H),0.79(d,J=6.5Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ174.8,170.4,165.8,158.8(J=253.5Hz),158.3,153.5,138.5,135.5(J=9.0Hz),130.0,129.5,129.3(J=13.5Hz),127.8,127.4,124.9(J=4.5Hz),123.3,119.4,117.4(J=21.0Hz),116.8,115.7,102.5,56.1,41.8,24.4,23.4,21.6.HRMS,m / z calcd.for C 27 H 24 FN2O6S[M-H] - :523.1345;found:523.1353.

[0158] T18:

[0159]

[0160] Pale yellow solid, yield 98%. 11H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.64 (dt, J = 7.9, 1.1 Hz, 1H), 7.58 - 7.60 (m, 1H), 7.51 (dt, J = 8.1, 5.5 Hz, 1H), 7.43 - 7.48 (m, 4H), 7.35 (dt, J = 8.6, 2.6 Hz, 1H), 6.95 (dd, J = 8.8, 2.2 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 3.98 (dd, J = 9.4, 5.7 Hz, 1H), 1.60 - 1.66 (m, 1H), 1.48 - 1.53 (m, 1H), 1.40 - 1.45 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 170.1, 164.2, 162.0 (J = 246.0 Hz), 158.0, 153.8, 143.6 (J = 6.0 Hz), 138.4, 131.6 (J = 7.5 Hz), 129.4, 127.7, 127.55, 123.4, 123.1 (J = 3.0 Hz), 119.7 (J = 21.0 Hz), 119.4, 116.5, 116.1, 114.1 (J = 24.0 Hz), 102.6, 56.3, 42.0, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 27 H 24 FN2O6S [M - H] - : 523.1345; found: 523.1351. T19:

[0161]

[0162] Pale yellow solid, yield 96%. 11H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.32 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.77 - 7.80 (m, 2H), 7.52 - 7.54 (m, 2H), 7.48 - 7.50 (m, 2H), 7.39 - 7.40 (m, 2H), 6.93 (dd, J = 8.8, 2.2 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 3.95 (dd, J = 9.3, 5.7 Hz, 1H), 1.60 - 1.66 (m, 1H), 1.46 - 1.51 (m, 1H), 1.39 - 1.43 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 170.0, 164.1, 158.0, 153.7, 140.3, 138.3, 137.6, 129.44, 129.35, 128.9, 127.7, 127.6, 123.5, 119.5, 116.6, 116.1, 102.6, 56.0, 41.9, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 27 H 24 ClN2O6S [M - H] - : 539.1049; found: 539.1054.

[0163] T20:

[0164]

[0165] Off - white solid, yield 95%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.32 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.74 (dt, J = 7.9, 1.3 Hz, 1H), 7.54 (ddd, J = 8.1, 2.3, 1.1 Hz, 1H), 7.43 - 7.48 (m, 5H), 6.93 (dd, J = 8.9, 2.2 Hz, 1H), 6.86 (s, 1H), 3.98 (dd, J = 9.4, 5.7 Hz, 1H), 1.60 - 1.67 (m, 1H), 1.50 - 1.54 (m, 1H), 1.41 - 1.46 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 174.9, 170.1, 165.1, 158.1, 153.6, 143.4, 138.4, 134.0, 132.5, 131.3, 129.4, 127.8, 127.4, 126.7, 125.6, 123.4, 119.4, 116.5, 116.1, 102.5, 56.4, 42.0, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 27 H 24 ClN2O6S [M-H] - : 539.1049; found: 539.1054.

[0166] T21:

[0167]

[0168] Pale yellow solid, yield 93%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.29 (s, 1H), 8.00 (d, J = 12.0 Hz, 2H), 7.96 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.44 - 7.45 (m, 2H), 7.35 - 7.36 (m, 2H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 6.90 (s, 1H), 3.99 (dd, J = 9.5, 5.6 Hz, 1H), 1.61 - 1.68 (m, 1H), 1.51 - 1.56 (m, 1H), 1.41 - 1.46 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 169.9, 164.1, 158.0, 153.6, 145.2, 138.3, 132.4 (J = 32.0 Hz), 129.3, 128.0, 127.7, 127.6, 126.4 (J = 3.5 Hz), 123.9 (J = 271.5 Hz), 123.4, 119.4, 116.6, 116.1, 102.6, 56.4, 41.8, 24.5, 23.2, 21.8. HRMS, m / z calcd. for C 28 H 24 F3N2O6S [M-H] - : 573.1313; found: 573.1320.

[0169] T22:

[0170]

[0171] Pale yellow solid, yield 92%. 1 H NMR(600MHz, DMSO-d6)δ10.09(s, 1H), 8.34(s, 1H), 8.20(d, J = 7.9Hz, 1H), 7.96(d, J = 8.7Hz, 1H), 7.90(dd, J = 7.8, 1.3Hz, 1H), 7.78(dt, J = 7.7, 1.3Hz, 1H), 7.73(t, J = 7.6Hz, 1H), 7.48(d, J = 8.6Hz, 2H), 7.43(d, J = 8.8Hz, 2H), 6.94(dd, J = 8.7, 2.2Hz, 1H), 6.86(t, J = 3.0Hz, 1H), 4.05(dd, J = 9.9, 5.2Hz, 1H), 1.66 - 1.73(m, 1H), 1.60 - 1.65(m, 1H), 1.41 - 1.46(m, 1H), 0.89(d, J = 6.6Hz, 3H), 0.81(d, J = 6.5Hz, 3H). 13 C NMR(150MHz, DMSO-d6)δ174.9, 170.3, 164.0, 158.0, 153.8, 140.1, 138.4, 133.2, 131.1, 129.6, 128.5(J = 6.0Hz), 127.7, 127.6, 126.4(J = 32.0Hz), 123.5, 123.4(J = 272.0Hz), 119.5, 116.6, 116.1, 102.6, 56.2, 41.8, 24.4, 23.3, 21.6. HRMS, m / z calcd. for C 28 H 24 F3N2O6S[M - H] - : 573.1313; found: 573.1319.

[0172] T23:

[0173]

[0174] Pale yellow solid, yield 96%. 11H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.34 (s, 1H), 8.05 - 8.07 (m, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.88 - 7.89 (m, 1H), 7.73 - 7.77 (m, 2H), 7.44 - 7.48 (m, 4H), 6.94 (dt, J = 8.8, 1.8 Hz, 1H), 6.87 (s, 1H), 4.07 (dd, J = 9.8, 5.2 Hz, 1H), 1.68 - 1.77 (m, 1H), 1.59 - 1.63 (m, 1H), 1.46 - 1.50 (m, 1H), 0.90 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6) δ 174.9, 170.3, 164.0, 158.0, 153.8, 147.7, 138.4, 134.1, 134.0, 132.7, 130.2, 129.6, 127.7, 127.6, 124.6, 123.5, 119.5, 116.6, 116.0, 102.6, 56.5, 42.0, 24.5, 23.4, 21.7. HRMS, m / z calcd. for C 27 H 24 N3O8S [M - H] - : 550.1290; found: 550.1297.

[0175] T24:

[0176]

[0177] Pale yellow solid, yield 93%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.55 - 7.57 (m, 1H), 7.48 - 7.49 (m, 2H), 7.42 - 7.46 (m, 3H), 7.38 - 7.41 (m, 1H), 6.95 (dd, J = 8.8, 2.2 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 4.03 (dd, J = 10.0, 5.2 Hz, 1H), 1.64 - 1.72 (m, 1H), 1.56 - 1.61 (m, 1H), 1.41 - 1.45 (m, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H). 1313C NMR (150 MHz, DMSO-d6) δ 174.9, 170.1, 163.9, 158.0, 157.4 (J = 242.3, 2.3 Hz), 155.0 (J = 249.8, 2.3 Hz), 153.8, 138.4, 130.4 (J = 17.3, 6.8 Hz), 129.5, 127.7, 127.6, 123.5, 121.9 (J = 24.0, 9.0 Hz), 119.40 (J = 21.8, 11.3 Hz), 119.38, 116.7, 116.6 (J = 21.0 Hz), 116.0, 102.6, 56.1, 41.6, 24.4, 23.4, 21.6. HRMS, m / z calcd. for C 27 H 23 F2N2O6S [M-H] - : 541.1250; found: 541.1258.

[0178] Example 3 Detection of the biological activity of the target compound

[0179] The inhibitory rate of cancer cell proliferation of all target compounds was detected by the MTT colorimetric method. The experimental method is briefly described as follows. The test compound was first dissolved in DMSO to prepare a stock solution, and then gradient diluted with the corresponding cell culture medium to prepare a test sample. The final concentration range of the compound was 5 μM. Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate at an appropriate density. After culturing overnight under the corresponding conditions, the sample was prepared into solutions with 6 concentration gradients of 0.625, 1.25, 2.5, 5, 10, and 20 μmol / L. Each sample was set with 3 replicates and placed in an incubator for 48 h. After the culture was completed, an appropriate volume of MTT detection solution was added to each well and incubated at 37 °C for 4 h. The culture medium was carefully discarded, and then 100 μL of DMSO was added to each well to dissolve the crystals at the bottom of the well. The mixture was placed on a micro oscillator and shaken at room temperature in the dark for 10 min. After the crystals were fully dissolved, the absorbance value of each well at 492 nm was detected with an enzyme-linked immunosorbent assay (ELISA) reader, and the inhibition rate of each compound against human cervical cancer Hela cells was calculated. The inhibition rates are shown in Table 1, and the compound T18 has the best activity. Further, the growth inhibition curve of T18 against tumor cells was obtained. Thus, the IC 50 values of T18 against Hela cells, MCF-7 cells, MDA-MB231 cells, and H460 cells were 1.94 ± 0.26, 4.75 ± 0.38, 8.56 ± 0.19, and 4.36 ± 0.11 μmol / L, respectively.

[0180] Table 1 Inhibition rate of the target compound against HeLa tumor cells (5 μM)

[0181]

[0182]

[0183] The anti-tumor activity of compound T18 was detected in Hela cells by Western blot. It was found that compound T18 could promote the increase of the apoptosis marker cleaved-PARP in a concentration-dependent manner, indicating that compound T18 could promote apoptosis in a concentration-dependent manner. After treating Hela cells with compound T18 for 12 h, flow cytometry was performed, and significant changes occurred in the cell cycle, manifested as a significant increase in the number of cells in the G2 / M phase, indicating that compound T18 could induce cell cycle arrest, thereby producing anti-proliferative activity.

[0184] Therefore, compound T18 has obvious activity in inhibiting the proliferation of tumor cells and can be applied to the preparation of related anti-tumor drugs.

Claims

1. A sulfonylated amino acid-conjugated isoflavone derivative, characterized in that, A compound having a structure shown in general formula I, its optical isomers, solvates or pharmaceutically acceptable salts thereof; In formula I, R1 is one or more H, alkyl, alkoxy, nitro, trifluoromethyl or halogen; R2 is phenyl or C1-C4 alkyl.

2. The sulfonylated amino acid-spliced isoflavone derivative according to claim 1, characterized in that, Said R1 is one or more H, C1-C5 alkyl, C1-C5 alkoxy, nitro, trifluoromethyl, fluorine or chlorine; R2 is phenyl or isobutyl.

3. The sulfonylated amino acid-conjugated isoflavone derivative according to claim 2, wherein, Said R1 is one or more H, methyl, methoxy, nitro, trifluoromethyl, fluorine or chlorine.

4. The sulfonylated amino acid-conjugated isoflavone derivative according to claim 1, wherein, The sulfonylated amino acid-conjugated isoflavone derivative is the following compound, its optical isomers, solvates or pharmaceutically acceptable salts thereof; 5. Use of a sulfonylated amino acid-conjugated isoflavone derivative according to any one of claims 1 to 4 in the preparation of an anti-tumor drug, characterized in that, The active ingredient of the anti-tumor drug is one or more of the sulfonylated amino acid-conjugated isoflavone derivatives.

6. The application according to claim 5, characterized in that, The anti-tumor drug is used for treating cervical cancer, non-small cell lung cancer or breast cancer.

7. The application according to claim 6, wherein The anti-tumor drug is used for inhibiting the proliferation or migration of tumor cells; The tumor cells are human cervical cancer cells, human breast cancer cells, human non-small cell lung cancer cells and human triple-negative breast cancer cells.

8. The application according to claim 1, wherein The anti-tumor drug further comprises a pharmaceutically acceptable carrier.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises one or more sulfonylated amino acid-conjugated isoflavone derivatives according to any one of claims 1-4 and one or more pharmaceutically acceptable carriers.

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