A quinazoline derivative containing a benzofuran structure and its application

Abstract

This invention discloses a quinazoline derivative containing a benzofuran structure and its applications, the general structural formula of which is shown in Figure I. This class of compounds exhibits significant inhibitory activity against VEGFR and HDAC, and can be used to treat VEGFR and HDAC-mediated diseases such as tumors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a quinazoline derivative containing a benzofuran structure and its applications. Background Technology

[0002] Tumor growth depends on angiogenesis, and there is a close relationship between angiogenesis and tumor metastasis leading to death. Angiogenesis is regulated by many growth factors. Among these growth factors, vascular endothelial growth factor (VEGF) is one of the most potent and specific known angiogenesis factors. VEGF is a highly specific vascular endothelial mitogen that promotes the formation of blood vessels near tumor tissue by increasing vascular permeability, and has a strong stimulatory effect on endothelial cell proliferation. Therefore, it plays a crucial role in the proliferation and migration of tumor vascular endothelial cells. VEGF achieves various biological functions by binding to the high-affinity vascular endothelial growth factor receptor (VEGFR). During tumor growth, new blood vessels are needed to supply nutrients and excrete metabolites. The VEGF / VEGFR-mediated signaling cascade can regulate the proliferation, migration, and survival of vascular endothelial cells, causing changes in vascular permeability and controlling angiogenesis. When VEGF secreted by tumor cells binds to VEGFR, VEGFR is automatically phosphorylated, which then initiates downstream angiogenesis signaling pathways, causing tumor growth and proliferation. Therefore, inhibitors targeting the VEGF / VEGFR pathway can block tumor angiogenesis in various types of tumors, thereby inhibiting tumor growth and metastasis.

[0003] While VEGFR inhibitors can improve the survival rate of cancer patients, these drugs often lead to primary or acquired resistance in cancer treatment. The possible reason for resistance is that tumors escape through angiogenesis signaling pathways other than the VEGF / VEGFR pathway. Compared with other anti-tumor therapies, anti-angiogenic therapies directly target endothelial cells rather than tumor cells, thus only temporarily inhibiting tumor growth and metastasis, rather than completely eradicating the tumor. Combining anti-angiogenic drugs with traditional cytotoxic drugs or targeted anti-tumor drugs, as well as designing multi-target drugs, is a strategy to address these issues. Histone deacetylases (HDACs) are a class of proteases that play important roles in gene expression regulation and chromosome structural modification. Histone deacetylation makes the DNA wrapped around histones more tightly, making it difficult for gene transcription factors to access this DNA, ultimately inhibiting the expression of proteins related to cell differentiation, apoptosis, and tumor immunity, thereby inducing cancer. Silencing or inhibiting HDACs has significant effects on cell cycle, cell growth, chromatin isomerization, cell differentiation, apoptosis, and angiogenesis. Over the past two decades, HDAC has proven to be a highly attractive therapeutic target for cancer. Clinical studies have shown that a phase I trial combining a VEGFR inhibitor with an HDAC inhibitor demonstrated good therapeutic effects in patients (reference DOI:10.1007 / s10637-014-0174-6). However, multi-drug combination therapy suffers from problems such as significant side effects, difficulty in dose control, poor patient compliance, complex pharmacokinetic properties, and a high risk of drug-drug interactions. Based on these analyses, designing a class of dual-target small molecule inhibitors targeting both VEGFR and HDAC demonstrates significant research value and importance. Summary of the Invention

[0004] This invention provides a quinazoline derivative compound containing a benzofuran structure. This type of compound exhibits significant inhibitory activity against VEGFR and HDAC, respectively, and can be used to treat diseases mediated by the VEGF / VEGFR signaling pathway and HDAC.

[0005] The technical solution of the present invention is as follows:

[0006] A quinazoline derivative containing a benzofuran structure, the general structural formula of which is shown in Figure I.

[0007]

[0008] Where R1 is selected from methyl, ethyl, and isopropyl; R2 is selected from... R3 is selected from Where n = 3 - 5.

[0009] Preferably, a quinazoline derivative containing a benzofuran structure is selected from:

[0010] 6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0011] 6-((6-((7-(hydroxyamino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0012] 6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0013] 6-((6-((4-(((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0014] (E)-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0015] 6-((6-((6-((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0016] 6-((6-((7-(((2-aminophenyl)amino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0017] 6-((6-((8-(((2-aminophenyl)amino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0018] 6-((6-((4-(((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0019] (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide;

[0020] N-Ethyl-6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide;

[0021] N-Ethyl-6-((6-((7-(hydroxyamino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide;

[0022] N-Ethyl-6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide;

[0023] N-Ethyl-6-((6-((4-(hydroxycarbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide;

[0024] (E)-N-ethyl-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide;

[0025] 6-((6-((6-(((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide;

[0026] 6-((6-((7-(((2-aminophenyl)amino)-7-oxoheptyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide;

[0027] 6-((6-((8-(((2-aminophenyl)amino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide;

[0028] 6-((6-((4-((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide;

[0029] (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide;

[0030] 6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0031] 6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0032] 6-((6-((4-(hydroxycarbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0033] (E)-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0034] 6-((6-((6-(((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0035] 6-((6-((4-((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0036] (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide;

[0037] The present invention also provides the use of the quinazoline derivative containing the benzofuran structure in the preparation of VEGFR and / or HDAC pathway inhibitors.

[0038] The present invention also provides the use of the above-described compounds in the preparation of medicaments for inhibiting or treating VEGFR and / or HDACs-mediated diseases.

[0039] The applications described in this invention include the treatment of tumors associated with the VEGF signaling pathway.

[0040] The applications described in this invention include the treatment of HDACs-mediated tumor diseases.

[0041] The tumor diseases described in this invention include lung cancer, liver cancer, breast cancer, kidney cancer, stomach cancer, colorectal cancer, thyroid cancer, soft tissue sarcoma, leukemia, lymphoma, and myeloma. Attached Figure Description

[0042] Figure 1 This is a graph showing the relationship between the inhibition rate of HDAC1 and its concentration in Example 2.

[0043] Figure 2 This is a graph showing the relationship between the inhibition rate of VEGFR-2 and its concentration in Example 2. Detailed Implementation

[0044] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0045] All raw materials and reagents used in the following examples are commercially available analytical grade or chemically pure pharmaceutical products, and the proton NMR spectra of the compounds were determined using a Bruker ARX-400.

[0046] Synthetic routes of Examples 1-27:

[0047]

[0048] Preparation of intermediate i-1

[0049] At room temperature, 5.60 g (24 mmol) of 7-methoxy-4-oxo-3,4-dihydroquinazoline-6-ol acetate was added to 70 mL of SOCl2 and 1 mL of DMF. The mixture was stirred to dissolve and then heated to 80 °C for 4 h. As the reaction proceeded, the reaction solution gradually changed from gray and insoluble to orange and transparent. TLC analysis (petroleum ether: ethyl acetate = 8:1) showed that after the reaction was complete, the reaction solution was concentrated under reduced pressure to give 5.72 g of yellow solid, i.e., intermediate i-1, with a yield of 92%.

[0050] Preparation of intermediate i-2

[0051] At room temperature, intermediate i-1 (5.70 g, 23 mmol) was added to 60 mL of a THF-H2O (4:1 v / v) mixed solvent, and LiOH (1.10 g, 46 mmol) was added. The mixture was stirred at 35 °C for 1 hour. After the reaction was confirmed to be complete by TLC, the reaction solution was concentrated under reduced pressure to remove THF. Then, ice water was added, and the pH was adjusted to 3-4 with 1.0 M hydrochloric acid. The filter cake was collected by vacuum filtration and dried to obtain 4.75 g of yellow solid, i.e., intermediate i-2, with a yield of 86%.

[0052] Preparation of intermediate i-3a

[0053] At room temperature, intermediate i-2 (0.35 g, 1.6 mmol), Cs2CO3 (1.12 g, 3.1 mmol), and methyl bromide p-methylcinnamate (1.82 g, 0.8 mmol) were added to 3 mL of DMF and stirred at room temperature for 2 h. After the reaction was confirmed to be complete by TLC, the mixture was washed with water for 30 min and filtered to obtain 0.45 g of yellow solid, i.e., intermediate i-3a, with a yield of 74%. 1 H NMR(400MHz,Chloroform-d)δ8.88(s,1H),7.39(s,1H),7.35(s,1H),4.21(d,J=6.2Hz,2H ),4.07(s,3H),3.70(s,3H),2.40(s,2H),1.99(s,2H),1.77(s,2H),1.60(q,J=7.1Hz,2H).

[0054] Preparation of intermediate i-3b

[0055] At room temperature, intermediate i-2 (0.51 g, 2.3 mmol), Cs2CO3 (1.16 g, 3.5 mmol), and methyl 4-bromomethylbenzoate (0.71 g, 3.1 mmol) were used as raw materials. Following the preparation method of intermediate i-3a, 0.59 g of intermediate i-3b was prepared, with a yield of 72%. 1 H NMR(400MHz,Chloroform-d)δ8.88(s,1H),7.39(s,1H),7.35(d,J=3.7Hz,1H),4.26-4.16(m,2H),4.06(s,3H) ,3.68(s,3H),2.43-2.30(m,2H),2.02-1.93(m,2H),1.78-1.68(m,2H),1.62-1.53(m,2H),1.52-1.41(m,2H).

[0056] Preparation of intermediate i-3c

[0057] At room temperature, intermediate i-2 (1.25 g, 0.48 mmol), K₂CO₃ (1.39 g, 10.1 mmol), and methyl 6-bromohexanoate (2.11 g, 10.1 mmol) were added to 3 mL of acetonitrile, and the mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot, and the filtrate was subjected to thin-layer chromatography to obtain 1.22 g of yellow solid, i.e., intermediate i-3c, with a yield of 61%. 1H NMR(400MHz,Chloroform-d)δ8.86(s,1H),7.39(s,1H),7.35(s,1H),4.21(s,2H),4.02(s,3H),3.7 0(s,3H),2.41(q,J=6.6Hz,2H),2.00(q,J=6.8Hz,2H),1.78(q,J=7.1Hz,2H),1.61(t,J=7.2Hz,2H). 1 H NMR(500MHz,DMSO-d6)δ8.86(s,1H),7.44(s,1H),7.36(s,1H),4.17(t,J=6.5Hz,2H),4.01(s,3H),3.58(s,3H),2.30 (t,J=7.4Hz,2H),1.81(p,J=6.8Hz,2H),1.60-1.50(m,2H),1.50-1.41(m,2H),1.40-1.32(m,2H),1.32-1.24(m,2H).

[0058] Preparation of intermediate i-3d

[0059] At room temperature, intermediate i-2 (0.61 g, 2.8 mmol), K₂CO₃ (0.67 g, 2.5 mmol), and methyl 7-bromoheptanoate (1.08 g, 4.8 mmol) were added to 7 mL of acetonitrile, and the mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot, and the filtrate was subjected to thin-layer chromatography to obtain 0.62 g of a yellow solid, i.e., intermediate i-3d, with a yield of 63%.

[0060] Preparation of intermediate i-3e

[0061] At room temperature, intermediate i-2 (0.3 g, 1.4 mmol), K₂CO₃ (0.34 g, 2.5 mmol), and methyl 8-bromooctanoate (0.6 g, 2.5 mmol) were added to 7 mL of acetonitrile, and the mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot, and the filtrate was subjected to thin-layer chromatography to obtain 0.33 g of a yellow solid, i.e., intermediate i-3e, with a yield of 65%.

[0062] Preparation of intermediate i-4

[0063] At room temperature, 10.12 g (66 mmol) of 2-hydroxy-4-methoxybenzaldehyde, 14.11 g (101 mmol) of K₂CO₃, and 9.4 mL (72.6 mmol) of 2-bromopropionate were added to 40 mL of DMF, and the mixture was stirred at room temperature for 2 h. The reaction mixture changed from pale yellow to green, and finally to yellow. After the reaction was confirmed to be complete by TLC, 40 mL of ice water was added to the reaction solution, and the mixture was stirred for 30 min. The solution was then extracted with ethyl acetate (3 × 40 mL), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give 9.98 g of colorless liquid, i.e., intermediate i-4, yield: 60%. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 10.28 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 6.68 (dd, J = 8.7, 1.5 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 5.25 (q, J = 6.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). Preparation of intermediate i-5: At room temperature, intermediate i-4 (10.00 g, 40 mmol) and NaOH (2.00 g, 50 mmol) were added to 40 mL of ethanol. The reaction system changed from brown to light brown. After stirring for 1 hour and TLC detection showed that the reaction was complete, the reaction solution was poured into 100 mL of water, and the pH was adjusted to 2-3 with 1.0 M hydrochloric acid. After stirring for 30 min, a large amount of white solid precipitated out. After filtration and drying, 7.91 g of white solid, i.e. intermediate i-5, was obtained, with a yield of 89%. 1 H NMR(500MHz,DMSO-d6)δ10.27(s,1H),7.68(d,J=8.7Hz,1H),6.69(dd,J=8.7,2.2Hz, 1H), 6.59 (d, J = 2.2Hz, 1H), 5.15 (q, J = 6.8Hz, 1H), 3.83 (s, 3H), 1.57 (d, J = 6.7Hz, 3H).

[0064] Preparation of intermediate i-6

[0065] At room temperature, intermediate i-5 (8.89 g, 40 mmol) and NaOAc (9.84 g, 120 mmol) were added to 30 mL of acetic anhydride, and the mixture was refluxed and stirred for 2 h. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature and poured into 100 mL of ice water. The solution was neutralized with 1.0 M sodium hydroxide in an ice bath and stirred for 30 min. The solution was extracted three times with ethyl acetate (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 5.16 g of brown liquid, i.e., intermediate i-6, with a yield of 80%. 1 H NMR (500MHz, DMSO-d6) δ7.37(d,J=8.4Hz,1H),7.10(d,J=1.5Hz,1H),6.81(dd,J=8.5,2.3Hz,1H),6.52-6.34(m,1H),3.77(s,3H),2.39(d,J=1.2Hz,3H).

[0066] Preparation of intermediate i-7

[0067] At 0°C, AlCl3 (15.11 g, 110 mmol) was added to dichloromethane (50 mL), followed by dropwise addition of oxaloyl chloride (9.6 mL, 110 mmol). After the addition was complete, stirring was continued for 30 min, and the mixture was kept below 0°C. Intermediate i-6 (7.62 g, 0.047 mol) was then added. The reaction mixture changed from yellow to wine red. After the addition was complete, the mixture was heated to room temperature and stirred for 30 min. The reaction was confirmed to be complete by TLC. The dichloromethane was then concentrated, and ice water was added. After stirring for 30 min, the mixture was filtered to obtain 7.86 g of green precipitate, i.e., intermediate i-7, with a yield of 82%. 1 HNMR (500MHz, DMSO-d6) δ7.74(d,J=8.6Hz,1H),7.20(d,J=2.3Hz,1H),6.93(dd,J=8.7,2.3Hz,1H),3.80(s,3H),2.69(s,3H).

[0068] Preparation of intermediate i-8

[0069] At temperatures below 0°C, intermediate i-7 (3.25 g, 15 mmol) was added to 20 mL of dichloromethane solution. While stirring, boron tribromide (7.58 mL, 75 mmol) was added dropwise, with the temperature maintained below 0°C throughout the addition. After the addition was complete, the mixture was heated to room temperature and stirred for 1 h. The reaction system changed from yellow to wine red. After TLC analysis confirmed the reaction was complete, the reaction solution was poured into ice water (50 mL), resulting in the precipitation of a large amount of brown solid. Stirring continued until no more bubbles were released. Filtering yielded 2.51 g of brown solid, intermediate i-8, with a yield of 87%.

[0070] Preparation of intermediate i-9a

[0071] At room temperature, intermediate i-8 (0.54 g, 2.8 mmol) was dissolved in 5 mL of DMF. HATU (1.8 g, 4.2 mmol) and DIEA (1.16 mL, 5.6 mmol) were added sequentially, and the reaction mixture changed from brown to yellow. Finally, an aqueous solution of methylamine (0.42 mL, 5.6 mmol) was added. The reaction solution turned brown, and the mixture was stirred at room temperature for 1 h. After the reaction was confirmed to be complete by TLC, 20 mL of ice water was added, and the mixture was extracted three times with dichloromethane (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 0.43 g of yellow solid, i.e., intermediate i-9a, with a yield of 70%. 1 H NMR (500MHz, DMSO-d6) δ9.63 (s, 1H), 7.79 (d, J = 4.7Hz, 1H), 7.51 (d, J = 8.5Hz, 1H), 6. 89(d,J=2.1Hz,1H),6.77(dd,J=8.5,2.1Hz,1H),2.79(d,J=4.6Hz,3H),2.55(s,3H).

[0072] Intermediate i-9b was prepared using intermediate i-8 (0.3 g, 1.5 mmol) and ethylamine (0.08 g, 1.9 mmol) as raw materials, and following the preparation method of intermediate i-9a, 0.26 g of intermediate i-9b was obtained, with a yield of 77%. 1 H NMR(400MHz,Chloroform-d)δ7.50-7.38(m,1H),6.98(d,J=3.7Hz,1H),6.89-6.81 (m,1H),5.86(s,1H),5.40(s,1H),3.56(d,J=6.0Hz,2H),2.70(s,3H),1.30(s,3H).

[0073] Intermediate i-9c was prepared using intermediate i-8 (1 g, 5.2 mmol) and isopropylamine (0.94 mL, 10.4 mmol) as raw materials, and following the preparation method of intermediate i-9a, 0.91 g of intermediate i-9c was obtained, with a yield of 75%. 1 H NMR(500MHz,Chloroform-d)δ7.39(d,J=8.5Hz,1H),6.99(d,J=2.2Hz,1H),6.88(dd,J=8.5 ,2.2Hz,1H),5.77(d,J=8.0Hz,1H),4.42-4.29(m,1H),2.68(s,3H),1.32(d,J=6.5Hz,6H).

[0074] Preparation of intermediate 10a

[0075] A mixture of intermediates i-3c (0.12 g, 0.35 mmol) and i-9a (0.09 g, 0.44 mmol) was placed in 3 mL of acetonitrile, followed by the addition of K₂CO₃ (0.071 g, 0.51 mmol). The mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot. The filtrate was subjected to thin-layer chromatography to obtain 0.12 g of a yellow solid, i.e., intermediate i-10a, with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.99(s,1H),7.81(t,J=8.8Hz,3H),7.75(s,1H),7.70(d,J=16.0Hz,1H),7.63(s,1H),7. 58(d,J=7.2Hz,2H),7.43(s,1H),7.26(s,1H),6.66(s,1H),5.37(s,2H),4.02(s,3H),3.74(s,3H),2.84(s,3H),2.66(s,3H).

[0076] Preparation of intermediate i-10b

[0077] A mixture of intermediates i-3c (0.56 g, 1.7 mmol) and i-9b (0.36 g, 1.7 mmol) was placed in 3 mL of acetonitrile, followed by the addition of K₂CO₃ (0.38 g, 2.8 mmol). The mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot. The filtrate was subjected to thin-layer chromatography to obtain 0.62 g of a yellow solid, i.e., intermediate i-10b, with a yield of 72%.

[0078] Preparation of intermediate i-10c

[0079] A mixture of intermediates i-3c (0.78 g, 2.3 mmol) and i-9c (0.53 g, 2.3 mmol) was placed in 3 mL of acetonitrile, followed by the addition of K₂CO₃ (0.54 g, 3.9 mmol). The mixture was stirred at 80 °C for 8 h. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered while hot. The filtrate was subjected to thin-layer chromatography to obtain 0.96 g of a yellow solid, i.e., intermediate i-11c, with a yield of 78%.

[0080] Preparation of intermediate i-10d

[0081] Using intermediate 3d (2.1 g, 5.8 mmol) and i-9a (1.2 g, 5.8 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 2.18 g of intermediate i-10d can be prepared, with a yield of 67%.

[0082] Preparation of intermediate i-10e

[0083] Using intermediates 3d (0.25 g, 0.71 mmol) and 9b (0.16 g, 0.71 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 0.24 g of intermediate i-10e can be prepared with a yield of 63%. 1 H NMR(400MHz,Chloroform-d)δ8.62(s,1H),7.73(d,J=6.7Hz,1H),7.58(s,1H),7.42( s,1H),7.34(s,1H),7.29(s,2H),7.24(d,J=8.3Hz,1H),5.90(d,J=6.2Hz,1H),4.22(s ,2H),4.07(s,3H),3.68(s,3H),3.58(q,J=6.2Hz,2H),2.76(s,3H),2.36(s,2H),2.00 (d,J=9.8Hz,2H),1.70(d,J=8.4Hz,2H),1.58(s,2H),1.52-1.43(m,2H),1.33(s,3H).

[0084] Preparation of intermediate i-10f

[0085] Using intermediates i-3d (1.51 g, 4.3 mmol) and i-9c (0.99 g, 4.3 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 2.33 g of intermediate i-10f can be prepared, with a yield of 63%.

[0086] Preparation of intermediate i-10g

[0087] Using intermediates i-3e (2.42 g, 6.6 mmol) and i-9a (1.36 g, 6.6 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 2.37 g of intermediate i-10g can be prepared, with a yield of 67%.

[0088] Preparation of intermediate i-10h

[0089] Using intermediates i-3e (1.24 g, 0.34 mmol) and i-9b (0.74 g, 0.34 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.26 g of intermediate i-10h can be prepared with a yield of 68%.

[0090] Preparation of intermediate i-10i

[0091] Using intermediates i-3e (1.49 g, 4.1 mmol) and i-9c (0.95 g, 4.1 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.44 g of intermediate i-10i can be prepared, with a yield of 63%.

[0092] Preparation of intermediate i-10j

[0093] Using intermediates i-3a (1.78 g, 4.6 mmol) and i-9a (0.95 g, 4.6 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.72 g of intermediate i-10j can be prepared, with a yield of 67%.

[0094] Preparation of intermediate i-10k

[0095] Using intermediates i-3a (1.38 g, 3.5 mmol) and i-9b (0.78 g, 3.5 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.22 g of intermediate i-10k can be prepared, with a yield of 60%. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.04(d,J=7.9Hz,2H),7.98(s,1H),7.82(d,J=7.6Hz,1H),7.77(s,1H),7.69(d,J=7.8 Hz,2H),7.63(s,1H),7.45(s,1H),7.25(d,J=8.5Hz,1H),5.45(s,2H),4.03(s,3H),3.88(s,3H),2.84(s,3H),2.65(s,3H).

[0096] Preparation of intermediate i-10l

[0097] Using intermediates i-3a (1.15 g, 2.99 mmol) and i-9c (0.71 g, 3.04 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.21 g of intermediate i-10l can be prepared, with a yield of 69%.

[0098] Preparation of intermediate i-10m

[0099] Using intermediates i-3b (1.22 g, 3.4 mmol) and i-9a (0.69 g, 3.4 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.11 g of intermediate i-10m can be prepared, with a yield of 62%. 1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.98(s,1H),7.79(d,J=8.2Hz,3H),7.75(s,1H),7.70(d,J=16.1Hz,1H),7.63(s,1H),7.58(d,J=7 .8Hz,2H),7.43(s,1H),7.25(d,J=8.3Hz,1H),6.68(d,J=13.5Hz,1H),5.37(s,2H),4.02(s,3H),3.74(s,3H),2.84(s,3H),2.65(s,3H).

[0100] Preparation of intermediate i-10n

[0101] Using intermediates i-3b (1.25 g, 3.5 mmol) and i-9b (0.76 g, 3.5 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.24 g of intermediate i-10n can be prepared, with a yield of 66%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.55 (s, ¹H), 8.04 (d, J = 7.4Hz, 2H), 7.99 (s, ¹H), 7.82 (d, J = 8.7Hz, 1H), 7.77 (s, ¹H), 7.68 (d, J = 7.3Hz, 2H), 7.63 (s, ¹H), 7.45 (s, ¹H), 7.25 (d, J = 7.6Hz, 1H), 5.45 (s, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 2.84 (s, 3H), 2.65 (s, 3H). 3.2.30. Preparation of intermediate i-10o

[0102] Using intermediates i-3b (1.07 g, 2.99 mmol) and i-9c (0.68 g, 2.92 mmol) as raw materials, and referring to the preparation method of intermediate i-10a, 1.11 g of intermediate i-10o can be prepared, with a yield of 69%.

[0103] Preparation of intermediate i-11a

[0104] At room temperature, intermediate i-10a (1.72 g, 3.4 mmol) was added to THF / H2O (4:1, 20 mL), followed by LiOH (0.33 g, 13.61 mmol). The mixture was stirred at 35 °C for 8 h. After the reaction was confirmed to be complete by TLC, the THF was evaporated to dryness, and the mixture was filtered. The filter cake was collected, dried, and subjected to thin-layer chromatography to obtain 1.32 g of yellow solid, which was intermediate i-11a, with a yield of 79%.

[0105] Preparation of intermediate i-11b

[0106] Intermediate i-10b (1.18 g, 2.26 mmol) was dissolved in 20 mL of THF / H2O (4:1), and then LiOH (0.21 g, 8.75 mmol) was added. Following the preparation method of intermediate i-11a, 0.88 g of intermediate i-11b was obtained, with a yield of 77%.

[0107] Preparation of intermediate i-11c

[0108] Intermediate i-10c (1.28 g, 2.39 mol) was dissolved in 20 mL of THF / H2O (4:1), and then LiOH (0.23 g, 9.57 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 0.97 g of intermediate i-11c was obtained, with a yield of 78%.

[0109] Preparation of intermediate i-11d

[0110] Intermediate i-10d (1.79 g, 3.2 mmol) was dissolved in 20 mL of THF / H2O (4:1), and then LiOH (0.31 g, 12.9 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 1.39 g of intermediate i-11d was obtained, with a yield of 80%.

[0111] Preparation of intermediate i-11e

[0112] Intermediate i-10e (1.21 g, 2.26 mol) was dissolved in 20 mL of THF / H2O (4:1), and then LiOH (0.22 g, 9.04 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 0.99 g of intermediate i-11e was obtained, with a yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 11.2Hz, 1H), 7.6 3(s,1H),7.59(s,1H),7.39(s,1H),7.26(d,J=8.4Hz,1H),4.17(s,2H),4.00( s,3H),2.64(s,3H),2.26-2.20(m,2H),1.82(t,J=7.3Hz,2H),1.54(t,J=7.5H z,2H),1.50-1.43(m,2H),1.40-1.33(m,2H),1.24(s,2H),1.20-1.15(m,3H).

[0113] Preparation of intermediate i-11f

[0114] Intermediate i-10f (0.92 g, 1.68 mmol) was dissolved in 15 mL of THF / H2O (4:1), and then LiOH (0.16 g, 6.51 mmol) was added. Following the preparation method of intermediate i-11a, 0.75 g of intermediate i-11f was obtained, with a yield of 84%.

[0115] Preparation of intermediate i-11g

[0116] Intermediate i-10g (0.88g, 1.64mmol) was dissolved in 15mL of THF / H2O (4:1), and then LiOH (0.16g, 6.51mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 0.73g of intermediate i-11g was obtained, with a yield of 86%.

[0117] Preparation of intermediate i-11h

[0118] Intermediate i-10h (1.62 g, 2.95 mmol) was dissolved in 15 mL of THF / H2O (4:1), and then LiOH (0.28 g, 11.8 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 1.33 g of intermediate i-11h was obtained, with a yield of 84%.

[0119] Preparation of intermediate i-11i

[0120] By dissolving intermediate i-11i (1.38 g, 2.45 mol) in 15 mL of THF / H2O (4:1), and then adding LiOH (0.23 g, 9.81 mmol) as a raw material, and referring to the preparation method of intermediate i-11a, 1.17 g of intermediate i-11i can be prepared, with a yield of 87%.

[0121] Preparation of intermediate i-11j

[0122] Intermediate i-10j (1.29 g, 2.33 mol) was dissolved in 15 mL of THF / H2O (4:1), and then LiOH (0.22 g, 9.31 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 1.11 g of intermediate i-11j was obtained, with a yield of 88%.

[0123] Preparation of intermediate i-11k

[0124] By dissolving intermediate i-10k (0.86 g, 1.52 mmol) in 15 mL of THF / H2O (4:1), and then adding LiOH (0.5 g, 6.07 mmol) as a starting material, and referring to the preparation method of intermediate i-11a, 0.73 g of intermediate i-11k can be prepared with a yield of 87%.

[0125] Preparation of intermediate i-11l

[0126] By dissolving intermediate i-10l (1.66 g, 2.86 mol) in 15 mL of THF / H2O (4:1), and then adding LiOH (0.27 g, 11.41 mmol) as a raw material, and referring to the preparation method of intermediate i-11a, 1.42 g of intermediate i-11l can be prepared, with a yield of 88%.

[0127] Preparation of intermediate i-11m

[0128] Intermediate i-10m (1.36 g, 2.5 mmol) was dissolved in 15 mL of THF / H2O (4:1), and then LiOH (0.25 g, 10.32 mmol) was added. Following the preparation method of intermediate i-11a, 1.17 g of intermediate i-11m was obtained, with a yield of 89%.

[0129] Preparation of intermediate i-11n

[0130] By dissolving intermediate i-10n (1.80 g, 3.33 mmol) in 20 mL of THF / H2O (4:1), and then adding LiOH (0.32 g, 13.32 mmol) as a raw material, and referring to the preparation method of intermediate i-11a, 1.38 g of intermediate i-11n can be prepared, with a yield of 79%.

[0131] Preparation of intermediate i-11o

[0132] Intermediate i-11o (1.64 g, 2.95 mmol) was dissolved in 20 mL of THF / H2O (4:1), and then LiOH (0.28 g, 11.81 mmol) was added as a raw material. Following the preparation method of intermediate i-11a, 1.34 g of intermediate i-12o was obtained, with a yield of 84%.

[0133] Example 1

[0134] At room temperature, hydroxylamine hydrochloride (24 mg, 0.36 mmol) and DIEA (58 μl, 0.36 mmol) were added to 2 mL of DMF and stirred at 35 °C for 1 h to prepare solution A. i-11a (0.12 g, 0.23 mmol) was added to 2 mL of DMF and stirred at room temperature until dissolved. Then, HATU (0.13 g, 0.36 mmol) and DIEA (77 μL, 0.48 mmol) were quickly added, and stirring continued for 3-5 min. TLC confirmed that the acid had been completely converted to the active ester, which was then added dropwise to solution A. After the addition was complete, the reaction continued for 1 h. TLC confirmed the reaction was complete, and 10 mL of ice water was added to the reaction solution. The mixture was filtered to obtain a white solid, which was dried to obtain 0.08 g of white powder, i.e., Example 1, with a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.70(s,1H),8.53(s,1H),7.99(q,J=4.5Hz,1H ),7.81(d,J=8.5Hz,1H),7.63(d,J=2.1Hz,1H),7.59(s,1H),7.39(s,1H),7.25(dd,J =8.5,2.1Hz,1H),4.17(t,J=6.4Hz,2H),4.00(s,3H),2.84(d,J=4.5Hz,3H),2.65(s, 3H), 1.99 (t, J = 7.3Hz, 2H), 1.86-1.77 (m, 2H), 1.64-1.55 (m, 2H), 1.48-1.39 (m, 2H).

[0135] Example 2

[0136] Using intermediate i-11d (0.25 g, 0.49 mmol) as a raw material, and following the preparation method of Example 1, 0.15 g of white solid final product Example 2 can be prepared, with a yield of 60%. 1H NMR (500MHz, DMSO-d6) δ10.43(s,1H),8.73(s,1H),8.50(s,1H),8.02(d,J=4.7Hz,1H),7.79( d,J=8.5Hz,1H),7.59(d,J=2.1Hz,1H),7.54(s,1H),7.35(s,1H),7.23(dd,J=8.5,2.2Hz,1H) ,4.13(t,J=6.5Hz,2H),3.98(s,3H),2.83(d,J=4.4Hz,3H),2.63(s,3H),1.96(t,J=7.3Hz,2H ),1.79(t,J=7.4Hz,2H),1.51(p,J=7.5Hz,2H),1.43(t,J=7.7Hz,2H),1.32(q,J=8.2Hz,2H).

[0137] Example 3

[0138] Using intermediate i-11g (0.56g, 1.07mmol) as a raw material, and referring to the preparation method of Example 1, 0.35g of final product Example 3 can be prepared, with a yield of 60%. 1 H NMR (500MHz, DMSO-d6) δ10.34(s,1H),8.67(s,1H),8.52(s,1H),7.99(d,J=4.7Hz,1H),7.81(d ,J=8.4Hz,1H),7.62(d,J=2.1Hz,1H),7.58(s,1H),7.39(s,1H),7.25(dd,J=8.5,2.1Hz,1H),4 .17(t,J=6.5Hz,2H),4.00(s,3H),2.84(d,J=4.5Hz,3H),2.65(s,3H),1.95(t,J=7.3Hz,2H),1 .83-1.77(m,2H),1.54-1.48(m,2H),1.47-1.42(m,2H),1.38-1.33(m,2H),1.30-1.24(m,2H).

[0139] Example 4

[0140] Using intermediate i-11j (0.44 g, 0.81 mmol) as a raw material, and following the preparation method of Example 1, 0.33 g of white solid, i.e. Example 4, can be prepared with a yield of 73%. 1H NMR (400MHz, DMSO-d6) δ11.27(s,1H),9.09(s,1H),8.55(s,1H),8.00(s,1H),7.81(t,J=5.8Hz,3H),7.76(s, 1H),7.63(s,2H),7.60(s,2H),7.44(s,1H),7.26(s,1H),5.39(s,2H),4.02(s,3H),2.84(s,3H),2.65(s,3H).

[0141] Example 5

[0142] Using intermediate i-11m (0.44 g, 0.86 mmol) as a raw material, and following the preparation method of Example 1, 0.28 g of final product Example 5 can be prepared, with a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.05(s,1H),8.56(s,1H),7.99(s,1H),7.82(s,1H),7.75(s,1H),7.63(s,3H),7.57(s,2H ),7.49(d,J=16.1Hz,1H),7.43(s,1H),7.25(s,1H),6.50(d,J=15.0Hz,1H),5.35(s,2H),4.01(s,3H),2.84(s,3H),2.65(s,3H).

[0143] Example 6

[0144] At room temperature, i-11a (0.15 g, 0.30 mmol) was added to 4 mL of DMF and stirred to dissolve. Then, HATU (0.16 g, 0.42 μL), DIEA (140 mg, 0.84 mmol), and o-phenylenediamine (46 mg, 0.42 mmol) were added sequentially, and the mixture was stirred for 1 h. After the reaction was confirmed to be complete by TLC, 15 mL of ice water was added, and the mixture was filtered to obtain a white solid. After drying, 0.13 g of white powder was obtained, which is Example 6, yield: 73%. 1H NMR (500MHz, DMSO-d6) δ9.11(s,1H),8.52(s,1H),7.97(d,J=4.6Hz,1H),7.81(d,J=8.5Hz,1H),7.61(d,J=2.1H z,1H),7.58(s,1H),7.38(s,1H),7.25(dd,J=8.5,2.2Hz,1H),7.15(d,J=6.1Hz,1H),6.89(t,J=6.8Hz,1H),6.7 2(d,J=6.5Hz,1H),6.53(t,J=6.8Hz,1H),4.17(t,J=6.5Hz,2H),4.00(s,3H),2.84(d,J=4.4Hz,3H),2.65(s,3H ), 2.33 (t, J = 7.4Hz, 2H), 1.83 (p, J = 6.7Hz, 2H), 1.62 (p, J = 7.3Hz, 2H), 1.48 (q, J = 7.3Hz, 2H), 1.41-1.37 (m, 2H).

[0145] Example 7

[0146] Using intermediate i-11d (0.32 g, 0.63 mmol) as a raw material, and referring to the preparation method of Example 6, 0.28 g of white solid, i.e. Example 7, can be prepared with a yield of 74%. 1 H NMR (500MHz, DMSO-d6) δ9.11(s,1H),8.52(s,1H),7.97(d,J=4.6Hz,1H),7.81(d,J=8.6Hz,1H),7.62(d,J=2.1Hz,1H) ,7.58(s,1H),7.38(s,1H),7.25(dd,J=8.5,2.1Hz,1H),7.16(dd,J=7.8,1.6Hz,1H),6.88(td,J=7.6,1.6Hz,1H),6.7 2(dd,J=8.0,1.5Hz,1H),6.52(td,J=7.5,1.5Hz,1H),4.18(t,J=6.5Hz,2H),4.00(s,3H),2.84(d,J=4.4Hz,3H),2.65 (s,3H),2.34(t,J=7.4Hz,2H),1.89-1.78(m,2H),1.71-1.59(m,2H),1.58-1.47(m,2H),1.43(td,J=8.3,3.9Hz,2H).

[0147] Example 8

[0148] Using intermediate i-11g (0.30g, 0.58mmol) as a raw material, and referring to the preparation method of Example 6, 0.27g of white solid, i.e. Example 7, can be prepared with a yield of 77%. 1 H NMR (500MHz, DMSO-d6) δ9.13(s,1H),8.52(s,1H),7.98(q,J=4.6Hz,1H),7.81(d,J=8.5Hz,1H),7.62(d,J=2.1H z,1H),7.60(s,1H),7.39(s,1H),7.25(dd,J=8.5,2.1Hz,1H),7.16(dd,J=7.8,1.6Hz,1H),6.89(td,J=7.6,1.6H z,1H),6.72(dd,J=8.0,1.5Hz,1H),6.53(td,J=7.5,1.5Hz,1H),4.20(t,J=6.5Hz,2H),4.00(s,3H),2.84(d,J= 4.5Hz,3H),2.65(s,3H),2.37(t,J=7.4Hz,2H),1.87(p,J=6.8Hz,2H),1.71(p,J=7.6Hz,2H),1.58-1.49(m,2H).

[0149] Example 9

[0150] Using intermediate i-11j (0.29 g, 0.53 mmol) as a raw material, and referring to the preparation method of Example 6, 0.25 g of white solid, i.e. Example 9, can be prepared with a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.56 (s, 1H), 8.05 (d, J = 7.9Hz, 2H), 7.99 (s, 1H), 7 .83(d,J=8.4Hz,1H),7.79(s,1H),7.68(s,1H),7.65(d,J=6.4Hz,2H),7.46(s,1H),7.2 6(d,J=8.5Hz,1H),7.19(d,J=7.9Hz,1H),6.99(t,J=7.7Hz,1H),6.80(d,J=8.0Hz,1H), 6.61(t,J=7.7Hz,1H),5.44(s,2H),4.93(s,2H),4.04(s,3H),2.84(s,3H),2.66(s,3H).

[0151] Example 10

[0152] Using intermediate i-11m (0.41 g, 0.84 mmol) as a raw material, and referring to the preparation method of Example 6, 0.42 g of white solid, i.e. Example 10, can be prepared with a yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.55(s,1H),8.00(s,1H),7.79(d,J=13.5Hz,2H),7.69(s,2H),7.61(s,4H),7.45(s,1H),7.35(s ,1H),7.27(s,1H),6.94(d,J=13.6Hz,2H),6.77(s,1H),6.59(s,1H),5.37(s,2H),4.97(s,2H),4.02(s,3H),2.84(s,3H),2.65(s,3H).

[0153] Example 11

[0154] Using intermediate i-11b (0.12 g, 0.24 mmol) as a raw material, and following the preparation method of Example 1, 0.09 g of white solid, i.e. Example 11, can be prepared with a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.69(s,1H),8.52(s,1H),8.09(s,1H), 7.79(d,J=5.1Hz,1H),7.61(dd,J=13.1,3.8Hz,2H),7.39(s,1H),7.26(d,J=7. 4Hz,1H),4.17(s,2H),4.00(s,3H),3.35(s,2H),2.64(s,3H),1.98(d,J=6.5H z,2H),1.81(d,J=9.2Hz,2H),1.60(s,2H),1.45(s,2H),1.18(q,J=6.4Hz,3H).

[0155] Example 12

[0156] Using intermediate i-11e (0.22 g, 0.42 mmol) as a raw material, and following the preparation method of Example 1, 0.18 g of white solid, i.e. Example 12, can be prepared with a yield of 70%. 1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.68(s,1H),8.52(s,1H),8.10(s,1H),7.7 8(d,J=8.4Hz,1H),7.63(s,1H),7.59(s,1H),7.39(s,1H),7.26(d,J=8.5Hz,1H),4 .17(s,2H),4.00(s,3H),2.64(s,3H),2.04-1.88(m,2H),1.87-1.74(m,2H),1.53 (t,J=7.7Hz,2H),1.45(q,J=7.7Hz,2H),1.40-1.28(m,2H),1.17(t,J=7.2Hz,3H).

[0157] Example 13

[0158] Using intermediate i-11h (0.42 g, 0.78 mmol) as a raw material, and following the preparation method in Example 1, 0.29 g of white solid, i.e., Example 13, can be prepared with a yield of 67%. 1 H NMR (400MHz, Chloroform-d) δ15.10 (s, 1H), 13.43 (s, 1H), 13.27 (s, 1H), 12.85 (t, J = 5.5Hz, 1H), 12. 53(d,J=8.5Hz,1H),12.37(s,1H),12.34(s,1H),12.14(s,1H),12.00(d,J=8.5Hz,1H),8.92(t,J=6. 5Hz,2H),8.75(s,3H),8.07(s,2H),7.39(s,3H),6.70(t,J=7.4Hz,2H),6.56(t,J=7.2Hz,2H),6.31- 6.23(m,2H),6.22-6.16(m,2H),6.11(t,J=7.6Hz,2H),6.00(d,J=12.2Hz,2H),5.92(t,J=7.2Hz,3H).

[0159] Example 14

[0160] Using intermediate i-11k (0.22 g, 0.40 mmol) as a raw material, and following the preparation method in Example 1, 0.16 g of white solid, i.e., Example 14, can be prepared with a yield of 70%. 1H NMR(500MHz,DMSO-d6)δ8.54(s,1H),8.10(t,J=5.7Hz,1H),8.02(s,1H),8.00( s,1H),7.79(d,J=8.5Hz,1H),7.76(s,1H),7.66(s,1H),7.64(s,1H),7.62(d,J =2.2Hz,1H),7.44(s,1H),7.25(dd,J=8.5,2.2Hz,1H),5.42(s,2H),4.02(s,3H ),3.34-3.32(m,2H),2.64(s,3H),1.23(d,J=6.2Hz,1H),1.17(t,J=7.1Hz,3H).

[0161] Example 15

[0162] Using intermediate i-11n (0.26 g, 0.49 mmol) as a raw material, and following the preparation method in Example 1, 0.18 g of white solid, i.e., Example 15, can be prepared with a yield of 67%. 1 H NMR(500MHz,DMSO-d6)δ8.82(s,1H),8.10(t,J=5.6Hz,1H),7.85(s,1H),7.82(d,J=8.5Hz, 1H),7.75(dd,J=17.2,8.1Hz,1H),7.66(d,J=2.1Hz,1H),7.63(d,J=8.0Hz,1H),7.57(d,J= 8.1Hz,2H),7.50(s,1H),7.47(d,J=2.7Hz,1H),7.29(dd,J=8.5,2.1Hz,1H),6.51(d,J=15. 8Hz,1H),5.39(s,2H),4.05(s,3H),3.38-3.29(m,2H),2.65(s,3H),1.18(t,J=7.2Hz,3H).

[0163] Example 16

[0164] Using intermediate i-11b (0.28 g, 0.55 mmol) as a raw material, and referring to the preparation method of Example 6, 0.25 g of white solid, i.e. Example 16, can be prepared with a yield of 76%. 1H NMR (500MHz, DMSO-d6) δ9.13(s,1H),8.52(s,1H),8.10(t,J=5.6Hz,1H),7.78(d,J=8.5Hz,1H),7.62(d,J=2.1Hz,1H) ,7.60(s,1H),7.39(s,1H),7.26(dd,J=8.5,2.1Hz,1H),7.16(dd,J=7.7,1.6Hz,1H),6.92-6.85(m,1H),6.71(d,J=6. 6Hz,1H),6.53(t,J=7.3Hz,1H),4.84(s,1H),4.20(t,J=6.5Hz,2H),4.00(s,3H),3.34(d,J=5.0Hz,2H),2.64(s,3H), 2.36(d,J=7.4Hz,2H), 1.87(p,J=6.7Hz,2H), 1.70(p,J=7.5Hz,2H), 1.53(h,J=7.4,6.3Hz,2H), 1.18(t,J=7.2Hz,3H).

[0165] Example 17

[0166] Using intermediate i-11e (0.21 g, 0.40 mmol) as a raw material, and referring to the preparation method of Example 6, 0.19 g of white solid, namely Example 17, can be prepared with a yield of 77%. 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.53(s,1H),8.09(t,J=5.4Hz,1H),7.79(d,J=8.5Hz,1H),7.63(s,1H) ,7.60(s,1H),7.40(s,1H),7.26(d,J=8.5Hz,1H),7.15(d,J=7.8Hz,1H),6.88(t,J=7.5Hz,1H),6.71(d,J=7. 9Hz,1H),6.52(t,J=7.5Hz,1H),4.82(s,2H),4.19(t,J=6.2Hz,2H),4.01(s,3H),2.65(s,3H),2.34(t,J=7. 3Hz,2H),1.92-1.77(m,2H),1.71-1.58(m,2H),1.58-1.47(m,2H),1.47-1.37(m,2H),1.18(t,J=7.1Hz,3H).

[0167] Example 18

[0168] Using intermediate i-11h (0.24 g, 0.45 mmol) as a raw material, and following the preparation method in Example 6, 0.19 g of white solid, i.e., Example 18, can be prepared with a yield of 68%. 1 H NMR (500MHz, DMSO-d6) δ9.34(s,1H),8.51(s,1H),8.21-8.09(m,1H),7.78(d,J=8.5Hz,1H),7.61(dd,J=5.8,2.7Hz,2H),7.57(d, J=4.5Hz,1H),7.37(d,J=2.7Hz,1H),7.33-7.28(m,1H),7.24(dt,J=8.5,1.3Hz,1H),7.18(dd,J=7.9,1.6Hz,1H),6.89-6.81(m,1 H),6.71(d,J=7.9Hz,1H),6.59-6.46(m,1H),4.16(d,J=6.5Hz,2H),3.99(d,J=5.1Hz,3H),2.63(s,3H),2.35(t,J=7.5Hz,2H),1. 82(dt,J=14.2,7.1Hz,2H),1.46(s,2H),1.38(s,2H),1.34(d,J=24.4Hz,2H),1.28(dd,J=13.9,6.9Hz,2H),1.17(t,J=7.1Hz,3H).

[0169] Example 19

[0170] Using intermediate i-11k (0.29 g, 0.52 mmol) as a raw material, and referring to the preparation method in Example 6, 0.26 g of white solid, i.e. Example 19, can be prepared with a yield of 77%. 1 H NMR (400MHz, DMSO-d6) δ9.71(s,1H),8.55(s,1H),8.10(t,J=5.7Hz,1H),8.05(s,1H),8.03(s,1 H),7.80(d,J=9.4Hz,2H),7.68(s,1H),7.66(s,1H),7.64(d,J=2.0Hz,1H),7.45(s,1H),7.26(d, J=8.4Hz,1H),7.19(d,J=7.8Hz,1H),6.99(t,J=7.6Hz,1H),6.80(d,J=7.9Hz,1H),6.62(t,J=7.5 Hz,1H),5.44(s,2H),4.92(s,2H),4.03(s,3H),3.34(s,2H),2.65(s,3H),1.18(t,J=7.2Hz,3H).

[0171] Example 20

[0172] Using intermediate i-11n (0.19 g, 0.36 mmol) as a raw material, and referring to the preparation method of Example 6, 0.17 g of white solid, i.e. Example 20, can be prepared with a yield of 76%. 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.55(d,J=1.4Hz,1H),8.10(t,J=5.7Hz,1H),7.80(d,J =8.8Hz,1H),7.78(s,1H),7.70(d,J=7.9Hz,2H),7.61(dd,J=16.0,8.8Hz,4H),7.45(s,1H), 7.35(d,J=7.9Hz,1H),7.26(d,J=8.5Hz,1H),6.99-6.89(m,2H),6.77(d,J=7.9Hz,1H),6.59 (t,J=7.6Hz,1H),5.37(s,2H),4.97(s,2H),4.02(s,3H),2.65(s,3H),1.18(t,J=7.2Hz,3H).

[0173] Example 21

[0174] Using intermediate i-11c (0.24 g, 0.46 mmol) as a raw material, and following the preparation method of Example 1, 0.17 g of white solid, i.e. Example 21, can be prepared with a yield of 69%. 1 H NMR(500MHz,DMSO-d6)δ8.50(s,1H),8.00(d,J=7.8Hz,1H),7.71(d,J=8.5Hz,1H),7 .59(d,J=2.0Hz,1H),7.56(d,J=4.3Hz,1H),7.36(d,J=3.1Hz,1H),7.24(dd,J=8.5, 2.0Hz,1H),4.23-4.09(m,3H),3.99(s,3H),2.61(s,3H),2.25(t,J=7.3Hz,2H),1.8 1(t,J=7.4Hz,2H),1.59(p,J=7.4Hz,2H),1.50-1.42(m,2H),1.21(d,J=6.5Hz,6H).

[0175] Example 22

[0176] Using intermediate i-11i (0.46 g, 0.83 mmol) as a raw material, and following the preparation method of Example 1, 0.29 g of white solid, i.e., Example 22, can be prepared with a yield of 61%. 1H NMR(500MHz,DMSO-d6)δ10.36(s,1H),8.50(d,J=5.3Hz,1H),7.98(d,J=7.9Hz,1H),7.71(dd,J=8.6,3.6Hz,1H), 7.59(dd,J=5.4,2.2Hz,1H),7.56(d,J=7.9Hz,1H),7.36(d,J=9.7Hz,1H),7.24(dt,J=8.0,2.2Hz,1H),4.15(dt,J =13.1,6.6Hz,3H),3.99(d,J=5.3Hz,3H),2.61(d,J=3.4Hz,3H),1.95(t,J=7.3Hz,2H),1.80(t,J=7.3Hz,2H),1. 50(p,J=7.3Hz,2H),1.44(q,J=7.5Hz,2H),1.38-1.32(m,2H),1.27(d,J=3.8Hz,2H),1.21(dd,J=6.7,2.6Hz,6H).

[0177] Example 23

[0178] Using intermediate i-11o (0.48 g, 0.89 mmol) as a raw material, and following the preparation method of Example 1, 0.34 g of white solid, i.e. Example 23, can be prepared with a yield of 69%. 1 H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.01(d,J=8.0Hz,1H),7.74(s,1H),7.7 2(d,J=8.1Hz,1H),7.60(s,1H),7.57-7.46(m,4H),7.41(s,1H),7.24(d,J=8 .5Hz,1H),7.16(d,J=15.5Hz,1H),6.42(d,J=15.9Hz,1H),5.30(s,2H),4.17 -4.10(m,1H),4.00(s,3H),2.89(s,3H),2.61(s,3H),1.21(d,J=6.6Hz,6H).

[0179] Example 24

[0180] Using intermediate i-11l (0.31 g, 0.54 mmol) as a raw material, and following the preparation method of Example 1, 0.22 g of white solid, i.e., Example 24, can be prepared with a yield of 69%. 1H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.01(d,J=8.0Hz,1H),7.74(s,1H),7.7 2(d,J=8.1Hz,1H),7.60(s,1H),7.57-7.46(m,4H),7.41(s,1H),7.24(d,J=8 .5Hz,1H),7.16(d,J=15.5Hz,1H),6.42(d,J=15.9Hz,1H),5.30(s,2H),4.17 -4.10(m,1H),4.00(s,3H),2.89(s,3H),2.61(s,3H),1.21(d,J=6.6Hz,6H).

[0181] Example 25

[0182] Using intermediate i-11c (0.32 g, 0.61 mmol) as a raw material, and referring to the preparation method of Example 6, 0.31 g of white solid, i.e. Example 25, can be prepared with a yield of 83%. 1 H NMR (500MHz, DMSO-d6) δ9.25(s,1H),8.51(s,1H),8.00(d,J=7.9Hz,1H),7.72(d,J=8.5Hz,1H),7.60(d,J=2.0Hz, 1H),7.57(s,1H),7.37(s,1H),7.24(dd,J=8.5,2.1Hz,1H),7.18(dd,J=7.8,1.5Hz,1H),6.88(t,J=8.3Hz,1H),6.7 1(d,J=9.4Hz,1H),6.52(t,J=8.3Hz,1H),4.89(s,2H),4.16(dt,J=14.6,6.8Hz,3H),3.99(s,3H),2.62(s,3H),2.3 8(t,J=7.4Hz,2H),1.86(p,J=6.8Hz,2H),1.70(p,J=7.5Hz,2H),1.53(h,J=7.5,6.4Hz,2H),1.21(d,J=6.4Hz,6H).

[0183] Example 26

[0184] Using intermediate i-11o (0.21 g, 0.39 mmol) as a raw material, and referring to the preparation method of Example 6, 0.19 g of white solid, i.e. Example 26, can be prepared with a yield of 78%. 1H NMR(500MHz,DMSO-d6)δ10.60(s,1H),8.75-8.64(m,1H),8.17(d,J=2.2Hz,1H),8.15(s,1H),7.99(d, J=7.8Hz,1H),7.83(d,J=2.8Hz,1H),7.77-7.74(m,1H),7.73(s,1H),7.71(s,1H),7.65(d,J=2.0Hz,1H ),7.59-7.53(m,1H),7.49(s,1H),7.48-7.45(m,1H),7.45-7.41(m,1H),7.40(d,J=8.4Hz,1H),7.28(d d,J=8.6,2.4Hz,1H),5.48(s,2H),4.17-4.12(m,1H),4.06(s,3H),2.63(s,3H),1.22(d,J=6.6Hz,6H).

[0185] Example 27

[0186] Using intermediate i-11l (0.24 g, 0.42 mmol) as a raw material, and referring to the preparation method of Example 6, 0.22 g of white solid, i.e. Example 27, can be prepared with a yield of 79%. 1 H NMR(500MHz,DMSO-d6)δ10.58(s,1H),8.68(s,1H),7.99(d,J=7.9Hz,1H),7.83(s,1H),7 .75(d,J=3.3Hz,1H),7.75-7.72(m,2H),7.64(d,J=2.2Hz,2H),7.63(s,1H),7.47(s,1H) ,7.40(d,J=7.8Hz,2H),7.37-7.33(m,1H),7.27(dd,J=8.5,2.1Hz,1H),6.96(d,J=15.7H z,1H),5.41(s,2H),4.17-4.12(m,1H),4.04(s,3H),2.63(s,3H),1.22(d,J=6.5Hz,6H).

[0187] The configurations of the above embodiments 1-27 are shown in Table 1.

[0188] Table 1 Chemical names and structural formulas of Examples 1-27

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] VEGFR-2 inhibitory activity test

[0197] use The Tb-PY20 antibody kit (Cat#PV3552, Invitrogen) was used to test the VEGFR-2 inhibitory activity of 27 compound samples using the LanthaScreen kinase activity assay.

[0198] Experimental steps

[0199] (1) Preparation of 1X kinase buffer

[0200] The 1x kinase buffer system consists of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 4 mM DTT, 0.01% Tween-20, and 0.01% BSA.

[0201] (2) Preparation of compound working solution

[0202] The compounds were diluted and source plates were prepared by diluting them with 100% DMSO to 100 times the highest concentration ultimately required for the reaction, i.e., 10 μM. For all compounds, the compound in the test tube was transferred to one well of a 96-well storage plate, and the compound was serially diluted by transferring 10 μL to 30 μL of 100% DMSO to the next well, and so on, for a total of 10 concentrations. In the same 96-well plate, 100 μL of 100% DMSO was added to two empty wells, without a compound control and without an enzyme control. This plate was labeled the source plate. 40 μL of the compound was transferred from the source plate to a new 384-well microplate as an intermediate plate.

[0203] 2) Prepare the test board

[0204] Transfer 200 nm of each well from one 384 microwell plate (intermediate plate) to another 384 microwell plate, in duplicate. Transfer A1 of the intermediate plate to A1 and A2 of the new 384 microwell plate; transfer A2 of the intermediate plate to A3 and A4 of the new 384 microwell plate, and so on.

[0205] (3) Kinase response

[0206] 1) Preparation of 2x kinase solution

[0207] Prepare the kinase solution in 1X kinase buffer at twice the final concentration of each reagent required for the assay. Specifically, use 4 μL HEPES, 4 μL MgCl2, 4 μL LTT, 4 μL Tween-20, and 4 μL BSA. Add 10 μL of the kinase solution to each well of the assay plate, except for the control wells (which contain 5 μL of 1X kinase buffer instead of enzyme). Shake the plate and incubate at room temperature for 1 hour.

[0208] 2) Preparation of 2x substrate solution

[0209] Prepare substrate solutions of luciferin-polyGT and ATP in 1x kinase reaction buffer at concentrations twice the final concentrations of each reagent required for the assay, i.e., 100 μM ATP and 0.02 μM luciferin-polyGT. Add 10 μL of substrate solution to each well of the assay plate to initiate the reaction. Shake the plate.

[0210] 3) Kinase response

[0211] Cover with the test plate and incubate at room temperature for 1 hour.

[0212] (4) Kinase detection

[0213] Prepare a 2-fold final concentration detection solution in antibody dilution buffer. Add 20 μL of detection solution to each well of the detection plate to stop the reaction. Briefly mix using a centrifuge and incubate at room temperature for 60 minutes, then read the fluorescence on a plate reader.

[0214] (5) Data reading

[0215] Data was collected on Envision at an excitation wavelength of 340 nm and emission wavelengths of 520 nm and 495 nm.

[0216] (6) Data processing

[0217] Copy the RFU values ​​from the Envision project. Calculate the RFU 520nm / RFU 495nm ratio and convert the ratio to an inhibition percentage value. Inhibition percentage = (max - sample ratio) / (max - min) * 100. "Minimum" represents the ratio of the enzyme-free control, and "maximum" represents the ratio of the DMSO control. The curve was fitted using the XLFit Excel plugin version 5.4.0.8, IC50... 50 The calculation formula is: Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X) ^ HillSlope.

[0218] HDAC1 inhibition activity test

[0219] To verify whether the compounds prepared in Examples 1-27 have a significant inhibitory effect on HDAC1 protein, the HDAC1 inhibitory activity of the compounds in Examples 1-27 was tested using the HDAC1 fluorescence detection kit (Cat#50051) from BPS Corporation and the fluorescence assay.

[0220] Experimental steps:

[0221] (1) Prepare 1x analytical buffer (modified Tris buffer).

[0222] (2) Dilution of the compound: The compound was transferred to the analytical plate in 100% DMSO using an Echo. The final fraction of DMSO was 1%.

[0223] (3) Preparation of enzyme solution: Prepare enzyme solution in 1x detection buffer.

[0224] (4) Preparation of substrate solution: Add trypsin and Ac-peptide substrate to 1x detection buffer to prepare substrate solution.

[0225] (5) Transfer 15 μL of enzyme solution to the assay plate, or for the low control, transfer 15 μL of 1x assay buffer. Incubate at room temperature for 15 minutes. Add 10 μL of substrate solution to each well to begin the reaction.

[0226] (6) Data reading

[0227] Read the board on Envision; the excitation wavelength is 355nm and the emission wavelength is 460nm.

[0228] (6) Data processing and curve fitting

[0229] Use formula (1) to fit the data in Excel to obtain the inhibition value: Inhibition rate = (Max-Signal) / (Max-Min)*100. Use formula (2) to fit the data in XL-Fit to obtain the IC. 50 Value, Equation (2): Y = Bottom + (Top - Bottom) / (1 + (IC) 50 / X)*HillSlope), where y is the % inhibition rate and X is the compound concentration.

[0230] The experimental results are shown in Table 2.

[0231] Table 2 shows the inhibitory activity of compounds from Examples 1-27 against HDAC1 and VEGFR-2 at a concentration of 100 nM.

[0232]

[0233] As shown in Table 2, Examples 1, 2, 3, 11, and 15 exhibited significant inhibitory activity against both VEGFR-2 and HDAC1 at a concentration of 100 nM. In particular, Example 2 showed the strongest inhibitory activity against both VEGFR-2 and HDAC1, with inhibition rates of 93.20% and 90.24% at a concentration of 100 nM, respectively, which were significantly higher than those of the positive control drugs Fruquintinib and SAHA.

[0234] To investigate the concentration dependence of VEGFR-2 and HDAC1 in Example 2, we further studied the relationship between the inhibitory activity and concentration in Example 2, such as... Figure 1 As shown, Example 2 exhibited significant concentration dependence on both HDAC1 and VEGFR-2, with the IC50 value for HDAC1 being significantly lower. 50 The concentration was 9.21 nM, higher than the positive control SAHA (IC). 50 =14.14 nM). Simultaneously, LF-2 also exhibited good inhibitory activity against VEGFR-2, IC50 = 14.14 nM. 50 It is 57.52 nM.

[0235] Based on the above test results, it can be seen that the compounds disclosed in this invention exhibit significant inhibitory activity against VEGFR and HDAC, and can be used to treat diseases mediated by the VEGFR signaling pathway and / or HDAC.

[0236] The above-described embodiments should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A quinazoline derivative containing a benzofuran structure, the general structural formula of which is shown in Figure I. R1 is selected from one of methyl, ethyl, and isopropyl; R2 is selected from... R3 is selected from One of them, where n = 3-5.

2. A quinazoline derivative containing a benzofuran structure, comprising at least one of the following compounds: 6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((7-(hydroxyamino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((4-(((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; (E)-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; 6-((6-((6-((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((7-(((2-aminophenyl)amino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((8-(((2-aminophenyl)amino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; 6-((6-((4-(((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide; N-Ethyl-6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide; N-Ethyl-6-((6-((7-(hydroxyamino)-7-oxohepyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide; N-Ethyl-6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide; N-Ethyl-6-((6-((4-(hydroxycarbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide; (E)-N-ethyl-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-2-methylbenzofuran-3-carboxamide; 6-((6-((6-(((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide; 6-((6-((7-(((2-aminophenyl)amino)-7-oxoheptyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide; 6-((6-((8-(((2-aminophenyl)amino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide; 6-((6-((4-((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide; (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-ethyl-2-methylbenzofuran-3-carboxamide; 6-((6-((6-(hydroxyamino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; 6-((6-((8-(hydroxyamino)-8-oxooctyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; 6-((6-((4-(hydroxycarbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; (E)-6-((6-((4-(3-(hydroxyamino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; 6-((6-((6-(((2-aminophenyl)amino)-6-oxohexyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; 6-((6-((4-((2-aminophenyl)carbamoyl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide; (E)-6-((6-((4-(3-(((2-aminophenyl)amino)-3-oxopropyl-1-en-1-yl)benzyl)oxy)-7-methoxyquinazoline-4-yl)oxy)-N-isopropyl-2-methylbenzofuran-3-carboxamide.

3. The use of the quinazoline derivative containing a benzofuran structure as described in any one of claims 1 to 2 in the preparation of VEGFR and / or HDAC pathway inhibitors.

4. The use of the quinazoline derivative containing a benzofuran structure as described in any one of claims 1 to 2 in the preparation of medicaments for inhibiting or treating VEGFR and / or HDACs-mediated diseases.

5. The application as described in claim 4, characterized in that, The related diseases mentioned are selected from tumor diseases related to the VEGF signaling pathway.

6. The application as described in claim 4, characterized in that, The related diseases mentioned are selected from HDAC-mediated tumor diseases.

7. The application as described in claim 4, wherein the related disease is selected from at least one of lung cancer, liver cancer, breast cancer, kidney cancer, stomach cancer, colorectal cancer, thyroid cancer, soft tissue sarcoma, leukemia, lymphoma, and myeloma.

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