(4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1, 2-diketone compound as well as preparation method and application thereof

Abstract

The invention discloses a (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1, 2-diketone compound as well as a preparation method, a pharmaceutical composition and application of the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1, 2-diketone compound. According to the present invention, the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1, 2-diketone compound can be specifically combined with the B3GAT3 protein so as to provide the anti-tumor effect, and can be used for the treatment of a variety of tumors. The structural general formula of the compounds is shown as (I), and the compounds further comprise pharmaceutically acceptable salts of the compounds. In addition, the preparation method disclosed by the invention is mature, simple and convenient, and relatively high in yield. (I).

Description

Technical Field

[0001] This invention relates to a (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound, its preparation method, pharmaceutical composition, and application, and particularly to a (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound capable of targeting the B3GAT3 protein, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Hepatocellular carcinoma (HCC) accounts for 85%–90% of primary liver cancers, characterized by high malignancy, early dissemination, significant heterogeneity, and a five-year survival rate of less than 20%. In recent years, with the deepening understanding of the tumor-microenvironment interaction network and key signaling nodes, systemic therapy has gradually shifted from traditional cytotoxic drugs to molecularly targeted therapies. Multi-kinase inhibitors such as sorafenib and lenvatinib, by simultaneously blocking angiogenesis-related receptors such as VEGFR, PDGFR, and FGFR, can extend the median overall survival (mOS) of advanced-stage patients to approximately 12–13 months and are considered first-line standard treatments. However, acquired resistance and dose-limiting toxicities such as hand-foot skin reactions and hypertension result in an objective response rate of less than 10%, making it difficult to overcome the clinical benefit plateau. Furthermore, HCC exhibits significant heterogeneity at the genomic, epigenetic, and proteomic levels, limiting the efficacy of single-target drugs; while the lack of biomarkers, inappropriate endpoint selection, and flawed patient stratification strategies further amplify the failure rate in phase III clinical trials. Therefore, finding new intervention targets and building a precision treatment system based on molecular subtyping has become an urgent research topic.

[0003] Proteoglycans (PGs) are a class of anionic macromolecules formed by the covalent coupling of core proteins and glycosaminoglycans (GAGs). They are widely anchored in the cell membrane and extracellular matrix and can influence tumorigenesis and development by regulating growth factor binding, signal transduction, and cell cycle progression. Multiple studies have shown that aberrant expression of PGs is closely related to angiogenesis, epithelial-mesenchymal transition (EMT), and immune escape.

[0004] β-1,3-glucuronyltransferase 3 (B3GAT3), as the rate-limiting enzyme in the initiation step of GAG synthesis, is responsible for transferring glucuronic acid (GlcA) to the core protein to link the tetrasaccharide backbone, a key node for PGs to acquire biological activity. Loss-of-function studies confirmed that GAG chain synthesis was completely undetectable in embryonic fibroblasts of mice with systemic B3GAT3 knockout; however, after reintroducing cDNA of this enzyme into the B3GAT3-deficient CHO mutant, PG production recovered to 2.1 times that of the wild type, suggesting that its expression level is dose-dependent on PG abundance. Further analysis of clinical samples showed that B3GAT3 was highly expressed in approximately 65% ​​of HCC tissues and was significantly positively correlated with microvascular invasion, satellite nodules, and early postoperative recurrence (p < 0.01). In vitro functional experiments showed that knocking down HepG2 cells B3GAT3 with CRISPR-Cas9 reduced cell proliferation by 42%, migration and invasion by 55% and 48%, respectively, accompanied by downregulation of Cyclin D1 and MMP-2 / 9 expression and upregulation of E-cadherin, suggesting that it drives tumor progression by regulating cell cycle and EMT program.

[0005] In summary, the B3GAT3-mediated PG synthesis pathway not only provides a novel metabolic-epidemic cross-regulatory axis for HCC, but also holds promise as an alternative intervention point to overcome the bottlenecks of multi-kinase inhibitor resistance and toxicity. Developing highly selective small-molecule inhibitors or PROTAC degraders targeting this enzyme could both block tumor angiogenesis and malignant proliferation and avoid the systemic toxicity caused by pan-kinase inhibition, demonstrating significant clinical translational potential and public health value. Summary of the Invention

[0006] Objectives of the Invention: The first objective of this invention is to provide a (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt; the second objective is to provide a method for preparing the compound; the third objective is to provide a pharmaceutical composition or B3GAT3 inhibitor with the compound and its pharmaceutically acceptable salt as active ingredients; and the fourth objective is to provide a pharmaceutical application of the compound and its pharmaceutical composition.

[0007] Technical solution: The present invention relates to a (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt, wherein the general structural formula of the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound is shown in formula (I):

[0008]

[0009] (I)

[0010] in:

[0011] Ring A is selected from 5-6 membered heterocycles with N atoms at both ends, 4-6 membered saturated or unsaturated bicyclic heterocycles, 4-6 membered saturated or unsaturated spirocyclic or bridged rings, and 2-8 alkane or ether-containing alkoxy straight chains.

[0012] R1 is selected from substituted or unsubstituted C6~C6. 12 Aryl group, 5-10 membered aromatic heterocycle containing 1-2 nitrogen, oxygen and / or sulfur heteroatoms, substituted or unsubstituted benzo5-6 membered heterocycle; wherein the substituted group of the aromatic group of R1 is monosubstituted or polysubstituted, and the substituent is a halogen group, methyl, methoxy, or trifluoromethyl.

[0013] R2 is selected from the 5-position indole ester group substituted by R3 or the 5-position indole ether group substituted by R4; wherein,

[0014] R3 is selected from methyl or ethyl;

[0015] R4 is selected from C4-C8 straight-chain alkyl groups, C4-C8 straight-chain or straight-chain groups containing N and / or O heteroatoms and cycloalkoxy groups, C4-C8 ester groups, substituted or unsubstituted C6-C8 groups. 10 Aromatic group; wherein the substituent is selected from hydrogen atoms.

[0016] Preferably, in the structure, ring A is selected from any of the following structures:

[0017] , , , , , , , , , , , , ;

[0018] R1 is selected from any of the following structures:

[0019] , , , , , , , , , , , , , , , , , , , , , , , , ;

[0020] R2 is selected from any of the following structures:

[0021] , ;

[0022] R3 is selected from methyl or ethyl;

[0023] R4 is selected from any of the following structures:

[0024] , , , , , , .

[0025] More preferably, the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound is selected from any of the following compounds:

[0026] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0027] Preferably, the pharmaceutically acceptable salt is a salt formed by the compound with any of the following acids or bases: the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid; and the base is a base containing an alkali metal cation, an alkaline earth metal cation, or an ammonium cation salt.

[0028] The method for preparing the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound of the present invention is synthesized according to the following route:

[0029]

[0030] in,

[0031] Step 1: Compound 5-methoxyindigo (1a) and compound 2a are refluxed in an alkaline ethanol solution. After the reaction is completed, the mixture is acidified to obtain compound 3a.

[0032] Step 2: Compound 3a reacts with different substituted Boc-containing amino groups via an acid-amine condensation reaction to give compound 4a;

[0033] Step 3: Compound 4a is deactivated by trifluoroacetic acid to remove the Boc group and then basified to obtain compound 5a;

[0034] Step 4: Compound 1b reacts with oxalyl chloride in diethyl ether to give compound 2b;

[0035] Step 5: Compound 2b reacts with compound 5a in alkaline DCM at room temperature to give compound 3b.

[0036] The present invention discloses a pharmaceutical composition comprising a 4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, and one or more carriers / excipients conforming to pharmacopoeia standards. The carriers / excipients refer to functional materials used in formulation design and industrial production to regulate drug solubility, stability, bioavailability, and targeting, including but not limited to: solvents and cosolvents, surfactants and emulsifying systems, sustained-release and controlled-release matrices, targeting carriers, stabilizing and antioxidant excipients, and other functional excipients such as fillers (microcrystalline cellulose, lactose), disintegrants (cross-linked sodium carboxymethyl cellulose), lubricants (magnesium stearate), pH buffers (phosphates, citrates), and flavoring / preservatives (sucralose, sodium benzoate), etc. The composition can be administered via intravenous injection, arterial perfusion, oral administration, transdermal administration, or inhalation. The preferred composition is an active ingredient + carrier.

[0037] Preferably, the composition may further contain conventional excipients such as flavoring agents, sweeteners, liquid / solid fillers or diluents, and be converted into commonly used clinical dosage forms such as tablets, capsules, syrups, suspensions or injections through a formulation process.

[0038] The present invention provides a B3GAT3 inhibitor comprising the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound described herein and its pharmaceutically acceptable salt.

[0039] The (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compounds and their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present invention, or the use of the B3GAT3 inhibitors of the present invention in the preparation of medicaments for the treatment and / or prevention of diseases related to B3GAT3 inhibition.

[0040] Among the diseases associated with B3GAT3 inhibition are malignant tumors, skeletal dysplasia with inappropriate short stature, kyphosis, scoliosis and long bone deformities, spoon-shaped distal phalanges and facial deformities, embryonic developmental abnormalities, and abnormal cell metabolism and / or differentiation. Malignant tumors include liver cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, colorectal cancer, glioma, breast cancer, intrahepatic cholangiocarcinoma, adrenocortical carcinoma, cervical cancer, and / or leukemia.

[0041] Experimental evidence shows that the above-mentioned compounds and their pharmaceutically acceptable salts have significant inhibitory activity against the B3GAT3 protein and can be used to prepare anti-tumor drugs targeting B3GAT3. These drugs have shown therapeutic potential against various solid tumors, including liver cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, colorectal cancer, glioma, breast cancer, intrahepatic cholangiocarcinoma, adrenocortical carcinoma, cervical cancer, and leukemia.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0043] This invention relates to a class of (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compounds that exhibit nanomolar (nM) binding affinity (KD) for B3GAT3, demonstrating nM-level antitumor activity in various liver cancer cell models, and also showing significant inhibitory activity against multiple cancer types. Furthermore, the synthetic route for this compound is simple, it is easy to scalable, and it has potential clinical translational value. Attached Figure Description

[0044] Figure 1 This is a graph showing the KD values ​​of representative compounds bound to B3GAT3. Detailed Implementation

[0045] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0046] The following examples are merely illustrative of the synthetic routes for compounds of general formula (I) and are not intended to limit the scope of protection of this invention in any way. In fact, those skilled in the art can, based on the disclosure of this specification and in conjunction with known synthetic strategies in the prior art, arbitrarily combine, optimize, or modify these methods to obtain the target compounds.

[0047] Experimental procedures used in the examples, unless otherwise specified, were performed in accordance with standard laboratory procedures or reagent supplier recommendations; all commonly used chemical reagents were commercially available analytical grade or higher. Unless otherwise stated, the terminology and scientific terms used herein are consistent with their common definitions in the art. The compound structures were confirmed by ¹H / ¹³C NMR and / or high-resolution mass spectrometry (HRMS), with NMR chemical shifts expressed as δ (ppm), and solvents such as d6-DMSO, CDCl3, and CD3OD were used, with tetramethylsilane (TMS) as the internal standard. IC 50 Defined as the molar concentration required to achieve a 50% maximum inhibition effect.

[0048] The following abbreviations are used in the following examples and experimental examples:

[0049] DCM: dichloromethane; EA: ethyl acetate; PE: petroleum ether; MeOH: methanol; EtOH: ethanol; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; DIPEA: N,N-diisopropylethylamine; HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate; TMS: tetramethylsilane; Boc: tert-butyloxycarbonyl; NaHCO3: sodium bicarbonate; Na2SO4: sodium sulfate; Cs2CO3: cesium carbonate; TFA: trifluoroacetic acid; KOH: potassium hydroxide; HCl: hydrochloric acid; (EtO)2O: diethyl ether; TLC: thin-layer chromatography.

[0050] Example 1: Preparation of methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0051] Synthesize according to the following route:

[0052]

[0053] (1) Preparation of intermediate 3a-1: 6-methoxy-2-(naphth-2-yl)quinoline-4-carboxylic acid

[0054] In a 50 mL single-necked flask, 5-methoxyindigo (1a) (708 mg, 4 mmol, 1 equiv), KOH (450 mg, 8 mmol, 2 equiv), and anhydrous EtOH (20 mL) were added, and the mixture was refluxed and stirred at 90 °C for 30 min. Then, intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) (4.8 mmol, 1.2 equiv) was added to the reaction mixture, and the reaction was continued to be heated for 4–6 h. After the reaction was completed by TLC monitoring, EtOH was removed by vacuum distillation, dissolved in an appropriate amount of water, and the pH was adjusted to acidic with 4 M HCl solution. The precipitated solid was filtered, recrystallized with MeOH, and dried in a vacuum oven to obtain intermediate 6-methoxy-2-(naphthyl-2-yl)quinoline-4-carboxylic acid (3a-1). The product was a yellow solid with a yield of 86.74%.

[0055] (2) Preparation of intermediate 4a-1: tert-butyl 4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazine-1-carboxylic acid ester

[0056] Under nitrogen protection, 6-methoxy-2-(naphth-2-yl)quinoline-4-carboxylic acid (3a-1) (2 mmol, 1 equiv), HATU (912 mg, 2.4 mmol, 1.2 equiv), and DIPEA (1 mL, 4 mmol, 2.0 equiv) were dissolved in anhydrous DCM (15 mL). The mixture was stirred at room temperature for 30 minutes, and then tert-butylpiperazine-1-carboxylic acid ester (2 mmol, 1 equiv) was added, and the reaction was continued for 4–6 hours. After the reaction was completed by TLC monitoring, 50 mL of water was added, and the mixture was extracted three times with 20 mL of DCM. The organic phases were combined, dried over anhydrous sodium sulfate (Na₂SO₄), and concentrated under vacuum. The crude product was purified by column chromatography (PE:EA volume ratio = 2:1) to give the intermediate tert-butyl 4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazine-1-carboxylic acid ester (4a-1). The product was a white solid with a yield of 69.5%.

[0057] (3) Preparation of intermediate 5a-1: (6-methoxy-2-(naphth-2-yl)quinoline-4-yl)(piperazin-1-yl)methyl ketone

[0058] The intermediate tert-butyl-4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazine-1-carboxylic acid ester (4a-1) (2 mmol, 1 equiv) was dissolved in 10 mL of anhydrous DCM at room temperature. Then, 2 mL of TFA was slowly added, and the reaction was carried out under nitrogen protection for 4–6 hours. The progress of the reaction was monitored using TLC. After the reaction was complete, a saturated NaHCO3 solution was added. The pH of the solution was adjusted to alkaline, and 50 mL of water was added. The mixture was then extracted with DCM (20 mL x 3). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was further purified by column chromatography (developing solvent volume ratio DCM : EtOH = 25 : 1) to give the intermediate (6-methoxy-2-(naphth-2-yl)quinoline-4-yl)(piperazine-1-yl) methyl ketone (5a-1). The product was a white solid in 49.6% yield.

[0059] (4) Preparation of intermediate 2b-1: methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate

[0060] In a 50 mL single-necked flask, methyl-1H-indole-5-carboxylic acid ester (1b) (2 mmol, 1 equiv) and 10 mL of anhydrous (EtO)₂O were added. Oxaloyl chloride (6 mmol, 3 equiv) was slowly added dropwise at 0 °C. After the addition was complete, the reaction was continued at 0 °C for approximately 1.5 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was directly filtered and washed with 30 mL of anhydrous (EtO)₂O in portions to obtain a yellow powder, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1). No further purification was required; it was used directly in the next reaction.

[0061] (5) Preparation of methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0062] At 0 °C, intermediate 5a-1 (2 mmol, 1 equiv) and DIPEA (1 mmol, 2 equiv) were added to 10 mL of anhydrous DCM, followed by the slow addition of intermediate 2b-1 (2 mmol, 1 equiv), and the reaction was allowed to proceed for 2 h. After the reaction was completed by TLC, the mixture was extracted three times with 20 mL of DCM, and the organic layers were combined. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The product was purified by column chromatography, and the product was eluented with a solvent (DCM:EtOH = 25:1, v / v), concentrated under reduced pressure, and dried to obtain a white solid, which was methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 29.7%.

[0063] The methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR(300 MHz, DMSO-d6) δ 12.71 (d, J = 3.3 Hz, 1H), 8.94 – 8.68 (m, 2H), 8.57 –8.24 (m, 3H), 8.18 – 7.83 (m, 5H), 7.72 – 7.46 (m, 4H), 7.08 (dd, J = 9.6,2.8 Hz, 1H), 4.11 – 3.99 (m, 1H), 3.99 – 3.76 (m, 8H), 3.70 – 3.55 (m, 2H),3.47 – 3.37 (m, 2H), 3.29 – 3.21 (m, 1H)。 13 C NMR (151 MHz, DMSO-d6) δ 186.47,186.35, 166.83, 166.14, 166.09, 158.62, 158.55, 153.75, 144.38, 144.31,142.25, 142.11, 140.09, 139.64, 139.47, 136.09, 133.94, 133.89, 133.59,133.54, 131.94, 131.88, 129.17, 129.14, 128.84, 128.77, 128.10, 128.06,127.45, 127.40, 127.08, 127.04, 126.99, 126.95, 125.11, 125.08, 124.99,124.97, 124.94, 124.90, 124.48, 124.45, 124.39, 124.35, 123.63, 123.49,123.34, 123.23, 116.72, 113.36, 113.25, 103.03, 103.01, 56.23, 56.19, 52.48,52.41, 47.24, 46.59, 46.31, 45.80, 42.06, 41.58, 41.33, 41.03。HRMS (ESI):calced for C 37 H 30 N4O6, [M+H] + 627.2244, found 627.2247。

[0064] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0065] Example 2 Preparation of methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0066] The preparation process is the same as in the example, except that the intermediate tert-butylpiperazine-1-carboxylate in step (2) is replaced with tert-butyl4-aminopiperidine-1-carboxylate. After completing the reactions in steps (2) and (3), the intermediate 6-methoxy-2-(naphth-2-yl)-N-(piperidine-4-yl)quinoline-4-carboxamide is obtained. Then, 6-methoxy-2-(naphth-2-yl)-N-(piperidine-4-yl)quinoline-4-carboxamide is used to replace intermediate 5a-1 in step (5), while keeping everything else unchanged. Finally, a white solid is obtained, which is methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)piperidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 34.5%.

[0067] The methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.89 (d, J = 25.3 Hz, 3H), 8.50 (d,J = 8.7 Hz, 1H), 8.32 (d, J = 11.7 Hz, 2H), 8.09 (t, J = 7.8 Hz, 3H), 8.02 –7.89 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.54 (ddd, J = 16.3, 10.1, 3.8 Hz,4H), 4.54 – 4.21 (m, 2H), 3.89 (s, 6H), 3.71 (d, J = 13.4 Hz, 1H), 3.18 (t, J = 12.3 Hz, 1H), 2.10 (dd, J = 49.8, 12.5 Hz, 2H), 1.81 – 1.37 (m, 2H), 1.20 (d, J = 17.1 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 187.07, 167.17, 166.63,165.83, 158.16, 153.46, 144.53, 142.13, 139.99, 139.13, 136.08, 133.82,133.51, 131.60, 129.13, 128.79, 128.03, 127.35, 127.01, 126.83, 124.94,124.31, 123.52, 122.93, 117.51, 114.15, 113.28, 103.65, 55.85, 52.41, 46.80,44.90, 32.08, 31.31. HRMS (ESI): calculated for C 38 H 32 N4O6, [M+H] + 641.2400, found627.2402.

[0068] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0069] Example 3 Preparation of methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0070] The preparation process is the same as in Example 1, except that the intermediate tert-butylpiperazine-1-carboxylate in step (2) is replaced with tert-butylpiperidin-4-ylcarbamate. After completing the reactions in steps (2) and (3), the intermediate (4-aminopiperidin-1-yl)(6-methoxy-2-(naphth-2-yl)quinoline-4-yl) ketone is obtained. Then, the intermediate 5a-1 in step (5) is replaced with (4-aminopiperidin-1-yl)(6-methoxy-2-(naphth-2-yl)quinoline-4-yl) ketone, while keeping everything else unchanged. Finally, a white solid is obtained, which is methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 34.7%.

[0071] The methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, Chloroform-d) δ 9.88 – 9.72 (m, 1H), 9.10 – 8.97 (m, 2H), 8.57 (t, J = 2.2 Hz, 1H), 8.33 – 8.20 (m, 2H), 8.01 – 7.85 (m, 5H), 7.63 –7.35 (m, 5H), 7.07 (dd, J = 31.7, 2.7 Hz, 1H), 5.01 – 4.80 (m, 1H), 3.94 (t,J = 4.8 Hz, 6H), 3.67 – 3.48 (m, 1H), 3.34 – 3.07 (m, 2H), 2.34 – 2.11 (m,2H), 2.01 – 1.34 (m,3H). 13C NMR (75 MHz, DMSO-d6) δ 183.32,167.27, 166.31,153.68, 144.20, 142.89, 140.40, 139.42, 135.98, 133.84, 133.52, 131.87,129.14, 128.77, 128.00, 127.36, 126.96, 126.15, 124.83, 124.27, 123.81,123.27, 116.21, 113.14, 102.61, 56.11, 52.40, 46.64, 46.28, 45.85, 31.52. HRMS(ESI): calculated for C 38 H 32 N4O6, [M+H] + 641.2400, found 641.2400.

[0072] As can be seen from the above analysis, the structure of the methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0073] Example 4 Preparation of methyl 3-(2-(4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0074] The preparation process is the same as in Example 1, except that the intermediate tert-butylpiperazine-1-carboxylate in step (2) is replaced with tert-butyl4-(aminomethyl)piperidine-1-carboxylate. After completing the reactions in steps (2) and (3), the intermediate tert-butyl4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidine-1-carboxylate is obtained. Then, tert-butyl4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidine-1-carboxylate is used to replace intermediate 5a-1 in step (5), while keeping everything else unchanged. Finally, a white solid is obtained, which is methyl 3-(2-(4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 24.8%.

[0075] The methyl 3-(2-(4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 12.59 (d, J = 3.2 Hz, 1H), 8.93 (t, J = 5.9 Hz,1H), 8.83 – 8.79 (m, 2H), 8.48 (dd, J = 8.6, 1.8 Hz, 1H), 8.32 (d, J = 3.1Hz, 1H), 8.26 (s, 1H), 8.11 – 8.06 (m, 3H), 7.98 (dt, J = 7.3, 3.6 Hz, 1H), 7.90 (dd, J = 8.6, 1.7 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58 (dt, J = 6.9,3.4 Hz, 2H), 7.52 – 7.48 (m, 2H), 4.48 (d, J = 12.7 Hz, 1H), 3.87 (d, J =23.0 Hz, 6H), 3.64 (d, J = 13.8 Hz, 1H), 3.40 – 3.34 (m, 2H), 3.18 – 3.12 (m,1H), 2.90 (td, J = 12.8, 2.9 Hz, 1H), 2.02 – 1.93 (m, 2H), 1.38 (qd, J =12.4, 4.3 Hz, 1H), 1.20 (ddd, J = 24.2, 12.1, 3.9 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 187.26, 167.53, 165.89, 153.57, 144.62, 142.37, 139.02, 133.88,133.57, 131.64, 129.19, 128.85, 128.07, 127.41, 127.06, 126.89, 125.03,124.99, 124.95, 124.33, 123.51, 123.00, 117.45, 113.32, 103.80, 55.85, 52.46,46.00, 44.79, 40.89, 40.57, 36.29, 30.54, 29.63. HRMS (ESI): calculated forC 39 H 34 N4O6, [M+H] + 655.2500, found 654.2504.

[0076] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-((6-methoxy-2-(naphth-2-yl)quinoline-4-carboxamido)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0077] Example 5 Preparation of methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0078] Synthesize according to the following route:

[0079]

[0080] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) in step (1) is replaced with 1-(benzofuran-2-yl)ethane-1-one (2a-2). After the reaction in steps (1), (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl)methyl ketone (5a-2) is obtained. Then, intermediate 5a-1 in step (5) was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone (5a-2), while keeping everything else unchanged. Finally, a white solid was obtained, which is methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 38.1%.

[0081] The methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (dd, J = 18.9, 3.5 Hz, 1H), 8.89 – 8.72 (m,1H), 8.41 (dd, J = 10.2, 3.1 Hz, 1H), 8.18 – 8.01 (m, 2H), 7.98 – 7.29 (m,9H), 7.06 (dd, J = 9.8, 2.8 Hz, 1H), 4.15 – 4.00 (m, 1H), 4.00 – 3.67 (m,9H), 3.67 – 3.54 (m, 2H), 3.42 (s, 1H), 3.30 – 3.20 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.46, 186.35, 166.41, 166.12, 166.08, 158.95, 158.88, 155.31,154.97, 146.16, 146.07, 144.32, 144.24, 142.11, 141.97, 140.08, 139.99,139.64, 139.48, 131.76, 131.70, 128.85, 126.29, 126.24, 125.09, 124.98,124.79, 124.47, 124.36, 124.06, 124.02, 123.75, 123.63, 123.47, 122.49,122.45, 116.14, 113.35, 113.26, 112.03, 111.99, 106.64, 106.60, 103.19,103.17, 56.28, 56.24, 52.48, 52.42, 47.18, 46.51, 46.29, 45.74, 42.05, 41.56,41.33, 40.96. HRMS (ESI): calculated for C 35 H 28 N4O7, [M+H] + 617.2032, found617.2036.

[0082] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0083] Example 6 Preparation of methyl 3-(2-(4-(6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0084] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) in step (1) is replaced with 1-(5-methylfuran-2-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 in step (5) was replaced with (6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which is methyl 3-(2-(4-(6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 42.8%.

[0085] The methyl 3-(2-(4-(6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (d, J = 21.9 Hz, 1H), 8.80 (dd, J = 45.6,1.7 Hz, 1H), 8.40 (d, J = 13.9 Hz, 1H), 8.01 – 7.79 (m, 3H), 7.68 (s, 1H),7.46 (ddd, J = 19.7, 9.3, 2.8 Hz, 1H), 7.25 (d, J = 3.3 Hz, 1H), 7.01 (d, J =2.8 Hz, 1H), 6.37 – 6.30 (m, 1H), 3.97 (ddd, J = 17.6, 7.8, 4.6 Hz, 2H), 3.92– 3.86 (m, 5H), 3.83 (d, J = 17.9 Hz, 3H), 3.60 (tt, J = 12.8, 6.4 Hz, 2H), 3.19 (d, J = 5.7 Hz, 2H), 2.41 (d, J = 14.5 Hz, 3H). 13C NMR (151 MHz, DMSO-d6)δ 186.45, 186.34, 166.57, 166.12, 166.07, 158.27, 158.19, 154.47, 146.53,144.15, 144.07, 141.88, 141.75, 140.09, 139.65, 139.49, 131.32, 131.27,125.10, 125.07, 125.00, 124.98, 124.46, 124.35, 123.91, 123.85, 123.62,123.49, 123.24, 123.13, 115.02, 114.25, 113.35, 113.27, 111.96, 111.91,109.37, 109.31, 103.26, 103.24, 56.19, 56.15, 52.47, 52.43, 47.14, 46.48,46.28, 45.72, 41.97, 41.55, 41.24, 40.95, 14.08, 14.05. HRMS (ESI): calculated forC 32 H 28 N4O7, [M+H] + 581.2032, found 581.2034.

[0086] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(5-methylfuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0087] Example 7 Preparation of methyl 3-(2-(4-(6-methoxy-2-(thiazo-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0088] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) in step (1) is replaced with 1-(thiazol-2-yl)ethane-1-one. After the reactions in steps (1), (2) and (3), the intermediate (6-methoxy-2-(thiazol-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, the intermediate 5a-1 in step (5) is replaced with (6-methoxy-2-(thiazol-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid is obtained, which is methyl 3-(2-(4-(6-methoxy-2-(thiazol-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 44.9%.

[0089] The methyl 3-(2-(4-(6-methoxy-2-(thiazo-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.77 – 12.59 (m, 1H), 8.80 (dd, J = 36.3, 1.7 Hz, 1H), 8.40 (d, J = 10.8 Hz, 1H), 8.22 (d, J = 14.8 Hz, 1H), 8.13 – 7.85 (m, 4H),7.71 – 7.49 (m, 2H), 7.07 (dd, J = 9.2, 2.8 Hz, 1H), 4.06 – 3.76 (m, 9H),3.68 – 3.54 (m, 2H), 3.44 – 3.38 (m, 1H), 3.36 – 3.15 (m, 2H). 13C NMR (151MHz, DMSO-d6) δ 186.46, 186.36, 168.58, 168.50, 167.25, 166.28, 166.11,166.08, 159.27, 159.21, 148.75, 148.66, 144.79, 144.74, 143.86, 143.78,142.43, 140.08, 139.64, 139.49, 131.60, 131.54, 125.91, 125.83, 125.09,124.98, 124.47, 124.36, 123.93, 123.82, 123.76, 123.62, 123.48, 115.38,114.25, 113.34, 113.26, 103.34, 56.33, 56.29, 52.48, 52.42, 47.12, 46.45,46.28, 45.68, 42.03, 41.55, 41.31, 40.91, 21.21, 14.54. HRMS (ESI): calculated forC 30 H 25 N5O6S, [M+H] + 584.1606, found 584.1607.

[0090] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(thiazo-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0091] Example 8 Preparation of methyl 3-(2-(4-(6-methoxy-2-(5-thiophenol-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0092] The preparation process was the same as in Example 1, except that intermediate 1-(naphthio-2-yl)ethane-1-one (2a-1) was replaced with 1-(5-methylthiophen-2-yl)ethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (6-methoxy-2-(5-methylthiophen-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 in step (5) was replaced with (6-methoxy-2-(5-methylthiophen-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(5-methylthiophen-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 43.1%.

[0093] The methyl 3-(2-(4-(6-methoxy-2-(thiazo-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR(300 MHz, Chloroform-d) δ 10.38 – 10.13 (m, 1H), 8.93 (d, J = 40.2 Hz, 1H), 8.18 – 7.82 (m, 3H), 7.69 – 7.30 (m, 4H), 6.96 (dd, J = 6.3, 2.7 Hz, 1H), 6.78 (dd, J = 9.8, 3.5 Hz, 1H), 4.09 – 3.82 (m, 9H), 3.76 – 3.61 (m, 2H), 3.50 – 3.26 (m, 3H), 2.53 (d, J = 8.5 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ186.44, 167.24, 167.18, 166.60, 166.12, 166.08, 158.20, 158.12, 150.09,150.02, 143.91, 143.84, 143.59, 141.86, 141.72, 140.08, 140.00, 139.64,139.47, 131.07, 131.01, 127.43, 127.40, 127.37, 127.31, 125.10, 125.08,124.99, 124.47, 124.36, 124.08, 124.02, 123.62, 123.49, 123.15, 123.03,115.17, 114.26, 113.35, 113.26, 103.36, 56.16, 56.12, 52.47, 52.42, 47.18,46.53, 46.26, 45.78, 42.02, 41.54, 41.30, 41.00, 15.82, 15.79. HRMS (ESI):calced for C 32 H 28 N4O6S, [M+H] + 597.1810, found 597.1811.

[0094] As can be seen from the above analysis, the structure of the methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0095] Example 9 Preparation of methyl 3-(2-(4-(6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0096] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(4-(trifluoromethyl)phenyl)ethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 in step (5) was replaced with (6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 41.2%.

[0097] The methyl 3-(2-(4-(6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (dd, J = 17.5, 3.1 Hz, 1H), 8.80 (dd, J =36.9, 1.7 Hz, 1H), 8.55 – 8.37 (m, 3H), 8.28 – 8.05 (m, 2H), 7.98 – 7.85 (m,3H), 7.70 – 7.49 (m, 2H), 7.07 (dd, J = 8.2, 2.8 Hz, 1H), 4.08 – 3.76 (m,9H), 3.62 (d, J = 5.7 Hz, 2H), 3.45 – 3.37 (m, 2H), 3.23 (s, 1H). 13C NMR (151MHz, DMSO-d6) δ 186.44, 167.25, 166.61, 166.13, 158.97, 158.89, 152.27,144.32, 144.26, 142.50, 142.44, 142.27, 140.11, 140.02, 139.64, 139.49,132.08, 132.01, 128.17, 128.13, 126.22, 126.19, 126.15, 126.12, 125.11,125.07, 124.99, 124.84, 124.79, 124.47, 124.36, 123.67, 123.62, 123.56,123.48, 116.76, 114.26, 113.36, 113.26, 102.92, 56.26, 56.22, 52.47, 52.41,47.21, 46.54, 46.27, 45.77, 42.08, 41.53, 41.35, 40.99. HRMS (ESI): calculated for C 34 H 27 F3N4O6, [M+H] + 645.1960, found 645.1964.

[0098] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(4-(trifluoromethyl)phenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0099] Example 10 Preparation of methyl 3-(2-(4-(2-cyclohexyl-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0100] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-cyclohexylethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (2-cyclohexyl-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (2-cyclohexyl-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-cyclohexyl-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 31.9%.

[0101] The methyl 3-(2-(4-(2-cyclohexyl-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (d, J = 16.6 Hz, 1H), 8.82 (d, J = 30.0 Hz, 1H), 8.46 – 8.35 (m, 1H), 7.91 (dd, J = 17.1, 8.9 Hz, 2H), 7.71 – 7.59 (m, 1H),7.42 (dd, J = 15.7, 8.4 Hz, 2H), 7.06 – 6.95 (m, 1H), 4.00 – 3.77 (m, 9H),3.74 – 3.42 (m, 2H), 2.96 – 2.62 (m, 2H), 2.08 – 1.51 (m, 8H), 1.51 – 1.10(m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 186.45, 186.34, 167.24, 166.98, 166.11,163.86, 163.77, 157.91, 157.83, 143.89, 143.85, 141.30, 141.12, 140.08,139.61, 139.48, 131.25, 131.18, 125.09, 125.07, 125.02, 124.98, 124.46,124.36, 123.86, 123.63, 123.53, 122.52, 122.40, 117.89, 117.86, 113.33,113.25, 102.97, 56.08, 56.03, 52.45, 52.41, 47.18, 46.49, 46.44, 46.23,45.77, 41.97, 41.49, 41.25, 40.99, 32.56, 26.48, 26.43, 26.10, 26.06. HRMS(ESI): calculated for C 33 H 34 N4O6, [M+H] + 583.2558, found 583.2559.

[0102] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-cyclohexyl-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0103] Example 11 Preparation of methyl 3-(2-(4-(6-methoxy-2-phenylquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0104] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with acetophenone. Following steps (1), (2), and (3), intermediate (6-methoxy-2-phenylquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-phenylquinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-phenylquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 35.9%.

[0105] The methyl 3-(2-(4-(6-methoxy-2-(thiazo-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 HNMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.84 (d, J = 36.4 Hz, 1H), 8.46 (s,1H), 8.30 (dd, J = 18.5, 7.3 Hz, 2H), 8.21 – 8.03 (m, 2H), 8.02 – 7.86 (m,1H), 7.71 – 7.47 (m, 5H), 7.09 (dd, J = 8.6, 2.8 Hz, 1H), 4.09 – 3.78 (m,10H), 3.66 (s, 2H), 3.26 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 186.46, 186.36,167.25, 167.18, 166.79, 166.09, 158.54, 158.46, 153.89, 153.84, 144.33,144.26, 142.17, 142.02, 140.09, 140.00, 139.62, 139.46, 138.71, 138.67,131.90, 131.84, 130.00, 129.93, 129.33, 129.26, 127.45, 127.41, 125.10,125.08, 125.00, 124.98, 124.47, 124.40, 124.35, 123.63, 123.50, 123.30,123.18, 116.47, 114.26, 113.35, 113.26, 102.97, 56.20, 56.16, 52.47, 52.42,47.22, 46.56, 46.26, 45.78, 42.06, 41.53, 41.33, 41.00. HRMS (ESI): calculated forC 33 H 28 N4O6, [M+H] + 577.2085, found 577.2088.

[0106] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-phenylquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0107] Example 12 Preparation of methyl 3-(2-(4-(6-methoxy-2-(naphth-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0108] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(naphthyl)acetone. After the reactions in steps (1), (2), and (3), intermediate (6-methoxy-2-(naphthyl-1-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(naphthyl-1-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(naphthyl-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 35.2%.

[0109] The methyl 3-(2-(4-(6-methoxy-2-(naphth-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.81 – 12.58 (m, 1H), 8.81 (d, J = 26.3 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.23 ​​– 8.00 (m, 4H), 7.90 (ddd, J = 13.9, 8.6, 1.7 Hz,1H), 7.83 – 7.66 (m, 3H), 7.64 – 7.43 (m, 4H), 7.14 (dd, J = 8.5, 2.8 Hz,1H), 4.04 – 3.77 (m, 10H), 3.68 – 3.55 (m, 2H), 3.48 (s, 1H), 3.31 (s, 1H). 13CNMR (151 MHz, DMSO-d6) δ 186.47, 167.24, 166.61, 166.12, 158.73, 156.30,156.24, 144.30, 144.22, 141.62, 141.50, 140.08, 139.61, 139.49, 138.07,134.01, 133.95, 131.87, 131.80, 131.10, 131.04, 129.53, 129.46, 128.88,128.81, 128.51, 128.44, 127.23, 127.11, 126.57, 126.49, 125.93, 125.89, 125.87, 125.09, 125.01, 124.47, 124.38, 124.20, 124.14, 123.62, 123.52, 123.33, 123.24, 120.70, 120.65, 113.34, 113.27, 103.05, 56.26, 56.22, 52.46, 52.44, 47.30, 46.63, 46.30, 45.74, 42.07, 41.55, 41.34, 40.95, 28.47, 21.22,14.55. HRMS (ESI): calculated for C 37 H 30 N4O6, [M+H] + 627.2246, found 627.2248.

[0110] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0111] Example 13 Preparation of methyl 3-(2-(4-(6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0112] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(5,6,7,8-tetrahydronaphthyl-2-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-yl)(piperazin-1-yl)methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 32.7%.

[0113] The methyl 3-(2-(4-(6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.65 (d, J = 18.7 Hz, 1H), 8.79 (d, J =35.8 Hz, 1H), 8.38 (dt, J = 10.5, 2.4 Hz, 1H), 8.07 – 7.83 (m, 5H), 7.71 –7.55 (m, 1H), 7.53 – 7.37 (m, 1H), 7.17 (dd, J = 12.9, 7.9 Hz, 1H), 7.01 (dt,J = 9.4, 2.4 Hz, 1H), 3.85 (dd, J = 18.4, 3.2 Hz, 10H), 3.61 (s, 2H), 3.27 –3.10 (m, 1H), 2.87 – 2.69 (m, 5H), 1.81 – 1.68 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 186.46, 186.34, 167.24, 167.18, 166.86, 166.13, 166.08, 158.35, 158.27,154.09, 154.02, 144.30, 144.23, 142.03, 141.89, 140.09, 140.00, 139.62,139.46, 138.88, 138.81, 137.57, 137.51, 135.93, 135.89, 131.77, 131.71,129.88, 129.81, 127.89, 127.84, 125.11, 125.08, 125.00, 124.97, 124.55, 124.51, 124.47, 124.35, 124.20, 124.15, 123.64, 123.51, 123.11, 123.00, 116.30, 114.27, 113.34, 113.24, 102.98, 102.96, 56.16, 56.12, 52.46, 52.41, 47.21, 46.55, 46.26, 45.77, 42.02, 41.54, 41.30, 40.99, 29.44, 29.40, 29.17, 29.14, 23.23, 23.20, 23.15, 23.13. HRMS (ESI): calculated for C 37 H 34 N4O6, [M+H] + 631.2560, found 631.2560.

[0114] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(5,6,7,8-tetrahydronaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0115] Example 14 Preparation of methyl 3-(2-(4-(2-(2,3-dihydro-1H-indo[1,2-b]pyridin-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0116] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) is replaced with 1-(2,3-dihydro-1H-indene-5-yl)ethane-1-one, and then the intermediate 1-(2,3-dihydro-1H-indene-5-yl)ethane-1-one is obtained after the reaction in steps (1), (2) and (3). Then, intermediate 5a-1 was replaced with 1-(2,3-dihydro-1H-inden-5-yl)ethane-1-one, while keeping everything else unchanged. The final product was a white solid, namely methyl 3-(2-(4-(2-(2,3-dihydro-1H-inden[1,2-b]pyridin-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 35.7%.

[0117] The methyl 3-(2-(4-(2-(2,3-dihydro-1H-inden[1,2-b]pyridin-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.63 (d, J = 18.5 Hz, 1H), 8.75 (d, J = 35.9 Hz, 1H), 8.40 – 8.28 (m, 1H), 8.13 – 7.78 (m, 5H), 7.66 –7.25 (m, 3H), 6.98 (dd, J = 9.1, 2.8 Hz, 1H), 3.99 – 3.69 (m, 10H), 3.57 (s,2H), 3.17 (s, 2H), 2.89 (dd, J = 14.2, 7.6 Hz, 4H), 2.02 (p, J = 7.6 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 186.47, 186.35, 167.25, 166.86, 166.13, 166.09,158.34, 158.26, 154.33, 145.97, 145.90, 145.00, 144.93, 144.32, 144.25,142.03, 141.89, 140.09, 140.00, 139.61, 139.46, 136.93, 136.88, 131.77,131.71, 125.67, 125.63, 125.10, 125.08, 125.02, 124.98, 124.95, 124.47, 124.36, 124.21, 123.63, 123.51, 123.27, 123.22, 123.13, 123.01, 116.44, 113.34, 113.25, 102.99, 102.97, 56.16, 56.12, 52.47, 52.41, 47.22, 46.56, 46.26, 45.78, 42.04, 41.53, 41.32, 41.00, 32.78, 32.74, 32.67, 32.64, 25.56,25.53. HRMS (ESI): calculated for C 36 H 32 N4O6, [M+H] + 617.2402, found 617.2404.

[0118] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(2,3-dihydro-1H-indo[1,2-b]pyridin-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0119] Example 15 Preparation of methyl 3-(2-(4-(2-[(1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0120] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) is replaced with 1-([1,1'-biphenyl]-4-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (2-([1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, following the synthesis method in step five, intermediate 5a-1 was replaced with (2-([1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-[(1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 40.8%.

[0121] The methyl 3-(2-(4-(2-[(1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, Chloroform-d) δ 10.17 – 9.98 (m, 1H), 9.09 – 8.81 (m,1H), 8.27 – 8.08 (m, 3H), 8.03 – 7.56 (m, 7H), 7.53 – 7.30 (m, 5H), 7.03 (dd,J = 6.0, 2.8 Hz, 1H), 4.13 – 3.86 (m, 9H), 3.84 – 3.63 (m, 2H), 3.63 – 3.19 (m, 3H). 13C NMR (151 MHz, DMSO-d6) δ 186.45, 166.79, 166.14, 166.10, 158.56,158.48, 153.42, 153.36, 144.38, 144.32, 142.01, 141.57, 141.50, 140.13,140.04, 139.89, 139.67, 139.51, 137.69, 137.65, 131.91, 131.85, 129.51,129.49, 128.31, 128.01, 127.97, 127.55, 127.48, 127.19, 127.16, 125.11,125.07, 125.01, 124.97, 124.46, 124.44, 124.39, 123.62, 123.48, 123.33,123.22, 116.43, 113.37, 113.28, 103.00, 56.21, 56.17, 52.48, 52.42, 47.22,46.57, 46.26, 45.78, 42.06, 41.53, 41.34, 40.99, 38.71. HRMS (ESI): calculated forC 39 H 32 N4O6, [M+H] + 653.2400, found 653.2401.

[0122] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-[(1,1'-biphenyl]-4-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0123] Example 16 Preparation of methyl 3-(2-(4-(6-methoxy-2-(6-methoxynaphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0124] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(6-methoxynaphthyl-2-yl)ethane-1-one. Following steps (1), (2), and (3), intermediate (6-methoxy-2-(6-methoxynaphthyl-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(6-methoxynaphthyl-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(6-methoxynaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 32.6%.

[0125] The methyl 3-(2-(4-(6-methoxy-2-(6-methoxynaphth-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.72 – 12.57 (m, 1H), 8.86 – 8.65 (m, 2H), 8.45 – 8.31 (m, 2H), 8.22 (d, J = 17.3 Hz, 1H), 8.07 – 7.82 (m, 4H), 7.64 –7.30 (m, 3H), 7.24 – 7.15 (m, 1H), 7.01 (dd, J = 9.8, 2.8 Hz, 1H), 4.05 –3.70 (m, 13H), 3.65 – 3.53 (m, 2H), 3.42 – 3.37 (m, 1H), 3.25 – 3.14 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.47, 167.25, 167.17, 166.89, 166.14, 166.09,158.64, 158.46, 158.38, 153.94, 153.88, 144.37, 142.15, 142.01, 140.09,140.00, 139.64, 139.48, 135.44, 135.38, 133.87, 133.83, 131.83, 131.77,130.76, 130.72, 128.97, 127.74, 127.67, 126.85, 126.81, 125.39, 125.36, 125.11, 125.09, 125.00, 124.98, 124.48, 124.35, 124.28, 124.22, 123.63, 123.49, 123.23, 123.12, 119.62, 119.58, 116.49, 113.36, 113.26, 106.47, 106.43, 103.06, 103.03, 56.20, 56.16, 55.78, 55.76, 52.48, 52.41, 47.24,46.58, 46.31, 45.81, 42.05, 41.58, 41.32, 41.03, 36.24, 31.25. HRMS (ESI):calced for C 38 H 32 N4O7, [M+H] + 657.2350, found 657.2352.

[0126] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(6-methoxynaphthyl-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0127] Example 17 Preparation of methyl 3-(2-(4-(6-methoxy-2-(4-methoxynaphth-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0128] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(4-methoxynaphthyl-1-yl)ethane-1-one. Following steps (1), (2), and (3), intermediate (6-methoxy-2-(4-methoxynaphthyl-1-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(4-methoxynaphthyl-1-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(4-methoxynaphthyl-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 35.1%.

[0129] The methyl 3-(2-(4-(6-methoxy-2-(4-methoxynaphth-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (d, J = 16.2 Hz, 1H), 8.80 (d, J = 27.1Hz, 1H), 8.45 – 8.17 (m, 3H), 7.98 (ddd, J = 43.5, 16.2, 8.8 Hz, 2H), 7.80 –7.43 (m, 6H), 7.21 – 7.04 (m, 2H), 4.11 – 3.76 (m, 13H), 3.67 – 3.55 (m, 2H), 3.47 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.47, 167.24, 166.69, 166.13,166.09, 158.53, 158.45, 156.39, 156.33, 155.95, 144.27, 144.20, 141.53,141.41, 140.08, 140.01, 139.61, 139.49, 132.02, 131.96, 131.75, 131.69,130.40, 130.37, 129.34, 129.27, 127.63, 127.51, 125.95, 125.92, 125.87, 125.53, 125.08, 125.00, 124.46, 124.37, 123.93, 123.87, 123.62, 123.52, 123.16, 123.06, 122.32, 122.25, 120.72, 120.68, 113.34, 113.27, 104.54, 104.48, 103.06, 56.32, 56.28, 56.23, 56.19, 52.47, 52.43, 47.30, 46.63, 46.30, 45.75, 42.05, 41.56, 41.32, 40.96, 31.61, 30.32. HRMS (ESI): calculated for C 38 H 32 N4O7, [M+H] + 657.2352, found 657.2352.

[0130] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(4-methoxynaphth-1-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0131] Example 18 Preparation of methyl 3-(2-(4-(2-(benzo[b]thiophen-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0132] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(benzo[b]thiophene-2-yl)ethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (2-(benzo[b]thiophene-2-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (2-(benzo[b]thiophene-2-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(benzo[b]thiophene-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 41.8%.

[0133] The methyl 3-(2-(4-(2-(benzo[b]thiophene-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.73 – 12.60 (m, 1H), 8.89 – 8.70 (m, 1H), 8.45 – 8.22 (m, 3H), 7.97 (ddd, J = 27.4, 10.8, 7.7 Hz, 4H), 7.69 – 7.39 (m,4H), 7.06 (d, J = 2.8 Hz, 1H), 4.05 – 3.73 (m, 10H), 3.67 – 3.58 (m, 2H), 3.44 – 3.41 (m, 1H), 3.30 – 3.18 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.45,167.25, 167.17, 166.49, 166.13, 158.77, 149.82, 149.74, 143.96, 141.97,141.82, 140.74, 140.69, 140.09, 140.00, 139.65, 139.49, 131.43, 131.37,126.10, 126.06, 125.31, 125.26, 125.10, 124.99, 124.91, 124.87, 124.78,124.72, 124.48, 124.36, 123.89, 123.87, 123.63, 123.49, 123.38, 123.19,123.14, 115.96, 114.26, 113.36, 113.27, 103.40, 56.26, 56.22, 52.48, 52.42,47.22, 46.56, 46.29, 45.81, 42.10, 41.55, 41.37, 41.03, 21.22, 14.55. HRMS(ESI): calculated for C 35 H 28 N4O6S, [M+H] + 633.1810, found 633.1811.

[0134] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(benzo[b]thiophen-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0135] Example 19 Preparation of methyl 3-(2-(4-(2-(benzo[d][1,3]dioxolane-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0136] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(benzo[d][1,3]dioxacyclopenten-5-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (2-(benzo[d][1,3]dioxacyclopenten-5-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzo[d][1,3]dioxolane-5-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(benzo[d][1,3]dioxolane-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 43.1%.

[0137] The methyl 3-(2-(4-(2-(benzo[d][1,3]dioxolane-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 12.73 – 12.63 (m, 1H), 8.80 (d, J =69.5 Hz, 1H), 8.38 (dd, J = 19.7, 3.1 Hz, 1H), 8.10 – 7.79 (m, 5H), 7.64 (dd,J = 36.8, 8.6 Hz, 1H), 7.48 (ddd, J = 28.8, 9.2, 2.8 Hz, 1H), 7.12 – 6.98 (m,2H), 6.12 (d, J = 18.2 Hz, 2H), 4.04 – 3.74 (m, 9H), 3.66 – 3.53 (m, 3H),3.25 – 3.08 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 186.48, 167.25, 166.81,166.78, 166.12, 166.08, 158.31, 158.23, 153.33, 153.26, 149.09, 149.03,148.59, 144.17, 144.10, 142.05, 141.90, 140.09, 139.65, 139.49, 133.05,133.01, 131.70, 131.64, 125.09, 124.99, 124.46, 124.34, 124.11, 124.06, 123.62, 123.50, 123.16, 123.05, 121.85, 121.81, 116.13, 114.25, 113.36, 113.27, 108.99, 108.92, 107.37, 107.34, 107.30, 102.97, 101.96, 101.91, 65.81, 56.15, 56.13, 56.11, 54.09, 52.47, 52.42, 47.21, 46.55, 46.23, 45.78, 42.32, 42.04, 41.49, 41.31, 40.99, 18.53, 17.17, 12.92. HRMS (ESI): calculated forC 34 H 28 N4O8, [M+H] + 621.2220, found 621.2223.

[0138] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(benzo[d][1,3]dioxolane-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0139] Example 20 Preparation of methyl 3-(2-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxazine-6-yl)-6-methoxyquinoline-4-carbonyl)piperazine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0140] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) is replaced with 1-(2,3-dihydrobenzo[b][1,4]dioxazine-6-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (2-(2,3-dihydrobenzo[b][1,4]dioxazine-6-yl)-6-methoxyquinoline-4-yl)(piperazine-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(2,3-dihydrobenzo[b][1,4]dioxazin-6-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which is the prepared methyl 3-(2-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxazin-6-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 43.1%.

[0141] The methyl 3-(2-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxazin-6-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.75 – 12.60 (m, 1H), 8.88 –8.72 (m, 1H), 8.40 (d, J = 10.1 Hz, 1H), 8.08 – 7.72 (m, 5H), 7.70 – 7.58 (m,1H), 7.46 (ddd, J = 14.3, 9.2, 2.7 Hz, 1H), 7.05 – 6.91 (m, 2H), 4.31 (d, J =8.5 Hz, 4H), 4.05 – 3.72 (m, 10H), 3.67 – 3.56 (m, 2H), 3.48 – 3.39 (m, 1H),3.27 – 3.12 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.48, 186.36, 167.24,167.17, 166.81, 166.11, 166.07, 158.26, 158.18, 153.27, 153.20, 145.40,145.34, 144.22, 144.18, 141.99, 141.83, 140.08, 139.99, 139.64, 139.48,132.11, 132.04, 132.00, 131.70, 131.64, 129.16, 125.08, 124.99, 124.45, 124.34, 124.08, 124.03, 123.62, 123.50, 123.12, 123.00, 120.61, 120.57, 117.85, 117.78, 116.06, 116.03, 114.24, 113.35, 113.26, 102.97, 64.84, 64.81, 64.60, 64.56, 56.15, 56.11, 52.48, 52.43, 47.21, 46.55, 46.22, 45.78, 42.04, 41.48, 41.32, 40.99. HRMS (ESI): calculated for C 35 H 30 N4O8, [M+H] + 634.2145, found635.2147.

[0142] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(2,3-dihydrobenzo[b][1,4]dioxazine-6-yl)-6-methoxyquinoline-4-carbonyl)piperazine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0143] Example 21 Preparation of methyl 3-(2-(4-(6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0144] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) is replaced with 1-(7-methoxybenzofuran-2-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-yl)(piperazin-1-yl)methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 32.9%.

[0145] The methyl 3-(2-(4-(6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.77 – 12.57 (m, 1H), 8.90 – 8.71 (m,1H), 8.40 (dd, J = 10.6, 3.2 Hz, 1H), 8.16 – 8.03 (m, 2H), 7.97 – 7.49 (m,4H), 7.39 – 7.19 (m, 2H), 7.11 – 6.98 (m, 2H), 4.11 – 3.74 (m, 13H), 3.63(tt, J = 4.4, 1.9 Hz, 2H), 3.43 – 3.38 (m, 1H), 3.27 – 3.16 (m, 1H). 13C NMR(151 MHz, DMSO-d6) δ 186.47, 167.25, 166.41, 166.13, 166.08, 158.96, 158.89,154.96, 146.15, 146.07, 145.68, 144.30, 144.22, 142.18, 142.04, 140.09,140.00, 139.63, 139.47, 131.75, 131.69, 130.41, 130.36, 125.11, 125.08,124.99, 124.82, 124.77, 124.69, 124.48, 124.36, 123.74, 123.63, 123.49,116.06, 114.39, 114.35, 114.27, 113.35, 113.25, 108.43, 108.40, 106.88,106.85, 103.14, 56.28, 56.26, 56.24, 52.47, 52.41, 47.18, 46.51, 46.30,45.72, 42.04, 41.57, 41.32, 40.95. HRMS (ESI): calculated for C 36 H 30 N4O8, [M+H] + 647.2142, found 647.2145.

[0146] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0147] Example 22 Preparation of methyl 3-(2-(4-(6-methoxy-2-(pyrazin-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0148] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(pyrazin-2-yl)ethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(pyrazin-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(pyrazin-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 31.9%.

[0149] The methyl 3-(2-(4-(6-methoxy-2-(pyrazin-2-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 HNMR (300 MHz, DMSO-d6) δ 13.69 – 11.57 (m, 1H), 9.71 (dd, J = 18.1, 1.4 Hz,1H), 8.90 – 8.70 (m, 3H), 8.40 (dd, J = 13.1, 2.4 Hz, 2H), 8.15 (dd, J =17.1, 9.2 Hz, 1H), 7.90 (ddd, J = 21.1, 8.6, 1.7 Hz, 1H), 7.71 – 7.51 (m,2H), 7.10 (dd, J = 9.1, 2.8 Hz, 1H), 4.01 (s, 1H), 3.97 – 3.89 (m, 5H), 3.84 (d, J = 5.7 Hz, 3H), 3.60 (dt, J = 12.2, 4.8 Hz, 3H), 3.28 – 3.16 (m, 2H). 13CNMR (151 MHz, DMSO-d6) δ 186.44, 186.33, 166.54, 166.08, 159.42, 151.57,151.49, 150.40, 145.67, 145.62, 144.52, 144.47, 143.99, 143.92, 143.18,143.11, 142.42, 142.29, 140.13, 139.69, 139.54, 132.22, 132.17, 125.66,125.59, 125.10, 125.06, 124.99, 124.96, 124.45, 124.33, 123.83, 123.72,123.62, 123.47, 116.39, 113.36, 113.27, 103.06, 56.33, 56.30, 52.47, 52.42,47.13, 46.45, 46.31, 45.69, 42.01, 41.57, 41.29, 40.92. HRMS (ESI): calculated forC 31 H 26 N6O6, [M+H] + 579.1990, found 579.1994.

[0150] As can be seen from the above analysis, the structure of the methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0151] Example 23 Preparation of methyl 3-(2-(4-(2-(2,3-dihydrobenzofuran-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0152] The preparation process is the same as in Example 1, except that the intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) is replaced with 1-(2,3-dihydrobenzofuran-5-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (6-methoxy-2-(7-methoxybenzofuran-2-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(2,3-dihydrobenzofuran-5-yl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(2,3-dihydrobenzofuran-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 33.8%.

[0153] The methyl 3-(2-(4-(2-(2,3-dihydrobenzofuran-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (dd, J = 18.3, 3.2 Hz, 1H), 8.80 (dd, J = 35.4, 1.7 Hz, 1H), 8.40 (dd, J = 9.5, 3.1 Hz, 1H), 8.18 (dd, J =16.6, 1.8 Hz, 1H), 8.11 – 7.84 (m, 4H), 7.64 (dd, J = 18.7, 8.5 Hz, 1H), 7.47 (ddd, J = 14.5, 9.2, 2.8 Hz, 1H), 7.04 – 6.83 (m, 2H), 4.63 (q, J = 8.7 Hz,2H), 4.08 – 3.72 (m, 9H), 3.62 (d, J = 5.5 Hz, 2H), 3.36 – 3.19 (m, 5H). 13CNMR (151 MHz, DMSO-d6) δ 186.47, 167.24, 166.88, 166.12, 161.70, 158.13,153.98, 144.24, 142.00, 141.86, 140.08, 140.00, 139.62, 139.47, 131.55,131.49, 131.32, 128.72, 127.83, 127.79, 125.09, 124.99, 124.47, 124.37,124.35, 124.33, 123.89, 123.84, 123.62, 123.50, 123.05, 122.93, 116.04,114.25, 113.35, 113.26, 109.56, 109.49, 103.04, 72.01, 71.97, 56.15, 56.11,52.47, 52.43, 47.21, 46.55, 46.25, 45.78, 42.03, 41.52, 41.30, 41.00, 29.36,29.33. HRMS (ESI): calculated for C 35 H 30 N4O7, [M+H] + 619.2194, found 619.2196.

[0154] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(2,3-dihydrobenzofuran-5-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0155] Example 24 Preparation of methyl 3-(2-(4-(6-methoxy-2-(4-methoxyphenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0156] The preparation process was the same as in Example 1, except that intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) was replaced with 1-(4-methoxyphenyl)ethane-1-one. Following steps (1), (2), and (3), intermediate (6-methoxy-2-(4-methoxyphenyl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(4-methoxyphenyl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(4-methoxyphenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 35.7%.

[0157] The methyl 3-(2-(4-(6-methoxy-2-(4-methoxyphenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.80 (dd, J = 35.8, 1.7 Hz, 1H), 8.40 (d, J = 9.9 Hz, 1H), 8.30 – 8.17 (m, 2H), 8.12 – 7.84 (m, 3H), 7.64 (dd,J = 18.9, 8.6 Hz, 1H), 7.47 (ddd, J = 14.5, 9.2, 2.8 Hz, 1H), 7.16 – 6.98 (m,3H), 4.06 – 3.77 (m, 12H), 3.62 (d, J = 5.2 Hz, 2H), 3.22 (s, 1H). 13C NMR (151MHz, DMSO-d6) δ 186.46, 167.24, 166.87, 166.13, 166.08, 161.06, 161.00,158.21, 158.13, 153.66, 153.59, 144.29, 144.22, 142.03, 141.88, 140.09,140.00, 139.63, 139.47, 131.66, 131.60, 131.20, 131.16, 128.87, 128.83,125.10, 125.07, 124.97, 124.47, 124.35, 123.96, 123.91, 123.62, 123.49,123.09, 122.97, 115.99, 114.71, 114.65, 114.25, 113.35, 113.26, 103.01,56.15, 56.12, 55.80, 55.76, 52.47, 52.42, 47.20, 46.54, 46.25, 45.78, 42.02,41.52, 41.30, 40.99. HRMS (ESI): calculated for C 34 H 30 N4O7, [M+H] + 607.2188, found607.2189.

[0158] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(4-methoxyphenyl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0159] Example 25 Preparation of methyl 3-(2-(4-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0160] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(tetrahydro-2H-pyran-4-yl)ethane-1-one, and then after the reaction in steps (1), (2) and (3), the intermediate (6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-yl)(piperazin-1-yl)methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 31.9%.

[0161] The methyl 3-(2-(4-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (d, J = 15.5 Hz, 1H), 8.80 (d, J = 30.0Hz, 1H), 8.39 (dd, J = 7.9, 2.8 Hz, 1H), 8.00 – 7.84 (m, 2H), 7.64 (dd, J =15.8, 8.6 Hz, 1H), 7.51 – 7.37 (m, 2H), 7.01 (dd, J = 7.0, 2.8 Hz, 1H), 4.05– 3.74 (m, 12H), 3.65 – 3.39 (m, 5H), 3.21 – 3.02 (m, 2H), 1.93 – 1.78 (m,4H). 13C NMR (151 MHz, DMSO-d6) δ 186.35, 167.24, 166.90, 166.10, 162.27,162.18, 158.04, 157.95, 143.88, 143.84, 141.46, 141.27, 140.07, 140.00,139.61, 139.49, 131.31, 131.24, 125.08, 125.00, 124.46, 124.36, 123.97,123.95, 123.61, 123.51, 122.67, 122.56, 117.87, 114.24, 113.34, 113.27,102.98, 67.57, 67.52, 56.10, 56.06, 52.47, 52.43, 47.18, 46.49, 46.22, 45.76,43.26, 43.22, 41.98, 41.48, 41.26, 40.99. HRMS (ESI): calculated for C 32 H 32 N4O7, [M+H] + 585.2350, found 585.2352.

[0162] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(tetrahydro-2H-pyran-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0163] Example 26 Preparation of methyl 3-(2-(4-(6-methoxy-2-(pyridin-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0164] The preparation process was the same as in Example 1, except that intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) was replaced with 1-(pyridin-4-yl)ethane-1-one. After the reactions in steps (1), (2), and (3), intermediate (6-methoxy-2-(pyridin-4-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (6-methoxy-2-(pyridin-4-yl)quinoline-4-yl)(piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(6-methoxy-2-(pyridin-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 34.8%.

[0165] The methyl 3-(2-(4-(6-methoxy-2-(pyridin-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 HNMR (300 MHz, DMSO-d6) δ 12.75 – 12.61 (m, 1H), 8.90 – 8.70 (m, 3H), 8.41 (dd, J = 8.9, 2.7 Hz, 1H), 8.30 – 8.07 (m, 4H), 7.91 (ddd, J = 20.6, 8.6, 1.7Hz, 1H), 7.72 – 7.50 (m, 2H), 7.09 (dd, J = 8.2, 2.8 Hz, 1H), 4.07 – 3.80 (m,10H), 3.69 – 3.59 (m, 2H), 3.23 (s, 1H), 2.00 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.44, 186.36, 167.24, 166.53, 166.09, 159.19, 159.12, 151.41, 151.34,150.90, 150.83, 145.58, 145.54, 144.33, 144.27, 142.47, 142.31, 140.08,139.62, 139.46, 132.19, 132.13, 125.28, 125.22, 125.09, 124.98, 124.47,124.36, 123.80, 123.69, 123.62, 123.47, 121.49, 121.46, 116.63, 113.35,113.26, 102.91, 56.29, 56.25, 52.47, 52.42, 47.20, 46.53, 46.26, 45.77, 42.09, 41.52, 41.36, 41.00, 14.54. HRMS (ESI): calculated for C 32 H 27 N5O6, [M+H] + 578.2660, found 578.2664.

[0166] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(6-methoxy-2-(pyridin-4-yl)quinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0167] Example 27 Preparation of methyl 3-(2-(4-(2-(2-chlorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0168] The preparation process was the same as in Example 1, except that intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) was replaced with 1-(2-chlorophenyl)ethane-1-one. Following steps (1), (2), and (3), intermediate (2-(2-chlorophenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (2-(2-chlorophenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(2-chlorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 29.5%.

[0169] The methyl 3-(2-(4-(2-(2-chlorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 HNMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.80 (dd, J = 28.3, 1.7 Hz, 1H), 8.38 (d, J = 9.5 Hz, 1H), 8.05 (dd, J = 17.1, 9.2 Hz, 1H), 7.90 (ddd, J = 15.7,8.6, 1.7 Hz, 1H), 7.79 – 7.58 (m, 4H), 7.58 – 7.46 (m, 3H), 7.10 (dd, J =7.5, 2.8 Hz, 1H), 3.98 – 3.77 (m, 9H), 3.61 (s, 2H), 3.41 (s, 2H), 3.24 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.45, 186.33, 167.23, 166.46, 166.09,158.89, 158.82, 154.28, 154.25, 144.29, 144.20, 140.76, 140.67, 140.07,139.62, 139.52, 139.13, 132.31, 132.21, 131.85, 131.83, 131.78, 130.94,130.86, 130.38, 130.30, 127.96, 127.87, 125.08, 125.02, 124.98, 124.46,124.40, 124.35, 123.62, 123.53, 123.35, 123.24, 120.30, 120.25, 113.34,113.26, 103.05, 56.25, 56.21, 52.47, 52.43, 47.23, 46.56, 46.21, 45.73,42.05, 41.50, 41.34, 40.96. HRMS (ESI): calculated for C 33 H 27 ClN4O6, [M+H] + 611.1702, found 611.1700.

[0170] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(2-chlorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0171] Example 28 Preparation of methyl 3-(2-(4-(2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0172] The preparation process was the same as in Example 1, except that intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) was replaced with 1-(2,4-dimethoxyphenyl)ethane-1-one. Following steps (1), (2), and (3), intermediate (2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, namely 3-(2-(4-(2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 28.4%.

[0173] The 3-(2-(4-(2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.80 (dd, J = 32.1, 1.7 Hz, 1H), 8.39 (d, J = 9.6 Hz, 1H), 8.06 – 7.75 (m, 4H), 7.63 (dd, J = 17.2, 8.6 Hz, 1H), 7.45 (ddd, J = 13.9, 9.2, 2.8 Hz, 1H), 7.04 (dd, J = 9.3, 2.8 Hz, 1H), 6.78 – 6.62 (m, 2H), 3.98 (d, J = 5.5 Hz, 1H), 3.93 – 3.78 (m, 15H), 3.61 (d,J = 5.0 Hz, 2H), 3.22 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.47, 167.24,167.02, 166.97, 166.07, 162.06, 162.01, 158.20, 158.14, 153.57, 153.50,144.46, 144.38, 140.08, 140.02, 140.00, 139.65, 139.50, 132.33, 132.29,131.63, 131.59, 125.10, 125.08, 125.01, 124.98, 124.47, 124.35, 123.82, 123.73, 123.63, 123.52, 122.69, 122.59, 121.34, 121.27, 120.62, 120.57, 113.34, 113.24, 106.39, 106.32, 103.02, 102.97, 99.18, 99.14, 56.36, 56.24, 56.12, 56.09, 55.89, 55.86, 52.46, 52.42, 47.20, 46.54, 46.30, 45.79, 41.97, 41.58, 41.25, 41.01. HRMS (ESI): calculated for C 35 H 32 N4O8, [M+H] + 637.2300, found637.2302.

[0174] As can be seen from the above analysis, the structure of the 3-(2-(4-(2-(2,4-dimethoxyphenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0175] Example 29 Preparation of methyl 3-(2-(4-(2-(4-fluorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0176] The preparation process was the same as in Example 1, except that intermediate 1-(naphth-2-yl)ethane-1-one (2a-1) was replaced with 1-(4-fluorophenyl)ethane-1-one. Following steps (1), (2), and (3), intermediate (2-(4-fluorophenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone was obtained. Then, intermediate 5a-1 was replaced with (2-(4-fluorophenyl)-6-methoxyquinoline-4-yl)(piperazin-1-yl) methyl ketone, while other steps remained unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(4-fluorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 30.2%.

[0177] The methyl 3-(2-(4-(2-(4-fluorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.67 (d, J = 16.3 Hz, 1H), 8.89 – 8.72 (m, 1H), 8.44 – 8.36 (m, 1H), 8.36 – 8.21 (m, 2H), 8.19 – 8.07 (m, 1H), 8.06 – 7.98(m, 1H), 7.90 (ddd, J = 20.1, 8.6, 1.8 Hz, 1H), 7.70 – 7.58 (m, 1H), 7.49(ddd, J = 14.2, 9.2, 2.8 Hz, 1H), 7.36 (dt, J = 13.0, 8.8 Hz, 2H), 7.11 –6.99 (m, 1H), 4.15 – 4.02 (m, 1H), 3.88 (s, 5H), 3.80 (s, 1H), 3.63 (d, J =7.2 Hz, 2H), 3.17 (d, J = 5.2 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 186.45,186.35, 167.25, 167.18, 166.75, 166.13, 166.10, 164.47, 164.41, 162.83,158.55, 158.47, 152.88, 152.82, 144.25, 144.19, 142.25, 142.09, 140.08,140.00, 139.61, 139.46, 135.21, 135.19, 131.83, 131.77, 129.70, 129.67, 129.65, 129.61, 128.82, 125.09, 124.99, 124.48, 124.36, 124.31, 124.26, 123.63, 123.49, 123.35, 123.24, 116.30, 116.26, 116.18, 116.11, 116.04, 114.26, 114.17, 113.34, 113.26, 102.95, 56.19, 56.15, 52.46, 52.41, 47.21, 46.55, 46.26, 45.78, 42.06, 41.53, 41.33, 41.00, 29.43. HRMS (ESI): calculated forC 33 H 27 FN4O6, [M+H] + 595.1994, found 595.1996.

[0178] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(4-fluorophenyl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0179] Example 30 Preparation of ethyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0180] Synthesize according to the following route:

[0181]

[0182] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylate (1b) was replaced with ethyl 1H-indole-5-carboxylate (1b-2), while other aspects remained unchanged, to obtain intermediate ethyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-2). Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with ethyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-2), while other aspects remained unchanged, finally yielding a white solid, which was ethyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 35.9%.

[0183] The ethyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.74 (d, J = 19.4 Hz, 1H), 8.83 (d, J = 37.1Hz, 1H), 8.44 (d, J = 10.4 Hz, 1H), 8.19 – 7.31 (m, 10H), 7.09 (d, J = 9.9Hz, 1H), 4.36 (dq, J = 21.8, 7.4 Hz, 2H), 3.95 (q, J = 21.3, 20.1 Hz, 6H), 3.55 – 3.15 (m, 4H), 1.42 – 1.10 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 186.45,186.34, 166.76, 166.40, 166.15, 166.12, 158.96, 158.89, 155.32, 154.91,146.12, 146.03, 144.24, 144.17, 142.16, 142.02, 140.08, 139.98, 139.60,139.44, 131.68, 131.63, 128.84, 126.29, 126.25, 125.08, 124.98, 124.96, 124.80, 124.76, 124.64, 124.05, 124.01, 123.76, 123.65, 123.51, 123.37, 122.49, 122.45, 116.15, 113.31, 113.21, 112.02, 111.98, 106.69, 106.65, 103.19, 103.17, 61.03, 60.96, 56.28, 56.24, 47.19, 46.53, 46.30, 45.74, 42.07, 41.56, 41.35, 40.97, 14.77, 14.71. HRMS (ESI): calculated for C 36 H 30 N4O7, [M+H] + 647.2140, found 647.2142.

[0184] As can be seen from the above analysis, the structure of the ethyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0185] Example 31 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(benzyloxy)-1H-indol-3-yl)ethane-1,2-dione

[0186] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) was replaced with 5-(benzyloxy)-1H-indole, while keeping everything else unchanged, to obtain the intermediate 2-(5-(benzyloxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-(benzyloxy)-1H-indole-3-yl)-2-oxoacetyl chloride, while keeping everything else unchanged, and finally a white solid was obtained, which is the preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(benzyloxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 34.7%.

[0187] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(benzyloxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.30 – 12.15 (m, 1H), 8.17 – 7.89 (m, 3H), 7.70 (ddd, J = 20.6, 16.2, 7.9 Hz, 4H), 7.38 (dddd, J = 34.3, 20.4, 13.9, 4.5Hz, 9H), 7.07 – 6.82 (m, 2H), 5.08 (d, J = 28.8 Hz, 2H), 4.08 – 3.65 (m, 6H), 3.57 (s, 2H), 3.21 (s, 1H), 2.83 (s, 1H), 2.68 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.20, 186.09, 166.51, 166.42, 158.95, 158.87, 155.59, 155.47, 155.32,155.27, 154.98, 146.16, 146.07, 144.33, 144.27, 142.12, 141.98, 137.97,137.86, 137.82, 137.77, 132.40, 132.32, 131.75, 131.70, 128.86, 128.82,128.80, 128.19, 128.13, 128.09, 128.01, 126.32, 126.27, 126.22, 124.80, 124.76, 124.05, 124.01, 123.73, 123.62, 122.48, 122.44, 116.14, 114.50, 114.37, 113.99, 113.90, 113.53, 112.03, 111.99, 106.63, 106.58, 104.87, 104.77, 103.20, 70.21, 70.13, 56.28, 56.25, 47.18, 46.57, 46.32, 45.75,42.08, 41.48, 41.40, 40.89. HRMS (ESI): calculated for C 40 H 32 N4O6, [M+H] + 665.2403, found 665.2404.

[0188] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(benzyloxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0189] Example 32 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-methoxyethoxy)-1H-indol-3-yl)ethane-1,2-dione

[0190] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) was replaced with 5-(2-methoxyethoxy)-1H-indole, while other aspects remained unchanged, to obtain the intermediate 2-(5-(2-methoxyethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-(2-methoxyethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride, while other aspects remained unchanged, finally yielding a white solid, namely 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-methoxyethoxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 34.1%.

[0191] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-methoxyethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (d, J = 18.1 Hz, 1H), 8.25 –8.03 (m, 3H), 7.87 – 7.63 (m, 4H), 7.56 – 7.32 (m, 4H), 7.10 – 6.83 (m, 2H), 4.22 – 3.74 (m, 9H), 3.74 – 3.47 (m, 5H), 3.33 (s, 2H), 3.26 (d, J = 7.8 Hz, 2H. 13C NMR (151 MHz, DMSO-d6) δ 186.21, 166.56, 166.52, 166.42, 158.95,158.87, 155.58, 155.31, 146.16, 146.07, 144.32, 144.26, 142.13, 141.98,137.89, 137.72, 132.30, 132.22, 131.75, 131.69, 128.85, 128.81, 126.31,126.27, 126.23, 124.80, 124.75, 124.05, 124.01, 123.72, 123.62, 122.48, 122.44, 116.14, 114.40, 114.27, 114.00, 113.91, 113.51, 112.02, 111.99, 106.63, 106.58, 104.27, 104.15, 103.21, 103.18, 71.00, 70.91, 67.90, 67.82, 58.66, 58.60, 56.28, 56.25, 47.19, 46.57, 46.32, 45.74, 42.08, 41.47, 41.39, 40.88. HRMS (ESI): calculated for C 36 H 32 N4O7, [M+H] + 633.2350, found 633.2352.

[0192] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-methoxyethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0193] Example 33 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-morpholinylethoxy)-1H-indol-3-yl)ethane-1,2-dione

[0194] The preparation process is the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) is replaced with 4-(2-((1H-indole-5-yl)oxy)ethyl)morpholine, while the others remain unchanged, to obtain the intermediate 2-(5-(2-morpholinethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-3-yl)-2-oxoacetyl chloride was replaced with methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1), while keeping everything else unchanged. Finally, a white solid was obtained, which was 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-morpholinylethoxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 32.8%.

[0195] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-morpholinylethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (d, J = 19.1 Hz, 1H), 8.26 –7.99 (m, 3H), 7.76 (dd, J = 25.4, 13.2 Hz, 4H), 7.59 – 7.33 (m, 4H), 7.13 –6.84 (m, 2H), 4.42 – 3.75 (m, 10H), 3.59 (td, J = 17.8, 12.8, 5.9 Hz, 8H), 3.27 (s, 1H), 2.71 (dt, J = 22.7, 5.9 Hz, 2H), 2.43 (d, J = 4.8 Hz, 1H), 1.38– 1.17 (m, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.22, 186.11, 166.51, 166.41,158.94, 158.86, 155.67, 155.55, 155.31, 154.96, 146.15, 146.06, 144.32,144.25, 142.12, 141.97, 137.93, 137.78, 132.28, 131.75, 131.69, 128.85,128.81, 126.32, 126.28, 126.22, 124.79, 124.74, 124.06, 124.01, 123.74, 123.63, 122.48, 122.44, 116.14, 114.35, 114.21, 113.98, 113.87, 112.03, 111.99, 106.63, 106.59, 104.70, 104.38, 104.27, 103.18, 103.15, 66.67, 66.66, 66.61, 66.34, 66.30, 66.26, 57.61, 57.58, 57.52, 56.27, 56.24, 54.15, 54.08,47.19, 46.57, 46.32, 45.75, 42.07, 41.47, 41.38, 40.88, 14.41. HRMS (ESI):calced for C 39 H 37 N5O7, [M+H] + 688.2774, found 688.2775.

[0196] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(2-morpholinylethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0197] Example 34 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(cyclohexylmethoxy)-1H-indol-3-yl)ethane-1,2-dione

[0198] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) was replaced with 5-(cyclohexylmethoxy)-1H-indole, while other aspects remained unchanged, to obtain the intermediate 2-(5-(cyclohexylmethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-(cyclohexylmethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride, while other aspects remained unchanged, finally yielding a white solid, namely 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(cyclohexylmethoxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 39.1%.

[0199] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(cyclohexylmethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.26 (d, J = 19.6 Hz, 1H), 8.25 –7.93 (m, 3H), 7.86 – 7.56 (m, 4H), 7.56 – 7.26 (m, 4H), 7.15 – 6.81 (m, 2H),4.07 – 3.54 (m, 10H), 3.40 (s, 1H), 2.93 – 2.68 (m, 2H), 1.76 (dt, J = 32.7,14.3 Hz, 6H), 1.14 (ddd, J = 42.4, 19.6, 9.9 Hz, 5H). 13C NMR (151 MHz, DMSO-d6) δ 186.21, 186.12, 166.55, 166.52, 166.40, 158.94, 158.86, 156.10, 155.31,155.26, 154.97, 146.15, 146.06, 144.32, 144.25, 142.12, 141.97, 137.83,137.69, 132.15, 131.75, 131.69, 128.85, 128.81, 126.33, 126.27, 126.23,124.79, 124.74, 124.05, 124.00, 123.73, 123.62, 122.47, 122.44, 116.14, 114.37, 114.25, 113.92, 113.82, 113.47, 112.02, 111.98, 106.62, 106.58, 104.04, 103.16, 73.75, 73.67, 56.27, 56.24, 47.20, 46.57, 46.32, 45.74, 42.08, 41.45, 41.38, 40.87, 37.75, 37.66, 29.82, 29.75, 26.55, 26.50, 25.80,25.74. HRMS (ESI): calculated for C 40 H 38 N4O6, [M+H] + 671.2872, found 671.2874.

[0200] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(cyclohexylmethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0201] Example 35 Preparation of tert-butyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate

[0202] The preparation process is the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) is replaced with tert-butyl 2-((1H-indole-5-yl)oxy)acetic acid ester, while the others remain unchanged, to obtain the intermediate tert-butyl 2-((3-(2-chloro-2-oxoacetyl)-1H-indole-5-yl)oxy)acetic acid ester. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate was replaced with tert-butyl 2-((3-(2-chloro-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate (2b-1), while keeping everything else unchanged. Finally, a white solid was obtained, which was tert-butyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate, with a yield of 41.3%.

[0203] The tert-butyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indol-5-yl)oxy)acetate prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.34 – 12.21 (m, 1H), 8.24 – 8.03(m, 3H), 7.85 – 7.67 (m, 3H), 7.65 – 7.28 (m, 5H), 7.10 – 6.86 (m, 2H), 4.64(d, J = 30.0 Hz, 2H), 4.07 – 3.71 (m, 6H), 3.69 – 3.54 (m, 2H), 3.41 (d, J =4.8 Hz, 1H), 3.33 – 3.19 (m, 1H), 2.69 (s, 1H), 1.43 (d, J = 27.6 Hz, 9H). 13CNMR (151 MHz, DMSO-d6) δ 186.21, 186.10, 166.43, 166.40, 158.94, 158.86,155.30, 155.26, 154.96, 154.87, 154.77, 146.15, 146.05, 144.31, 144.25,142.13, 141.97, 138.02, 137.87, 132.51, 132.44, 131.75, 131.69, 128.85,128.81, 126.28, 126.24, 126.17, 126.06, 124.79, 124.75, 124.06, 124.02, 123.75, 123.64, 122.49, 122.44, 116.15, 113.99, 113.89, 113.46, 112.04, 112.00, 106.64, 106.59, 104.44, 104.33, 103.16, 66.30, 66.23, 56.28, 56.25, 47.16, 46.56, 46.28, 45.71, 42.03, 41.46, 41.37, 40.87, 28.18, 28.10. HRMS(ESI): calculated for C 39 H 36 N4O8, [M+H] + 689.2610, found 689.2613.

[0204] As can be seen from the above analysis, the structure of the tert-butyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate prepared in this embodiment is shown in Table 1.

[0205] Example 36 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indol-3-yl)ethane-1,2-dione

[0206] The preparation process is the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) is replaced with 5-((4-(difluoromethoxy)benzyl)oxy)-1H-indole, while the others remain unchanged, to obtain the intermediate 2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indole-3-yl)-2-oxoacetyl chloride, while keeping everything else unchanged. Finally, a white solid was obtained, which was 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 33.7%.

[0207] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.29 (dd, J = 19.1, 3.4 Hz,1H), 8.24 – 8.03 (m, 3H), 7.76 (dt, J = 18.5, 5.7 Hz, 4H), 7.62 – 7.15 (m,9H), 7.12 – 6.93 (m, 2H), 5.13 (d, J = 29.2 Hz, 2H), 3.94 (d, J = 5.1 Hz,5H), 3.85 (d, J = 7.7 Hz, 2H), 3.62 (s, 2H), 3.26 (s, 1H), 2.90 (s, 2H). 13CNMR (151 MHz, DMSO-d6) δ 186.21, 166.47, 166.40, 162.77, 158.94, 158.86,155.45, 155.31, 154.96, 154.92, 150.94, 146.15, 146.06, 144.32, 144.26,142.13, 141.97, 138.03, 137.87, 134.84, 134.75, 132.41, 132.33, 132.11,131.75, 131.70, 129.90, 129.82, 129.16, 128.85, 128.81, 126.29, 126.24, 126.19, 124.79, 124.75, 124.06, 124.02, 123.75, 123.64, 122.49, 122.45, 119.20, 119.14, 116.84, 116.79, 116.14, 114.48, 114.35, 114.01, 113.91, 113.50, 112.04, 112.00, 106.64, 106.60, 104.83, 104.73, 103.17, 69.45, 69.38,56.28, 56.25, 47.17, 46.57, 46.31, 45.74, 42.06, 41.46, 41.38, 40.88, 36.24. HRMS (ESI): calculated for C 41 H 32 F2N4O7, [M+H] + 731.2318, found 731.2320.

[0208] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-((4-(difluoromethoxy)benzyl)oxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0209] Example 37 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(naphth-2-ylmethoxy)-1H-indol-3-yl)ethane-1,2-dione

[0210] The preparation process is the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) is replaced with 5-(naphth-2-ylmethoxy)-1H-indole, while the others remain unchanged, to obtain the intermediate 2-(5-(naphth-2-ylmethoxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-3-yl)-2-oxoacetyl chloride was replaced with methyl 1-(2b-1)-indole-5-carboxylate (2b-1), while keeping everything else unchanged. The final product was a white solid, 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(naphthyl-2-ylmethoxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 30.2%. 1

[0211] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(naphthyl-2-ylmethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.29 (dd, J = 20.3, 3.4 Hz, 1H), 8.23–7.97 (m, 4H), 7.96–7.62 (m, 8H), 7.52 (tdd, J = 14.5, 8.3, 2.5 Hz, 4H), 7.44–7.28 (m, 2H), 7.06 (dtd, J = 13.2, 8.9, 7.9, 4.5 Hz, 2H), 5.31 (d, J =27.7 Hz, 2H), 4.04 – 3.79 (m, 6H), 3.62 (s, 2H), 3.24 (s, 1H). 13C NMR (151MHz, DMSO-d6) δ 186.21, 186.10, 166.52, 166.49, 166.40, 158.94, 158.87,155.59, 155.45, 155.31, 154.97, 146.16, 146.07, 144.32, 144.26, 142.13,141.97, 137.87, 135.51, 133.30, 133.01, 132.44, 132.35, 131.76, 131.70,128.85, 128.81, 128.48, 128.42, 128.26, 128.19, 128.08, 128.02, 126.76, 126.68, 126.60, 126.56, 126.53, 126.46, 126.32, 126.29, 126.25, 126.22, 126.19, 126.11, 124.80, 124.06, 124.03, 123.75, 123.65, 122.49, 122.46, 116.15, 114.52, 114.41, 114.02, 113.92, 112.04, 112.01, 106.65, 106.61,105.02, 104.95, 103.18, 70.33, 70.25, 56.28, 56.25, 47.16, 46.56, 46.30,45.74, 42.07, 41.46, 41.38, 40.87. HRMS (ESI): calculated for C 44 H 34 N4O6, [M+H] + 715.2561, found 715.2560.

[0212] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(naphth-2-ylmethoxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0213] Example 38 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-butoxy-1H-indol-3-yl)ethane-1,2-dione

[0214] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) was replaced with 5-butoxy-1H-indole, while other aspects remained unchanged, to obtain the intermediate 2-(5-butoxy-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-butoxy-1H-indole-3-yl)-2-oxoacetyl chloride, while other aspects remained unchanged, finally yielding a white solid, namely 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-butoxy-1H-indole-3-yl)ethane-1,2-dione, with a yield of 23.8%.

[0215] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-butoxy-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (dd, J = 19.4, 3.3 Hz, 1H), 8.20 – 8.02(m, 3H), 7.84 – 7.57 (m, 4H), 7.57 – 7.29 (m, 4H), 7.07 (dd, J = 8.8, 2.8 Hz,1H), 6.90 (ddd, J = 22.8, 8.9, 2.5 Hz, 1H), 4.04 – 3.79 (m, 8H), 3.62 (s,2H), 3.26 (s, 1H), 1.72 (dp, J = 21.7, 6.7 Hz, 2H), 1.46 (dp, J = 21.9, 7.3Hz, 2H), 0.93 (dt, J = 18.4, 7.3Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 186.21,166.55, 166.51, 166.39, 158.94, 158.86, 155.92, 155.80, 155.31, 155.26,146.15, 144.32, 144.25, 142.13, 141.98, 137.83, 137.68, 132.16, 131.75,131.69, 128.85, 128.81, 126.33, 126.28, 126.23, 124.79, 124.74, 124.06, 124.01, 123.74, 123.63, 122.49, 122.44, 116.14, 114.38, 114.25, 113.94, 113.84, 112.04, 112.00, 106.64, 106.59, 104.13, 104.03, 103.18, 103.15, 68.05, 67.96, 56.28, 56.25, 47.19, 46.57, 46.32, 45.74, 42.07, 41.45, 41.38, 40.87, 31.41, 31.31, 19.28, 19.21, 14.22, 14.15. HRMS (ESI): calculated forC 37 H 34 N4O6, [M+H] + 631.2556, found 631.2559.

[0216] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-butoxy-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0217] Example 39 Preparation of methyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate

[0218] The preparation process is the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) is replaced with methyl 2-((1H-indole-5-yl)oxy)acetate, while the others remain unchanged, to obtain methyl 2-((3-(2-chloro-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indol-5-yl)oxy)acetate (2b-1) was replaced with methyl 2-((3-(2-chloro-2-oxoacetyl)-1H-indol-5-yl)oxy)acetate, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indol-5-yl)oxy)acetate, with a yield of 25.8%.

[0219] The methyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indol-5-yl)oxy)acetate prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.23 ​​– 8.03 (m, 3H), 7.86 – 7.68 (m, 3H), 7.64 – 7.29 (m, 5H), 7.10 – 6.87 (m, 2H), 4.81 (d, J =27.7 Hz, 2H), 4.08 – 3.87 (m, 5H), 3.78 (d, J = 27.4 Hz, 3H), 3.63 (d, J =17.5 Hz, 3H), 3.25 (s, 1H), 3.00 (s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 186.17,186.04, 169.93, 166.49, 166.46, 166.40, 158.95, 158.88, 155.32, 154.97,154.93, 154.80, 154.69, 146.16, 146.07, 144.32, 142.13, 141.99, 138.13,137.97, 132.69, 132.60, 131.76, 131.70, 128.86, 126.28, 126.24, 126.18, 126.08, 124.80, 124.06, 124.02, 123.74, 123.63, 122.49, 122.45, 116.13, 114.08, 114.05, 113.95, 113.48, 112.04, 112.00, 106.64, 106.59, 104.74, 104.59, 103.21, 103.18, 65.82, 65.74, 56.29, 56.26, 52.26, 52.19, 47.18, 46.55, 46.30, 45.72, 42.06, 41.46, 41.37, 40.88. HRMS (ESI): calculated forC 36 H 30 N4O8, [M+H] + 647.2140, found 647.2144.

[0220] As can be seen from the above analysis, the structure of the methyl 2-((3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-yl)oxy)acetate prepared in this embodiment is shown in Table 1.

[0221] Example 40 Preparation of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(hexyloxy)-1H-indol-3-yl)ethane-1,2-dione

[0222] The preparation process was the same as in Example 1, except that the intermediate methyl-1H-indole-5-carboxylic acid ester (1b) was replaced with 5-(hexyloxy)-1H-indole, while keeping everything else unchanged, to obtain 2-(5-(hexyloxy)-1H-indole-3-yl)-2-oxoacetyl chloride. Then, methyl 3-(2-chloro-2-oxoacetyl)-1H-indole-5-carboxylate (2b-1) was replaced with 2-(5-(hexyloxy)-1H-indole-3-yl)-2-oxoacetyl chloride, while keeping everything else unchanged, to finally obtain a white solid, which is 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(hexyloxy)-1H-indole-3-yl)ethane-1,2-dione, with a yield of 28.3%.

[0223] The 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(hexyloxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (dd, J = 19.3, 3.4 Hz, 1H), 8.27 –8.03 (m, 3H), 7.88 – 7.28 (m, 8H), 7.10 (dd, J = 9.2, 2.8 Hz, 1H), 6.92 (ddd,J = 22.7, 8.8, 2.5 Hz, 1H), 4.10 – 3.81 (m, 8H), 3.74 – 3.56 (m, 2H), 3.43(s, 1H), 3.29 (s, 1H), 1.74 (dp, J = 21.8, 6.9 Hz, 2H), 1.54 – 1.18 (m, 7H),0.88 (dt, J = 13.7, 6.7 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 186.20, 166.54,166.42, 158.94, 158.87, 155.93, 155.32, 154.98, 146.16, 146.07, 144.33,144.26, 142.12, 141.97, 137.80, 137.66, 132.18, 132.10, 131.75, 131.68,128.86, 128.82, 126.25, 126.20, 124.80, 124.75, 124.03, 123.99, 123.71, 123.60, 122.46, 122.42, 116.13, 114.36, 114.24, 113.92, 113.82, 112.01, 111.97, 106.60, 106.56, 104.20, 104.09, 103.20, 103.18, 68.38, 68.29, 56.26, 56.24, 47.20, 46.57, 46.33, 45.74, 42.08, 41.47, 41.39, 40.88, 31.52, 31.45, 29.29, 29.19, 25.72, 25.65, 22.55, 22.49, 14.35, 14.30. HRMS (ESI): calculated forC 39 H 38 N4O6, [M+H] + 659.2870, found 659.2871.

[0224] As can be seen from the above analysis, the structure of 1-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)-2-(5-(hexyloxy)-1H-indol-3-yl)ethane-1,2-dione prepared in this embodiment is shown in Table 1.

[0225] Example 41 Preparation of methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0226] Synthesize according to the following route:

[0227]

[0228] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl4-aminopiperidine-1-carboxylate. After steps (2) and (3), intermediate 2-(benzofuran-2-yl)-6-methoxy-N-(piperidine-4-yl)quinoline-4-carboxamide (5a-3) was obtained. Then, intermediate 5a-1 was replaced with 2-(benzofuran-2-yl)-6-methoxy-N-(piperidine-4-yl)quinoline-4-carboxamide (5a-3), while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)piperidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 37.9%.

[0229] The methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.96 (d, J = 6.9 Hz, 1H), 8.82(s, 1H), 8.32 (s, 1H), 8.08 (d, J = 17.2 Hz, 2H), 7.96 – 7.29 (m, 9H), 4.33(d, J = 35.1 Hz, 2H), 3.88 (s, 6H), 3.74 – 3.60 (m, 2H), 2.15 – 1.91 (m, 1H), 1.59 (d, J = 34.4 Hz, 2H), 1.30 – 1.18 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ166.29, 165.91, 158.59, 155.32, 154.94, 145.92, 144.54, 142.13, 140.04,139.07, 131.46, 128.87, 126.27, 125.36, 125.00, 124.40, 124.06, 123.55,123.41, 122.48, 116.79, 113.33, 112.05, 106.57, 103.95, 56.00, 52.46, 46.84,44.91, 32.07, 31.29, 29.44. HRMS (ESI): calculated for C 36 H30 N4O7, [M+H] + 631.2752, found 631.2755.

[0230] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0231] Example 42 Preparation of methyl 3-(2-(3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pyrrolidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0232] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl2-aminopyrrolidine-1-carboxylate. After steps (2) and (3), intermediate 2-(benzofuran-2-yl)-6-methoxy-N-(pyrrolidine-2-yl)quinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with 2-(benzofuran-2-yl)-6-methoxy-N-(pyrrolidine-2-yl)quinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pyrrolidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 34.8%.

[0233] The methyl 3-(2-(3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pyrrolidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 9.20 (dd, J = 26.8, 6.5 Hz,1H), 8.85 (s, 1H), 8.43 – 8.33 (m, 1H), 8.19 – 8.01 (m, 2H), 7.90 (dd, J =8.6, 1.9 Hz, 1H), 7.84 – 7.71 (m, 3H), 7.61 (t, J = 8.4 Hz, 1H), 7.56 – 7.29(m, 4H), 4.77 – 4.56 (m, 1H), 3.94 – 3.82 (m, 5H), 3.78 – 3.62 (m, 4H), 2.39– 2.05 (m, 2H), 1.28 (d, J = 42.6 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 186.43,167.27, 167.07, 165.27, 158.56, 155.33, 155.31, 154.94, 145.92, 145.85,144.52, 141.82, 141.66, 139.88, 139.80, 131.49, 131.42, 128.86, 126.26,126.24, 125.40, 125.36, 125.28, 124.96, 124.94, 124.37, 124.04, 123.66,123.61, 123.46, 123.44, 122.47, 117.06, 116.99, 113.25, 112.04, 106.60,106.55, 103.94, 103.75, 55.99, 55.78, 52.44, 52.24, 50.89, 50.37, 48.64, 45.59, 44.11, 31.78, 29.37. HRMS (ESI): calculated for C 35 H 28 N4O7, [M+H] + 617.2034, found 617.2039.

[0234] As can be seen from the above analysis, the structure of the methyl 3-(2-(3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pyrrolidine-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0235] Example 43 Preparation of methyl 3-(2-(8-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0236] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl2,8-diazaspiro[4.5]decane-2-carboxylate. After the reaction in steps (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(2,8-diazaspiro[4.5]decane-8-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(2,8-diazaspiro[4.5]decane-8-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(8-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 30.7%.

[0237] The methyl 3-(2-(8-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.87 (d, J = 17.6Hz, 1H), 8.38 (t, J = 4.1 Hz, 1H), 8.19 – 7.90 (m, 3H), 7.89 – 7.71 (m, 3H),7.70 – 7.32 (m, 4H), 7.13 – 6.93 (m, 1H), 4.02 – 3.76 (m, 8H), 3.68 – 3.47(m, 3H), 3.25 (d, J = 18.0 Hz, 2H), 2.02 – 1.22 (m, 7H). 13C NMR (151 MHz, DMSO-d6) δ 186.58, 167.27, 165.86, 165.82, 165.55, 158.75, 155.30, 154.95,146.19, 146.12, 144.22, 144.19, 142.86, 139.95, 139.92, 139.61, 139.49,131.72, 128.84, 126.24, 125.36, 125.29, 124.93, 124.89, 124.78, 124.74,124.29, 124.03, 123.70, 123.59, 123.50, 122.45, 115.72, 115.66, 113.85, 113.25, 112.03, 106.61, 103.18, 103.14, 56.42, 56.17, 56.07, 54.85, 52.45, 52.40, 45.27, 44.79, 44.54, 43.88, 41.78, 39.80, 39.24, 39.00, 35.72, 35.03, 34.35, 34.24, 33.70, 33.47, 33.37. HRMS (ESI): calculated for C 39 H 34 N4O7, [M+H] + 671.2503, found 671.2505.

[0238] As can be seen from the above analysis, the structure of the methyl 3-(2-(8-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0239] Example 44 Preparation of methyl 3-(2-(4-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperidin-4-yl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0240] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl4-(piperidin-4-yl)piperazine-1-carboxylate. After the reaction in steps (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(4-(piperazine-1-yl)piperidin-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(4-(piperazin-1-yl)piperidin-1-yl)methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperidin-4-yl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 30.3%.

[0241] The methyl 3-(2-(4-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperidin-4-yl)piperazin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.81 (s, 1H), 8.33(s, 1H), 8.14 – 8.00 (m, 2H), 7.91 (dd, J = 8.6, 1.7 Hz, 1H), 7.87 – 7.70 (m,3H), 7.64 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 9.4, 2.7 Hz, 1H), 7.47 – 7.39(m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.00 (dd, J = 25.5, 2.7 Hz, 1H), 4.70 (t,J = 14.3 Hz, 1H), 3.95 – 3.81 (m, 6H), 3.63 (t, J = 4.8 Hz, 2H), 3.32 (d, J =15.2 Hz, 3H), 3.17 – 2.86 (m, 2H), 2.61 (d, J = 10.4 Hz, 3H), 2.46 (d, J =5.8 Hz, 1H), 1.97 (d, J = 17.7 Hz, 1H), 1.70 – 1.04 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 186.83, 167.22, 165.78, 165.75, 155.29, 154.91, 146.19, 144.14, 140.01, 139.17, 131.74, 128.83, 126.25, 124.96, 124.77, 124.35, 124.02,123.50, 122.45, 115.71, 114.25, 113.31, 112.03, 106.64, 102.95, 61.14, 61.01,56.16, 56.09, 52.43, 49.31, 48.69, 48.45, 46.44, 46.22, 41.52, 40.97, 40.82,29.25, 28.66, 28.44. HRMS (ESI): calculated for C 40 H 37 N5O7, [M+H] + 700.2770, found 700.2772.

[0242] As can be seen from the above analysis, the structure of the methyl 3-(2-((1-(6-methoxy-2-(naphth-2-yl)quinoline-4-carbonyl)piperidin-4-yl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0243] Example 45 Preparation of methyl 3-(2-(6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0244] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate. After the reaction in steps (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(2,6-diazaspiro[3.3]heptane-2-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(2,6-diazaspiro[3.3]heptane-2-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 19.2%.

[0245] The methyl 3-(2-(6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (d, J = 3.2 Hz, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 3.1 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J = 9.2Hz, 1H), 7.91 – 7.81 (m, 2H), 7.79 – 7.69 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 9.2, 2.8 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.32 (t, J = 7.4 Hz,1H), 4.61 (q, J = 10.9 Hz, 2H), 4.42 (s, 2H), 4.28 (d, J = 12.3 Hz, 4H), 3.90 (d, J = 13.0 Hz, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 183.34, 167.31, 167.00,163.08, 158.81, 155.32, 154.87, 145.87, 144.66, 140.36, 139.56, 139.52,131.58, 128.84, 126.26, 125.96, 124.94, 124.87, 124.31, 124.04, 123.81,123.46, 122.44, 116.95, 113.18, 112.04, 106.70, 104.12, 62.43, 61.40, 58.64,58.53, 56.17, 52.41, 33.83, 20.96. HRMS (ESI): calculated for C 36 H 28 N4O7, [M+H] + 629.2036, found 629.2039.

[0246] As can be seen from the above analysis, the structure of the methyl 3-(2-(6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-2,6-diazaspiro[3.3]heptane-2-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0247] Example 46 Preparation of methyl 3-(2-(9-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0248] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl3,9-diazaspiro[5.5]undecane-3-carboxylate. After the reaction in steps (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(3,9-diazaspiro[5.5]undecane-3-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(3,9-diazaspiro[5.5]undecane-3-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(9-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 32.8%.

[0249] The methyl 3-(2-(9-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.60 (d, J = 3.2 Hz, 1H),8.78 (s, 1H), 8.31 (d, J = 3.1 Hz, 1H), 8.12 – 8.00 (m, 2H), 7.89 (dd, J =8.6, 1.7 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.74 (q, J = 9.4, 8.8 Hz, 2H),7.62 (d, J = 8.6 Hz, 1H), 7.52 (td, J = 8.9, 2.7 Hz, 1H), 7.42 (q, J = 7.0Hz, 1H), 7.33 (t, J = 7.1 Hz, 1H), 7.01 (dd, J = 12.6, 2.8 Hz, 1H), 3.93 (s,1H), 3.86 (d, J = 5.7 Hz, 5H), 3.64 (dd, J = 18.7, 11.2 Hz, 2H), 3.17 (s,2H), 1.66 (s, 4H), 1.46 (q, J = 4.0 Hz, 3H), 1.31 (d, J = 11.5 Hz, 1H), 1.24(d, J = 9.9 Hz, 4H)。 13 C NMR (151 MHz, DMSO-d6) δ 187.19, 167.23, 165.86,165.82, 158.77, 155.30, 154.93, 146.19, 144.19, 142.98, 140.01, 138.98,131.72, 128.84, 126.24, 124.96, 124.93, 124.76, 124.31, 124.02, 123.64,123.47, 122.45, 115.67, 114.25, 113.30, 112.03, 106.65, 103.10, 56.19, 56.13,52.44, 42.99, 41.95, 37.34, 36.80, 35.70, 35.22, 34.95, 34.72, 31.36, 29.45。HRMS (ESI): calced for C 40 H 36 N4O7, [M+H] + 685.2661, found 685.2664。

[0250] As can be seen from the above analysis, the structure of the methyl 3-(2-(9-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0251] Example 47 Preparation of methyl 3-(2-(4-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0252] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl4-(piperazine-1-ylmethyl)piperidine-1-carboxylate. After the reaction in steps (2) and (3), the intermediate (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(4-(piperidine-4-ylmethyl)piperazine-1-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)(4-(piperidin-4-ylmethyl)piperazin-1-yl) methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(4-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 40.7%.

[0253] The methyl 3-(2-(4-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.79 (d, J =1.7 Hz, 1H), 8.30 (s, 1H), 8.11 – 8.03 (m, 2H), 7.91 (dd, J = 8.6, 1.7 Hz,1H), 7.83 (s, 1H), 7.75 (t, J = 8.8 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.53(dd, J = 9.3, 2.8 Hz, 1H), 7.47 – 7.38 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H),7.03 (d, J = 2.8 Hz, 1H), 4.41 (d, J = 12.7 Hz, 1H), 3.90 (d, J = 8.9 Hz,6H), 3.76 – 3.50 (m, 2H), 3.26 – 3.00 (m, 3H), 2.82 (t, J = 12.3 Hz, 1H),2.60 (s, 1H), 2.36 (s, 2H), 2.18 (s, 3H), 1.85 (d, J = 12.1 Hz, 2H), 1.67 (d,J = 12.6 Hz, 1H), 1.18 (d, J = 15.2 Hz, 1H), 1.07 – 0.89 (m, 1H)。 13 C NMR (151MHz, DMSO-d6) δ 187.23, 167.23, 165.88, 165.83, 158.78, 155.29, 154.90,146.17, 144.22, 142.55, 140.00, 138.92, 131.73, 128.83, 126.25, 124.96,124.91, 124.72, 124.30, 124.03, 123.70, 123.50, 122.45, 115.88, 114.25,113.29, 112.04, 106.68, 103.09, 63.76, 56.19, 54.16, 53.31, 52.44, 47.08,46.00, 41.78, 40.94, 33.09, 31.10, 30.11。HRMS (ESI): calced for C 41 H 39 N5O7, [M+H] +714.2928, found 714.2930.

[0254] As can be seen from the above analysis, the structure of the methyl 3-(2-(4-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0255] Example 48 Preparation of methyl 3-(2-(3-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)azacyclobutane-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0256] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl3-(piperazine-1-yl)azacyclobutane-1-carboxylate. After the reaction in steps (2) and (3), the intermediate (4-(azacyclobutane-3-yl)piperazine-1-yl)(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl) methyl ketone is obtained. Then, intermediate 5a-1 was replaced with (4-(azacyclobutane-3-yl)piperazin-1-yl)(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)methyl ketone, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-(3-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)azacyclobutane-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 41.3%.

[0257] The methyl 3-(2-(3-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)azacyclobutane-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.08 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.82 (s,1H), 7.74 (t, J = 9.1 Hz, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 9.2,2.7 Hz, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 7.02 (d, J = 2.7 Hz, 1H), 4.40 (s,1H), 4.21 (s,1H), 3.89 (d, J = 13.7 Hz, 8H), 3.73 (s, 1H), 3.23 (s, 4H), 2.62 (s, 1H), 2.39 (s, 2H), 2.15 (s, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 166.01,163.55, 158.82, 155.30, 154.90, 146.18, 144.22, 142.46, 140.25, 139.54,131.75, 128.83, 126.25, 125.90, 124.91, 124.71, 124.03, 123.83, 123.71,122.46, 115.93, 113.18, 112.04, 106.67, 103.05, 56.31, 56.19, 54.64, 52.41,49.98, 49.30, 46.81, 41.47, 21.21, 14.54. HRMS (ESI): calculated for C 38 H 33 N5O7, [M+H] + 672.2453, found 672.2457.

[0258] As can be seen from the above analysis, the structure of the methyl 3-(2-(3-(4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carbonyl)piperazin-1-yl)azacyclobutane-1-yl)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0259] Example 49 Preparation of methyl 3-(2-((2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0260] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(2-aminoethyl)carbamate. After steps (2) and (3), intermediate N-(2-aminoethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(2-aminoethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 39.1%.

[0261] The methyl 3-(2-((2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.57 – 12.50 (m, 1H), 9.11 – 8.89 (m, 4H), 8.19 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 8.5, 1.8 Hz, 1H), 7.76– 7.59 (m, 5H), 7.49 (dd, J = 9.2, 2.8 Hz, 1H), 7.40 – 7.27 (m, 2H), 3.88 (d,J = 9.0 Hz, 6H), 3.68 – 3.50 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ 182.59,167.36, 167.33, 163.93, 158.56, 155.26, 154.98, 145.86, 144.62, 141.76,140.66, 139.42, 131.36, 128.81, 126.38, 126.17, 125.45, 124.88, 124.39,123.99, 123.92, 123.38, 122.39, 117.22, 113.16, 111.92, 106.39, 104.28,55.92, 52.44, 39.34, 39.14. HRMS (ESI): calculated for C 33 H 26 N4O7, [M+H] + 591.1880, found 591.1882.

[0262] As can be seen from the above analysis, the structure of the methyl 3-(2-((2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0263] Example 50 Preparation of methyl 3-(2-((3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)propyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0264] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(3-aminopropyl)carbamate. After steps (2) and (3), intermediate N-(3-aminopropyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(3-aminopropyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)propyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 32.9%.

[0265] The methyl 3-(2-((3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)propyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows:1 H NMR (300 MHz, DMSO-d6) δ 12.55 (d, J = 3.2 Hz, 1H), 9.01 – 8.82 (m,4H), 8.17 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.93 – 7.80 (m, 2H), 7.75 (t, J= 7.2 Hz, 2H), 7.66 – 7.55 (m, 2H), 7.50 (dd, J = 9.2, 2.8 Hz, 1H), 7.42 (t,J = 7.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 3.88 (d, J = 5.3 Hz, 6H), 1.91 (t,J = 6.8 Hz, 1H), 1.31 – 1.17 (m, 5H). 13 C NMR (151 MHz, DMSO-d6) δ 182.98,167.06, 163.88, 158.61, 155.31, 145.93, 144.60, 142.18, 140.58, 139.44,131.43, 128.87, 126.30, 126.24, 125.43, 124.87, 124.35, 124.04, 123.92,123.41, 122.46, 116.88, 113.15, 112.04, 106.52, 104.13, 56.01, 52.43, 37.39, 36.88, 29.22. HRMS (ESI): calculated for C 34 H 28 N4O7, [M+H] + 605.2032, found605.2037.

[0266] As can be seen from the above analysis, the structure of the methyl 3-(2-((3-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)propyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0267] Example 51 Preparation of methyl 3-(2-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)butyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0268] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(4-aminobutyl)carbamate. After the reaction in steps (2) and (3), intermediate N-(4-aminobutyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(4-aminobutyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)butyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 34.0%.

[0269] The methyl 3-(2-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)butyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.52 (d, J = 3.2 Hz, 1H), 8.97 – 8.90 (m,2H), 8.89 – 8.82 (m, 2H), 8.12 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.89 (dd, J= 8.6, 1.7 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 7.73 (ddd, J = 7.9, 6.0, 1.2Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.40 (ddd, J = 8.5,7.2, 1.4 Hz, 1H), 7.31 (td, J = 7.4, 1.0 Hz, 1H), 3.87 (d, J = 4.7 Hz, 6H), 3.44 (d, J = 5.6 Hz, 2H), 3.33 (d, J = 6.2 Hz, 2H), 1.72 – 1.67 (m, 3H), 1.20(s, 1H). 13C NMR (151 MHz, DMSO-d6) δ 183.05, 167.35, 166.90, 163.79, 158.55,155.29, 154.96, 145.93, 144.59, 142.29, 140.51, 139.43, 131.43, 128.86,126.31, 126.20, 125.44, 124.85, 124.34, 124.02, 123.92, 123.40, 122.44,116.76, 113.15, 112.02, 106.49, 104.02, 55.94, 52.43, 39.38, 38.83, 29.45, 27.00, 26.97. HRMS (ESI): calculated for C 35 H 30 N4O7, [M+H] + 619.2192, found619.2194.

[0270] As can be seen from the above analysis, the structure of the methyl 3-(2-((4-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)butyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0271] Example 52 Methyl 3-(2-((5-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pentyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0272] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(5-aminopentyl)carbamate. After steps (2) and (3), intermediate N-(5-aminopentyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(5-aminopentyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((5-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pentyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 32.2%.

[0273] The methyl 3-(2-((5-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pentyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.90 (d, J = 5.0 Hz, 2H), 8.85 (s, 1H), 8.80 (t, J = 6.1 Hz, 1H), 8.12 – 8.01 (m, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.79(s, 1H), 7.74 (t, J = 7.2 Hz, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.50 (dt, J =8.7, 2.8 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 3.88(d, J = 5.0 Hz, 6H), 3.28 (d, J = 6.6 Hz, 4H), 1.65 (dp, J = 14.0, 7.1 Hz, 4H), 1.46 (q, J = 7.8 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 183.07, 167.36,166.90, 163.78, 158.55, 155.28, 145.93, 144.57, 142.30, 140.47, 139.41,131.42, 128.86, 126.28, 126.21, 125.43, 124.83, 124.31, 124.01, 123.92,123.37, 122.45, 116.74, 113.12, 112.01, 106.47, 104.02, 55.97, 52.42, 39.60,39.01, 29.14, 29.02, 24.43. HRMS (ESI): calculated for C 36 H 32 N4O7, [M+H] + 633.2350, found 633.2352.

[0274] As can be seen from the above analysis, the structure of the methyl 3-(2-((5-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)pentyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0275] Example 53 Preparation of methyl 3-(2-((6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)hexyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0276] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(6-aminohexyl)carbamate. After steps (2) and (3), intermediate N-(6-aminohexyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(6-aminohexyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which is the methyl 3-(2-((6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)hexyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 22.8%.

[0277] The methyl 3-(2-((6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)hexyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (d, J = 3.2 Hz, 1H), 8.89 (dd, J =13.5, 4.2 Hz, 3H), 8.79 (t, J = 6.1 Hz, 1H), 8.12 – 8.03 (m, 2H), 7.89 (dd, J= 8.6, 1.7 Hz, 1H), 7.76 (dd, J = 15.7, 8.8 Hz, 3H), 7.63 (d, J = 8.5 Hz,1H), 7.55 – 7.47 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H),3.88 (s, 6H), 3.26 (q, J = 6.7 Hz, 2H), 1.61 (dt, J = 18.1, 7.0 Hz, 4H), 1.51– 1.14 (m, 6H).13 C NMR (151 MHz, DMSO-d6) δ 183.10, 167.36, 166.87, 163.74,158.55, 155.29, 154.95, 145.94, 144.58, 142.34, 140.47, 139.42, 131.43,128.86, 126.29, 126.21, 125.44, 124.84, 124.32, 124.02, 123.92, 123.36,122.46, 116.74, 113.14, 112.01, 106.48, 104.03, 55.95, 52.43, 39.58, 39.03,29.42, 29.31, 26.69, 26.64. HRMS (ESI): calculated for C 37 H 34 N4O7, [M+H] + 647.2501, found 647.2509.

[0278] As can be seen from the above analysis, the structure of the methyl 3-(2-((6-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)hexyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0279] Example 54 Preparation of methyl 3-(2-((2-(2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethoxy)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0280] The preparation process was the same as in Example 1, except that tert-butylpiperazine-1-carboxylate was replaced with tert-butyl(2-(2-aminoethoxy)ethyl)carbamate. After steps (2) and (3), intermediate N-(2-(2-aminoethoxy)ethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide was obtained. Then, intermediate 5a-1 was replaced with N-(2-(2-aminoethoxy)ethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((2-(2-(2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethoxy)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylate, with a yield of 24.5%.

[0281] The methyl 3-(2-((2-(2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethoxy)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.02 – 8.68 (m,4H), 8.11 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.80 –7.67 (m, 3H), 7.58 (dd, J = 12.6, 5.7 Hz, 2H), 7.50 – 7.35 (m, 2H), 7.30 (t,J = 7.5 Hz, 1H), 3.87 (d, J = 11.0 Hz, 6H), 3.70 (dt, J = 13.0, 5.7 Hz, 4H),3.64 – 3.56 (m, 2H), 3.48 (q, J = 6.1 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ182.55, 167.18, 163.83, 158.55, 155.26, 154.92, 145.86, 144.56, 142.07,140.47, 139.36, 131.33, 128.84, 126.23, 126.16, 125.38, 124.85, 124.30,123.97, 123.89, 123.32, 122.41, 116.82, 113.08, 111.98, 106.38, 104.08,69.03, 68.68, 55.97, 52.38, 38.98. HRMS (ESI): calculated for C 35 H 30 N4O8, [M+H] + 635.2142, found 635.2145.

[0282] As can be seen from the above analysis, the structure of the methyl 3-(2-((2-(2-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamido)ethoxy)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0283] Example 55 Preparation of methyl 3-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)-1,12-dioxo-5,8-dioxa-2,11-diazatriadecan-13-acyl)-1H-indole-5-carboxylic acid ester

[0284] The preparation process is the same as in Example 1, except that tert-butylpiperazine-1-carboxylic acid ester is replaced with tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate. After the reaction in steps (2) and (3), the intermediate N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide is obtained. Then, intermediate 5a-1 was replaced with N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-(benzofuran-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)-1,12-dioxo-5,8-dioxa-2,11-diazatriadecan-13-acyl)-1H-indole-5-carboxylic acid ester, with a yield of 27.6%.

[0285] The methyl 3-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)-1,12-dioxo-5,8-dioxa-2,11-diazatriadecan-13-acyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 9.01 – 8.84 (m, 3H), 8.71(t, J = 5.9 Hz, 1H), 8.15 – 8.00 (m, 2H), 7.89 (dd, J = 8.6, 1.8 Hz, 1H),7.81 – 7.72 (m, 3H), 7.67 – 7.56 (m, 2H), 7.53 – 7.29 (m, 3H), 3.89 (d, J =8.0 Hz, 6H), 3.73 – 3.56 (m, 11H), 1.02 (dt, J = 6.6, 3.9 Hz, 1H). 13C NMR (151MHz, DMSO-d6) δ 167.09, 163.70, 158.57, 155.28, 154.98, 145.89, 144.59,142.10, 140.62, 139.41, 131.39, 128.86, 126.28, 126.19, 125.41, 124.86,124.34, 124.01, 123.91, 123.31, 122.44, 116.83, 113.13, 111.99, 106.39,104.18, 70.08, 70.00, 69.33, 68.96, 55.99, 52.40, 39.55, 38.96. HRMS (ESI):calced for C 37 H 34 N4O9, [M+H] + 679.2402, found 679.2406.

[0286] As can be seen from the above analysis, the structure of the methyl 3-(1-(2-(benzofuran-2-yl)-6-methoxyquinoline-4-yl)-1,12-dioxo-5,8-dioxa-2,11-diazatriadecan-13-acyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0287] Example 56 Preparation of methyl 3-(2-((2-(6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0288] Synthesize according to the following route:

[0289]

[0290] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(5-methoxybenzofuran-2-yl)ethane-1-one to obtain (2a-3) to intermediate 3a-3. Then, the synthesis methods in steps (2) and (3) are followed, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl(2-aminoethyl)carbamate, while the others remain unchanged. After the reaction, intermediate N-(2-aminoethyl)-6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamide (5a-4) is obtained. Then, intermediate 5a-1 was replaced with N-(2-aminoethyl)-6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamide (5a-4), while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((2-(6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 22.8%.

[0291] The methyl 3-(2-((2-(6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.10 – 8.87 (m,5H), 8.15 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.89 (dt, J = 8.6, 1.9 Hz, 1H), 7.65 – 7.58 (m, 3H), 7.53 – 7.44 (m, 2H), 7.15 (d, J = 2.7 Hz, 1H), 6.95 (dd,J = 9.0, 2.6 Hz, 1H), 3.87 (d, J = 7.1 Hz, 6H), 3.80 (s, 3H), 3.59 (dt, J =11.3, 5.6 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 182.59, 167.35, 167.33, 163.93,158.52, 156.49, 155.64, 150.22, 145.90, 144.60, 141.74, 140.66, 139.41,131.33, 129.45, 126.37, 125.40, 124.89, 124.38, 123.92, 123.36, 117.13,115.17, 113.30, 113.16, 112.48, 106.52, 104.27, 104.20, 56.09, 55.91, 52.44,39.12. HRMS (ESI): calculated for C 34 H 28 N4O8, [M+H] + 621.1902, found 621.1906.

[0292] As can be seen from the above analysis, the structure of the methyl 3-(2-((2-(6-methoxy-2-(5-methoxybenzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0293] Example 57 Preparation of methyl 3-(2-((2-(6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0294] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(5-(trifluoromethoxy)benzofuran-2-yl)ethane-1-one to obtain the intermediate carboxylic acid. Then, the synthesis methods in steps (2) and (3) are followed, except that tert-butylpiperazine-1-carboxylic acid ester is replaced with tert-butyl(2-aminoethyl)carbamate, while the others remain unchanged. After the reaction, the intermediate N-(2-aminoethyl)-6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamide is obtained. Then, intermediate 5a-1 was replaced with N-(2-aminoethyl)-6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((2-(6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 29.1%.

[0295] The methyl 3-(2-((2-(6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 9.14 – 8.88 (m, 4H), 8.20 (s,1H), 8.07 (d, J = 9.2 Hz, 1H), 7.91 (dd, J = 8.6, 1.7 Hz, 1H), 7.78 – 7.68(m, 3H), 7.66 – 7.58 (m, 2H), 7.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.37 (dd, J =9.0, 2.5 Hz, 1H), 3.88 (d, J = 4.8 Hz, 6H), 3.61 (dt, J = 11.5, 5.4 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) δ 182.58, 167.34, 167.23, 163.93, 158.76, 157.00,153.44, 145.30, 144.99, 144.61, 141.85, 140.66, 139.40, 131.45, 129.85,126.36, 124.86, 124.38, 123.91, 123.55, 119.54, 117.30, 114.87, 113.29,113.14, 106.40, 104.24, 55.94, 52.42, 39.08. HRMS (ESI): calculated forC 34 H 25 F3N4O8, [M+H] + 675.1604, found 675.1610.

[0296] As can be seen from the above analysis, the structure of the methyl 3-(2-((2-(6-methoxy-2-(5-(trifluoromethoxy)benzofuran-2-yl)quinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0297] Example 58 Preparation of methyl 3-(2-((2-(2-(furan[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester

[0298] The preparation process is the same as in Example 1, except that the intermediate 1-(naphthyl-2-yl)ethane-1-one (2a-1) is replaced with 1-(furan[2,3-b]pyridin-2-yl)ethane-1-one to obtain the intermediate carboxylic acid. Then, the synthesis methods in steps (2) and (3) are followed, except that tert-butylpiperazine-1-carboxylate is replaced with tert-butyl(2-aminoethyl)carbamate, while the others remain unchanged. After the reaction, the intermediate N-(2-aminoethyl)-2-(furan[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamide is obtained. Then, intermediate 5a-1 was replaced with N-(2-aminoethyl)-2-(furano[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamide, while keeping everything else unchanged. Finally, a white solid was obtained, which was methyl 3-(2-((2-(2-(furano[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester, with a yield of 25.6%.

[0299] The methyl 3-(2-((2-(2-(furan[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this example was analyzed by 1H NMR, 1C NMR, and mass spectrometry. The results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.01 (d, J = 50.3 Hz,4H), 8.41 (d, J = 4.8 Hz, 1H), 8.29 – 8.15 (m, 2H), 8.08 (d, J = 9.0 Hz, 1H), 7.96 – 7.73 (m, 2H), 7.71 – 7.36 (m, 4H), 3.96 – 3.80 (m, 6H), 3.61 (d, J =15.5 Hz, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 182.59, 167.34, 167.20, 163.93,158.78, 154.21, 145.66, 145.28, 144.65, 141.86, 140.66, 139.39, 131.84,131.49, 126.35, 125.71, 124.86, 124.35, 123.90, 123.60, 121.05, 120.86,117.18, 113.28, 113.15, 105.39, 104.26, 55.96, 52.44. HRMS (ESI): calculated for C 35 H 25 N5O7, [M+H] + 592.1914, found 592.1916.

[0300] As can be seen from the above analysis, the structure of the methyl 3-(2-((2-(2-(furan[2,3-b]pyridin-2-yl)-6-methoxyquinoline-4-carboxamido)ethyl)amino)-2-oxoacetyl)-1H-indole-5-carboxylic acid ester prepared in this embodiment is shown in Table 1.

[0301] Table 1. Compounds prepared in Examples 1-58

[0302]

[0303] Example 59: Study on the antiproliferative activity of the compounds prepared in Examples 1-58 in liver cancer cells.

[0304] Tumor cell viability was assessed using the Cell Counting Kit-8 (CCK-8) reagent, and the inhibitory activity of compounds against B3GAT3 was screened accordingly. The experimental procedure was as follows: Two human hepatocellular carcinoma cell lines, Huh7 and Hep3B (purchased from the Cell Bank of the Chinese Academy of Sciences), were cultured at approximately 1 × 10⁻⁶ cells per well. 4 Cells were seeded at a density of 100 μL per well in 96-well plates, with three replicates per group. After pre-culturing the cells at 37°C and 5% CO2 for 12 h, different concentrations of the test compounds prepared in Examples 1-58 were added, and incubation continued for 48 h. Subsequently, 10 μL of CCK-8 solution was added to each well, and the cells were incubated in the dark for 1-4 h. The absorbance (OD value) at 450 nm was measured using a microplate reader.

[0305] The formula for calculating cell viability is:

[0306]

[0307] Among them, OD treated OD value of the drug-treated group control OD value of the untreated group. blank This represents the OD value of the cell-free blank well.

[0308] Nonlinear regression analysis was performed using GraphPad Prism 9.0 software to fit the dose-response curve and calculate the half-maximal inhibitory concentration (IC50). 50 IC 50 The lower the value, the stronger the inhibitory activity of the compound on cell proliferation. The experimental results are summarized in Table 2.

[0309] Table 2. Antiproliferative activity (IC50) of compounds prepared in Examples 1-58 against cells. 50， μM)

[0310] Example Huh7 Hep3B Example Huh7 Hep3B 1 0.90 ± 0.25 0.82 ± 0.08 2 1.00 ± 0.21 1.23 ± 0.12 3 1.14 ± 0.27 0.87 ± 0.09 4 1.9 ± 0.49 1.35 ± 0.45 5 0.85 ± 0.09 0.69 ± 0.14 6 2.01 ± 0.70 1.78 ± 0.28 7 2.02 ± 0.67 3.64 ± 0.39 8 0.94 ± 0.26 1.60 ± 0.07 9 1.92 ± 0.68 1.22 ± 0.09 10 10.35 ± 0.87 6.01 ± 0.18 11 2.60 ± 0.20 2.16 ± 0.06 12 1.09 ± 0.20 0.45 ± 0.07 13 1.06 ± 0.27 0.66 ± 0.05 14 1.94 ± 0.76 1.34 ± 0.47 15 15.17 ± 1.58 37.68 ± 1.40 16 0.80 ± 0.41 0.69 ± 0.08 17 0.63 ± 0.17 0.69 ± 0.18 18 2.98 ± 0.21 3.48 ± 0.21 19 4.37 ± 0.99 1.51 ± 0.37 20 4.37 ± 0.18 1.29 ± 0.13 21 0.29 ± 0.09 0.24 ± 0.04 22 16.03 ± 3.28 ＞ 80 23 1.39 ± 0.19 1.31 ± 0.10 24 2.02 ± 0.30 1.29 ± 0.08 25 18.38 ± 1.50 16.96 ± 0.61 26 4.30 ± 0.41 2.08 ± 0.44 27 3.91 ± 0.48 4.93 ± 0.5 28 3.92 ± 0.21 5 ± 0.47 29 1.83 ± 0.16 2.25 ± 0.05 30 1.19 ± 0.17 0.91 ± 0.05 31 4.05 ± 0.47 4.34 ± 0.38 32 0.98 ± 0.09 0.79 ± 0.06 33 1.06 ± 0.22 0.35 ± 0.01 34 6.09 ± 0.28 5.79 ± 0.71 35 1.28 ± 0.15 2.01 ± 0.17 36 8.06 ± 0.71 42.09 ± 1.80 37 8.19 ± 0.83 23.22 ± 0.66 38 3.30 ± 0.34 2.33 ± 0.66 39 10.38 ± 1.05 12.37 ± 0.65 40 17.73 ± 2.42 11.95 ± 0.65 41 42.77 ± 2.06 1.98 ± 0.10 42 4.24 ± 0.60 5.46 ± 0.27 43 5.47 ± 0.82 2.42 ± 0.31 44 3.09 ± 0.72 1.65 ± 0.16 45 1.40 ± 0.41 0.65 ± 0.01 46 18.86 ± 3.34 2.70 ± 0.07 47 1.91 ± 0.18 0.85 ± 0.13 48 1.20 ± 0.06 0.96 ± 0.10 49 0.36 ± 0.17 0.31 ± 0.05 50 9.93 ± 0.81 6.94 ± 0.39 51 ＞ 80 4.52 ± 0.43 52 ＞ 80 2.56 ± 0.15 53 8.91 ± 0.68 3.89 ± 0.44 54 26.5 ± 2.08 5.94 ± 0.24 55 2.86 ± 0.48 2.07 ± 0.12 56 1.45 ± 0.20 1.27 ± 0.097 57 ＞ 80 ＞ 80 58 3.03 ± 0.02 1.29 ± 0.14

[0311] As shown in Table 2, most of the compounds in this example showed inhibitory activity of less than 5 μM against the liver cancer cell lines Huh7 and Hep3B. Among them, the cell activity of 15 compound examples (Example 1, Example 3, Example 8, Example 12, Example 13, Example 16, Example 17, Example 21, Example 30, Example 32, Example 33, Example 45, Example 47, Example 48, and Example 49) was at the nM level, demonstrating significant anti-proliferative effects.

[0312] Example 60: Interaction Verification of Representative Compounds with B3GAT3 – Surface Plasmon Resonance (SPR) Analysis

[0313] Affinity assays were performed on a Biacore T200 instrument at 25 °C. Run buffer consisted of 10 mmol L⁻¹ HEPES (pH 7.4), 150 mmol L⁻¹ NaCl, 3 mmol L⁻¹ EDTA, and 0.005% (v / v) Tween-20 containing 5% (v / v) DMSO. Preliminary experiments optimized coupling conditions using 10 mmol L⁻¹ sodium acetate (pH 4.0, 4.5, 5.0, 5.5). After selecting the optimal pH, recombinant B3GAT3 was immobilized on a CM5 chip using amino-coupling, with a target protein loading of approximately 3000 RU. Compounds were serially diluted 1:2, with 30 μL min⁻¹ flowing sequentially through the chip, followed by a binding phase of 60 s and a dissociation phase of 80 s. Run buffer was used as a blank, and DMSO was applied as solvent to correct for baseline drift. The original sensor images were fitted using Biacore S200Evaluation software, and the equilibrium dissociation constant KD was calculated based on the 1:1 Langmuir model. A smaller KD value indicates a stronger binding affinity between the compound and B3GAT3. The results are summarized in […]. Figure 1 .

[0314] Figure 1 The results showed that the compounds prepared in Examples 1, 5, 21, and 48 had a high affinity for the B3GAT3 protein, indicating that the tested compounds had the ability to bind to B3GAT3. Simultaneously, the compounds prepared in Examples 1, 5, 21, and 48 exhibited significant inhibitory effects on the proliferation of liver cancer cells. This demonstrates that the compounds prepared in Examples 1, 5, 21, and 48, by acting on the B3GAT3 target, inhibit the proliferation and malignant development of liver cancer cells, exhibiting a strong inhibitory effect on malignant tumors.

[0315] The specific embodiments described above are merely illustrative of the technical concept of the present invention and are not intended to exhaustively limit its scope of protection. Those skilled in the art can make equivalent substitutions or adjustments to the experimental schemes, parameters, or procedures in form or detail without departing from the inventive essence contained in the claims; such modifications still fall within the scope of the claims of this invention.

Claims

1. A (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt, characterized in that, The general structural formula of the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compounds is shown in formula (1): （Ⅰ） in: Ring A is selected from 5-6 membered heterocycles with N atoms at both ends, 4-6 membered saturated or unsaturated bicyclic heterocycles, 4-6 membered saturated or unsaturated spirocyclic or bridged rings, and 2-8 alkane or ether-containing alkoxy straight chains. R1 is selected from substituted or unsubstituted C6~C6. 12 Aryl group, 5-10 membered aromatic heterocycle containing 1-2 nitrogen, oxygen and / or sulfur heteroatoms, substituted or unsubstituted benzo5-6 membered heterocycle; wherein the substituted group of the aromatic group of R1 is monosubstituted or polysubstituted, and the substituent is a halogen group, methyl, methoxy, or trifluoromethyl. R2 is selected from the 5-position indole ester group substituted by R3 or the 5-position indole ether group substituted by R4; wherein, R3 is selected from methyl or ethyl; R4 is selected from C4-C8 straight-chain alkyl groups, C4-C8 straight-chain or straight-chain groups containing N and / or O heteroatoms and cycloalkoxy groups, C4-C8 ester groups, substituted or unsubstituted C6-C8 groups. 10 Aromatic group; wherein the substituent is selected from hydrogen atoms.

2. The (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt according to claim 1, characterized in that, Ring A is selected from any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 ； R1 is selected from any of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R2 is selected from any of the following structures: 、 ； R3 is selected from methyl or ethyl; R4 is selected from any of the following structures: 、 、 、 、 、 、 。 3. The (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt according to claim 2, characterized in that, The (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound is selected from any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. The (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt according to claim 1, characterized in that the pharmaceutically acceptable salt is a salt formed by the compound and any one of the following acids or bases: The acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid, and the base is a base containing an alkali metal cation, an alkaline earth metal cation, or an ammonium cation salt.

5. A method for preparing the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound and its pharmaceutically acceptable salt as described in any one of claims 1-4, characterized in that, Synthesize according to the following route: in, Step 1: Compound 5-methoxyindigo (1a) and compound 2a are refluxed in an alkaline ethanol solution. After the reaction is completed, the mixture is acidified to obtain compound 3a. Step 2: Compound 3a reacts with different substituted Boc-containing amino groups via an acid-amine condensation reaction to give compound 4a; Step 3: Compound 4a is deactivated by trifluoroacetic acid to remove the Boc group and then basified to obtain compound 5a; Step 4: Compound 1b reacts with oxalyl chloride in diethyl ether to give compound 2b; Step 5: Compound 2b reacts with compound 5a in alkaline DCM at room temperature to give compound 3b.

6. A pharmaceutical composition, characterized in that, The compound comprises the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound as described in any one of claims 1-4, and its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier or excipient.

7. A B3GAT3 inhibitor, characterized in that, Comprising the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compounds as described in any one of claims 1-4, and their pharmaceutically acceptable salts.

8. The use of the (4-(6-methoxyquinoline-4-carbonyl)-1-yl)-1,2-dione compound of any one of claims 1-4 and its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 6, or the B3GAT3 inhibitor of claim 7 in the preparation of a medicament for the treatment and / or prevention of diseases related to B3GAT3 inhibition.

9. The application according to claim 8, characterized in that, Diseases associated with B3GAT3 inhibition include malignant tumors, skeletal dysplasia with inappropriate short stature, kyphosis, scoliosis and long bone deformities, spoon-shaped distal phalanges and facial deformities, embryonic developmental abnormalities, and abnormal cell metabolism and / or differentiation.

10. The application according to claim 9, characterized in that, Malignant tumors include liver cancer, lung cancer, pancreatic cancer, stomach cancer, prostate cancer, colorectal cancer, glioma, breast cancer, intrahepatic bile duct cancer, adrenocortical carcinoma, cervical cancer, and / or leukemia.

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