Quinoline compound with aurora kinase B and epidermal growth factor receptor dual inhibition effects and application

Abstract

The invention discloses a quinoline compound. The structural general formula of the quinoline compound is selected from any one of # imgabs 0 #, # imgabs 1 # and the like. The invention also provides application of the compound in preparation of drugs with aurora kinase B and epidermal growth factor receptor dual inhibition effects. The medicine prepared from the compound has the effect of resisting non-small cell lung cancer.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to a class of quinoline compounds having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor and their uses. Background Art

[0002] Cancer, as one of the major global public health problems, seriously affects social development. The primary goal of cancer treatment is to inhibit the migration and proliferation of malignant tumor cells. Clinical means such as chemotherapy, targeted drug therapy, and immunotherapy have been widely used.

[0003] Epidermal growth factor receptor (EGFR) inhibitors have shown good efficacy in clinical practice, especially in the treatment of cancers such as non-small cell lung cancer (NSCLC). For patients carrying EGFR mutations (such as L858R, Exon 19 deletion mutations), EGFR inhibitors (such as gefitinib, erlotinib) usually have a remission rate of about 50 - 70% in the initial treatment stage of NSCLC patients with EGFR mutations, and the progression-free survival reaches 9 months. Although EGFR inhibitors are effective in the early stage, patients develop acquired resistance after 9 - 13 months of use. The most common resistance mechanism is the EGFR T790M mutation. The research and development of specific inhibitors based on resistant targets is one of the key ways to improve the survival rate of malignant tumor patients. The third-generation EGFR inhibitor osimertinib designed for the EGFR T790M mutation can form a covalent bond between its acrylamide group and the cysteine residue C797 in the ATP-binding pocket of the EGFR T790M mutation, and this binding is irreversible; the molecular skeleton of osimertinib has good flexibility and can adapt to the steric hindrance limitation of the ATP-binding pocket after the T790M mutation. Therefore, the remission rate of osimertinib is 80%, and the progression-free survival is 18.9 months. Unfortunately, however, some patients develop other resistance mechanisms (such as the C797S mutation) after use, resulting in a reduced treatment effect.

[0004] Aurora kinase B (Aurora-B) is a serine-threonine kinase that is mainly involved in chromosome condensation, segregation, and cytokinesis. During cell division, Aurora-B is located at the metaphase spindle and helps separate two daughter cells when cytokinesis is completed. Due to its importance for chromosome stability and the cell division process, abnormal activation or overexpression often leads to changes in chromosome number and structure, causing cells to lose control during mitosis. This chromosomal instability usually results in cell malignant transformation. Aneuploid cells, which mean cells containing abnormal numbers of chromosomes, are found in 90% of human malignant tumor cells and may be caused by functional defects such as mitotic checkpoints and chromosomal cohesion, and these defects have all been found to be related to the overexpression of Aurora-B. Therefore, Aurora-B has been established as a target for cancer treatment. Studies have found that knocking down Aurora-B expression inhibits the activation of the mTOR / ULK1 pathway, stimulates autophagy in osteosarcoma cells, and inhibits their metastasis and proliferation. Further research has found that in drug-resistant tumor cells, Aurora-B promotes the development of drug resistance in malignant tumor cells through multiple pathways: 1. The CDK7-Aurora-B pathway is upregulated in two types of AML cells resistant to FTL3 inhibitors, and Aurora-B and cyclin-dependent kinases 2 / 4 / 6 together slow down cell metabolic activities, thus enhancing the adaptability to FTL3 inhibitors; 2. Aurora-B and MYC activate each other to enhance the proliferative ability of malignant tumors; 3. Aurora-B inhibits apoptosis in malignant tumor cells through the AKT / PI3K pathway; and in the above studies, the combination of Aurora-B inhibitors restores the drug sensitivity of tumor cells and effectively improves the drug resistance of tumor cells. Given the multi-faceted connection between Aurora-B and drug resistance, the development of multi-target small molecule drugs targeting Aurora-B provides new possibilities for improving tumor drug resistance.

[0005] So far, corresponding drug resistance mechanisms have been found for the first to third generation single-target EGFR inhibitors in clinical practice. The inhibition of only a single pathway will promote the activation of related pathways, suggesting that when treating tumors with complex pathogenic mechanisms, a treatment strategy that simultaneously inhibits multiple targets should be chosen. Through literature research, it has been found that the EGFR inhibitor pelitinib, the Aurora-B inhibitor AL8326, and anlotinib all have a quinoline as the core structure. Therefore, in this study, quinoline was used as the molecular backbone, and through computer-aided drug design methods, the reasonable design and modification of quinoline substituents were carried out to construct quinoline-based Aurora-B / EGFR dual-target inhibitors.

[0006] Accordingly, the objective of the present invention is to provide quinoline-derived dual inhibitors of Aurora-B / EGFR, which have improved selectivity for osimertinib-resistant non-small cell lung cancer malignancies. Summary of the Invention

[0007] In view of the above technical problems in the prior art, the present invention provides a quinoline compound having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor and its use, and the quinoline compound having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor and its use are intended to solve the problem of osimertinib resistance in EGFR-mutated NSCLC patients in the prior art.

[0008] The present invention provides a quinoline compound selected from any one of the following structural formulas: 、 、 、 、 、 、 、 。

[0009] The present invention also provides pharmaceutically acceptable salts, solvates, polymorphs, isomers or prodrugs of the above quinoline compounds.

[0010] The present invention also provides a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier and / or excipient.

[0011] The present invention also provides a pharmaceutical composition comprising the above pharmaceutically acceptable salts, solvates, polymorphs, isomers or prodrugs and a pharmaceutically acceptable carrier and / or excipient.

[0012] Furthermore, the pharmaceutically acceptable auxiliary materials and / or excipients are diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers and / or disintegrants.

[0013] Furthermore, the dosage form of the drug is an aqueous dispersant, liquid, gel, syrup, medicated slurry, suspension, aerosol, controlled release agent, rapid solvent, effervescent agent, lyophilized agent, tablet, powder, pill, sugar-coated pill, capsule, delayed release agent, extended release agent, pulsed controlled release agent, multi-particle agent or immediate release agent.

[0014] The present invention also provides the use of the above compound in the preparation of a drug having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor.

[0015] The present invention also provides the use of the above-mentioned pharmaceutically acceptable salts, solvates, polymorphs, isomers or prodrugs in the preparation of a drug having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor.

[0016] The present invention also provides the use of the above-mentioned pharmaceutically acceptable compounds in the preparation of a drug for treating tumors associated with overexpression of aurora kinase B and epidermal growth factor receptor. The present invention also provides the use of the above-mentioned pharmaceutically acceptable salts, solvates, polymorphs, isomers or prodrugs in the preparation of a drug for treating tumors associated with overexpression of aurora kinase B and epidermal growth factor receptor.

[0017] The present invention also provides the use of the above compound in the preparation of a drug for treating non-small cell lung cancer.

[0018] The present invention also provides the use of the above-mentioned pharmaceutically acceptable salts, solvates, polymorphs, isomers or prodrugs in the preparation of a drug for treating non-small cell lung cancer.

[0019] Compared with the prior art, the technical progress of the present invention is remarkable. The present invention discloses a series of Aurora-B / EGFR dual-target compounds, providing a new direction for the research of anti-non-small cell lung cancer drugs and having important significance for the development of anti-non-small cell lung cancer drugs.

[0020] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Shows the molecular docking binding of the disclosed quinoline derivatives of the prior art with Aurora-B. DETAILED DESCRIPTION OF THE INVENTION

[0022] Through extensive and in-depth research, the present inventors unexpectedly discovered a series of new quinoline compounds, and these compounds have good dual inhibitory activities against EGFR and Aurora-B. The present invention was completed on this basis. The above-described compounds can be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described in the text. In addition, the solvents, temperatures and other reaction conditions mentioned here can be changed.

[0023] The starting materials for the synthesis of the compounds can be obtained by synthesis or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials. The general methods for the preparation of the compounds can be varied by using appropriate reagents and conditions for introducing different groups in the provided molecular formulas. The compounds described herein are synthesized according to the synthetic routes shown in the following schemes. In some embodiments, the compounds described herein can be prepared by the following methods. The following methods and examples are for illustrative purposes only. These procedures and examples should not be construed as limiting the present invention in any way. The compounds described herein can also be synthesized using standard synthetic techniques known to those skilled in the art, or by combining known methods in the art with the methods described herein.

[0024] The synthetic methods for a series of compounds may include the following steps:

[0025] Example 1 Synthesis of Intermediate 3:

[0026] 7 - Benzyloxy - 4 - chloro - 6 - methoxyquinoline and 4 - fluoro - 5 - hydroxy - 2 - methylindole were reacted in 2,6 - dimethylpyridine under the catalysis of 4 - dimethylaminopyridine. The temperature was raised to 140 °C for the reaction. After the reaction of the starting materials was complete as detected by TLC, it was cooled to room temperature, diluted with dichloromethane, and 50 mL of 1 mol / L aqueous HCl solution was slowly added dropwise. The aqueous layer was discarded, and the organic layer was washed with potassium carbonate solution (1 mol / L), dried over anhydrous sodium sulfate, filtered by suction, the solvent was removed by distillation under reduced pressure, and 1.74 g of Intermediate 3, a pale yellow solid, was obtained by column chromatography separation with a yield of 51.15%. 1 H NMR (400 MHz, DMSO - d 6) δ 11.42 (t, J J = 2.5 Hz, 1H), 8.41(d, J J = 5.2 Hz, 1H), 7.61 (s, 1H), 7.57 – 7.50 (m, 3H), 7.50 (s, 2H), 7.43(dd, J J = 8.2, 6.6 Hz, 2H), 7.40 – 7.32 (m, 1H), 7.22 (d, J J = 8.6 Hz, 1H),7.04 – 6.94 (m, 1H), 6.33 (dd, J= 5.2, 1.1 Hz, 1H), 6.30 – 6.25 (m, 1H), 5.31 (s, 2H), 3.97 (s, 3H), 3.32 (s, 2H), 2.42 (s, 3H). LC-MS (ESI) m / z 429.2[M+H] + 。

[0027] Example 2 Synthesis of Intermediate 4:

[0028] Synthetic route of Intermediate 4

[0029] Add 7-benzyloxy-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinoline (800 mg, 1.87 mmol) and 3 mL of H2O to a three-necked flask, stir and heat up to 85 °C, add 12 mL of trifluoroacetic acid, and stir for 2 hours. After detecting that the raw materials have completely reacted by TLC, cool to room temperature, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH value of the solution to 7 - 8, extract three times with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, filter by suction, distill off the organic solvent under reduced pressure, and purify by column chromatography to obtain 550 mg of Intermediate 4, a pale yellow solid, with a yield of 87%. 1 1H NMR (400 MHz, DMSO- d 6) δ 11.58 (t, J J =2.4 Hz, 1H), 8.68 (d, J J = 6.5 Hz, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 7.29 (d, J J = 8.6 Hz, 1H), 7.18 – 7.05 (m, 1H), 6.72 (dd, J J = 6.6, 1.1 Hz, 1H), 6.36 – 6.30 (m, 1H), 4.05 (s, 4H). LC-MS (ESI) m / z 339.1 [M+H] + 。

[0030] Example 3 Synthesis of Intermediate 5:

[0031] Synthetic routes of Intermediate 5 and 6

[0032] At room temperature, 2-bromoethylamine hydrobromide, H2O, and CH3COOH were added to a three-necked flask. Then, 2,5-dimethoxytetrahydrofuran and sodium acetate were added. The solution was stirred at room temperature until it became clear, and then heated to 55 °C. After the reaction was completed, saturated sodium bicarbonate was used to adjust the pH of the solution to 7-8. The solution was extracted with dichloromethane three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 1.10 g of intermediate 5, a pale yellow oil, with a yield of 63.20%. The reaction steps for intermediate 6 were the same as those for intermediate 5, and the column chromatography separation system was (dichloromethane:methanol = 70:1). 1 H NMR (400 MHz, DMSO- d 6) δ 6.81 (t, J = 2.2 Hz, 1H), 6.03 (t, J = 2.1 Hz, 1H), 4.27 (t, J = 6.4 Hz, 1H), 3.74 (t, J = 6.4 Hz, 1H). LC-MS(ESI) m / z 175.9 [M+H] + 。

[0033] Example 4 Synthesis of Intermediate 6: Synthesized by a procedure similar to that described in Example 3, except that 2-bromoethylamine hydrobromide was replaced with 3-bromopropylamine hydrobromide, to obtain 940 mg of a pale yellow oil with a yield of 54.01%. 1 H NMR (400 MHz, DMSO- d 6) δ 6.74 (t, J =2.1 Hz, 2H), 6.00 (t, J = 2.1 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 3.37 (t, J =6.5 Hz, 2H), 2.20 (p, J = 6.6 Hz, 2H). LC-MS (ESI) m / z 190.0 [M+H] + 。

[0034] Example 5 Synthesis of Intermediate 7

[0035] Synthesis route of intermediate 7

[0036] 1H-1,2,4-triazole, potassium bicarbonate, and 1,2-dibromopropane were added to a three-necked flask.N,N -Dimethylformamide, reaction at room temperature. After the reaction, extract with 30 mL of dichloromethane three times and wash with water once. Collect the organic phase, dry with anhydrous sodium sulfate, and concentrate under reduced pressure at low temperature to obtain 1.34 g of intermediate 7, a pale yellow oil, with a yield of 7.06%. 1 H NMR (600 MHz, DMSO- d 6) δ8.55 (s, 1H), 7.99 (s, 1H), 4.32 (t, J J = 6.8 Hz, 2H), 3.49 (t, J J = 6.5 Hz,2H), 2.33 (p, J J = 6.7 Hz, 2H); LC-MS (ESI) m / z 190.1 [M+H] + 。

[0037] Example 6 Synthesis of Compound 13:

[0038] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-pyrrol-1-yl)ethoxy]quinoline

[0039] Add the intermediate 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (200 mg, 591.12 μmol), 1-(2-bromoethyl)-1H-pyrrole (120 mg, 709.35 μmol), potassium carbonate (245 mg, 1.77 mmol), and N,N-dimethylformamide (4 mL) into a three-necked flask. React at 60 - 80 °C. After monitoring the reaction by TLC and the reaction is completed, add 20 mL of water, extract with 30 mL of ethyl acetate three times, discard the aqueous layer, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Separate by column chromatography (ethyl acetate: cyclohexane = 2:1) to obtain 120 mg of the final product 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-pyrrol-1-yl)ethoxy]quinoline, a pale yellow solid, with a yield of 47.05%. 1H NMR (600 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.42 (d, J = 5.2 Hz, 2H), 7.61 (s, 2H), 7.41 (s, 2H), 7.22 (d, J = 8.5 Hz, 1H), 7.02 – 6.97 (m, 1H), 6.90 (t, J = 2.1 Hz, 3H), 6.33 (d, J = 5.2 Hz, 1H), 6.28 (d, J = 1.1 Hz, 1H), 6.01 (t, J = 2.1 Hz, 3H), 4.42 (d, J = 5.2 Hz, 4H), 4.38 (t, J = 4.7 Hz, 4H), 3.98 (s, 5H), 2.42 (s, 3H). LC-MS (ESI) m / z 431.8 [M+H]+.

[0040] Example 7 Synthesis of Compound 14:

[0041] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-imidazol-1-yl)ethoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(2-chloroethyl)imidazole hydrochloride, and the yield was 19.56%. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (t, J = 2.4 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.04 – 6.93 (m, 1H), 6.91 (d, J = 1.2 Hz, 1H), 6.34 (dd, J = 5.3, 1.1 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 4.51 – 4.42 (m, J = 3.0 Hz, 4H), 3.98 (s, 3H), 2.42 (s, 3H). LC-MS (ESI) m / z 433.1 [M+H]+.

[0042] Example 8 Synthesis of Compound 15:

[0043] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-pyrazol-1-yl)ethoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(2-bromoethyl)pyrazole, and the yield was 7.82%. 1H NMR (600 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.43 (d, J = 5.2 Hz, 2H), 7.84 (d, J = 2.3 Hz, 2H), 7.59 (s, 2H), 7.49 (d, J = 1.9 Hz, 2H), 7.42 (s, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.99 (t, J = 8.1 Hz, 2H), 6.33 (d, J = 5.2 Hz, 1H), 6.28 (t, J = 2.1 Hz, 4H), 4.61 (t, J = 5.1 Hz, 4H), 4.54 (t, J = 5.2 Hz, 4H), 3.95 (s, 6H), 2.42 (s, 3H). LC-MS (ESI) m / z 433.2 [M+H]+.

[0044] Example 9 Synthesis of Compound 16:

[0045] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-1,2,4-triazol-1-yl)ethoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(2-chloroethyl)-1H-1,2,4-triazole, and the yield was 21.52%. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.60 (s, 1H), 8.43 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.03 – 6.96 (m, 1H), 6.34 (dd, J = 5.3, 1.1 Hz, 1H), 6.30 – 6.26 (m, 1H), 4.70 (t, J = 5.1 Hz, 2H), 4.56 (t, J = 5.0 Hz, 2H), 3.94 (s, 3H), 2.42 (s, 3H). LC-MS (ESI) m / z 434.2 [M+H]+.

[0046] Example 10 Synthesis of Compound 17:

[0047] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-pyrrol-1-yl)propoxy]quinoline Synthesized in a similar procedure as described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced by 1-(3-bromopropyl)-1H-pyrrole, with a yield of 7.82%. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.41 (d, J = 5.3 Hz, 1H), 7.61 (s, 1H), 7.35 (s, 1H), 7.22 (d, J = 9.4 Hz, 1H), 7.02 – 6.96 (m, 1H), 6.78 (t, J = 2.1 Hz, 2H), 6.33 (dd, J = 5.2, 1.1 Hz, 1H), 6.28 (s, 1H), 5.99 (t, J = 2.1 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 4.06 (t, J = 6.2 Hz, 3H), 3.99 (s, 3H), 2.42 (s, 3H), 2.25 (p, J = 6.6 Hz, 3H). LC-MS (ESI) m / z 446.2 [M+H]+.

[0048] Example 11 Synthesis of Compound 18:

[0049] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-imidazol-1-yl)propoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(3-bromopropyl)-1H-imidazole hydrobromide, and the yield was 9.47%. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 7.67 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.24 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.03 – 6.96 (m, 1H), 6.91 (s, 1H), 6.33 (dd, J = 5.2, 1.1 Hz, 1H), 6.31 – 6.25 (m, 1H), 4.20 (t, J = 6.9 Hz, 2H), 4.10 (t, J = 6.3 Hz, 2H), 3.99 (s, 3H), 2.42 (s, 3H), 2.29 (p, J = 6.5 Hz, 2H). LC-MS (ESI) m / z 447.2 [M+H]+.

[0050] Example 12 Synthesis of Compound 19:

[0051] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-pyrazol-1-yl)propoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(3-chloropropyl)-1H-pyrazole hydrochloride, and the yield was 11.37%. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.42 (d, J = 5.3 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.61 (s, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.03 – 6.96 (m, 1H), 6.33 (dd, J = 5.3, 1.1 Hz, 1H), 6.28 (s, 1H), 6.25 (t, J = 2.0 Hz, 1H), 4.35 (t, J = 6.8 Hz, 2H), 4.13 (t, J = 6.2 Hz, 2H), 3.99 (s, 2H), 2.42 (s, 2H), 2.33 (p, J = 6.6 Hz, 2H). LC-MS (ESI) m / z 447.2 [M+H]+.

[0052] Example 13 Synthesis of Compound 20:

[0053] 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(1H-1,2,4-triazol-1-yl)propoxy]quinoline Synthesized in a similar manner to the steps described in Example 6, except that 1-(2-bromoethyl)-1H-pyrrole was replaced with 1-(3-bromopropyl)-1H-1,2,4-triazole, and the yield was 16.26%. 1H NMR (600 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.57 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.02 – 6.98 (m, 1H), 6.33 (d, J = 5.2 Hz, 1H), 6.28 (s, 1H), 4.42 (t, J = 6.9 Hz, 2H), 4.18 (t, J = 6.2 Hz, 2H), 3.98 (s, 3H), 2.42 (s, 3H), 2.36 (p, J = 6.6 Hz, 2H). LC-MS (ESI) m / z 448.2 [M+H]+.

[0054] Example 14: Determination of the IC of the target compound against Aurora-B and EGFR using the HTRF method 50 value.

[0055] Experimental materials: EGFR was purchased from Carna, adenosine triphosphate, MgCl2 and MnCl2 were purchased from Sigma, and the EGFR detection kit was purchased from Revvity. The Aurora-B IC 50 was tested on behalf of BioDuro-Sundia (Jiangsu) Co., Ltd.

[0056] According to the instructions of the HTRF kinEASE TK / STK kit, prepare the stock solutions of TK / STK-Substrate-biotin, streptavidin-XL665, TK / STK antibody-cryptate, and EGFR / Aurora-B. Dilute each kinase stock solution with 1-fold kinase buffer as needed to prepare working solutions with the concentrations required for the enzymatic steps. Each test compound was diluted with 1-fold kinase buffer to ensure that the DMSO concentration in the solution was ≤2%, and then serially diluted 8 times by a factor of 3 to generate 9 concentration gradients in the enzymatic step, with each working concentration being 2.5 times the final concentration (range: 10 μM). The measurements were performed in white 96-well microplates using blanks and control compounds.

[0057] Calculate the ratio of the two fluorescence intensities. The inhibition rate of each compound against the kinase at a given concentration is expressed as (Ratio 待测化合物 -RatioHigh Control ) / (Ratio Low Control - Ratio High Control ), where Ratio Low Control and Ratio High Control are the release rates of the negative control well and the blank control well, respectively. The half-maximal inhibitory concentration value (IC 50 ) of each compound was determined from the dose-response curve obtained by GraphPad Prism9 software.

[0058] Table 1 IC 50

[0059] of the compounds against Aurora-B and EGFR 50 As shown in Table 1, a total of 8 target compounds were synthesized for the current compounds. After structural confirmation and purity verification, the inhibitory activities of the 8 target compounds and anlotinib against Aurora-B and EGFR were determined using homogeneous time-resolved fluorescence (HTRF) technology. For EGFR, the inhibition rates of the series of compounds showed varying degrees of decrease compared with anlotinib. Among them, the inhibitory activities of 14, 15, 16, 18, and 20 against Aurora-B were superior to anlotinib, and the IC

[0060] of 16 was 0.833 μM.

[0061] Example 15: The CCK-8 method (Cell Counting Kit-8) was used in this experiment to detect the in vitro cell anti-proliferation activity of the target compounds.

[0062] Construction of drug-resistant cells: The osimertinib-resistant strain H1975 was induced and established by the method of continuous induction with low concentration increment to ensure that the H1975 cell line could still grow at an osimertinib drug concentration of 5 μM. The drug-resistant strain showed characteristics of slow proliferation, less apoptosis, high migration, and invasion ability.

[0063] Preparation of complete medium: The proportion of the complete medium for osimertinib-resistant H1975 cells was 89% basal medium + 10% fetal bovine serum + 1% penicillin-streptomycin double antibody.

[0064] Dilution of the compound solution: Prepare a stock solution of the drug to be tested at an equal concentration of 20 mM. Add the required volume of dimethyl sulfoxide. To ensure complete dissolution, ultrasonic, vortex, heating and other means can be used to accelerate dissolution. When in use, dilute it to concentrations such as 2, 4, 6, 8, 10, 12 μM with complete medium in a laminar flow hood, mix well and set aside.

[0065] Seeding plates: Take tumor cells in the logarithmic growth phase, digest them with trypsin, remove the old medium after centrifugation; add 1 mL of complete medium and resuspend. Take 10 μL of the cell suspension into a new EP tube, dilute it with 90 μL of complete medium, transfer it to a cell counting plate, count the cells, and adjust the cell concentration to 5x10 4 / mL, inoculate 100 μL per well into a 96-well plate; place the 96-well plate in a cell incubator at 37 °C and 5% CO2 for 24 hours until the cells adhere to the wall; Adding drugs: Aspirate the old medium, wash once with PBS, and then add the pre-prepared drug solutions of each concentration at 100 μL per well to the 96-well plate. Set 3 replicates for each concentration. The control group adds an equal volume of complete medium containing 1‰ DMSO and continue to culture in the cell incubator for 24 hours; Adding CCK-8 reagent: Aspirate the old medium, wash once with PBS, and add 100 μL of basal medium + 10 μL of CCK8 reagent to each well in a light-proof environment. Cover with tin foil and continue to incubate in the incubator for 2 hours; Measure the OD value at 450 nm using an enzyme-linked immunosorbent assay (ELISA) reader.

[0066] Experimental data processing Calculate the cell growth inhibition rate according to the following formula: Inhibition rate = 1 - [(experimental group - blank group) / (control group - blank group)] * 100% Based on the inhibition rates of the drug on the cell proliferation rate at different concentrations, fit the IC of the compound through GraphPad Prism 8 software 50 curve and obtain the IC 50 value.

[0067] Table 2 Inhibition rates of the compound on osimertinib-resistant NSCLC cells

[0068] As shown in the results of Table 2, compound 20 exhibited the most significant inhibitory activity with an IC50 value of 2.47 μM, significantly superior to other compounds. Compounds 17 (8.83 μM) and 16 (11.53 μM) also showed moderate activity, while the IC50 values of the remaining compounds (such as 13, 18, etc.) were mostly distributed in the range of 13 - 15 μM. Compound 20 was superior to compound 5b (2.83 ± 0.24 μM) designed by Kshipra S. Karnik et al. ( Bioorganic Chemistry 107 (2021) 104612 ); The structural formula of compound 5b is as follows: .

[0069] Example 16 We compared the quinoline derivatives disclosed in Example 17 of the prior art (publication number: CN1446212A, publication date: October 1, 2003) and the molecular docking binding situation of Example 17 with Aurora-B (as Figure 1 shown). It can be seen that there are only two hydrogen bond binding interactions between this compound and Aurora-B, which is less than the number of hydrogen bond bindings of anlotinib and compounds 14, 16, etc. of the present invention. In addition, the results of our in vitro enzyme activity experiments showed that when the carbon chain length of the side chain at the 7th position of the quinoline compound was 3, it would affect the stability of the hydrogen bond binding interaction with ARG81, resulting in a decrease in the inhibitory activity of the small molecule against Aurora-B.

Claims

1. A quinoline compound, characterized in that, is any of the following structural formulas: 、 、 、 、 、 、 、 。 2. A pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug of the quinoline compound according to claim 1.

3. A pharmaceutical composition, characterized in that: Comprising the compound according to claim 1 and a pharmaceutically acceptable carrier and / or excipient.

4. A pharmaceutical composition, characterized in that: Comprising the pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug according to claim 2 and a pharmaceutically acceptable carrier and / or excipient.

5. A pharmaceutical composition according to claim 3 or 4, characterized in that, The pharmaceutically acceptable auxiliary materials and / or excipients are diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers and / or disintegrants.

6. A pharmaceutical composition according to claim 3 or 4, characterized in that, The dosage form of the drug is an aqueous dispersant, liquid, gel, syrup, medicated paste, suspension, aerosol, controlled release agent, rapid solvent, effervescent agent, freeze-dried agent, tablet, powder, pill, sugar-coated pill, capsule, delayed release agent, extended release agent, pulsed controlled release agent, multi-particle agent or immediate release agent.

7. Use of the compound according to claim 1 in the preparation of a drug having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor.

8. Use of the pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug according to claim 2 in the preparation of a drug having dual inhibitory effects on aurora kinase B and epidermal growth factor receptor.

9. Use of the pharmaceutically acceptable compound according to claim 1 in the preparation of a drug for treating tumors associated with overexpression of aurora kinase B and epidermal growth factor receptor.

10. Use of the pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug according to claim 2 in the preparation of a drug for treating tumors caused by overexpression of aurora kinase B and epidermal growth factor receptor.

11. Use of the compound according to claim 1 in the preparation of a drug for treating non-small cell lung cancer.

12. Use of the pharmaceutically acceptable salt, solvate, polymorph, isomer or prodrug according to claim 2 in the preparation of a drug for treating non-small cell lung cancer.

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