A urea derivative containing 1,3,4-oxadiazole biquinoline and its application

Abstract

The present invention provides a urea derivative containing 1,3,4-oxadiazole biquinoline and an application thereof, and relates to the field of pharmaceutical chemistry, and specifically relates to a novel urea derivative containing 1,3,4-oxadiazole biquinoline and a preparation method thereof, as well as an application of the compound in a drug for treating and / or preventing cancer; the general structural formula I of the urea derivative is as follows: the present invention obtains a urea derivative containing 1,3,4-oxadiazole biquinoline with a novel structure, and the cell activity test results of the compounds of the present invention show that the activities of some compounds on HCT-116 and HepG2 are equivalent to or better than those of positive control drugs tivozanib and lenvatinib, and can be preferably used in the preparation of drugs for treating liver cancer and colon cancer.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a urea derivative containing 1,3,4-oxadiazole biquinoline and application thereof. Background Art

[0002] Cancer, also known as malignant tumor, is a malignant disease caused by abnormal differentiation and proliferation of normal tissue cells in the human body, which seriously threatens people's life and health. With the growth of population and global aging, the number of cancer patients in the world has increased year by year. Cancer has become the main cause of premature death and reduced life expectancy of residents in many countries. According to statistics, in 2022, there were approximately 4.82 million and 2.37 million new cancer cases in China and the United States respectively, and approximately 3.21 million and 640,000 cancer deaths. Cancer has become the main cause of death among Chinese residents.

[0003] With the rapid development of tumor pathology and other related disciplines, people have gradually realized that the change of cell signal transduction pathways leading to uncontrolled cell proliferation is the essence of cell carcinogenesis. Vascular endothelialgrowth factor receptor (VEGFR), as a receptor tyrosine kinase, participates in the formation of new blood vessels and the growth of vascular endothelial cells, and plays an important role in the occurrence, development and migration of tumors.

[0004] In recent years, the research and development of anti-tumor drugs targeting VEGFR has achieved remarkable results, and small molecule VEGFR inhibitors of various structural types have been developed and marketed.

[0005]

[0006] Among them: sorafenib; regorafenib; lucitanib;

[0007] Cabozantinib; lenvatinib; tivozanib.

[0008] Tivozanib (AV-951, KRN-951) is a new type of VEGFR tyrosine kinase inhibitor first discovered by Kyowa Kirin Pharmaceutical Co., Ltd. in Japan and co-developed by Aevo Oncology in the United States and Astellas Pharmaceuticals in Japan. It has an IC of 1.14VEGFR-1, 1.2VEGFR-2 and 1.3VEGFR-3. 50They are 0.21, 0.16, and 0.24 nM, respectively. It has a significant inhibitory effect on a variety of tumor cells, such as breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer. The drug was launched in Europe and the United States in July 2017 and March 2021, respectively, for the treatment of relapsed and refractory advanced renal cell carcinoma (RCC). The trade name is Fotivda and it is not currently available in China. Tivozanib is in Phase I / II clinical research for the treatment of non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) to evaluate the safety and tolerability of the drug, as well as its therapeutic effects on patients with the target indications.

[0009] Therefore, it is of great value to study new compounds that can replace the anticancer activity of tivozanib, and it is also of great significance to study new compounds with multiple anticancer activities. Summary of the invention

[0010] In view of this, the present invention proposes a urea derivative containing 1,3,4-oxadiazole biquinoline and its application. The inventors designed and synthesized a series of urea derivatives containing 1,3,4-oxadiazole biquinoline with novel structures, and found through research and experiments that the compounds have anti-tumor activity.

[0011] The technical solution of the present invention is achieved in this way:

[0012] A urea derivative containing 1,3,4-oxadiazole biquinoline, wherein the general structural formula I of the urea derivative is as follows:

[0013]

[0014] wherein R1 is (C6-C10)aryl or 5-10 membered heteroaryl, the aryl or heteroaryl being optionally substituted by 1-3 identical or different R4; R4 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl or (C1-C6)alkoxy;

[0015] X is a halogen;

[0016] R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5;

[0017] or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6 groups;

[0018] R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen.

[0019] Preferably, R1 is phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1-3 identical or different R4;

[0020] R4 is selected from hydrogen, halogen, hydroxy, trifluoromethyl, (C1-C6)alkyl or (C1-C6)alkoxy;

[0021] X is a halogen;

[0022] R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5;

[0023] or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6 groups;

[0024] R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, (C1-C6) alkylacyl, (C1-C6) alkylsulfonyl, (C1-C6) alkyl unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen;

[0025] Preferably, R1 is a 5-6 membered heteroaryl group, which is optionally substituted by 1-3 identical or different R4 groups;

[0026] R4 is (C1-C6) alkyl;

[0027] X is a halogen;

[0028] R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5;

[0029] or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6 groups;

[0030] R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, (C1-C6) alkylacyl, (C1-C6) alkylsulfonyl, (C1-C6) alkyl unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen;

[0031] Preferably,

[0032] R1 is

[0033] X is Cl;

[0034] R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, dimethylaminoethyl, and the alkyl or cycloalkyl is optionally substituted by 1-3 same or different R5;

[0035] or R2 and R3 together with the nitrogen atom to which they are attached form

[0036] Furthermore, the urea derivative is at least one of the following compounds:

[0037] 1-(2-chloro-4-((7-methoxy-6-(5-(piperidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0038] 1-(2-chloro-4-((7-methoxy-6-(5-(piperazin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0039] 1-(2-chloro-4-((7-methoxy-6-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0040] 1-(2-chloro-4-((7-methoxy-6-(5-(4-methylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0041] 1-(2-chloro-4-((6-(5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0042] 1-(4-(6-(5-(4-acetylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)-3-(5-methylisoxazol-3-yl)urea,

[0043] 1-(2-chloro-4-((6-(5-(4-ethylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0044] 1-(2-chloro-4-((7-methoxy-6-(5-(thiomorpholinomethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0045] 1-(2-chloro-4-((6-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0046] 1-(4-((6-(5-(1,4-diazepin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)-3-(5-methylisoxazol-3-yl)urea,

[0047] 1-(2-chloro-4-((7-methoxy-6-(5-(4-methyl-1,4-diazepan-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0048] 1-(2-chloro-4-((7-methoxy-6-(5-(3-oxopiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0049] 1-(2-chloro-4-((6-(5-(4-hydroxypiperidin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea,

[0050] 1-(2-chloro-4-((6-(5-(3-hydroxypiperidin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea.

[0051] The present invention also provides another urea derivative containing 1,3,4-oxadiazole biquinoline, which is a salt formed by the urea derivative described in any one of the present invention and an acid.

[0052] Preferably, the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

[0053] The present invention also provides a pharmaceutical composition, which contains the urea derivatives described in any one of the present invention and pharmaceutically acceptable salts, solvates or prodrugs thereof.

[0054] The urea derivatives described in any one of the present invention are used in the preparation of drugs for preventing or treating liver cancer and / or colon cancer.

[0055] Use of any of the pharmaceutical compositions of the present invention in the preparation of a drug for preventing or treating liver cancer or / and colon cancer

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] The present invention obtains novel 1,3,4-oxadiazole biquinoline-containing urea derivatives, and the cell activity test results of the compounds of the present invention show that the activities of some compounds on HCT-116 and HepG2 are equivalent to or better than the positive control drugs tivozanib and lenvatinib. The urea derivatives containing 1,3,4-oxadiazole biquinoline prepared by the present invention can be used in the preparation of drugs for treating liver cancer, colon cancer, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 is the hydrogen spectrum of the final product obtained in Example 1;

[0059] Figure 2 is the hydrogen spectrum of the final product obtained in Example 2;

[0060] Figure 3 is the hydrogen spectrum of the final product obtained in Example 3;

[0061] Figure 4 is the hydrogen spectrum of the final product obtained in Example 4;

[0062] Figure 5 is the hydrogen spectrum of the final product obtained in Example 5;

[0063] Figure 6 is the hydrogen spectrum of the final product obtained in Example 6;

[0064] Figure 7 is the hydrogen spectrum of the final product obtained in Example 7;

[0065] Figure 8 is the hydrogen spectrum of the final product obtained in Example 8;

[0066] Fig. 9 is the hydrogen spectrum of the final product obtained in Example 9;

[0067] Fig.10 is the hydrogen spectrum of the final product obtained in Example 10;

[0068] Fig.11 is the hydrogen spectrum of the final product obtained in Example 11;

[0069] Fig.12 is the hydrogen spectrum of the final product obtained in Example 12;

[0070] Fig.13 is the hydrogen spectrum of the final product obtained in Example 13;

[0071] Fig.14 This is the hydrogen spectrum of the final product obtained in Example 14. DETAILED DESCRIPTION

[0072] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0073] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0074] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0075] Table 1 Chinese meaning or Chinese name corresponding to English or abbreviation

[0076] Serial number English or abbreviation Chinese 1 DMF N,N-Dimethylformamide 2 DMSO Dimethyl sulfoxide 3 Compound Compound 4 Concentration concentration 5 Cell Line Cell lines

[0077] The synthetic route of the urea derivatives of 1,3,4-oxadiazole biquinoline of the present invention is:

[0078]

[0079] Reagents and conditions:

[0080] (a) 4-amino-3-chlorophenol, sodium ethoxide, DMF, 110-120°C, 3-5h;

[0081] (b) 3-amino-5-methylisoxazole, phenyl chloroformate, triethylamine, DMF, 75-85°C, 4-5h,

[0082] (c) Hydrazine hydrate, ethanol, 75-85°C, 5-10h;

[0083] (d) Chloroacetic acid, phosphorus oxychloride, 100-110°C, 5-8h;

[0084] (e) Amine, potassium carbonate, DMF, room temperature, 3-5h.

[0085] Example

[0086] (1) Preparation of methyl 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxylate (M2)

[0087] Under nitrogen protection at room temperature, 4-amino-3-chlorophenol (10.0 g, 69.7 mmol) was added to 50 mL DMF, sodium ethoxide (6.6 g, 97.0 mmol) was added under ice bath, and stirred at room temperature for 1.5 h. 4-chloro-7-methoxyquinoline-6-carboxylic acid methyl ester (13.5 g, 53.6 mmol) was dissolved in 50 mL DMF and slowly injected into the above reaction solution. After the injection, the temperature was raised to 115 ° C and reacted for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature and added to 250 mL of water / methanol (1:1, v / v) solution. After stirring at room temperature for 2 h, the filter cake was washed with water (40 mL × 3) and methanol (20 mL × 1) in turn, and dried to obtain 12.6 g of purple solid. The yield was 75.6%. LC-MS (ESI) m / z (%): 359.0 [M + H] + ,381.0[M+Na] + .

[0088] (2) Preparation of methyl 4-{3-chloro-4-[3-(5-methylisoxazol-3-yl)ureido]phenoxy}-7-methoxyquinoline-6-carboxylate (M3)

[0089] At room temperature, 3-amino-5-methylisoxazole (10.0 g, 101.9 mmol) and 28.3 mL of triethylamine (20.6 g, 203.6 mmol) were added to 50 mL of DMF, and 12.8 mL of phenyl chloroformate (16.0 g, 102.2 mmol) was added dropwise under ice bath. After the addition was completed, the reaction solution was moved to room temperature and stirred for 2 h. After TLC detection of 3-amino-5-methylisoxazole reaction was complete, intermediate M2 (24.4 g, 68.0 mmol) was added. After the addition was completed, the temperature was raised to 80 ° C and the reaction was reacted for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into 500 mL of water and stirred at room temperature for 1 h, then filtered, the filter cake was washed with water, and after drying, the crude product was added to 60 mL of MeOH / H2O (v / v=5:1) mixed solvent at room temperature, heated under reflux and stirred for 0.5 h, and then filtered while hot, the filtrate was slowly cooled to room temperature, kept warm for crystallization for 1 h, filtered, and the filter cake was washed with 10 mL of recrystallization solvent. After drying, 23.1 g of yellow solid was obtained. The yield was 70.5%. LC-MS (ESI) m / z (%): 482.9 [M+H] + ,504.9[M+Na] + ,480.9[MH] - .

[0090] (3) Preparation of 1-{2-chloro-4-{[6-(hydrazinecarbonyl)-7-methoxyquinolin-4-yl]oxy}phenyl}-3-(5-methyl-3-isoxazolyl)urea (M4)

[0091] At room temperature, add intermediate M3 (10 g, 20.7 mmol) to 100 mL of ethanol, add 20 mL of hydrazine hydrate (80%), and heat to 80 ° C for 10 h. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, and the filter cake is washed with water and dried to obtain 8.5 g of a yellow solid. The yield is 85.0%. LC-MS (ESI) m / z (%): 483.0 [M + H] + ,504.9[M+Na] + .

[0092] (4) Preparation of 1-[2-chloro-4-({6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-7-methoxyquinolin-4-yl}oxy)phenyl]-3-(5-methylisoxazol-3-yl)urea (M5)

[0093] At room temperature, M4 (5 g, 10.3 mmol) was dissolved in 15 mL of phosphorus oxychloride, chloroacetic acid (1.2 g, 12.4 mmol) was added to the mixture, and the temperature was raised to 110°C for 8 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, then poured into ice water and stirred, the pH was adjusted to 10, filtered, the filter cake was washed with water, and dried, the crude product was added to ethanol and stirred for 1 h, filtered, and 3.5 g of yellow solid was obtained with a yield of 63.5%. LC-MS (ESI) m / z (%): 541.0 [M+H] + .

[0094] (5) General method for preparing Examples 1 to 14:

[0095] At room temperature, intermediate M5 (1.0 g, 1.8 mmol), potassium carbonate (0.4 g, 2.9 mmol) and the corresponding small molecular amine (2.4 mmol) were added to 5 mL of DMF. After the addition was completed, the reaction was allowed to react at room temperature for 5 h. After the reaction was completed, the reaction solution was poured into 50 mL of water and extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography and dried to obtain Example 1-14.

[0096] Table 1 The corresponding small molecule amines used in Examples 1 to 14 are shown in Table 1:

[0097] Example Small molecule amine Example 1 Piperidine Example 2 Piperazine Example 3 Morpholine Example 4 1-Methylpiperazine Example 5 2-(Piperazin-1-yl)ethanol-1-ol Example 6 1-(Piperazin-1-yl)ethan-1-one Example 7 1-Ethylpiperazine Example 8 Thiomorpholine Example 9 <![CDATA[N 1 , N 1 , N 2 -Trimethylethane-1,2-diamine]]> Example 10 1,4-Diazane Embodiment 11 1-Methyl-1,4-diazocyclohexane Example 12 Piperazine-2-one Example 13 Piperidin-4-ol Embodiment 14 Piperidin-3-ol

[0098] Table 2 Structural formula, chemical name and spectrum analysis of the products of Examples 1-14

[0099]

[0100]

[0101]

[0102]

[0103] Test example - in vitro anti-tumor cell proliferation experiment

[0104] 1. Cell Recovery

[0105] Take out the cells from the cryopreservation tube and thaw them quickly in a 37°C water bath. Under sterile conditions, transfer the liquid to a 50mL centrifuge bucket and add culture medium suitable for the growth of the cells to 10mL. Place the centrifuge tube in a centrifuge (1000rpm) for 5 minutes, discard the supernatant to obtain the cells. Place the cells in a culture dish, add 10mL of culture medium, and culture under standard conditions (37°C, saturated humidity, 5% CO2) for 24 hours.

[0106] 2. Cell passaging and culture

[0107] Discard the original culture medium in the culture dish, then add 1 mL of trypsin for rinsing, then add 3 mL of trypsin for digestion until a white film appears on the bottom of the culture dish, and discard the trypsin to terminate the digestion. Then add 10 mL of culture medium to the culture dish, mix with a pipette, transfer the cells to a 50 mL centrifuge bucket, seal the tube, place the centrifuge tube in a centrifuge (1000 rpm) for centrifugation for 5 minutes, then discard the culture medium, add 10 mL of culture medium suitable for the growth of the cells, pipette and mix, and then subculture at a ratio of 1 / 4, and culture under standard conditions. After the cells grow stably, they can be used for activity testing.

[0108] 3MTT assay to detect the growth inhibitory activity of compounds

[0109] Cells in the logarithmic growth phase were inoculated into a 96-well plate at 5000-10000 cells / well (different cells had different numbers of cells in each well), the volume of the cell suspension was 100 μL / well, and cultured under standard conditions. After 24 hours, the 96-well plate was taken out, 100 μL of culture medium of the test compound at different concentrations was added, three parallel controls were set for each concentration, a total of five concentration gradients, and cultured under standard conditions for 72 hours, and 50 μL of MTT solution (2 mg / mL) was added to each well, and the incubation continued. After 4 hours, the 96-well plate was taken out, the culture medium and MTT were discarded, 100 μL of DMSO solvent was added to each well, and the plate was placed on a microwave oscillator to oscillate until the crystals were completely dissolved, and the absorbance value (OD) was measured on a microplate reader at a wavelength of 570 nm. According to the formula: IR (Inhibition Rate, IR) % = (OD control -OD sample ) / (OD control -OD blank )×100%(OD control : OD value of the well without drug administration; OD sample : OD value of the dosing well; OD blank The inhibition rate of cell proliferation in vitro was calculated by fitting the IC values ​​of the compounds from the nonlinear regression equation using GraphPad Prism 8.0. 50 .

[0110] Table 1 Cell IC of some examples 50 Activity data

[0111]

[0112]

[0113] The results of the cell activity test of the compounds showed that the activities of some compounds against HCT-116 and HepG2 were comparable to or better than those of the positive control drugs tivozanib and lenvatinib. Among them, Example 14 had the highest inhibitory activity against HCT-116 and could be preferably used in the preparation of anti-colon cancer drugs; Example 7 had the highest inhibitory activity against HepG2 and could be preferably used in the preparation of anti-liver cancer drugs.

[0114] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A urea derivative containing 1,3,4-oxadiazole biquinoline, characterized in that: The general structural formula I of the urea derivative is as follows: R1 is (C6-C10) aryl or 5-10 membered heteroaryl, which is optionally substituted by 1-3 identical or different R4; R4 is selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, (C1-C6) alkyl, (C1-C6) haloalkyl or (C1-C6) alkoxy; X is a halogen; R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5; or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom, the heterocyclic group containing 0-2 carbon-carbon double bonds or carbon-carbon triple bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6; R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, cyano, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl or (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen.

2. The urea derivative containing 1,3,4-oxadiazole biquinoline according to claim 1, characterized in that: R1 is phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1-3 identical or different R4; R4 is selected from hydrogen, halogen, hydroxy, trifluoromethyl, (C1-C6)alkyl or (C1-C6)alkoxy; X is a halogen; R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5; or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6; R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen.

3. The urea derivative containing 1,3,4-oxadiazole biquinoline according to claim 2, characterized in that: R1 is a 5-6 membered heteroaryl group, which is optionally substituted by 1-3 identical or different R4 groups; R4 is (C1-C6) alkyl; X is a halogen; R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocycloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, dimethylaminoethyl, and the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by 1-3 identical or different R5; or R2 and R3 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group containing at least one heteroatom; the heterocyclic group contains 0-2 carbon-carbon double bonds, the heterocyclic group is optionally substituted with one or more oxo groups, or the heterocyclic group is optionally substituted with 0-3 identical or different R6; R5 and R6 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, amino substituted with 0-2 (C1-C6) alkyl groups, (C1-C6) alkyl acyl, (C1-C6) alkyl sulfonyl, (C1-C6) alkyl which is unsubstituted or substituted with at least one of the following groups, (C1-C6) alkoxy, (C3-C6) cycloalkyl, (C3-C10) cycloalkyl-(C1-C4) alkyl; the following groups are hydroxyl, amino or halogen.

4. The urea derivative containing 1,3,4-oxadiazole biquinoline according to claim 3, characterized in that: R1 is X is Cl; R2 and R3 are the same or different and are independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, dimethylaminoethyl, and the alkyl or cycloalkyl is optionally substituted by 1-3 same or different R5; or R2 and R3 together with the nitrogen atom to which they are attached form 5. The urea derivative according to claim 1, characterized in that: The urea derivative is at least one of the following compounds: 1-(2-chloro-4-((7-methoxy-6-(5-(piperidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(piperazin-1-ylmethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(4-methylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((6-(5-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(4-(6-(5-(4-acetylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((6-(5-(4-ethylpiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(thiomorpholinomethyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((6-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(4-((6-(5-(1,4-diazepin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)-2-chlorophenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(4-methyl-1,4-diazepan-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((7-methoxy-6-(5-(3-oxopiperazin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)quinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((6-(5-(4-hydroxypiperidin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea, 1-(2-chloro-4-((6-(5-(3-hydroxypiperidin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)-7-methoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea.

6. A urea derivative containing 1,3,4-oxadiazole biquinoline, characterized in that: A salt formed from the urea derivative according to any one of claims 1 to 5 and an acid.

7. The urea derivative according to claim 6, characterized in that: The acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

8. A pharmaceutical composition, characterized in that The composition contains the urea derivative described in any one of claims 1 to 5 and a pharmaceutically acceptable salt, solvate or prodrug thereof.

9. Use of the urea derivative according to any one of claims 1 to 7 in the preparation of a drug for preventing or treating liver cancer and / or colon cancer.

10. Use of the pharmaceutical composition according to any one of claims 8 in the preparation of a drug for preventing or treating liver cancer and / or colon cancer.

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