Chalcone derivative containing urea structure as well as preparation method and application of chalcone derivative

Abstract

The invention discloses a chalcone derivative containing a urea structure as well as a preparation method and application of the chalcone derivative, and relates to the technical field of medicinal chemistry. The chalcone derivative containing the 4-chloro-3-(trifluoromethyl) phenylurea fragment, which has a novel structure, is designed and synthesized by utilizing a splicing principle, and the chalcone derivative can be used for effectively inhibiting the proliferation of cancer cells.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and particularly relates to a chalcone derivative containing a urea structure, a preparation method thereof, and an application thereof. Background Art

[0002] The tyrosine kinase receptors of the vascular endothelial growth factor (VEGF) family are composed of three protein receptors (VEGFR-1, VEGFR-2, and VEGFR-3). VEGFR-2 is a VEGF receptor and a key angiogenic factor, which is secreted by malignant tumors and induces the proliferation and migration of vascular endothelial cells. Numerous studies have shown that directly inhibiting the activity of VEGFR-2 will lead to a reduction in angiogenesis, and inhibiting this signaling pathway has become a method for inhibiting tumor growth. Therefore, inhibiting VEGFR-2 is an effective method for treating cancer.

[0003] Currently, some small molecule VEGFR-2 inhibitors such as sorafenib (shown in Formula 1) and sunitinib (shown in Formula 2) have been approved by the FDA for the treatment of tumors. In addition, it has also been found that chalcone compounds can also be used as VEGFR-2 inhibitors. For example, the quinoline-fragment-containing chalcone shown in Formula 3 and the piperazine chalcone shown in Formula 4 have been reported to have good inhibitory effects on cancer cells as VEGFR-2 inhibitors.

[0004]

[0005] Although many VEGFR-2 inhibitors have been reported currently, VEGFR-2 inhibitors are prone to drug resistance in the treatment of cancer. Therefore, the development of new anti-cancer drugs has broad application prospects. Summary of the Invention

[0006] Based on the technical problems existing in the background art, the present invention provides a chalcone derivative containing a urea structure, a preparation method thereof, and an application thereof. The chalcone derivative can be used to prepare a drug for preventing and / or treating cancer.

[0007] The present invention provides a chalcone derivative containing a urea structure, and the structural formula of the chalcone derivative containing a urea structure is shown in Formula I:

[0008]

[0009] In Formula I, R 1 , R 2 , R 3 , R 4 , R 5Each independently selected from any one of H, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C3 alkoxy group, and R 1 、R 2 、R 3 、R 4 、R 5 may be the same or different.

[0010] Preferably, the halogen atom is Cl or F.

[0011] Preferably, the C1-C6 alkyl group is methyl, ethyl, propyl or isopropyl.

[0012] Preferably, the C1-C3 alkoxy group is methoxy or ethoxy.

[0013] Preferably, the chalcone derivative containing a urea structure is selected from any one of the following compounds:

[0014]

[0015] The present invention also provides a preparation method of the chalcone derivative containing a urea structure, comprising the following steps:

[0016] S1. In a solvent, in the presence of an organic base catalyst, 4-chloro-3-trifluoromethyl isocyanate undergoes a nucleophilic substitution reaction with 4-aminoacetophenone to obtain intermediate A;

[0017] The structural formula of the intermediate A is as follows:

[0018]

[0019] S2. In a solvent, in the presence of a catalyst, intermediate A undergoes a condensation reaction with the compound shown in formula II to obtain the chalcone derivative containing a urea structure;

[0020]

[0021] In formula II, R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from any one of H, a halogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C3 alkoxy group, and R 1 、R 2 、R 3 、R 4 、R 5 may be the same or different.

[0022] Preferably, in S1, the solvent is at least one of ethyl acetate, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, and toluene, and the organic base catalyst is at least one of triethylamine, pyridine, and N,N-diisopropylethylamine.

[0023] Preferably, in S2, the solvent is methanol and the catalyst is an inorganic base catalyst, or the solvent is ethanol and the catalyst is boric acid, thionyl chloride, or a combination thereof.

[0024] Preferably, the inorganic base catalyst is at least one of potassium hydroxide, sodium hydroxide, and lithium hydroxide.

[0025] Preferably, in S1, the molar ratio of 4-chloro-3-(trifluoromethyl)phenyl isocyanate to 4-aminoacetophenone is 1:0.9 to 1.2.

[0026] Preferably, in S2, the molar ratio of intermediate A to the compound represented by formula II is 1:1 to 1.1.

[0027] The present invention also provides an application of the chalcone derivative containing a urea structure in the preparation of a drug for treating and / or preventing cancer.

[0028] Preferably, the cancer is cervical cancer and / or leukemia.

[0029] The beneficial effects of the present invention are as follows:

[0030] The present invention designs and synthesizes a chalcone derivative containing a 4-chloro-3-(trifluoromethyl)phenylurea fragment with a novel structure by using the principle of splicing, which can effectively inhibit the proliferation of cancer cells and provides a new drug option for treating and / or preventing cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the 1H NMR spectrum of intermediate A.

[0032] Figure 2 It is the 1H NMR spectrum of compound BG-13.

[0033] Figure 3 It is the 13C NMR spectrum of compound BG-13.

[0034] Figure 4 It is the 1H NMR spectrum of compound BG-16.

[0035] Figure 5 It is the 13C NMR spectrum of compound BG-16. DETAILED DESCRIPTION OF THE INVENTION

[0036] Hereinafter, the technical solutions of the present invention will be described in detail through specific examples.

[0037] Synthesis of Intermediate A in Example 1

[0038] Add 4 - aminoacetophenone (1.35 g, 10.0 mmol), triethylamine (4 mL) and ethyl acetate (50 mL) into a 100 mL three - necked flask. Cool the mixture to 0 °C, and then add 4 - chloro - 3 - (fluoromethyl)phenyl isocyanate (2.2 g, 10.0 mmol) portionwise under stirring. After the addition is complete, continue stirring the reaction at 0 °C overnight. When TLC monitoring shows that 4 - aminoacetophenone has reacted completely, filter and dry to obtain 2.675 g of white solid, which is Intermediate A, with a yield of 75.4%. The 1H NMR spectrum of Intermediate A is as shown Figure 1 follows. The data are as follows: 1H NMR (600 MHz, DMSO - d6) δ 9.28 (d, J = 4.6 Hz, 2H), 8.11 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.64 (dt, J = 16.6, 5.6 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 2.52 (s, 3H).

[0039]

[0040] Synthesis of Compound BG - 1 in Example 2

[0041] Synthesis of Compound BG - 1:

[0042] Add benzaldehyde (25 mg, 0.24 mmol) and intermediate A (72 mg, 0.2 mmol) to a 50 mL single-necked flask, then add methanol (3 mL) and potassium hydroxide (0.033 g, 0.59 mmol), stir, and react at room temperature for 24 h. When TLC monitoring shows that intermediate A has reacted completely, add 2 mL of water, stir for 1 h, filter, wash with water, and dry under vacuum to obtain 65 mg of a yellow solid, which is compound BG-1, with a yield of 73.2%. The nuclear magnetic resonance data of compound BG-1 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.30 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 15.6 Hz, 1H), 7.88 (dd, J = 7.3, 1.9 Hz, 2H), 7.72 (d, J = 15.6 Hz, 1H), 7.69–7.61 (m, 4H), 7.49–7.42 (m, 3H). 13C NMR (151 MHz, DMSO-d6) 187.37, 152.14, 144.02, 143.31, 139.01, 134.83, 132.08, 131.39, 130.47, 130.10, 128.93, 128.82, 126.76 (q, J = 31.1 Hz), 123.38, 122.81 (q, J = 273.2 Hz), 122.75, 121.99, 117.71, 117.04 (q, J = 5.6 Hz).

[0043]

[0044] Example 3 Synthesis of Compound BG-2

[0045] The synthesis method of compound BG-2 is the same as that of compound BG-1, except that benzaldehyde is replaced by 4-methoxybenzaldehyde. 77 mg of yellow solid was obtained, which is compound BG-2, and the yield was 81.0%. The nuclear magnetic resonance data of compound BG-2 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.35 (s, 2H), 8.13 (d, J = 8.6 Hz, 3H), 7.84 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 15.5 Hz, 1H), 7.70 (s, 1H), 7.68–7.58 (m, 4H), 7.01 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H). 13C NMR (151 MHz, DMSO-d6) 187.24, 161.22, 152.14, 143.81, 143.14, 139.02, 132.03, 131.65, 130.64, 129.89, 127.46, 126.64 (q, J = 30.5 Hz), 123.33, 122.79 (q, J = 273.3 Hz), 122.69, 119.46, 117.66, 117.01 (q, J = 5.7 Hz), 114.38, 51.36.

[0046]

[0047] Example 4 Synthesis of Compound BG-3

[0048] The synthesis method of compound BG-3 is the same as that of compound BG-1, except that benzaldehyde is replaced by 4-fluorobenzaldehyde. 58 mg of off-white solid was obtained, which is compound BG-3, and the yield was 61.2%. The nuclear magnetic resonance data of compound BG-3 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.37 (s, 2H), 8.14 (d, J = 8.7 Hz, 2H), 8.12 (d, J = 2.2 Hz, 1H), 7.96 (dd, J = 8.4, 5.8 Hz, 2H), 7.91 (d, J = 15.6 Hz, 1H), 7.72 (d, J = 15.6 Hz, 1H), 7.69–7.60 (m, 4H), 7.30 (t, J = 8.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 187.27, 163.31 (d, J = 248.7 Hz), 152.14, 144.05, 141.92, 139.01, 133.03, 131.51 (J = 3.1 Hz), 131.35, 131.11 (d, J = 8.4 Hz), 130.06, 126.74 (q, J = 30.5 Hz), 123.35, 122.79 (q, J = 273.3 Hz) 122.72, 121.89, 117.67, 117.03 (q, J = 5.7 Hz), 115.90 (d, J = 21.6 Hz).

[0049]

[0050] Example 5 Synthesis of Compound BG-4

[0051] The synthesis method of compound BG-4 is the same as that of compound BG-1, except that benzaldehyde is replaced by 4-chlorobenzaldehyde. 77 mg of off-white solid was obtained, which is compound BG-4, and the yield was 80.5%. The nuclear magnetic resonance data of compound BG-4 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.38 (s, 2H), 8.15 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 15.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 15.8 Hz, 1H), 7.64 (dd, J = 20.2, 8.8 Hz, 4H), 7.52 (d, J = 8.4 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 187.22, 152.12, 144.12, 141.67, 139.00, 134.89, 133.81, 132.03, 131.25, 130.47, 130.10, 128.92, 126.74 (q, J = 30.5 Hz), 123.69, 123.34, 122.78 (J = 273.2 Hz), 122.74, 117.67, 117.02 (J = 5.7 Hz).

[0052]

[0053] Example 6 Synthesis of Compound BG-5

[0054] The synthesis method of compound BG-5 is the same as that of compound BG-1, except that benzaldehyde is replaced by 3,4,5-trimethoxybenzaldehyde. 82 mg of off-white solid was obtained, which is compound BG-5, and the yield was 76.6%. The nuclear magnetic resonance data of compound BG-5 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.34 (s, 2H), 8.16 (d, J = 8.3 Hz, 2H), 8.11 (s, 1H), 7.89 (d, J = 15.5 Hz, 1H), 7.72–7.60 (m, 5H), 7.22 (s, 2H), 3.87 (s, 6H), 3.72 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.31, 153.10, 152.13, 143.96, 143.69, 139.60, 139.00, 132.05, 131.50, 130.38, 130.03, 126.75 (q, J = 30.6 Hz), 123.36, 122.79 (q, J = 273.6 Hz), 122.73, 121.16, 117.65, 117.03 (q, J = 5.6 Hz), 106.44, 60.14, 56.13.

[0055]

[0056] Synthesis of Compound BG-6 in Example 7

[0057] The synthesis method of Compound BG-6 is the same as that of Compound BG-1, except that benzaldehyde is replaced by 4-methylbenzaldehyde. 64 mg of off-white solid was obtained, which is Compound BG-6, and the yield was 69.9%. The nuclear magnetic resonance data of Compound BG-6 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.36 (s, 2H), 8.13 (dd, J = 10.0, 5.6 Hz, 3H), 7.88 (d, J = 15.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.72–7.59 (m, 5H), 7.27 (d, J = 7.9 Hz, 2H), 2.35 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.32, 152.13, 143.94, 143.23, 140.45, 139.02, 132.10, 132.03, 131.48, 129.98, 129.52, 128.80, 126.74 (q, J = 30.4 Hz), 123.34, 122.79 (q, J = 273.5 Hz), 122.70, 120.91, 117.67, 117.02 (q, J = 5.6 Hz), 21.08.

[0058]

[0059] Synthesis of Compound BG-7 in Example 8

[0060] The synthesis method of compound BG-7 is the same as that of compound BG-1, except that benzaldehyde is replaced by 3,5-dimethoxybenzaldehyde. 74 mg of off-white solid was obtained, which is compound BG-7, and the yield was 73.3%. The nuclear magnetic resonance data of compound BG-7 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.37 (s, 2H), 8.16 (d, J = 8.5 Hz, 2H), 8.11 (s, 1H), 7.94 (d, J = 15.5 Hz, 1H), 7.72–7.58 (m, 4H), 7.06 (s, 2H), 6.58 (s, 1H), 3.81 (s, 6H). 13C NMR (151 MHz, DMSO-d6) δ 187.38, 160.72, 152.15, 144.10, 143.34, 139.02, 136.77, 132.06, 131.34, 130.15, 126.76 (q, J = 30.6 Hz), 123.37, 122.81 (q, J = 273.3 Hz), 122.73, 122.46, 117.67, 117.04 (q, J = 5.5 Hz), 106.66, 102.72, 55.47, 55.45.

[0061]

[0062] Example 9 Synthesis of compound BG-8:

[0063] The synthesis method of compound BG-8 is the same as that of compound BG-1, except that benzaldehyde is replaced by 4-ethylbenzaldehyde. 58 mg of off-white solid was obtained, which is compound BG-8, and the yield was 61.4%. The nuclear magnetic resonance data of compound BG-8 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.31 (s, 2H), 8.14 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.78 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 15.6 Hz, 1H), 7.68–7.60 (m, 4H), 7.29 (d, J = 8.0 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.36, 152.13, 146.71, 143.94, 143.28, 139.00, 132.38, 132.05, 131.51, 130.01, 128.92, 128.36, 126.77 (q, J = 30.6 Hz), 123.36, 122.81 (q, J = 273.3 Hz), 122.76, 120.99, 117.70, 117.04 (q, J = 5.5 Hz).

[0064]

[0065] Example 10 Synthesis of compound BG-9:

[0066] The synthesis method of compound BG-9 is the same as that of compound BG-1, except that benzaldehyde is replaced by 2,3,4-trimethoxybenzaldehyde. 55 mg of off-white solid was obtained, which is compound BG-9, and the yield was 51.4%. The nuclear magnetic resonance data of compound BG-9 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.31 (d, J = 5.3 Hz, 2H), 8.14–8.11 (m, 2H), 8.10 (s, 1H), 7.85 (dd, J = 45.4, 15.7 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.69–7.61 (m, 4H), 6.92 (d, J = 8.9 Hz, 1H), 3.87 (d, J = 4.0 Hz, 6H), 3.78 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.37, 155.62, 153.03, 152.13, 143.82, 141.78, 139.01, 137.63, 132.06, 131.67, 129.89, 126.75 (q, J = 30.5 Hz), 123.35, 122.80 (q, J = 273.3 Hz), 122.73, 121.15, 120.39, 117.70, 117.02 (q, J = 5.5 Hz), 108.47, 61.50, 60.47, 56.06

[0067]

[0068] Example 11 Synthesis of compound BG-10:

[0069] The synthesis method of compound BG-10 is the same as that of compound BG-1, except that benzaldehyde is replaced by 3,4-dimethylbenzaldehyde. 61 mg of off-white solid was obtained, which is compound BG-10, and the yield was 64.5%. The nuclear magnetic resonance data of compound BG-10 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.30 (s, 1H), 8.14 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 15.5 Hz, 1H), 7.68 - 7.63 (m, 6H), 7.57 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 2.27 (s, 3H), 2.26 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.30, 152.12, 143.90, 143.46, 139.36, 138.99, 136.86, 132.41, 132.05, 130.01, 129.98, 129.61, 129.59, 126.74 (q, J = 32.8 Hz), 123.36, 122.80 (q, J = 273.5 Hz), 122.73, 120.67, 117.67, 117.53, 117.03 (q, J = 5.5 Hz), 19.46, 19.29.

[0070]

[0071] Example 12 Synthesis of compound BG-11:

[0072] The synthesis method of compound BG-11 is the same as that of compound BG-1, except that benzaldehyde is replaced by 3-chlorobenzaldehyde. 49 mg of off-white solid was obtained, which is compound BG-11, and the yield was 51.1%. The nuclear magnetic resonance data of compound BG-11 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.31 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 2.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J = 15.6 Hz, 1H), 7.82–7.79 (m, 1H), 7.71–7.60 (m, 5H), 7.51–7.45 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 187.20, 152.10, 144.16, 141.45, 138.96, 137.11, 133.80, 132.05, 131.21, 130.66, 130.21, 129.96, 127.86, 127.81, 126.75 (q, J = 30.8 Hz), 123.53, 123.37, 122.80 (q, J = 273.2 Hz), 122.76, 117.67, 117.05 (q, J = 5.8 Hz).

[0073]

[0074] Example 13 Synthesis of compound BG-12:

[0075] The synthesis method of compound BG-12 is the same as that of compound BG-1, except that benzaldehyde is replaced by 3,5-difluorobenzaldehyde. 44 mg of off-white solid was obtained, which is compound BG-12, and the yield was 45.8%. The nuclear magnetic resonance data of compound BG-12 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.31 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 15.6 Hz, 1H), 7.71 (d, J = 6.8 Hz, 2H), 7.69–7.61 (m, 5H), 7.31 (t, J = 9.1 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 187.11, 162.65 (dd, J = 245.9, 13.3 Hz), 152.09, 144.28, 140.48, 138.95, 138.69 (t, J = 9.8 Hz), 132.05, 131.06, 130.27, 126.75 (d, J = 30.3 Hz), 124.71, 123.38, 122.79 (q, J = 273.5 Hz), 122.78, 117.67, 117.05 (d, J = 5.8 Hz), 111.68 (dd, J = 20.4, 5.2 Hz), 105.35 (t, J = 26.2 Hz).

[0076]

[0077] Example 14 Synthesis of compound BG-13:

[0078] Add 30 mL of absolute ethanol to a 100 mL single-necked flask, cool down to 0 °C, then control the temperature below 5 °C, dropwise add thionyl chloride (1.2 g, 10 mmol), then add 3-hydroxy-4-methoxybenzaldehyde (160 mg, 1.05 mmol) and intermediate A (356 mg, 1.0 mmol), react at 0–5 °C for 2 h, then naturally warm up to room temperature. After TLC monitoring shows that intermediate A has reacted completely, add 10 mL of water, stir for 1 h, then filter, wash with water, and dry under vacuum to obtain 327 mg of brown solid, which is compound BG-13, and the yield is 66.7%. The 1H NMR spectrum and 13C NMR spectrum of compound BG-13 are shown in Figure 2 、 Figure 3As shown below, the nuclear magnetic resonance data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.29 (s, 2H), 9.15 (s, 1H), 8.11 (d, J = 8.6 Hz, 3H), 7.71–7.58 (m, 6H), 7.32 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.84 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.24, 152.13, 150.17, 146.66, 143.75, 143.68, 139.01, 132.06, 131.72, 129.88, 127.77, 126.76 (q, J = 30.5 Hz), 123.35, 122.81 (q, J = 273.3 Hz), 122.75, 121.92, 119.33, 117.69, 117.03 (q, J = 5.8 Hz), 114.80, 119.91, 55.69.

[0079]

[0080] Synthesis of Compound BG-14 in Example 15:

[0081] The synthesis method of Compound BG-14 is the same as that of Compound BG-13, except that 3-hydroxy-4-methoxybenzaldehyde is replaced by 4-hydroxy-3-methoxybenzaldehyde. 342 mg of a brownish solid was obtained, which is Compound BG-14, and the yield was 69.8%. The nuclear magnetic resonance data of Compound BG-14 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.30 (s, 2H), 8.14 (d, J = 8.8 Hz, 2H), 8.12 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 15.4 Hz, 1H), 7.70–7.62 (m, 5H), 7.51 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.2, 1.8 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 3.88 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 187.22, 152.13, 149.54, 147.98, 144.10, 143.70, 139.01, 132.05, 131.80, 129.87, 126.75 (q, J = 30.8 Hz), 126.41, 123.99, 123.35, 122.80 (q, J = 273.2 Hz), 122.71, 118.56, 117.64, 117.02 (q, J = 5.9 Hz), 115.57, 111.57, 55.82.

[0082]

[0083] Synthesis of Compound BG-15 in Example 16:

[0084] The synthesis method of Compound BG-15 is the same as that of Compound BG-13, except that 3-hydroxy-4-methoxybenzaldehyde is replaced by 3,4-dihydroxybenzaldehyde. 257 mg of a brownish solid was obtained, which is Compound BG-15, and the yield was 53.9%. The nuclear magnetic resonance data of Compound BG-15 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.31 (s, 1H), 9.30 (s, 1H), 9.11 (s, 1H), 8.12 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.70–7.53 (m, 6H), 7.25 (d, J = 1.4 Hz, 1H), 7.20–7.15 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 187.21, 152.14, 148.16, 145.59, 144.12, 143.65, 139.02, 132.06, 131.84, 129.79, 126.76 (q, J = 30.7 Hz), 126.42, 123.34, 122.80 (q, J = 270.0 Hz), 122.71, 122.02, 118.31, 117.68, 117.01 (d, J = 5.6 Hz), 115.74, 115.48.

[0085]

[0086] Synthesis of Compound BG-16 in Example 17:

[0087] The synthesis method of Compound BG-16 is the same as that of Compound BG-13, except that 3-hydroxy-4-methoxybenzaldehyde is replaced by 3-hydroxy-3,5-dimethoxybenzaldehyde. 361 mg of a brownish solid was obtained, which is Compound BG-16, and the yield was 69.4%. The 1H NMR spectrum and 13C NMR spectrum of Compound BG-16 are shown in Figure 4 and Figure 5As shown below, the nuclear magnetic resonance data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.32 (s, 1H), 9.02 (s, 1H), 8.15 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 2.5 Hz, 1H), 7.80 (d, J = 15.4 Hz, 1H), 7.69–7.62 (m, 5H), 7.19 (s, 2H), 3.85 (s, 6H). 13C NMR (151 MHz, DMSO-d6) δ 187.21, 152.17, 148.08, 144.51, 143.76, 139.04, 138.58, 132.07, 131.79, 129.93, 126.77 (q, J = 30.5 Hz), 125.21, 123.37, 122.82 (q, J = 273.2 Hz), 122.72, 118.93, 117.65, 117.04 (q, J = 5.4 Hz), 106.84, 56.20.

[0088]

[0089] Synthesis of Compound BG-17 in Example 18:

[0090] The synthesis method of Compound BG-17 is the same as that of Compound BG-13, except that 3-hydroxy-4-methoxybenzaldehyde is replaced with 4-hydroxybenzaldehyde. 213 mg of a brownish solid was obtained, which is Compound BG-17, and the yield was 46.3%. The nuclear magnetic resonance data of Compound BG-17 are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.31 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 15.6 Hz, 1H), 7.71 (d, J = 6.8 Hz, 2H), 7.69–7.61 (m, 5H), 7.31 (t, J = 9.1 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 187.11, 162.65 (dd, J = 245.9, 13.3 Hz), 152.09, 144.28, 140.48, 138.95, 138.69 (t, J = 9.8 Hz), 132.05, 131.06, 130.27, 126.75 (d, J = 30.3 Hz), 124.71, 123.38, 122.79 (q, J = 273.5 Hz), 122.78, 117.67, 117.05 (d, J = 5.8 Hz), 111.68 (dd, J = 20.4, 5.2 Hz), 105.35 (t, J = 26.2 Hz).

[0091]

[0092] Experimental Example: Determination of the cytotoxicity of compounds BG-1 to BG-17 against cervical cancer cells Siha and chronic myeloid leukemia cells K562 by CCK8 method

[0093] Siha cells were cultured in a dedicated medium (CM-0210, Procell), and K562 cells were cultured in a dedicated cell medium (CM-0130, Procell) at 37°C in a cell incubator containing 5% CO 2 and air. Logarithmic growth phase Siha cells and K562 cells were taken respectively, and about 2×10 3 cells were added to each well of a 96-well plate and incubated in the incubator for 12 h. Then, different concentrations of compounds BG-1 to BG-17 were added and incubated for another 48 h. Then, 10 μL of CCK8 solution (10 mg / mL, Adamas life) was added and incubated for 2 h. The absorbance of each well was measured at 450 nm using a microplate reader, and the IC 50 value was calculated using Prism 8.0 software.

[0094] Table 2 Inhibitory activities of compounds BG-1 to BG-17 against Siha cells and K562 cells in vitro

[0095]

[0096]

[0097] As can be seen from Table 1, compounds BG-1 to BG-17 have strong inhibitory effects on cervical cancer cells Siha and chronic myeloid leukemia cells K562, and the IC 50 values are in the range of 0.91 - 12.65 μM. Compounds BG-3, BG-5, BG-6, BG-8, BG-10, BG-11, BG-12, BG-13, BG-15 and BG-16 have significantly better inhibitory effects on K562 than the control sorafenib. The inhibitory effects of compounds BG-1 to BG-17 on Siha are stronger than those of the control sorafenib, among which the inhibitory effects of BG-3, BG-5, BG-12 and BG-13 are more prominent, and the IC 50 values are lower than 2.0 μM. In particular, compounds BG-3, BG-5, BG-12, BG-13 and BG-16 have significantly stronger inhibitory effects on K562 and Siha cells than the positive control sorafenib.

[0098] The above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.

Claims

1. A chalcone derivative containing a urea structure, characterized in that: The structural formula of the chalcone derivative containing a urea structure is shown in Formula I: In formula I, R1, R2, R3, R4, and R5 are each independently selected from any one of H, a halogen atom, a hydroxyl group, a C1-6 alkyl group, and a C1-3 alkoxy group, and R1, R2, R3, R4, and R5 may be the same or different.

2. The chalcone derivative containing a urea structure according to claim 1, characterized in that: The halogen atom is Cl or F; The C1-6 alkyl group is methyl, ethyl, propyl or isopropyl; The C1-3 alkoxy group is a methoxy group or an ethoxy group.

3. The chalcone derivative containing a urea structure according to claim 1, characterized in that: The chalcone derivative containing a urea structure is selected from any one of the following compounds:

4. A method for preparing a chalcone derivative containing a urea structure as claimed in any one of claims 1 to 3, characterized in that: The steps include: S1. In a solvent, in the presence of an organic base catalyst, 4-chloro-3-trifluoromethyl isocyanate and 4-aminoacetophenone undergo a nucleophilic substitution reaction to obtain an intermediate A; The structural formula of the intermediate A is as follows: S2. In a solvent, in the presence of a catalyst, the intermediate A undergoes a condensation reaction with the compound represented by formula II to obtain the urea-containing chalcone derivative; In formula II, R1, R2, R3, R4, and R5 are each independently selected from any one of H, a halogen atom, a hydroxyl group, a C1-6 alkyl group, and a C1-3 alkoxy group, and R1, R2, R3, R4, and R5 may be the same or different.

5. The method for preparing a chalcone derivative containing a urea structure according to claim 4, characterized in that: In S1, the solvent is at least one of ethyl acetate, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, and toluene, and the organic base catalyst is at least one of triethylamine, pyridine, and N,N-diisopropylethylamine; In S2, the solvent is methanol, and the catalyst is an inorganic base catalyst, or the solvent is ethanol, and the catalyst is boric acid, thionyl chloride or a combination thereof.

6. The method for preparing a chalcone derivative containing a urea structure according to claim 4, characterized in that: In S1, the molar ratio of 4-chloro-3-trifluoromethyl isocyanate to 4-aminoacetophenone is 1:0.9-1.

2.

7. The method for preparing a chalcone derivative containing a urea structure according to claim 4, characterized in that: In S2, the molar ratio of the intermediate A to the compound represented by formula II is 1:1 to 1.

1.

8. Use of the urea-containing chalcone derivative according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing cancer.

9. The use according to claim 8, characterized in that: The cancer is cervical cancer and / or leukemia.

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