Biphenyl aryl amide compound and application thereof in preparation of medicine for treating leukemia

Abstract

The invention relates to the technical field of biological medicines, in particular to a biphenyl aromatic amide compound and application thereof in preparation of a medicine for treating leukemia. The biphenyl aryl amide compound has the activity of efficiently inhibiting leukemia cell proliferation, and provides a safe and efficient candidate drug molecule for treating leukemia; the preparation process of the biphenyl aromatic amide compound is simple and easy to implement, and the reaction conditions are mild; the biphenyl aryl amide compound has excellent performance of inhibiting mouse tumor growth, can be used for anti-leukemia drugs, and has a good development prospect.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to biphenyl aromatic amide compounds and their use in the preparation of drugs for treating leukemia. Background Art

[0002] Leukemia is a malignant clonal disease of the hematopoietic system, characterized by the abnormal proliferation of leukemia cells and the inhibition of normal hematopoietic function. At the same time, it infiltrates organs and tissues such as the liver, spleen, and lymph nodes, causing clinical manifestations such as anemia, bleeding, infection, and bone pain, and has become a major global health burden. Acute myeloid leukemia (AML) is a specific subtype of leukemia, which originates from the malignant clonal proliferation of myeloid progenitor cells in the bone marrow.

[0003] The current means for treating leukemia have significant limitations: chemotherapy, as a basic treatment, can kill tumor cells, but lacks specific recognition ability. While causing serious side effects such as hair loss and bone marrow suppression, it is prone to induce drug resistance and increase the risk of recurrence; radiotherapy destroys the DNA of leukemia cells through high-energy rays, but due to the large damage to normal tissues, it causes complications such as radiation pneumonia, and its clinical application is limited; although hematopoietic stem cell transplantation can reconstruct the immune system for radical cure, it is difficult to popularize due to the scarcity of donors, difficult matching, and high costs; targeted therapy improves the curative effect by precisely intervening in molecular targets, but the types of drugs are limited and still face the problem of drug resistance. Summary of the Invention

[0004] In order to improve the treatment effect of leukemia, the present invention provides biphenyl aromatic amide compounds and their use in the preparation of drugs for treating leukemia.

[0005] In the first aspect of the present invention, a biphenyl aromatic amide compound or a pharmaceutically acceptable salt thereof is provided, and the above biphenyl aromatic amide compound has the structure shown in Formula 5-1, Formula 5-2, or Formula 5-3: , , ; wherein, R 1 is selected from alkoxy groups with 1 to 4 carbon atoms, halogen atoms, trifluoromethyl; R 2 is selected from any one of the following groups: , , , ; R 3 is selected from a hydrogen atom, halogen atoms, cyano; X is C or N.

[0006] The above-mentioned biphenyl aromatic amide compound or its pharmaceutically acceptable salt has the property of highly inhibiting the proliferation of leukemia cells and can be used for the treatment of leukemia, especially for the treatment of acute myeloid leukemia. The pharmaceutically acceptable salt of the above-mentioned biphenyl aromatic amide compound can be easily prepared from the above-mentioned biphenyl aromatic amide compound as a raw material. For example, the hydrochloride salt of the above-mentioned biphenyl aromatic amide compound can be prepared by reacting the above-mentioned biphenyl aromatic amide compound with hydrochloric acid.

[0007] In some alternative embodiments, the above-mentioned R 1 is selected from methoxy, ethoxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl; the above-mentioned R 2 is N-methylpiperazinyl; the above-mentioned R 3 is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group.

[0008] In some alternative embodiments, the above-mentioned biphenyl aromatic amide compound has one of the structures shown in Formula 5a - Formula 5o: , , , , , , , , , , , , , , .

[0009] The second aspect of the present invention provides a preparation method of the above-mentioned biphenyl aromatic amide compound, which includes the following steps: Under the participation of a palladium catalyst, the compound shown in Formula 1-1, Formula 1-2 or Formula 1-3 reacts with the compound shown in Formula 2 to undergo a Suzuki coupling reaction to obtain the compound shown in Formula 3-1, Formula 3-2 or Formula 3-3; The compound shown in Formula 3-1, Formula 3-2 or Formula 3-3 reacts with the compound shown in Formula 4 to undergo an amidation reaction to obtain the above-mentioned biphenyl aromatic amide compound; , , , , , , , ; Among them, R 1 , R 2 , R 3 and X are defined the same as above.

[0010] In some alternative embodiments, the palladium catalyst described above is bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, or 1,1'-bis(diphenylphosphino)ferrocene dichloride. Preferably, the palladium catalyst described above is bis(triphenylphosphine)palladium dichloride.

[0011] In some alternative embodiments, the above Suzuki coupling reaction is carried out in the presence of sodium carbonate.

[0012] In some alternative embodiments, the above Suzuki coupling reaction is carried out under the condition of 80 - 98 °C.

[0013] In some alternative embodiments, the above Suzuki coupling reaction is carried out in a mixed solvent of tetrahydrofuran and water.

[0014] In some alternative embodiments, the above amidation reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine, and 4-dimethylaminopyridine.

[0015] In some alternative embodiments, the above amidation reaction is carried out under the condition of 20 - 30 °C.

[0016] In some alternative embodiments, the above amidation reaction is carried out in dichloromethane solvent.

[0017] The third aspect of the present invention provides the use of the above biphenyl aromatic amide compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing leukemia.

[0018] In some alternative embodiments, the above leukemia is acute myeloid leukemia. Among them, the cell line of acute myeloid leukemia can be Kasumi-1 or Skno-1.

[0019] The fourth aspect of the present invention provides a drug for treating and / or preventing leukemia, which comprises the above biphenyl aromatic amide compound or a pharmaceutically acceptable salt thereof. The above biphenyl aromatic amide compound or a pharmaceutically acceptable salt thereof is the main active ingredient (main drug) in the above drug for treating and / or preventing leukemia.

[0020] In some alternative embodiments, the above drug for treating and / or preventing leukemia further comprises an excipient. The dosage form of the above drug for treating and / or preventing leukemia is any pharmaceutically acceptable dosage form. The above excipient has stable properties, no incompatibility with the main drug, no side effects, does not affect the efficacy, is not easily deformed, cracked, or mildewed at room temperature, and is harmless to the human body.

[0021] In some alternative embodiments, the above excipient is at least one of gum arabic, syrup, lanolin, and starch.

[0022] The technical solution of the embodiment of the present invention has the following beneficial effects: A novel biphenyl arylamide compound is obtained. This biphenyl arylamide compound has the activity of efficiently inhibiting the proliferation of leukemia cells, providing a safe and efficient candidate drug molecule for the treatment of leukemia; the preparation process of this biphenyl arylamide compound is simple and easy to perform, and the reaction conditions are mild; this biphenyl arylamide compound has excellent performance in inhibiting the growth of tumors in mice and can be used as an anti-leukemia drug, showing good development prospects. Description of the Drawings

[0023] Figure 1 It is the survival curve of the mice in Example 17 of the present invention. Detailed Embodiments

[0024] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0025] Example 1: Synthesis of the biphenyl arylamide compound shown in Formula 5a Under nitrogen protection, 2-iodo-5-methoxybenzoic acid (1.0 mmol, 1.0 eq) was dissolved in a mixed solvent of 10.0 ml of tetrahydrofuran and water (volume ratio 1:1). 3-(4-methylpiperazin-1-yl)phenylboronic acid (1.0 mmol, 1.0 eq), bis(triphenylphosphine)palladium dichloride (0.1 mmol, 0.1 eq), and sodium carbonate (2.0 mmol, 2.0 eq) were added in sequence. Subsequently, the system was placed in an oil bath at 90 °C for reaction. After the reaction was completed, water was added to the system to quench the reaction, and extraction was performed with ethyl acetate (10.0 ml * 3). The solid was collected by filtration, dissolved in water, and the pH was adjusted to 4 with 1N hydrochloric acid solution. Then extraction was performed with ethyl acetate (10.0 ml * 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was directly used for the next reaction.

[0026] Under nitrogen protection at 0 °C, the above-mentioned crude product (1.0 mmol, 1.0 eq) and aniline (1.0 mmol, 1.0 eq) were dissolved in 10.0 ml of dichloromethane. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 mmol, 1.1 eq), triethylamine (3.0 mmol, 3.0 eq) and 4-dimethylaminopyridine (0.1 mmol, 0.1 eq) were added successively, and the reaction was carried out at room temperature. After the reaction was completed, saturated ammonium chloride was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (10.0 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by column chromatography to obtain the biphenyl aromatic amide compound shown in Formula 5a (yield: 82%).

[0027]

[0028] The characterization results of the biphenyl aromatic amide compound shown in Formula 5a are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.74– 7.65 (m, 4H), 7.52 (s, 1H), 7.36 – 7.28 (m, 2H), 7.19 (t, J J = 7.5 Hz, 1H),7.16 (dd, J J = 7.5, 2.0 Hz, 1H), 7.07 (tt, J J = 7.5, 2.0 Hz, 1H), 6.99 (dt, J J =7.5, 1.9 Hz, 1H), 6.93 (dt, J J = 7.5, 2.0 Hz, 1H), 6.89 (t, J J = 2.0 Hz, 1H),3.83 (s, 3H), 3.20 (t, J J = 5.2 Hz, 4H), 2.98 (t, J J = 5.2 Hz, 4H), 2.60 (s,3H). 13 C NMR (100 MHz, CDCl3) δ 167.51, 159.09, 152.22, 138.13, 137.93,133.84, 132.63, 129.95, 128.55, 128.48, 123.53, 122.90, 120.63, 117.50,117.08, 116.60, 115.66, 55.80, 53.99, 48.63, 44.73. Example 2: Synthesis of the biphenyl aromatic amide compound shown in Formula 5b This example is basically the same as Example 1, except that the corresponding raw material compound is changed (aniline is replaced by 3,4-difluoroaniline), and the biphenyl aromatic amide compound shown in Formula 5b is obtained (yield: 80%).

[0029]

[0030] The characterization results of the biphenyl aromatic amide compound shown in Formula 5b are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.75(ddd, J = 7.6, 5.8, 2.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.54 (s, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 7.5, 2.0 Hz,1H), 7.08 – 7.00 (m, 2H), 6.95 (dt, J = 7.5, 2.0 Hz, 1H), 6.87 (t, J = 2.0Hz, 1H), 6.43 (ddd, J = 8.8, 5.7, 2.0 Hz, 1H), 3.83 (s, 3H), 3.20 (t, J = 5.2Hz, 4H), 2.98 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ167.51, 159.09, 152.22, 150.86, 150.70, 148.85, 148.69, 145.79, 145.63,143.77, 143.61, 137.93, 136.80, 136.78, 136.74, 136.71, 133.84, 132.63,129.95, 128.55, 122.90, 119.13, 119.11, 119.07, 119.05, 117.51, 117.45,117.35, 117.29, 117.08, 116.60, 115.66, 109.50, 109.44, 109.34, 109.28,55.80, 53.99, 48.63, 44.73. Example 3: Synthesis of the biphenyl aromatic amide compound shown in Formula 5c This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced with 5-chloro-3-fluoroaniline) to obtain the biphenyl aromatic amide compound shown in Formula 5c (yield: 83%).

[0031]

[0032] The characterization results of the biphenyl aromatic amide compound shown in Formula 5c are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.04(t, J J = 2.0 Hz, 1H), 7.72 (d, J J = 7.4 Hz, 1H), 7.69 (d, J J = 2.1 Hz, 1H), 7.59(s, 1H), 7.30 (t, J J = 7.5 Hz, 1H), 7.16 (dd, J J = 7.5, 2.0 Hz, 1H), 7.07 (ddt, J J = 15.0, 8.8, 1.9 Hz, 2H), 6.94 (dt, J J = 7.5, 2.0 Hz, 1H), 6.79 (t, J J = 2.0Hz, 1H), 6.54 (dt, J J = 8.8, 2.0 Hz, 1H), 3.83 (s, 3H), 3.20 (t, J= 5.2 Hz, 4H), 2.98 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.51, 163.85 (d, J = 251.8 Hz), 159.09, 152.22, 139.89 (d, J = 8.6 Hz), 137.93, 134.79 (d, J = 7.6 Hz), 133.84, 132.63, 129.95, 128.55, 122.90, 117.57 (d, J = 2.8 Hz), 117.50, 117.08, 116.60, 115.66, 105.19 (d, J = 20.0 Hz), 104.29 (d, J = 20.0 Hz), 55.80, 53.99, 48.63, 44.73. Example 4: Synthesis of the biphenyl aromatic amide compound shown in Formula 5d This example is basically the same as Example 1, only changing the corresponding starting compounds (replacing aniline with 3-fluoroaniline), to obtain the biphenyl aromatic amide compound shown in Formula 5d (yield: 86%).

[0033]

[0034] The characterization results of the biphenyl aromatic amide compound shown in Formula 5d are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.76–7.67 (m, 3H), 7.59–7.53 (m, 2H), 7.40 (td, J = 7.5, 5.7 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 7.5, 2.0 Hz, 1H), 7.09 (dt, J = 7.5, 2.0 Hz, 1H), 6.95 (dddd, J = 9.3, 7.6, 4.1, 2.0 Hz, 2H), 6.80 (t, J = 2.0 Hz, 1H), 3.83 (s, 3H), 3.20 (t,J = 5.2 Hz, 4H), 2.98 (t, J = 5.2 Hz, 4H), 2.60 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.51, 162.73 (d, J = 252.8 Hz), 159.09, 152.22, 139.25 (d, J = 8.6 Hz), 137.93, 133.84, 132.63, 130.35 (d, J = 7.6 Hz), 129.95, 128.55, 122.90, 119.05 (d, J = 3.8 Hz), 117.50, 117.08, 116.60, 115.66, 111.00 (d, J = 20.0 Hz), 110.07 (d, J = 20.0 Hz), 55.80, 53.99, 48.63, 44.73. Example 5: Synthesis of the biphenyl aromatic amide compound shown in Formula 5e This example is basically the same as Example 1, only changing the corresponding starting compound (replacing aniline with 3-chloroaniline), to obtain the biphenyl aromatic amide compound shown in Formula 5e (yield: 85%).

[0035]

[0036] The characterization results of the biphenyl aromatic amide compound shown in Formula 5e are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.99 (t, J = 2.0 Hz, 1H), 7.74 (dt, J = 7.5, 2.0 Hz, 1H), 7.71 (dd, J = 4.8, 2.8 Hz, 2H), 7.53 (s, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 – 7.14 (m, 2H), 7.09 (dt, J = 7.5, 2.0 Hz, 1H), 6.95 (dt, J= 7.5, 1.9 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 3.83 (s, 3H), 3.20 (t, J = 5.2 Hz, 4H), 2.98 (t, J = 5.1 Hz, 4H), 2.60 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.51, 159.09, 152.22, 139.43, 137.93, 134.01, 133.84, 132.63, 130.55, 129.95, 128.55, 123.57, 122.90, 120.56, 119.20, 117.50, 117.08, 116.60, 115.66, 55.80, 53.99, 48.63, 44.73. Example 6: Synthesis of the biphenyl aromatic amide compound shown in Formula 5f This example is basically the same as Example 1, only changing the corresponding starting compound (replacing aniline with 3-bromoaniline), to obtain the biphenyl aromatic amide compound shown in Formula 5f (yield: 84%).

[0037]

[0038] The characterization results of the biphenyl aromatic amide compound shown in Formula 5f are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.01 (t, J = 2.2 Hz, 1H), 7.69 (ddd, J = 7.9, 2.3, 1.4 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.31 – 7.24 (m, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.17 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.05 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (t, J = 1.9 Hz, 1H), 6.86 (ddd, J= 7.3, 1.9, 1.2 Hz, 1H), 3.81 (s, 3H), 3.28 – 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.4, 3.9 Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.03, 159.59, 151.53, 139.90, 139.58, 131.93, 130.93, 129.79, 129.68, 129.51, 126.40, 124.36, 123.36, 122.70, 120.43, 118.00, 115.99, 114.65, 114.39, 55.80, 54.13, 48.67, 45.29. Example 7: Synthesis of the biphenyl aromatic amide compound shown in Formula 5g This example is basically the same as Example 1, only changing the corresponding starting compounds (replacing aniline with 2-aminopyridine), to obtain the biphenyl aromatic amide compound shown in Formula 5g (yield: 84%).

[0039]

[0040] The characterization results of the biphenyl aromatic amide compound shown in Formula 5g are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.55 (s, 3H), 8.50 (dd, J = 4.3, 1.7 Hz, 1H), 8.25 (dd, J = 7.6, 1.3 Hz, 1H), 7.85– 7.78 (m, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 15.1 Hz, 1H), 7.17 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.12 (ddd, J = 6.9, 4.2, 1.3 Hz, 1H), 7.05 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (t,J = 1.9 Hz, 1H), 6.86 (ddd, J = 7.3, 1.9, 1.2 Hz, 1H), 3.81 (s, 3H), 3.28 – 3.17 (m, 4H), 2.80(ddd, J = 12.3, 5.4, 3.9 Hz, 2H), 2.57 (ddd, J = 12.4, 5.5, 3.9 Hz, 2H), 2.29(s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.40, 159.62, 153.42, 151.53, 148.85, 139.58, 138.52, 131.22, 129.82, 129.73, 129.51, 124.36, 119.44, 118.02, 116.07, 114.94, 114.61, 114.39, 55.80, 54.13, 48.67, 45.29. Example 8: Synthesis of the biphenyl aromatic amide compound shown in Formula 5h This example is basically the same as Example 1, only changing the corresponding starting compounds (replacing aniline with 3-aminobenzonitrile), to obtain the biphenyl aromatic amide compound shown in Formula 5h (yield: 84%).

[0041]

[0042] The characterization results of the biphenyl aromatic amide compound shown in Formula 5h are as follows: 1 H NMR (400 MHz, CDCl3) δ. 8.07– 8.03 (m, 1H), 7.88 – 7.81 (m, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.47 – 7.40 (m, 3H), 7.27 (d, J = 15.1 Hz, 1H), 7.17 (ddd, J = 7.9, 1.9, 1.2Hz, 1H), 7.05 (dd, J = 8.6, 2.7 Hz, 1H), 6.98 (t, J = 1.9 Hz, 1H), 6.86 (ddd, J= 7.3, 1.9, 1.2 Hz, 1H), 3.81 (s, 3H), 3.28 – 3.17 (m, 4H), 2.80 (ddd, J =12.3, 5.4, 3.9 Hz, 2H), 2.57 (ddd, J = 12.5, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.03, 159.59, 151.53, 139.58, 139.31, 131.93, 129.84, 129.79, 129.68, 129.51, 126.62, 124.36, 123.72, 122.94, 118.32, 118.00, 115.98, 114.65, 114.39, 112.24, 55.80, 54.13, 48.67, 45.29. Example 9: Synthesis of the biphenyl aromatic amide compound shown in Formula 5i This example is basically the same as Example 8, only changing the corresponding starting compounds (replacing 2-iodo-5-methoxybenzoic acid with 5-bromo-2-iodobenzoic acid), to obtain the biphenyl aromatic amide compound shown in Formula 5i (yield: 83%).

[0043]

[0044] The characterization results of the biphenyl aromatic amide compound shown in Formula 5i are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13(d, J = 2.4 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.88 – 7.81 (m, 1H), 7.80 – 7.66 (m, 3H), 7.47 – 7.40 (m, 2H), 7.27 (dd, J = 7.9, 7.3 Hz, 1H), 7.21 – 7.15 (m, 1H), 7.00 (t, J = 2.0 Hz, 1H), 6.86 (ddd, J = 7.3, 1.9, 1.2 Hz, 1H), 3.28 – 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.4, 3.9 Hz, 2H), 2.57 (ddd,J = 12.5, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 166.78, 151.56, 139.18, 139.08, 134.93, 134.20, 133.38, 133.06, 130.44, 129.84, 129.51, 126.62, 124.35, 123.71, 122.99, 121.75, 118.32, 114.64, 114.39, 112.24, 54.13, 48.67, 45.29. Example 10: Synthesis of the biphenyl aromatic amide compound shown in Formula 5j This example is basically the same as Example 9, only changing the corresponding starting compound (replacing 3-(4-methylpiperazin-1-yl)phenylboronic acid with 3-(1,4-oxazepan-4-yl)phenylboronic acid), to obtain the biphenyl aromatic amide compound shown in Formula 5j (yield: 80%).

[0045]

[0046] The characterization results of the biphenyl aromatic amide compound shown in Formula 5j are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.5 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.87 – 7.81 (m, 1H), 7.80 – 7.72 (m, 2H), 7.69 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.27 (dd, J = 7.9, 7.2 Hz, 1H), 7.21 – 7.15 (m, 1H), 6.98 (t, J = 1.9 Hz, 1H), 6.87 (ddd, J = 7.3, 1.9, 1.2 Hz, 1H), 3.80 (ddd, J = 9.5, 6.2, 3.5 Hz, 4H), 3.35 (td, J = 6.4, 3.4 Hz, 4H). 1313C NMR (100 MHz, CDCl3) δ 166.78, 150.70, 139.18, 139.09, 134.93, 134.20, 133.38, 133.06, 130.44, 129.84, 129.51, 126.62, 124.35, 123.71, 122.99, 121.75, 118.32, 115.61, 114.65, 112.24, 66.66, 48.19. Example 11: Synthesis of the biphenyl aromatic amide compound shown in Formula 5k This example is basically the same as Example 9, only changing the corresponding starting compound (replacing 3-(4-methylpiperazin-1-yl)phenylboronic acid with 3-(piperidin-1-yl)phenylboronic acid), to obtain the biphenyl aromatic amide compound shown in Formula 5k (yield: 80%).

[0047]

[0048] The characterization results of the biphenyl aromatic amide compound shown in Formula 5k are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J J = 2.5 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.87 – 7.81 (m, 1H), 7.80 – 7.72 (m, 2H), 7.69 (dd, J J = 8.6, 2.4 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.31 – 7.24 (m, 1H), 7.21 – 7.15 (m, 1H), 7.00 (t, J J = 1.9 Hz, 1H), 6.88 – 6.83 (m, 1H), 3.39 (ddd, J J = 5.9, 3.3, 2.5 Hz, 4H), 1.73 – 1.64 (m, 4H), 1.66 – 1.57 (m, 2H). 13CNMR (100 MHz, CDCl3) δ 166.78, 150.75, 139.18, 139.04, 134.93, 134.20, 133.38, 133.06, 130.44, 129.84, 129.52, 126.62, 124.35, 123.71, 122.99, 121.75, 118.32, 115.31, 114.64, 112.24, 49.75, 25.55, 24.41. Example 12: Synthesis of the biphenyl aromatic amide compound shown in Formula 5l This example is basically the same as Example 9, only changing the corresponding starting compound (replacing 3-(4-methylpiperazin-1-yl)phenylboronic acid with 3-(pyrrolidin-1-yl)phenylboronic acid), to obtain the biphenyl aromatic amide compound shown in Formula 5l (yield: 86%).

[0049]

[0050] The characterization results of the biphenyl aromatic amide compound shown in Formula 5l are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13(d, J J = 2.5 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.88 – 7.81 (m, 1H), 7.80 – 7.66(m, 3H), 7.47 – 7.40 (m, 2H), 7.27 (t, J J = 7.6 Hz, 1H), 7.21 – 7.15 (m, 1H),7.00 (t, J J = 1.9 Hz, 1H), 6.88 – 6.83 (m, 1H), 3.55 – 3.45 (m, 4H), 2.16 –2.03 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 166.78, 150.74, 139.18, 138.89, 134.93, 134.20, 133.38, 133.06, 130.44, 129.84, 129.59, 126.62, 124.25, 123.71, 122.99, 121.75, 118.32, 115.10, 114.14, 112.24, 47.97, 25.42. Example 13: Synthesis of the biphenyl aromatic amide compound shown in Formula 5m This example is basically the same as Example 8, except that the corresponding raw material compound is changed (2-iodo-5-methoxybenzoic acid is replaced with 6-iodoquinoline-7-carboxylic acid, and 6-iodoquinoline-7-carboxylic acid is purchased from Beijing Nanling Biotechnology Co., Ltd. with the product number NL0308), and the biphenyl arylamide compound shown in Formula 5m is obtained (yield: 83%).

[0051]

[0052] The characterization results of the biphenyl arylamide compound shown in Formula 5m are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.95(dd, J = 4.1, 1.9 Hz, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.32 – 8.25 (m, 2H),8.07 – 8.03 (m, 1H), 7.87 – 7.81 (m, 1H), 7.55 (dd, J = 8.3, 4.3 Hz, 1H),7.47 – 7.41 (m, 2H), 7.31 – 7.24 (m, 1H), 7.24 – 7.18 (m, 1H), 7.06 (t, J =1.9 Hz, 1H), 6.89 – 6.84 (m, 1H), 3.28 – 3.17 (m, 4H), 2.80 (ddd, J = 12.3,5.4, 3.9 Hz, 2H), 2.57 (ddd, J = 12.5, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR(100 MHz, CDCl3) δ 167.57, 151.51, 149.85, 149.16, 139.28, 138.97, 134.63,134.36, 129.92, 129.84, 129.51, 129.18, 126.65, 126.62, 124.31, 123.72,122.95, 122.23, 118.32, 114.81, 114.36, 112.24, 54.13, 48.67, 45.29. Example 14: Synthesis of the biphenyl arylamide compound shown in Formula 5n This example is basically the same as Example 8, except that the corresponding raw material compound is changed (2-iodo-5-methoxybenzoic acid is replaced with 5-iodo-1-benzofuran-6-carboxylic acid, and 5-iodo-1-benzofuran-6-carboxylic acid is purchased from Beijing Nanling Biotechnology Co., Ltd. with the product number NL0326), and the biphenyl aromatic amide compound shown in Formula 5n is obtained (yield: 81%).

[0053]

[0054] The characterization results of the biphenyl aromatic amide compound shown in Formula 5n are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.35– 8.29 (m, 2H), 8.07 – 8.02 (m, 2H), 7.85 (ddd, J = 4.4, 3.3, 2.2 Hz, 1H),7.71 (d, J = 1.6 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.35 (t, J = 1.8 Hz, 1H), 7.31– 7.24 (m, 1H), 7.20 (ddd, J = 7.9, 1.9, 1.2 Hz, 1H), 7.02 (t, J = 1.9 Hz,1H), 6.89 – 6.84 (m, 1H), 3.28 – 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.4, 3.9Hz, 2H), 2.57 (ddd, J = 12.5, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 167.14, 157.05, 151.51, 146.28, 139.31, 138.54, 133.31, 131.75,129.84, 129.51, 128.78, 126.62, 124.28, 123.72, 122.94, 119.28, 118.32,114.80, 114.36, 112.24, 111.57, 107.01, 54.13, 48.67, 45.29. Example 15: Synthesis of the biphenyl aromatic amide compound shown in Formula 5o This example is basically the same as Example 8, only changing the corresponding starting compound (replacing 2-iodo-5-methoxybenzoic acid with 2-iodo-5-(trifluoromethyl)benzoic acid), to obtain the biphenyl aromatic amide compound shown in Formula 5o (yield: 83%).

[0055]

[0056] The characterization results of the biphenyl aromatic amide compound shown in Formula 5o are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13(d, J = 2.2 Hz, 1H), 8.07 – 8.03 (m, 1H), 8.01 (d, J = 11.2 Hz, 1H), 7.95 –7.81 (m, 3H), 7.47 – 7.41 (m, 2H), 7.27 (dd, J = 7.9, 7.2 Hz, 1H), 7.19 (ddd, J = 7.7, 1.8, 1.1 Hz, 1H), 7.04 (t, J = 1.9 Hz, 1H), 6.89 – 6.84 (m, 1H),3.28 – 3.17 (m, 4H), 2.80 (ddd, J = 12.3, 5.4, 3.9 Hz, 2H), 2.57 (ddd, J =12.5, 5.5, 3.9 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.14,151.56, 139.18, 138.96, 135.19, 130.85, 130.80, 130.79, 130.60, 129.84,129.51, 129.24, 129.23, 129.21, 129.20, 129.07, 129.04, 129.01, 128.97,127.93, 127.90, 127.87, 127.84, 126.62, 125.08, 124.35, 123.71, 122.99,122.93, 118.32, 114.62, 114.39, 112.24, 54.13, 48.67, 45.29. Example 16: Experiment on the inhibition of the proliferation of acute myeloid leukemia cells by biphenyl aromatic amide compounds The acute myeloid leukemia cell lines (Kasumi-1 and Skno-1) were co-incubated with solutions of the biphenyl arylamide compounds shown in Formulas 4a - 4o at different concentrations for 72 hours, and the cell viability was detected using the Cell Counting Kit-8 (CCK-8) kit. Specifically, first, the cells were seeded into duplicate wells of a 96-well plate, with a volume of 90 µL per well; subsequently, 10 µL of the compound solutions of different concentrations shown in Formulas 4a - 4o were added to each well; after 72 hours of treatment, 10 µL of CCK-8 reagent was added to each well, and incubation was continued at 37 °C for 2 hours to promote the reaction; then, the absorbance was measured at a wavelength of 450 nm using a Thermo Fisher Multiskan FC microplate reader. The concentration of the compound required to inhibit cell growth by 50% (IC 50 value) was calculated using GraphPad Prism 9.5.1 software, and the results are shown in Table 1.

[0057] Table 1 Determination results of the inhibitory activities of biphenyl arylamide compounds against the proliferation of Kasumi-1 and Skno-1

[0058] It can be seen that the biphenyl arylamide compounds shown in Formulas 4a - 4o have inhibitory effects on both Kasumi-1 and Skno-1 cells, among which the inhibitory effects of the biphenyl arylamide compounds shown in Formulas 4a, 4k, and 4o are significantly better.

[0059] Example 17: Animal tumor inhibition experiment Patient-derived cells (acute myeloid leukemia cells, from the Department of Hematology and Oncology, General Hospital of Shenzhen University) were injected into the tail vein of 6-week-old NOG mice. Before tumor inoculation, the mice were first intraperitoneally injected with cyclophosphamide (dose: 150 mg / kg) continuously for two days, then rested for 24 hours, and then received a sub-lethal dose of ionizing radiation of 1 Gy. After that, the mice were randomly divided into 5 groups (n = 5 per group), and tumor cells were subcutaneously injected. 28 days after cell injection, 4 groups of mice were respectively given 5-Aza (azacitidine, 3 mg / kg, by gavage, once a day), the biphenyl arylamide compound shown in Formula 4a (20 mg / kg, by gavage, once a day), the biphenyl arylamide compound shown in Formula 4k (20 mg / kg, by gavage, once a day), and the biphenyl arylamide compound shown in Formula 4o (20 mg / kg, by gavage, once a day) for continuous treatment for 60 days, and 1 group of mice treated with an equal amount of sterile saline was used as a control group (Vehicle). The survival of the mice was analyzed by Kaplan-Meier survival curve, and the results are as Figure 1 shown. From Figure 1It can be seen that the biphenyl aromatic amide compounds shown in Formula 4a, Formula 4k and Formula 4o can significantly improve the survival period and survival rate of leukemia mice.

[0060] As described above, only the preferred embodiments of the present invention are provided, and there is no limitation in any form and substance to the present invention. It should be noted that for those of ordinary skill in the art in this technical field, several improvements and supplements can be made without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any person skilled in the art can make some changes, modifications and equivalent changes of evolution without departing from the spirit and scope of the present invention when using the technical content disclosed above, which are all equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the substantial technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A biphenyl aromatic amide compound or a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl aromatic amide compound has a structure shown in Formula 5-1, Formula 5-2 or Formula 5-3: 、 、 ； Among them, R 1 is selected from alkoxy groups having 1 to 4 carbon atoms, halogen atoms, and trifluoromethyl groups; R 2 Any one selected from the following groups: 、 、 、 ； R 3 selected from a hydrogen atom, a halogen atom, and a cyano group; X is C or N.

2. The biphenyl aromatic amide compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 is selected from methoxy, ethoxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl; the R 2 is N-methylpiperazinyl; the R 3 is selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group.

3. The biphenyl aromatic amide compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The biphenyl aromatic amide compound has a structure shown in one of Formula 5a - Formula 5o: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. A method for preparing a biphenyl aromatic amide compound, characterized in that, It includes the following steps: In the presence of a palladium catalyst, the compound shown in Formula 1-1, Formula 1-2 or Formula 1-3 reacts with the compound shown in Formula 2 through a Suzuki coupling reaction to obtain the compound shown in Formula 3-1, Formula 3-2 or Formula 3-3; The compound shown in Formula 3-1, Formula 3-2 or Formula 3-3 reacts with the compound shown in Formula 4 through an amidation reaction to obtain the biphenyl aromatic amide compound shown in Formula 5-1, Formula 5-2 or Formula 5-3; 、 、 、 、 、 、 、 、 、 、 ； wherein, R 1 is selected from alkoxy groups having 1 to 4 carbon atoms, halogen atoms, and trifluoromethyl groups; R 2 Selected from any one of the following groups: 、 、 、 ； R 3 selected from a hydrogen atom, a halogen atom, and a cyano group; X is C or N.

5. The method according to claim 4, characterized in that The palladium catalyst is bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium or 1,1'-bis(diphenylphosphino)ferrocene dichloride.

6. The method according to claim 4, wherein The Suzuki coupling reaction is carried out in the presence of sodium carbonate.

7. The method according to claim 4, characterized in that The amidation reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine and 4-dimethylaminopyridine.

8. Use of the biphenyl aromatic amide compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing leukemia.

9. The application according to claim 8, characterized in that, The leukemia is acute myeloid leukemia.

10. A drug for treating and / or preventing leukemia, characterized in that, It includes the biphenyl aromatic amide compound according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof.

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