Biphenyl arylamide compound and its application in preparing medicine for treating leukemia

Abstract

The present invention relates to the field of biomedicine, and more particularly to biphenyl arylamide compounds and their use in the preparation of leukemia treatment drugs. The biphenyl arylamide compounds have the activity of effectively inhibiting the proliferation of leukemia cells, providing safe and effective candidate drug molecules for the treatment of leukemia. The preparation process of the biphenyl arylamide compounds is simple and easy, and the reaction conditions are mild. The biphenyl arylamide compounds have excellent performance in inhibiting tumor growth in mice, and can be used as anti-leukemia drugs, showing good development prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a biphenyl arylamide compound and its application in preparing a drug for treating leukemia. Background Art

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

[0003] Current methods of treating leukemia have significant limitations: although chemotherapy as a basic therapy can kill tumor cells, it lacks specific recognition capabilities. While causing serious toxic side effects such as hair loss and bone marrow suppression, it can easily induce drug resistance and increase the risk of recurrence; radiotherapy destroys the DNA of leukemia cells through high-energy rays, but it causes severe damage to normal tissues and causes complications such as radiation pneumonia, limiting its clinical application; although hematopoietic stem cell transplantation can rebuild the immune system to achieve a cure, it is difficult to popularize due to the scarcity of donors, difficulty in matching and high costs; targeted therapy improves efficacy through precise intervention of 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 promote the therapeutic effect of leukemia, the present invention provides a biphenyl arylamide compound and its application in preparing a drug for treating leukemia.

[0005] The first aspect of the present invention provides a biphenyl arylamide compound or a pharmaceutically acceptable salt thereof, wherein the biphenyl arylamide compound has a structure shown in Formula 5-1, Formula 5-2 or Formula 5-3:

[0006] 、 、 ;

[0007] Among them, R 1 Selected from C1~C4 alkoxy, halogen atom, trifluoromethyl;

[0008] R 2 Any one of the following groups:

[0009] 、 、 、 ;

[0010] R 3 is selected from a hydrogen atom, a halogen atom, and a cyano group;

[0011] X is C or N.

[0012] The biphenylamide compound or its pharmaceutically acceptable salt has the property of effectively inhibiting the proliferation of leukemia cells and can be used to treat leukemia, particularly acute myeloid leukemia. The pharmaceutically acceptable salt of the biphenylamide compound can be easily prepared from the biphenylamide compound as a raw material. For example, the hydrochloride of the biphenylamide compound can be prepared by reacting the biphenylamide compound with hydrochloric acid.

[0013] In some optional embodiments, the above R 1 is selected from methoxy, ethoxy, fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl; the above R 2 is N-methylpiperazinyl; the above R 3 Select hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, cyano group.

[0014] In some optional embodiments, the biphenyl arylamide compound has a structure shown in one of Formula 5a to Formula 5o:

[0015] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 .

[0016] The second aspect of the present invention provides a method for preparing the above-mentioned biphenyl arylamide compound, which comprises the following steps:

[0017] In the presence of a palladium catalyst, a compound represented by Formula 1-1, Formula 1-2 or Formula 1-3 is subjected to a Suzuki coupling reaction with a compound represented by Formula 2 to obtain a compound represented by Formula 3-1, Formula 3-2 or Formula 3-3;

[0018] A compound represented by Formula 3-1, Formula 3-2 or Formula 3-3 is subjected to an amidation reaction with a compound represented by Formula 4 to obtain the above-mentioned biphenyl arylamide compound;

[0019] 、 、 、 、 、 、 、 ;

[0020] Among them, R 1 、R 2 、R 3 and X are defined as above.

[0021] In some optional embodiments, the palladium catalyst is bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride. Preferably, the palladium catalyst is bistriphenylphosphine palladium dichloride.

[0022] In some optional embodiments, the Suzuki coupling reaction is carried out in the presence of sodium carbonate.

[0023] In some optional embodiments, the Suzuki coupling reaction is carried out at 80-98°C.

[0024] In some optional embodiments, the Suzuki coupling reaction is carried out in a mixed solvent of tetrahydrofuran and water.

[0025] In some optional embodiments, the amidation reaction is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, triethylamine and 4-dimethylaminopyridine.

[0026] In some optional embodiments, the amidation reaction is carried out at 20-30°C.

[0027] In some optional embodiments, the amidation reaction is carried out in dichloromethane solvent.

[0028] The third aspect of the present invention provides the use of the above-mentioned biphenyl arylamide compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing leukemia.

[0029] In some optional embodiments, the leukemia is acute myeloid leukemia, wherein the cell line of acute myeloid leukemia can be Kasumi-1 or Skno-1.

[0030] A fourth aspect of the present invention provides a drug for treating and / or preventing leukemia, comprising the aforementioned biphenyl arylamide compound or a pharmaceutically acceptable salt thereof. The aforementioned biphenyl arylamide compound or a pharmaceutically acceptable salt thereof is the main active ingredient (primary drug) in the drug for treating and / or preventing leukemia.

[0031] In some optional embodiments, the drug for treating and / or preventing leukemia further comprises an excipient. The dosage form of the drug for treating and / or preventing leukemia is any pharmaceutically acceptable dosage form. The excipient is stable, has no incompatibility with the main drug, does not produce side effects, does not affect efficacy, is not easily deformed, cracked, or moldy at room temperature, and is harmless to the human body.

[0032] In some optional embodiments, the excipient is at least one of gum arabic, syrup, lanolin, and starch.

[0033] The technical solution of the embodiment of the present invention has the following beneficial effects:

[0034] A new biphenylamide compound has been obtained. The biphenylamide compound has the activity of effectively inhibiting the proliferation of leukemia cells, providing a safe and efficient candidate drug molecule for the treatment of leukemia. The preparation process of the biphenylamide compound is simple and easy, and the reaction conditions are mild. The biphenylamide compound has excellent performance in inhibiting mouse tumor growth and can be used as an anti-leukemia drug, with good development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is a survival curve diagram of mice in Example 17 of the present invention. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0037] Example 1: Synthesis of the biphenyl arylamide compound represented by formula 5a

[0038] Under nitrogen, 2-iodo-5-methoxybenzoic acid (1.0 mmol, 1.0 eq) was dissolved in 10.0 ml of a mixture of tetrahydrofuran and water (volume ratio 1:1). 3-(4-Methylpiperazin-1-yl)phenylboronic acid (1.0 mmol, 1.0 eq), bistriphenylphosphine palladium dichloride (0.1 mmol, 0.1 eq), and sodium carbonate (2.0 mmol, 2.0 eq) were added sequentially. The reaction was then allowed to react in a 90°C oil bath. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (10.0 ml × 3). The solid was collected by filtration and dissolved in water. The pH was adjusted to 4 with 1N hydrochloric acid. The mixture was then extracted 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 used directly in the next reaction.

[0039] Under nitrogen at 0°C, the 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 sequentially and allowed to react at room temperature. After completion, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate (10.0 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the biphenyl arylamide compound represented by Formula 5a (yield: 82%).

[0040]

[0041] The characterization results of the biphenyl arylamide compound represented by 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 = 7.5 Hz, 1H),7.16 (dd, J = 7.5, 2.0 Hz, 1H), 7.07 (tt, J = 7.5, 2.0 Hz, 1H), 6.99 (dt, J =7.5, 1.9 Hz, 1H), 6.93 (dt, J = 7.5, 2.0 Hz, 1H), 6.89 (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, 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.

[0042] Example 2: Synthesis of the biphenyl arylamide compound represented by formula 5b

[0043] 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), to obtain the biphenyl arylamide compound represented by Formula 5b (yield: 80%).

[0044]

[0045] The characterization results of the biphenyl arylamide compound represented by 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). 13 C 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.

[0046] Example 3: Synthesis of the biphenyl arylamide compound represented by formula 5c

[0047] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 5-chloro-3-fluoroaniline), to obtain the biphenyl arylamide compound represented by Formula 5c (yield: 83%).

[0048]

[0049] The characterization results of the biphenyl arylamide compound represented by formula 5c are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.04(t, J = 2.0 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 2.1 Hz, 1H), 7.59(s, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.16 (dd, J = 7.5, 2.0 Hz, 1H), 7.07 (ddt, J = 15.0, 8.8, 1.9 Hz, 2H), 6.94 (dt, J = 7.5, 2.0 Hz, 1H), 6.79 (t, J = 2.0Hz, 1H), 6.54 (dt,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) δ167.51, 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 = 20.0Hz), 104.29 (d, J = 20.0 Hz), 55.80, 53.99, 48.63, 44.73.

[0050] Example 4: Synthesis of the biphenyl arylamide compound represented by formula 5d

[0051] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 3-fluoroaniline), to obtain the biphenyl arylamide compound represented by Formula 5d (yield: 86%).

[0052]

[0053] The characterization results of the biphenyl arylamide compound represented by 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 = 7.6Hz), 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.

[0054] Example 5: Synthesis of the biphenyl arylamide compound represented by formula 5e

[0055] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 3-chloroaniline), to obtain the biphenyl arylamide compound represented by Formula 5e (yield: 85%).

[0056]

[0057] The characterization results of the biphenyl arylamide compound represented by 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, 2.8Hz, 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, 1.9Hz, 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.

[0058] Example 6: Synthesis of the biphenyl arylamide compound represented by formula 5f

[0059] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 3-bromoaniline), to obtain the biphenyl arylamide compound represented by Formula 5f (yield: 84%).

[0060]

[0061] The characterization results of the biphenyl arylamide compound represented by 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.

[0062] Example 7: Synthesis of the biphenyl arylamide compound shown in Formula 5g

[0063] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 2-aminopyridine), to obtain the biphenyl arylamide compound represented by Formula 5g (yield: 84%).

[0064]

[0065] The characterization results of the biphenyl arylamide compound represented by 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.

[0066] Example 8: Synthesis of the biphenyl arylamide compound represented by formula 5h

[0067] This example is basically the same as Example 1, except that the corresponding starting compound is changed (aniline is replaced by 3-aminobenzonitrile), to obtain the biphenyl arylamide compound represented by Formula 5h (yield: 84%).

[0068]

[0069] The characterization results of the biphenyl arylamide compound represented by 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.

[0070] Example 9: Synthesis of the biphenyl arylamide compound represented by formula 5i

[0071] This example is basically the same as Example 8, except that the corresponding starting compound is changed (2-iodo-5-methoxybenzoic acid is replaced by 5-bromo-2-iodobenzoic acid), to obtain the biphenyl arylamide compound represented by Formula 5i (yield: 83%).

[0072]

[0073] The characterization results of the biphenyl arylamide compound represented by 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.

[0074] Example 10: Synthesis of the biphenyl arylamide compound represented by formula 5j

[0075] This example is basically the same as Example 9, except that the corresponding raw material compound is changed (3-(4-methylpiperazin-1-yl)phenylboronic acid is replaced by 3-(1,4-oxazacyclohexane-4-yl)phenylboronic acid) to obtain the biphenyl arylamide compound represented by Formula 5j (yield: 80%).

[0076]

[0077] The characterization results of the biphenyl arylamide compound represented by 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). 13 C 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.

[0078] Example 11: Synthesis of the biphenyl arylamide compound represented by formula 5k

[0079] This example is basically the same as Example 9, except that the corresponding starting compound is changed (3-(4-methylpiperazin-1-yl)phenylboronic acid is replaced with 3-(piperidin-1-yl)phenylboronic acid) to obtain the biphenyl arylamide compound represented by Formula 5k (yield: 80%).

[0080]

[0081] The characterization results of the biphenyl arylamide compound represented by formula 5k 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), 7.31 – 7.24 (m,1H), 7.21 – 7.15 (m, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.88 – 6.83 (m, 1H), 3.39(ddd, 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.

[0082] Example 12: Synthesis of the biphenyl arylamide compound represented by formula 51

[0083] This example is basically the same as Example 9, except that the corresponding starting compound is changed (3-(4-methylpiperazin-1-yl)phenylboronic acid is replaced with 3-(pyrrolidin-1-yl)phenylboronic acid) to obtain the biphenyl arylamide compound represented by Formula 51 (yield: 86%).

[0084]

[0085] The characterization results of the biphenyl arylamide compound represented by formula 51 are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13(d, J = 2.5 Hz, 1H), 8.07 – 8.03 (m, 1H), 7.88 – 7.81 (m, 1H), 7.80 – 7.66(m, 3H), 7.47 – 7.40 (m, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.21 – 7.15 (m, 1H), 7.00 (t, 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.

[0086] Example 13: Synthesis of the biphenyl arylamide compound represented by formula 5m

[0087] This example is basically the same as Example 8, except that the corresponding raw material compound was changed (2-iodo-5-methoxybenzoic acid was replaced with 6-iodoquinoline-7-carboxylic acid, wherein 6-iodoquinoline-7-carboxylic acid was purchased from Beijing Nanling Biotechnology Co., Ltd. with the product number NL0308), to obtain the biphenyl arylamide compound represented by Formula 5m (yield: 83%).

[0088]

[0089] The characterization results of the biphenyl arylamide compound represented by 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.

[0090] Example 14: Synthesis of the biphenyl arylamide compound represented by formula 5n

[0091] This example is basically the same as Example 8, except that the corresponding starting compound is changed (2-iodo-5-methoxybenzoic acid is replaced with 5-iodo-1-benzofuran-6-carboxylic acid, wherein 5-iodo-1-benzofuran-6-carboxylic acid is purchased from Beijing Nanling Biotechnology Co., Ltd. with the product number NL0326), to obtain the biphenyl arylamide compound represented by Formula 5n (yield: 81%).

[0092]

[0093] The characterization results of the biphenyl arylamide compound represented by 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.

[0094] Example 15: Synthesis of the biphenyl arylamide compound represented by formula 5o

[0095] This example is basically the same as Example 8, except that the corresponding starting compound is changed (2-iodo-5-methoxybenzoic acid is replaced with 2-iodo-5-(trifluoromethyl)benzoic acid) to obtain the biphenyl arylamide compound represented by Formula 5o (yield: 83%).

[0096]

[0097] The characterization results of the biphenyl arylamide compound represented by 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.

[0098] Example 16: Experiment on the inhibition of acute myeloid leukemia cell proliferation by biphenylamide compounds

[0099] Acute myeloid leukemia cell lines (Kasumi-1 and Skno-1) were incubated with solutions of the biphenylamide compounds represented by Formulas 4a-4o at varying concentrations for 72 hours, and cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Specifically, cells were seeded in duplicate wells of a 96-well plate, with a volume of 90 µL per well. Subsequently, 10 µL of solutions of the compounds represented by Formulas 4a-4o at varying concentrations were added to each well. After 72 hours of treatment, 10 µL of CCK-8 reagent was added to each well, and the cells were incubated at 37°C for another 2 hours to promote the reaction. The absorbance was then measured at 450 nm using a Thermo Fisher Multiskan FC microplate reader. The compound concentration required to inhibit cell growth by 50% (IC) was calculated using GraphPad Prism 9.5.1 software. 50 The results are shown in Table 1.

[0100] Table 1 Results of the inhibition of Kasumi-1 and Skno-1 proliferation by biphenylamide compounds

[0101]

[0102] It can be seen that the biphenyl arylamide compounds represented by Formula 4a to Formula 4o have inhibitory effects on Kasumi-1 and Skno-1 cells, among which the biphenyl arylamide compounds represented by Formula 4a, Formula 4k and Formula 4o have significantly better inhibitory effects.

[0103] Example 17: Animal tumor inhibition experiment

[0104] Patient-derived cells (acute myeloid leukemia cells, obtained from the Department of Hematology and Oncology at Shenzhen University General Hospital) were injected into the tail vein of 6-week-old NOG mice. Prior to tumor inoculation, mice received two consecutive days of intraperitoneal injections of cyclophosphamide (150 mg / kg), followed by a 24-hour rest period and irradiation with a sublethal dose of 1 Gy of ionizing radiation. Subsequently, the mice were randomly divided into five groups (n = 5 per group) and subcutaneously injected with tumor cells. Twenty-eight days after cell injection, four groups of mice were treated with 5-Aza (azacitidine, 3 mg / kg, gavage, once daily), a biphenylamide compound represented by Formula 4a (20 mg / kg, gavage, once daily), a biphenylamide compound represented by Formula 4k (20 mg / kg, gavage, once daily), or a biphenylamide compound represented by Formula 4o (20 mg / kg, gavage, once daily) for 60 consecutive days. One group of mice received an equal amount of sterile saline as a control (vehicle). The survival of mice was analyzed by Kaplan-Meier survival curve. Figure 1 As shown. Figure 1 It can be seen that the biphenyl arylamide compounds represented by Formula 4a, Formula 4k and Formula 4o can significantly improve the survival period and survival rate of leukemia mice.

[0105] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form or substance. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention. Any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the spirit and scope of the present invention by using the technical content disclosed above 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 essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A biphenyl arylamide compound or a pharmaceutically acceptable salt thereof, characterized in that: The biphenyl arylamide compound has a structure shown in Formula 5-1, Formula 5-2 or Formula 5-3: 、 、 ； Among them, R 1 Selected from C1~C4 alkoxy, halogen atom, trifluoromethyl; R 2 Any one selected from the following groups: 、 、 、 ； R 3 is selected from a hydrogen atom, a halogen atom, and a cyano group; X is C or N.

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

3. The biphenyl arylamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The biphenyl arylamide compound has a structure shown in one of Formula 5a to Formula 5o: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. A method for preparing a biphenyl arylamide compound, characterized in that: The following steps are involved: In the presence of a palladium catalyst, a compound represented by Formula 1-1, Formula 1-2 or Formula 1-3 is subjected to a Suzuki coupling reaction with a compound represented by Formula 2 to obtain a compound represented by Formula 3-1, Formula 3-2 or Formula 3-3; A compound represented by Formula 3-1, Formula 3-2 or Formula 3-3 is subjected to an amidation reaction with a compound represented by Formula 4 to obtain a biphenyl arylamide compound represented by Formula 5-1, Formula 5-2 or Formula 5-3; 、 、 、 、 、 、 、 、 、 、 ； Among them, R 1 Selected from C1~C4 alkoxy, halogen atom, trifluoromethyl; R 2 Any one selected from the following groups: 、 、 、 ； R 3 is 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 bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium or 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride.

6. The method according to claim 4, characterized in that 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 arylamide compound or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 3 in the preparation of a medicament for treating and / or preventing leukemia.

9. The use 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: The invention comprises the biphenyl arylamide compound or a pharmaceutically acceptable salt thereof according to claim 1, 2 or 3.

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