O-acylamino benzoyl derivative as well as preparation method and application thereof

Abstract

The invention discloses an o-amido benzoyl derivative shown as a formula I-II and application of the o-amido benzoyl derivative in preparation of a myocardial protection medicine. R1 is NHR6, CH3 (CH2) 4O-and CH3 (CH2) 5O-or one of the following groups: # imgabs1, # R6 is # imgabs2, R '1 and R' 2, R '3 is-OCH3 and H, FR' 4 is H, CH3R2 is H or-OCH3, R1 is CH3 (CH2) 4O-and CH3 (CH2) 5O-, R2 is CH3 (CH3) 4O-and CH3 (CH2) 5O-, and R2 is CH3 (CH3) 4O-and CH3 (CH2) 5O-. R3 is H, F or-OCH3; r4 being H, # imgabs3 # R5 being # imgabs4 # R7 being # imgabs5 #

Description

Technical Field:

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to an o - amidebenzoyl derivative, a preparation method thereof, and an application thereof. Background Art:

[0002] Cardiac diseases such as asymptomatic myocardial ischemia, angina pectoris, acute coronary syndrome (unstable angina pectoris, myocardial infarction), and sudden cardiac death are mainly caused by a reduction in coronary blood flow due to coronary artery disease (CAD), and the most common cause of coronary artery disease is coronary atherosclerosis.

[0003] The main principles of drugs for treating ischemic heart disease include anticoagulation to prevent thrombosis formation; slowing heart rate, reducing arterial pressure, and weakening myocardial contraction to reduce the heart load and oxygen demand; dilating veins, arteries, and arterioles to reduce the pre - and post - load of the left ventricle, thereby reducing myocardial oxygen demand and alleviating myocardial ischemia; and using fibrinolytic drugs to dissolve thrombus for treating coronary atherosclerosis.

[0004] Drugs commonly used for treating coronary atherosclerosis and other myocardial ischemic diseases caused thereby mainly include anti - platelet drugs, anticoagulant drugs, β - receptor blockers, nitrates, fibrinolytic drugs, and other drugs, such as angiotensin - converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, statins, and PCSK - 9 inhibitors.

[0005] Most of these drugs treat coronary atherosclerosis and prevent further myocardial cell ischemia from causing damage to the heart as much as possible. In terms of protecting myocardial cells after myocardial ischemia and reducing myocardial cell ischemia damage, there are fewer drugs such as β - receptor blockers and nitrates, which can reduce the infarct size and mortality rate when used within the first few hours after myocardial infarction.

[0006] O - amidebenzoyl derivatives are an important part of bioactive compounds and commercial drugs, and their derivatives have broad biological activities in treating diseases and regulating pathogenic pathways. Currently, there are few literature reports on the biological activities of such compounds, and they also show certain potential in neuroprotection, anti - obesity, and antibacterial aspects, but there is no report on the biological activity research in myocardial protection. Summary of the Invention:

[0007] The object of the present invention is to provide an o - amidebenzoyl derivative, a preparation method thereof, and an application thereof.

[0008] The present invention is achieved by the following technical solutions:

[0009] o-Amidobenzoyl derivatives represented by Formula I-II:

[0010]

[0011] Wherein, R1 is NHR6, CH3(CH2)4O-, CH3(CH2)5O- or one of the following groups:

[0012]

[0013] R6 is

[0014] R2 is H or -OCH3; R3 is H, F or -OCH3; R4 is R5 is H, R7 is

[0015] When R1 is NHR6, R2 is H, R3 is H, and R5 is H, the synthesis route is:

[0016]

[0017] Including the following steps: reacting o-nitrobenzoyl chloride with 2-amino-3,4,5-monosubstituted or polysubstituted benzoate and triethylamine by stirring at room temperature for 3-7 hours to obtain an amide intermediate product, dissolving it in a solvent, adding palladium carbon, and stirring at room temperature for 3-7 hours under a H2 atmosphere to obtain an amino product, and then reacting it with nicotinyl chloride hydrochloride or 6-chloronicotinyl chloride hydrochloride in a basic solvent.

[0018] The present invention also protects the use of the o-aminobenzoic acid derivatives in the preparation of cardioprotective drugs.

[0019] The drug may further contain one or more pharmaceutically acceptable carriers or excipients.

[0020] The excipients include sustained-release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, adsorption carriers, surfactants or lubricants, etc.

[0021] The carrier is at least one of microcapsules, microspheres, nanoparticles and liposomes.

[0022] The drug can be further formulated into various dosage forms. The drugs in various dosage forms can be prepared by conventional methods in the pharmaceutical field.

[0023] The present invention also protects

[0024] The use in the preparation of cardioprotective drugs.

[0025] The beneficial effects of the present invention are as follows: It is found in this application that methyl 3,4,5-trimethoxy-2-(2-(nicotinamido)benzamido)benzoate (Compound 4) derived from the soft coral fungus Aspergillus sp. has good myocardial protection effects, and total synthesis and structural optimization are carried out to obtain a series of o-benzamidobenzoyl derivatives that protect cardiomyocyte injury caused by oxygen-glucose deprivation (OGD). Specific embodiments:

[0026] The following is a further description of the present invention, rather than a limitation to the present invention.

[0027] Example 1: Synthesis of Compounds 1-5 and Compounds 7-8

[0028] The route is as follows:

[0029]

[0030] Synthesis of Compound 1: Methyl 2-amino-3,4,5-trimethoxybenzoate was added to a round-bottom flask and dissolved in anhydrous dichloromethane. Triethylamine was added to the above solution. The reaction flask was sealed and protected by nitrogen, and stirred and cooled to 0 °C. o-Nitrobenzoyl chloride was dissolved in anhydrous dichloromethane and added dropwise to the above solution. After the addition was completed, it was transferred to room temperature and stirred for reaction for 4 h. The solvent was evaporated, and the reactant was dissolved in ethyl acetate. The ethyl acetate phase was washed with water, saturated sodium bicarbonate solution, and saturated brine, dehydrated, and rotary evaporated to dryness. Purification by silica gel column chromatography gave a yellow oily product 1 with a yield of 68%. 1 H NMR(400MHz,CDCl3)δ8.53(s,1H),8.08(dd,J=8.2,1.2Hz,1H),7.80(dd,J=7.6,1.5Hz,1H),7.73(td,J=7.5,1.3Hz,1H),7.61(ddd,J=8.1,7.4,1.6Hz,1H),7.26(s,1H),4.01(s,3H),3.96(s,3H),3.91(s,3H),3.90(s,3H). 13 C NMR(100MHz,CDCl3)δ166.98,165.00,151.45,148.93,147.32,146.61,133.78,133.08,130.75,128.98,124.77,124.69,119.97,108.66,61.36,61.10,56.38,52.59.

[0031]

[0032] Synthesis of Compound 2: Referring to the synthesis of Compound 1, the difference lies in that methyl 2-amino-3,4,5-trimethoxybenzoate is replaced by methyl 2-amino-4,5-trimethoxybenzoate, and the obtained Compound 2 is a yellow solid (272 mg, 0.76 mmol), with a yield of approximately 80%. 1 HNMR (400 MHz, CDCl3) δ 11.65 (s, 1H), 8.53 (s, 1H), 8.09–8.04 (m, 1H), 7.76–7.69 (m, 2H), 7.64 (ddd, J = 8.2, 6.6, 2.4 Hz, 1H), 7.49 (s, 1H), 4.02 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.40, 164.11, 154.03, 146.94, 144.34, 137.10, 133.53, 132.85, 130.71, 128.20, 124.59, 111.90, 106.85, 103.50, 56.15, 55.98, 52.09.

[0033]

[0034] Synthesis of Compound 3: Dissolve Compound 1 in ethanol, add 5% palladium on carbon, and stir the reaction at room temperature for 3 h under a hydrogen atmosphere. The obtained Compound 3 is a transparent solid (9 mg, 0.025 mmol), with a yield of 80%. 1 HNMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.65 (dt, J = 8.0, 1.6 Hz, 1H), 7.23 (d, J = 1.3 Hz, 1H), 7.22–7.18 (m, 1H), 6.71–6.64 (m, 2H), 5.60 (s, 2H), 3.94 (d, J = 1.7 Hz, 3H), 3.88 (d, J = 1.7 Hz, 3H), 3.87 (d, J = 2.0 Hz, 3H), 3.80 (d, J = 2.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.08, 167.46, 150.74, 148.94, 148.34, 146.59, 133.06, 129.07, 126.40, 119.21, 117.84, 117.42, 116.04, 108.63, 61.19, 61.14, 56.42, 52.51.

[0035]

[0036] Synthesis of Compound 4: Compound 3 was dissolved in anhydrous dichloromethane, the reaction flask was sealed, protected by nitrogen, and stirred and cooled to 0 °C. Nicotinoyl chloride hydrochloride was diluted with anhydrous dichloromethane, triethylamine was added to the dichloromethane solution of nicotinoyl chloride hydrochloride, and the dichloromethane solution of nicotinoyl chloride hydrochloride and triethylamine was added dropwise to the above solution. After the addition was completed, it was transferred to room temperature and stirred for reaction for 4 h. The solvent was rotary evaporated, the reactant was dissolved in ethyl acetate, the organic phase was washed with water once, washed with saturated sodium bicarbonate solution three times, and washed with saturated brine once. The organic phase was dehydrated and rotary evaporated to dryness. Compound 4 was obtained as a yellow solid (10 mg, 0.022 mmol), and the yield was 66%. 1 H NMR(400MHz,CDCl3)δ12.26(s,1H),9.25(s,1H),9.24(d,J=2.2Hz,1H),8.83(dd,J=8.5,1.1Hz,1H),8.72(dd,J=4.9,1.5Hz,1H),8.27(dt,J=8.0,2.0Hz,1H),7.91(dd,J=8.0,1.5Hz,1H),7.61(ddd,J=8.7,7.4,1.5Hz,1H),7.38(dd,J=8.0,4.8Hz,1H),7.28(s,1H),7.26–7.21(m,1H),3.98(s,3H),3.92(s,3H),3.91(s,3H),3.83(s,3H). 13 CNMR(100MHz,CDCl3)δ167.02,166.00,162.71,151.19,150.26,147.89,147.64,145.70,139.14,134.14,132.40,129.52,126.73,124.54,122.59,122.48,120.57,119.19,117.82,107.54,60.06,60.04,55.25,51.48.

[0037]

[0038] Synthesis of Compound 5: Referring to the synthesis of Compound 4, the difference was that 6-chloronicotinoyl chloride hydrochloride was used instead of nicotinoyl chloride hydrochloride as the raw material. Compound 5 was obtained as a white solid powder (29 mg, 0.058 mmol), and the yield was about 85%. 1HNMR (400 MHz, CDCl3) δ 12.34 (s, 1H), 9.28 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.81 (dd, J = 8.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.4, 2.6 Hz, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.29 (s, 1H), 7.24 (dd, J = 7.5, 1.2 Hz, 1H), 4.00 (s, 3H), 3.92 (s, 6H), 3.84 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.17, 167.18, 162.82, 154.61, 151.45, 149.46, 148.80, 146.91, 140.20, 137.86, 133.64, 129.55, 127.91, 125.69, 124.35, 123.90, 121.65, 120.22, 118.82, 108.70, 61.22 (C×2), 56.42, 52.65.

[0039]

[0040] Synthesis of Compound 7 (refer to the synthesis of Compound 4): Using 2 - amino - 3,5 - dimethoxybenzoate, o - nitrobenzoyl chloride and triethylamine as raw materials, (refer to the synthesis of Compound 1), and then using 5% palladium on carbon under H2 atmosphere to obtain the intermediate Using nicotinoyl chloride hydrochloride and triethylamine as raw materials, Compound 7 was obtained as a white solid (21 mg, 0.412 mmol), with a yield of approximately 44%. 1 HNMR (400 MHz, CDCl3) δ 12.14 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.86–8.77 (m, 2H), 8.72 (dd, J = 4.9, 1.6 Hz, 1H), 8.25 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.39 (ddd, J = 8.1, 4.9, 0.8 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.04 (d, J = 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 3.85 (d, J = 1.1 Hz, 6H), 3.83 (s, 3H).13 13C NMR (100 MHz, CDCl3) δ 168.09, 167.61, 164.19, 158.71, 155.21, 152.71, 149.49, 140.30, 135.47, 133.58, 130.93, 128.00, 126.75, 124.01, 123.88, 122.01, 121.12, 119.90, 105.74, 104.21, 56.70, 56.20, 52.96. ESI-HRMS m / z: 435.1499 [M+H] + (calcd for C 23 H 21 N3O6, 435.14304 [M+H] + ).

[0041]

[0042] Synthesis of Compound 8: Referring to the synthesis of Compound 4, methyl 2-amino-3-methoxybenzoate, triethylamine, and o-nitrobenzoic acid were first reacted to obtain Then 5% palladium on carbon, in an H2 atmosphere to obtain Nicotinoyl chloride hydrochloride and triethylamine gave Compound 8 as a yellowish-white solid (115 mg, 0.28 mmol), with a yield of approximately 57%. 1 1H NMR (400 MHz, CDCl3) δ 12.11 (s, 1H), 9.21 (s, 1H), 9.16 (s, 1H), 8.79 (dd, J = 8.5, 1.1 Hz, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.23 (dt, J = 8.0, 1.9 Hz, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.52 (dd, J = 7.9, 1.4 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H), 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 7.15 (dd, J = 8.3, 1.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 167.55, 167.51, 163.76, 153.40, 152.26, 148.97, 140.00, 135.13, 133.34, 130.54, 127.76, 126.40, 126.30, 125.30, 123.63, 123.50, 122.25, 121.62, 120.55, 115.73, 56.31, 52.50. ESI-HRMS m / z: 405.1393 [M+H] + (calcd for C 22 H 19 N3O5, 405.13247 [M+H] + ).

[0043] Example 2: Synthesis of Compounds 9-12 and Compounds 15-24

[0044] Among them, the synthetic routes of Compound 11, Compounds 16-21, and Compounds 23-24 are as follows:

[0045]

[0046]

[0047] Synthesis of Compound 9: Isatoic anhydride (100.0 mg, 0.613 mmol, 1.5 eq) was added to a 25 mL round-bottom flask and dissolved in 8 mL of ethanol. Then aniline (38.1 mg, 0.409 mmol, 1.0 eq) and iodine (10.4 mg, 0.041 mmol, 0.1 eq) were added, and the reaction was refluxed at 80 °C for 12 h. The solvent was evaporated, and the reactants were dissolved in 10 mL of ethyl acetate. The organic phase was washed once with 10 mL of water, three times with 10 mL of saturated sodium bicarbonate solution, and once with 10 mL of saturated brine. After drying the organic phase over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 10, v / v) as the eluent to obtain Compound 9 as a dark yellow solid (53 mg, 0.25 mmol), with a yield of approximately 40%. 1 1H NMR (400 MHz, CDCl3) δ 7.81–7.70 (m, 1H), 7.57 (dt, J = 8.5, 1.2 Hz, 2H), 7.47 (dt, J = 8.0, 1.4 Hz, 1H), 7.38 (qd, J = 8.5, 7.6, 3.0 Hz, 2H), 7.28–7.24 (m, 1H), 7.15 (td, J = 7.4, 1.2 Hz, 1H), 6.72 (ddt, J = 8.3, 4.7, 1.3 Hz, 2H), 5.49 (s, 2H). 1313C NMR (100 MHz, CDCl3) δ 167.58, 148.99, 137.87, 132.78, 129.09, 127.18, 124.52, 120.56, 117.57, 116.86, 116.25.

[0048]

[0049] Synthesis of Compound 10 (refer to the synthesis of Compound 9): Isatoic anhydride, 3,4-methylenedioxyaniline, iodine, gave Compound 10 as a white flocculent solid (155 mg, 0.61 mmol), with a yield of approximately 51%. 1 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.43 (dd, J = 7.8, 1.5 Hz, 1H), 7.26–7.21 (m, 2H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.69 (td, J = 7.9, 7.4, 1.2 Hz, 2H), 5.96 (s, 2H), 5.46 (s, 2H). 13 13C NMR (100 MHz, CDCl3) δ 167.66, 149.03, 147.99, 144.66, 132.81, 132.08, 127.23, 117.64, 116.93, 116.25, 114.17, 108.23, 103.73, 101.44.

[0050]

[0051] Synthesis of Compound 11: 4,5-Dimethoxybenzoic acid (80.0 mg, 0.41 mmol, 1.0 eq) and sodium hydroxide (16.2 mg, 0.41 mmol, 1.0 eq) were added to a 50 mL round-bottom flask, and 10 mL of water was added and stirred until dissolved. Then isatoic anhydride (66.2 mg, 0.41 mmol, 1.0 eq) was added and the mixture was refluxed for about 4 h. After cooling to room temperature, the pH was adjusted to 4 - 5 with 5% hydrochloric acid, and a large amount of solid precipitated. The solid was filtered by suction, washed with water, and dried. Compound 11 was obtained as a yellow-brown solid (90 mg, 0.28 mmol), with a yield of approximately 70%. 1HNMR(400MHz, DMSO-d6) δ 12.03 (s, 1H), 8.44 (s, 1H), 7.58 (dd, J = 8.1, 1.5 Hz, 1H), 7.48 (s, 1H), 7.23 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 6.80 (dd, J = 8.3, 1.2 Hz, 1H), 6.61 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H). 13 C NMR(100MHz, DMSO) δ 170.04, 167.52, 153.50, 150.74, 143.68, 137.55, 132.90, 127.42, 117.35, 115.40, 114.34, 113.12, 107.66, 103.32, 55.85, 55.82.

[0052]

[0053] Synthesis of Compound 12: Weigh Compound 11 (90.0 mg, 0.28 mmol, 1.0 eq) and add it to a 50 mL volumetric flask. Dissolve it in 20 mL of acetone, then add anhydrous potassium carbonate (157.3 mg, 1.1 mmol, 4.0 eq) and methyl iodide (35.4 mmol, 0.57 mmol, 2.0 eq). Stir vigorously at room temperature for 12 h. Rotavapor to remove acetone, dissolve the product in ethyl acetate, wash the organic phase 3 times with 20 mL of water and once with 10 mL of saturated brine to remove water, then rotavapor to dryness to obtain Compound 12 as a yellowish-white solid product (90 mg, 0.27 mmol), with a yield of approximately 95%. 1 HNMR(400MHz, CDCl3) δ 11.84 (s, 1H), 8.53 (s, 1H), 7.67 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (s, 1H), 7.23–7.19 (m, 1H), 6.73 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H), 6.68 (dd, J = 8.2, 1.2 Hz, 1H), 5.88 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H). 13 C NMR(100MHz, CDCl3) δ 168.62, 167.08, 154.81, 149.70, 143.79, 138.20, 132.78, 126.93, 117.52, 117.02, 115.92, 112.17, 106.05, 102.60, 56.17, 56.11, 52.24.

[0054]

[0055] Synthesis of Compound 15: Using Compound 9, 2,3-pyridinedicarboxylic anhydride, with acetic acid as the solvent, reacting at 118 °C in an oil bath for 3 h. Compound 15 was obtained as a white solid (11 mg, 0.035 mmol), with a yield of approximately 24.4%. 1 H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 9.29 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.47–7.40 (m, 4H), 7.25–7.20 (m, 1H), 7.05–7.00 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 167.47, 164.04, 152.63, 149.02, 139.23, 137.38, 134.97, 132.84, 130.94, 129.26, 129.27, 128.85, 127.05, 125.28, 123.44, 121.97, 121.32, 120.79, 120.27.

[0056]

[0057] Synthesis of Compound 16: Using anthranilic acid, sodium hydroxide, and isatoic anhydride as raw materials for the reaction to obtain Using potassium carbonate and iodomethane as raw materials for the reaction to obtain Using nicotinoyl chloride hydrochloride and triethylamine to obtain Compound 16 as a yellow solid (30 mg, 0.08 mmol), with a yield of approximately 79%. 1 H NMR (400 MHz, CDCl3) δ 12.54 (s, 1H), 12.21 (s, 1H), 9.33 (d, J = 2.2 Hz, 1H), 8.87 (ddd, J = 13.4, 8.5, 1.2 Hz, 2H), 8.79 (dd, J = 5.0, 1.6 Hz, 1H), 8.36 (dt, J = 8.0, 2.0 Hz, 1H), 8.11 (dd, J = 8.1, 1.7 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.68–7.63 (m, 1H), 7.63–7.59 (m, 1H), 7.47 (dd, J = 8.1, 4.9 Hz, 1H), 7.29 (ddd, J = 8.3, 7.5, 1.2 Hz, 1H), 7.18 (ddd, J = 8.2, 7.5, 1.2 Hz, 1H), 3.97 (s, 3H).13 13C NMR (100 MHz, CDCl3) δ 169.67, 167.49, 163.41, 151.96, 148.84, 141.37, 139.90, 135.30, 134.86, 133.45, 131.13, 130.13, 127.27, 123.76, 123.60, 123.04, 121.67, 120.82, 120.42, 116.25, 54.87.

[0058]

[0059] Synthesis of Compound 17 (refer to the synthesis of Compound 16): 2-Amino-5-methoxybenzoic acid, sodium hydroxide, and isatoic anhydride were reacted to obtain Dissolved in acetone, reacted with potassium carbonate anhydrous and iodomethane to obtain Nicotinoyl chloride hydrochloride, triethylamine, to obtain Compound 17 as a yellowish-white solid (100 mg, 0.247 mmol), with a yield of approximately 55%. 1 1H NMR (400 MHz, CDCl3) δ 12.59 (s, 1H), 11.94 (s, 1H), 9.32 (d, J = 2.6 Hz, 1H), 8.88 (dd, J = 8.4, 1.2 Hz, 1H), 8.81–8.74 (m, 2H), 8.36 (dt, J = 8.1, 2.0 Hz, 1H), 7.93 (dd, J = 8.1, 1.5 Hz, 1H), 7.63–7.56 (m, 2H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 7.28 (dd, J = 7.6, 1.2 Hz, 1H), 7.20 (dd, J = 9.2, 3.1 Hz, 1H), 3.97 (s, 3H), 3.85 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 168.70, 167.58, 163.59, 155.15, 152.25, 148.77, 140.44, 136.15, 134.54, 133.25, 130.74, 127.14, 123.74, 123.61, 122.43, 121.63, 121.05, 120.53, 116.87, 114.94, 55.69, 52.77. ESI-HRMS m / z: 405.1394 [M+H] + (calcd for C 22 H 19 N3O5, 405.13247 [M+H] + ).

[0060]

[0061] Synthesis of Compound 18 (refer to the synthesis of Compound 17): Referring to Compound 17, except that 2-amino-5-methoxybenzoic acid was replaced with 2-amino-4-methoxybenzoic acid to obtain Compound 18 as a yellowish-white solid (60 mg, 0.148 mmol), with a yield of approximately 44%. 1 H NMR (400 MHz, CDCl3) δ 12.48 (s, 1H), 12.39 (s, 1H), 9.32 (d, J = 2.3 Hz, 1H), 8.88 (dd, J = 8.4, 1.2 Hz, 1H), 8.79 (dd, J = 4.9, 1.6 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.39–8.34 (m, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.61 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.48 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.29 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 6.68 (dd, J = 8.9, 2.6 Hz, 1H), 3.93 (d, J = 1.0 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 167.90, 167.19, 163.55, 162.62, 151.27, 147.67, 141.99, 139.46, 134.42, 132.40, 131.79, 129.71, 126.35, 122.78, 122.60, 120.65, 119.47, 108.65, 107.31, 104.31, 54.69, 51.33. ESI-HRMS m / z: 405.1392 [M+H] + (calcd for C 22 H 19 N3O5, 405.13247 [M+H] + ).

[0062]

[0063] Synthesis of Compound 19 (refer to the synthesis of Compound 16): Compound 12, nicotinoyl chloride hydrochloride, and triethylamine were used to obtain Compound 19 as a yellowish-white solid (114 mg, 0.262 mmol), with a yield of approximately 96.6%. 1HNMR (400 MHz, CDCl3) δ 12.46 (s, 1H), 12.28 (s, 1H), 9.32–9.29 (m, 1H), 8.86 (dd, J = 8.5, 1.2 Hz, 1H), 8.78 (dd, J = 4.9, 1.7 Hz, 1H), 8.54 (s, 1H), 8.40–8.34 (m, 1H), 7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.52 (s, 1H), 7.47 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.32–7.26 (m, 1H), 4.04 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 169.16, 167.31, 163.62, 154.05, 152.23, 149.09, 144.94, 140.99, 136.49, 135.70, 133.91, 130.87, 127.36, 123.85, 123.67, 121.71, 120.71, 112.25, 107.48, 103.75, 56.37, 56.14, 52.46.

[0064]

[0065] Synthesis of Compound 20 (refer to the synthesis of Compound 16): Compound 12, 6-chloronicotinic acid chloride hydrochloride, triethylamine, gave Compound 20 as a white solid powder (25 mg, 0.053 mmol), with a yield of approximately 71%. 1 H NMR (400 MHz, CDCl3) δ 12.52 (s, 1H), 12.30 (s, 1H), 9.06 (dd, J = 2.6, 0.7 Hz, 1H), 8.83 (dd, J = 8.5, 1.2 Hz, 1H), 8.50 (s, 1H), 8.30 (dd, J = 8.3, 2.5 Hz, 1H), 7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 (ddd, J = 8.7, 7.3, 1.5 Hz, 1H), 7.51 (s, 1H), 7.47 (dd, J = 8.3, 0.8 Hz, 1H), 7.30 - 7.26 (m, 1H), 4.03 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 167.71, 166.79, 161.55, 153.46, 153.01, 147.75, 143.16, 139.23, 137.23, 135.96, 132.33, 128.70, 126.35, 123.39, 122.93, 120.57, 119.48, 111.18, 106.43, 102.65, 55.35, 55.09, 51.45. ESI-HRMS m / z: 469.1113 [M+H] + (calcd for C 23 H 20 ClN3O6, 469.10406 [M+H] + ).

[0066]

[0067] Synthesis of Compound 21 (refer to the synthesis of Compound 16): 2-Amino-4,5-difluorobenzoic acid, sodium hydroxide, and isatoic anhydride were added and reacted to obtain Potassium carbonate anhydrous and iodomethane were added and reacted to obtain an intermediate Nicotinoyl chloride hydrochloride and triethylamine were reacted to obtain Compound 21 as a yellow solid (50 mg, 0.122 mmol), and the yield was approximately 47%. 1 1H NMR (400 MHz, CDCl3) δ 12.38 (s, 1H), 12.21 (s, 1H), 9.33–9.28 (m, 1H), 8.88 (dd, J = 8.4, 1.2 Hz, 1H), 8.86–8.77 (m, 2H), 8.33 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 7.89 (ddd, J = 8.7, 6.5, 5.0 Hz, 2H), 7.61 (ddd, J = 8.7, 7.4, 1.5 Hz, 1H), 7.48 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.29–7.24 (m, 1H), 3.97 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 166.96, 166.52, 162.62, 154.14, 154.02, 151.60, 151.49, 147.82, 145.85, 145.72, 143.39, 143.26, 139.69, 137.63, 137.61, 137.53, 137.50, 134.12, 132.80, 129.43, 126.13, 122.72, 122.59, 120.72, 118.59, 118.36, 110.85, 109.20, 52.41, 52.04. 19 19F NMR (376 MHz, CDCl3) δ -124.15 (ddd, J = 22.4, 13.1, 8.7 Hz), -141.30 (ddd, J = 22.8, 10.8, 7.5 Hz). ESI-HRMS m / z: 411.1099 [M+H] + (calcd for C 21 H 15 F2N3O4, 411.10306 [M+H] + ).

[0068]

[0069] Synthesis of Compound 22 (refer to the synthesis of Compound 4): Methyl 2-amino-4,6-dimethoxybenzoate, triethylamine, o-nitrobenzoic acid, react to obtain 5% palladium on carbon, in a hydrogen atmosphere, react to obtain Nicotinoyl chloride hydrochloride, triethylamine, to obtain Compound 22 as a yellowish-white solid (70 mg, 0.161 mmol), with a yield of approximately 40%. 1 1H NMR (400 MHz, CDCl3) δ 12.40 (s, 1H), 11.76 (s, 1H), 9.34–9.27 (m, 1H), 8.85 (dd, J = 8.5, 1.2 Hz, 1H), 8.81–8.75 (m, 1H), 8.34 (dt, J = 8.1, 1.9 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.1, 1.5 Hz, 1H), 7.60 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.46 (dd, J = 8.0, 4.8 Hz, 1H), 7.30–7.26 (m, 1H), 6.30 (d, J = 2.4 Hz, 1H), 3.92 (s, 6H), 3.86 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 168.48, 166.94, 163.01, 162.65, 160.65, 151.30, 147.68, 141.25, 139.34, 134.39, 132.36, 129.69, 126.20, 122.79, 122.58, 120.69, 119.62, 100.47, 97.35, 94.38, 55.28, 54.68, 51.46. ESI-HRMS m / z: 435.1450 [M+H] + (calcd for C 23 H 21 N3O6, 435.14304 [M+H] + ).

[0070]

[0071] Synthesis of Compound 23 (refer to the synthesis of Compound 16): 2-Amino-4,5-dimethoxybenzoic acid, sodium hydroxide, 5-fluoro isatoic anhydride, reacted to obtain

[0072] Potassium carbonate anhydrous, methyl iodide, reacted to obtain Nicotinoyl chloride hydrochloride, triethylamine, to obtain Compound 23 as an off-white solid (45.5 mg, 0.10 mmol) with a yield of approximately 50%. 1 1H NMR (400 MHz, CDCl3) δ 12.31 (s, 1H), 12.24 (s, 1H), 9.28 (d, J = 2.4 Hz, 1H), 8.86 (dd, J = 9.3, 5.2 Hz, 1H), 8.79 (dd, J = 4.9, 1.7 Hz, 1H), 8.49 (s, 1H), 8.35 (dt, J = 8.0, 2.0 Hz, 1H), 7.65 (dd, J = 9.1, 2.9 Hz, 1H), 7.52 (s, 1H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 7.32 (ddd, J = 10.0, 7.6, 2.9 Hz, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H). 1313C NMR (100 MHz, CDCl3) δ 167.71, 165.58, 162.48, 158.36, 155.92, 153.02, 151.30, 147.36, 143.73, 135.69, 135.54, 134.64, 129.62, 122.67, 121.21, 119.20, 113.10, 111.19, 106.57, 102.69, 55.36, 55.11, 51.54. ESI-HRMS m / z: 453.1404 [M+H] + (calcd for C 23 H 20 FN3O6, 453.13361 [M+H] + ).

[0073]

[0074] Synthesis of Compound 24 (refer to the synthesis of Compound 16): 2-Amino-4,5-dimethoxybenzoic acid, sodium hydroxide, and 4,5-dimethoxyisatoic anhydride were reacted to obtain Iodomethane and potassium carbonate were reacted to obtain 6-Chloronicotinoyl chloride hydrochloride, triethylamine, gave Compound 24 as a yellow solid (87 mg, 0.164 mmol), with a yield of approximately 80%. 1 1H NMR (400 MHz, CDCl3) δ 12.82 (s, 1H), 12.30 (s, 1H), 9.08–9.06 (m, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.30 (dd, J = 8.3, 2.5 Hz, 1H), 7.50 (s, 1H), 7.47 (t, J = 4.2 Hz, 2H), 4.03 (s, 3H), 4.02 (s, 6H), 3.93 (s, 3H), 3.91 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 168.69, 167.32, 162.33, 154.23, 153.94, 152.60, 148.62, 144.69, 144.18, 137.88, 137.17, 136.07, 129.59, 124.22, 112.04, 111.36, 109.27, 107.01, 104.26, 103.21, 56.18, 56.02, 55.94, 52.12, 45.64. ESI-HRMS m / z: 529.1163 [M+H] + (calcd for C 25 H 24ClN3O8, 529.12519 [M+H] + ).

[0075] Example 3: Synthesis of Compounds 6 and 13 - 14

[0076] The route is as follows:

[0077]

[0078] Synthesis of Compound 6: Place Compound 4 (10.0 mg, 0.022 mmol, 1.0 eq) in a 25 mL flask, add 3 mL of methanol to dissolve it. Take sodium hydroxide (4.3 mg, 0.107 mmol, 5.0 eq), dissolve it in 1 mL of water and add it to the above solution. React under reflux at 65 °C for 3 - 5 h. Rotavapor to remove methanol, add 3 mL of water to dilute, adjust the pH to 5 - 6 with 5% HCl, extract the aqueous phase 3 times with 5 mL of ethyl acetate, combine the organic phases, remove water, and rotavapor to dryness to obtain Compound 6 as a white solid powder (9 mg, 0.02 mmol), with a yield of approximately 92.8%. 1 H NMR (400 MHz, DMSO - d6) δ 12.32 (s, 1H), 10.24 (s, 1H), 9.06 (d, J = 2.3 Hz, 1H), 8.78 (dd, J = 4.9, 1.6 Hz, 1H), 8.66 (d, J = 8.3 Hz, 1H), 8.22 (dt, J = 8.1, 2.0 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.60 (dd, J = 8.0, 4.8 Hz, 1H), 7.35 - 7.29 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.76 (s, 3H). 13 C NMR (100 MHz, DMSO - d6) δ 168.54, 166.78, 163.44, 152.95, 151.50, 150.38, 148.18, 145.45, 139.62, 134.62, 133.10, 130.39, 129.59, 125.01, 124.63, 124.46, 123.41, 121.51, 120.76, 109.73, 61.42, 61.08, 56.50.

[0079]

[0080] Synthesis of Compound 13 (referring to the synthesis of Compound 6): Hydrolyze Compound 18 with NaOH to obtain Compound 13 as a pale yellow - green solid powder (7.7 mg, 0.02 mmol), with a yield of approximately 80%. 11H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 11.45 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.77 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 8.26–8.23 (m, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.0, 4.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 6.78 (dd, J = 8.9, 2.6 Hz, 1H), 3.84 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 169.47, 166.49, 163.50, 163.38, 152.29, 148.21, 142.45, 137.16, 134.98, 133.02, 132.19, 129.92, 127.99, 125.53, 124.57, 123.63, 123.04, 109.09, 108.45, 105.24, 55.39. ESI-HRMS m / z: 391.1238 [M+H] + (calcd for C 21 H 17 N3O5, 391.11682 [M+H] + ).

[0081]

[0082] Synthesis of Compound 14 (refer to the synthesis of Compound 6): Compound 19 was reacted with NaOH to obtain Compound 14 as a brown solid powder (6 mg, 0.023 mmol), with a yield of approximately 50%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.62 (s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 4.7 Hz, 1H), 7.47 (s, 1H), 7.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.78 (t, J = 7.7 Hz, 1H), 6.72 (dd, J = 8.0, 4.8 Hz, 1H), 6.59 (s, 1H), 6.50 (t, J = 7.6 Hz, 1H), 2.99 (s, 3H), 2.92 (s, 3H). 13CNMR(100MHz, DMSO-d6) δ 169.83, 166.79, 164.10, 153.50, 152.92, 148.84, 144.56, 137.80, 136.64, 135.63, 132.70, 130.51, 128.69, 126.06, 125.13, 124.27, 123.57, 113.32, 109.29, 104.49, 56.15, 56.10. ESI-HRMS m / z: 421.1339 [M+H] + (calcd for C 22 H 19 N3O6, 421.12739 [M+H] + ).

[0083] Example 4: Synthesis of Compound 25-41

[0084] The route is as follows:

[0085]

[0086] Synthesis of Compound 26: Weigh 2,3-pyridinedicarboxylic anhydride (119.00 mg, 0.798 mmol, 1.0 eq) into a 50 mL flask, add 8 mL of glacial acetic acid and dissolve it by ultrasound. Then add methyl anthranilate (100.54 mmol, 0.798 mmol, 1.0 eq) and stir evenly. Gradually heat the oil bath to 118 °C and reflux for about 3 h. Add 20 mL each of ethyl acetate and water to dilute the glacial acetic acid solution to make it layer. Wash the organic layer 3 times with 10 mL of water and 3 times with 10 mL of saturated sodium chloride solution to remove water, and then rotary evaporate to dryness. Subsequently, sample and pass through a silica gel column, elute with petroleum ether / ethyl acetate (10 / 1 - 5 / 1, v / v) to obtain Compound 26 as a white solid product (112 mg, 0.44 mmol), with a yield of about 55%. 1 HNMR(400MHz, CDCl3) δ 12.18(s, 1H), 9.37–9.26(m, 1H), 8.90(dd, J = 8.4, 1.1 Hz, 1H), 8.80(dd, J = 5.0, 1.6 Hz, 1H), 8.33(ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 8.10(dd, J = 8.0, 1.7 Hz, 1H), 7.67–7.61(m, 1H), 7.52–7.44(m, 1H), 7.16(ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 3.97(s, 3H). 1313C NMR (100 MHz, CDCl3) δ 169.28, 163.98, 152.73, 149.08, 141.57, 135.12, 135.07, 131.15, 130.65, 123.69, 123.24, 121.09, 115.44, 53.12.

[0087]

[0088] Synthesis of Compound 25 (refer to the synthesis of Compound 6): Compound 26, sodium hydroxide, methanol, water were used for reaction to obtain a white solid product (45 mg, 0.186 mmol), with a yield of approximately 95%. 1 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.13 (s, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (dd, J = 8.4, 1.2 Hz, 1H), 8.32–8.27 (m, 1H), 8.05 (dd, J = 7.9, 1.7 Hz, 1H), 7.70–7.61 (m, 2H), 7.27–7.21 (m, 1H). 13 13C NMR (100 MHz, DMSO-d6) δ 169.80, 163.12, 152.16, 147.69, 140.45, 135.48, 134.22, 131.24, 130.38, 124.23, 123.51, 120.41, 117.47.

[0089]

[0090] Synthesis of Compound 27: Weighed Compound 25 (200 mg, 0.826 mmol) into a 50 mL volumetric flask, added 6 mL of thionyl chloride, refluxed for 3 - 5 h, rotary evaporated to remove thionyl chloride, added dichloromethane and rotary evaporated again to remove the residual thionyl chloride, obtaining an intermediate which was a white solid with a yield of approximately 93%. Took the intermediate (50 mg, 0.192 mmol, 1.0 eq) into a 25 mL volumetric flask, diluted it with 3 mL of ethanol, then added triethylamine dropwise (133.31 mml, 0.959 mmol, 5.0 eq) and reacted at room temperature for 12 h. Purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10 / 1, v / v), and obtained Compound 27 as a white solid (24.5 mg, 0.096 mmol), with a yield of approximately 50%. 11H NMR (400 MHz, CDCl3) δ 12.25 (s, 1H), 9.31 (s, 1H), 8.90 (dd, J = 8.5, 1.2 Hz, 1H), 8.82–8.77 (m, 1H), 8.34 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.48 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 168.83, 163.96, 152.68, 149.06, 141.56, 135.14, 134.93, 131.11, 130.65, 123.68, 123.18, 120.59, 115.69, 61.85, 14.72.

[0091]

[0092] Synthesis of Compound 28 (refer to the synthesis of Compound 27): Compound 25, thionyl chloride, to obtain triethylamine, n-butanol, to obtain Compound 28 as a yellow solid (11 mg, 0.037 mmol), with a yield of approximately 18%. 1 1H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 9.30 (dd, J = 2.4, 0.9 Hz, 1H), 8.89 (dd, J = 8.5, 1.1 Hz, 1H), 8.79 (dd, J = 4.8, 1.7 Hz, 1H), 8.32 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.62 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.46 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.16 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.37 (t, J = 6.6 Hz, 2H), 1.79 (ddt, J = 8.9, 7.9, 6.5 Hz, 2H), 1.55 - 1.45 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 168.90, 163.99, 152.72, 149.10, 141.59, 135.13, 134.94, 131.08, 130.66, 123.68, 123.21, 120.63, 115.74, 65.69, 30.71, 19.39, 13.86.

[0093]

[0094] Synthesis of Compound 29 (refer to the synthesis of Compound 27): Compound 25, thionyl chloride, gave triethylamine, n-pentanol, gave Compound 29 as an oily liquid (26 mg, 0.087 mmol), with a yield of approximately 50%. 1 1H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 9.35 - 9.25 (m, 1H), 8.88 (dd, J = 8.4, 1.2 Hz, 1H), 8.84 - 8.74 (m, 1H), 8.31 (dt, J = 8.0, 2.0 Hz, 1H), 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.61 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.45 (dd, J = 8.0, 4.8 Hz, 1H), 7.20–7.12 (m, 1H), 4.35 (t, J = 6.7 Hz, 2H), 1.85 - 1.73 (m, 2H), 1.41 (ttd, J = 15.0, 8.0, 7.2, 2.7 Hz, 4H), 0.93 (t, J = 7.0 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 167.73, 162.81, 151.54, 147.94, 140.43, 133.96, 133.76, 129.92, 129.50, 122.52, 122.04, 119.46, 114.58, 76.34, 76.02, 75.71, 64.82, 27.23, 27.12, 21.30, 12.95. ESI-HRMS m / z: 312.1544 [M+H] + (calcd for C 18 H 20 N2O3, 312.14739 [M+H] + ).

[0095]

[0096] Synthesis of Compound 30 (refer to the synthesis of Compound 27): Compound 25, thionyl chloride, reacted to give an intermediate Triethylamine and hexanol were used to obtain Compound 30 as a white solid (15 mg, 0.046 mmol), with a yield of approximately 24%. 1 H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 9.32–9.28 (m, 1H), 8.89 (dd, J = 8.5, 1.2 Hz, 1H), 8.79 (dd, J = 4.9, 1.7 Hz, 1H), 8.32 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.10 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.46 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 7.16 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.36 (t, J = 6.7 Hz, 2H), 1.84–1.75 (m, 2H), 1.71 (s, 1H), 1.50–1.41 (m, 2H), 1.35 (dq, J = 6.6, 3.5 Hz, 4H), 0.91 (td, J = 7.2, 6.0, 2.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.77, 163.87, 152.59, 148.99, 141.47, 135.00, 134.80, 130.95, 130.54, 123.54, 123.08, 120.51, 115.63, 65.87, 31.42, 28.53, 25.69, 22.55, 14.00. ESI-HRMS m / z: 326.1700 [M+H] + (calcd for C 19 H 22 N2O3, 326.16304 [M+H] + ).

[0097]

[0098] Synthesis of Compound 31: Weigh Compound 25 (50 mg, 0.206 mmol, 1.0 eq) into a 25 mL reaction flask, add 3 mL of DMF to dissolve it, then add ethyl bromoacetate (63.15 mg, 0.413 mmol, 2.0 eq) and cesium carbonate (134.51 mg, 0.413 mmol, 2.0 eq), and react at room temperature for about 12 h. Add 5 mL of water to the reaction solution, extract with 10 mL of ethyl acetate three times, wash the organic phase with 10 mL of saturated brine three times, remove water, rotary evaporate to dryness, and purify by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (3 / 1 - 2 / 1, v / v) to obtain Compound 31 as a yellow crystalline solid (40 mg, 0.12 mmol), with a yield of approximately 63%. 1 H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H), 9.26 (d, J = 2.3 Hz, 1H), 8.90 (dd, J = 8.6, 1.1 Hz, 1H), 8.78 (dd, J = 4.8, 1.7 Hz, 1H), 8.30 (dt, J = 8.0, 1.9 Hz, 1H), 8.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.65 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.45 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.19 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.88 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 168.00, 167.29, 163.85, 152.66, 148.81, 141.65, 135.49, 135.15, 131.39, 130.44, 123.58, 123.27, 120.57, 114.56, 62.38, 61.46, 14.14.

[0099]

[0100] Synthesis of Compound 32 (referring to the synthesis of Compound 31): Using Compound 25, methyl 3 - bromopropionate, and cesium carbonate, Compound 32 was obtained as a white solid (20 mg, 0.061 mmol), with a yield of approximately 30%. 1HNMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 9.30 (s, 1H), 8.89 (dd, J = 8.6, 1.2 Hz, 1H), 8.82 (s, 1H), 8.34 (dt, J = 8.0, 1.9 Hz, 1H), 8.06 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.50 (dd, J = 8.0, 4.8 Hz, 1H), 7.16 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 4.64 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H), 2.84 (t, J = 6.3 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 169.82, 167.40, 162.65, 151.34, 147.65, 140.47, 134.31, 134.11, 130.03, 122.72, 122.17, 119.52, 113.48, 59.20, 51.04, 31.50.

[0101]

[0102] Synthesis of Compound 33 (refer to the synthesis of Compound 31): Compound 25, ethyl bromoacetate, cesium carbonate, gave Compound 33 as a yellow oil (11 mg, 0.027 mmol), with a yield of 13%. 1 HNMR (400 MHz, CDCl3) δ 8.53 (dd, J = 2.2, 0.9 Hz, 1H), 8.43 (dd, J = 4.9, 1.7 Hz, 1H), 7.97 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 (dt, J = 7.9, 1.9 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.32 (ddd, J = 7.8, 6.9, 1.9 Hz, 1H), 7.09 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 5.13 (d, J = 17.4 Hz, 1H), 4.88 - 4.76 (m, 2H), 4.29 - 4.21 (m, 4H), 3.93 (d, J = 17.5 Hz, 1H), 1.30 (td, J = 7.1, 3.2 Hz, 6H). 1313C NMR (100 MHz, CDCl3) δ 169.00, 168.26, 167.26, 164.50, 150.58, 149.15, 142.98, 135.78, 133.89, 132.17, 131.89, 131.23, 128.47, 126.94, 122.71, 77.36, 77.04, 76.72, 61.76, 61.51, 61.38, 52.34, 14.17, 14.14.

[0103]

[0104] Synthesis of Compound 34 (refer to the synthesis of Compound 31): Compound 25, ethyl 4-bromobutyrate, cesium carbonate, gave Compound 34 as a colorless oily product (7 mg, 0.015 mmol), with a yield of approximately 8%. 1 1H NMR (400 MHz, CDCl3) δ 8.44 - 8.38 (m, 2H), 7.80 (dd, J = 7.8, 1.7 Hz, 1H), 7.58 (dt, J = 8.0, 2.0 Hz, 1H), 7.48 (td, J = 7.7, 1.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.07 (ddd, J = 7.9, 4.9, 0.8 Hz, 1H), 4.37 - 4.19 (m, 4H), 4.11 (dq, J = 9.9, 7.1 Hz, 4H), 2.45 - 2.36 (m, 4H), 2.09 - 1.97 (m, 4H), 1.23 (dt, J = 8.5, 7.1 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 173.13, 172.27, 168.05, 165.14, 149.98, 149.32, 142.91, 135.96, 133.53, 132.13, 132.08, 130.71, 128.46, 128.11, 122.72, 64.79, 60.73, 60.59, 50.69, 31.91, 30.88, 24.08, 23.07, 14.34 (C×2).

[0105]

[0106] Synthesis of Compound 35 (refer to the synthesis of Compound 31): Compound 25, 2-(dimethylamino)ethyl hydrobromide, cesium carbonate, gave Compound 35 as a colorless oily product (18 mg, 0.058 mmol), with a yield of approximately 28%. 11H NMR (400 MHz, CDCl3) δ 12.14 (s, 1H), 9.28 (dd, J = 2.3, 0.9 Hz, 1H), 8.88 (dd, J = 8.5, 1.2 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.31 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.11 (dd, J = 8.0, 1.7 Hz, 1H), 7.61 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.46 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 7.15 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 4.48 (t, J = 5.7 Hz, 2H), 2.78 (d, J = 5.7 Hz, 2H), 2.37 (s, 6H). 13 13C NMR (100 MHz, CDCl3) δ 167.58, 162.82, 151.57, 147.87, 140.45, 134.05, 133.95, 130.08, 129.50, 122.55, 122.11, 119.50, 114.32, 76.33, 76.02, 75.70, 62.31, 56.51, 44.64.

[0107]

[0108] Synthesis of Compound 36 (refer to the synthesis of Compound 31): Compound 25, 4-(bromomethyl)pyridine hydrobromide, cesium carbonate, gave Compound 36 as a pale yellow powder (40 mg, 0.12 mmol), with a yield of approximately 58%. 1 1H NMR (400 MHz, CDCl3) δ 12.03 (s, 1H), 9.29 (d, J = 2.4 Hz, 1H), 8.92 (dd, J = 8.6, 1.2 Hz, 1H), 8.80 (dd, J = 4.9, 1.6 Hz, 1H), 8.68 (d, J = 5.0 Hz, 2H), 8.31 (dt, J = 8.1, 2.0 Hz, 1H), 8.19 (dd, J = 8.0, 1.7 Hz, 1H), 7.66 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.47 (dd, J = 8.0, 4.8 Hz, 1H), 7.36 (d, J = 5.6 Hz, 2H), 7.22–7.16 (m, 1H), 5.42 (s, 2H). 1313C NMR (100 MHz, CDCl3) δ 168.16, 163.87, 152.70, 150.16, 148.77, 144.29, 141.76, 135.51, 135.13, 130.98, 130.44, 123.66, 123.27, 122.05, 120.72, 114.69, 77.36, 77.04, 76.73, 65.20.

[0109]

[0110] Synthesis of Compound 37 (refer to the synthesis of Compound 31): Compound 25, 1-(2-bromoethyl)piperidine hydrobromide, cesium carbonate, gave Compound 37 as a colorless oily product (40 mg, 0.113 mmol), with a yield of approximately 56%. 1 1H NMR (400 MHz, CDCl3) δ 12.18 (s, 1H), 9.28 (dd, J = 2.4, 0.9 Hz, 1H), 8.88 (dd, J = 8.6, 1.1 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.08 (dd, J = 8.0, 1.7 Hz, 1H), 7.61 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.45 (ddd, J = 7.9, 4.8, 0.9 Hz, 1H), 7.15 (ddd, J = 8.3, 7.4, 1.2 Hz, 1H), 4.48 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 5.3 Hz, 4H), 1.58 (p, J = 5.6 Hz, 4H), 1.43 (tq, J = 8.6, 5.7, 4.6 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 168.67, 163.40, 152.70, 149.04, 141.56, 135.11, 134.52, 131.12, 129.44, 123.65, 122.81, 120.59, 115.56, 63.53, 57.23, 54.93, 26.04, 24.20.

[0111]

[0112] Synthesis of Compound 38 (refer to the synthesis of Compound 31): Compound 25, bromomethylcyclopropane, cesium carbonate, gave Compound 38 as a yellow crystalline solid (28 mg, 0.095 mmol), with a yield of approximately 50%. 1HNMR(400MHz,CDCl3)δ12.31(s,1H),9.38(dd,J=2.4,0.9Hz,1H),8.98(dd,J=8.5,1.2Hz,1H),8.88(dd,J=4.8,1.7Hz,1H),8.41(ddd,J=8.0,2.4,1.7Hz,1H),8.25(dd,J=8.0,1.7Hz,1H),7.71(ddd,J=8.7,7.3,1.7Hz,1H),7.55(ddd,J=8.0,4.9,0.9Hz,1H),7.26(ddd,J=8.2,7.3,1.2Hz,1H),4.30(s,1H),4.28(s,1H),1.42–1.33(m,1H),0.78–0.71(m,2H),0.49(dt,J=6.2,4.7Hz,2H). 13 C NMR(100MHz,CDCl3)δ168.79,163.83,152.58,148.94,141.42,135.00,134.80,131.11,130.53,123.54,123.08,120.47,115.66,77.37,77.05,76.74,70.52,9.75,3.45.

[0113]

[0114] Synthesis of Compound 41 (refer to the synthesis of Compound 31): Compound 25, 2-bromoacetamide, cesium carbonate, gave Compound 41 as a white solid powder (20 mg, 0.067 mmol), with a yield of approximately 30%. 1 H NMR(400MHz,Methanol)δ9.03(d,J=2.3Hz,1H),8.64(dd,J=8.5,1.1Hz,1H),8.60–8.57(m,1H),8.19(dt,J=8.0,1.9Hz,1H),8.06(dd,J=8.0,1.6Hz,1H),7.51(ddd,J=8.6,7.3,1.6Hz,1H),7.39(dd,J=8.1,4.9Hz,1H),7.07(td,J=7.7,1.2Hz,1H),4.70(s,2H). 1313C NMR (100 MHz, CDCl3) δ 169.95, 167.58, 163.64, 152.03, 148.14, 140.90, 135.45, 135.28, 131.15, 130.48, 123.94, 123.49, 120.54, 114.85, 62.79. ESI-HRMS m / z: 299.0977 [M+H] + (calcd for C 15 H 13 N3O4, 299.09061 [M+H] + ).

[0115]

[0116] Synthesis of Compound 39: Take Compound 27 (100 mg, 0.390 mmol) in a pressure-resistant tube, add 5 mL of methanol solution of ammonia, seal it, and heat and stir at 70 °C for about 10 h. Rotate and evaporate to remove methanol, wash the raw materials with dichloromethane to obtain Compound 39 as a white solid (60 mg, 0.25 mmol), and the yield is about 64%. 1 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 9.30 (dd, J = 2.3, 0.9 Hz, 1H), 8.76 (dd, J = 4.8, 1.6 Hz, 1H), 8.49 (ddd, J = 8.1, 2.4, 1.7 Hz, 1H), 8.17 (ddd, J = 7.9, 1.6, 0.6 Hz, 1H), 7.86 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.77 (dt, J = 7.6, 0.9 Hz, 1H), 7.61 - 7.52 (m, 2H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.11, 151.84, 150.76, 148.76, 148.55, 135.40, 134.72, 128.73, 127.60, 126.98, 125.90, 123.54, 121.15.

[0117]

[0118] Synthesis of Compound 40: Weigh Compound 39 (10 mg, 0.041 mmol, 1.0 eq) into a 25 mL reaction flask, dissolve it with 3 mL of acetone, then add methyl iodide (5.88 mg, 0.041 mmol) and cesium carbonate (27.01 mg, 0.083 mmol), and stir at room temperature for about 3 h. Stir the sample and perform column chromatography, eluting the product spot with ethyl acetate / petroleum ether (1 / 2, v / v) to obtain Compound 40 as a light pink solid (6 mg, 0.024 mmol), with a yield of about 57%. 1 H NMR (400 MHz, CDCl3) δ 9.78 (dd, J = 2.3, 0.9 Hz, 1H), 8.84 (dt, J = 8.0, 2.0 Hz, 1H), 8.72 (dd, J = 4.8, 1.7 Hz, 1H), 8.18 (dd, J = 8.2, 1.5 Hz, 1H), 8.00 (dt, J = 8.4, 0.9 Hz, 1H), 7.84 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.55 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.43 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 4.30 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 166.24, 157.12, 150.61, 150.09, 149.24, 134.66, 132.72, 132.61, 126.96, 125.91, 122.53, 122.25, 114.49, 53.26.

[0119] Example 5: Synthesis of Compounds 42 - 44

[0120] The route is as follows:

[0121]

[0122] Synthesis of Compound 42: Weigh Compound 12 (30 mg, 0.091 mmol) and add it to a pressure - resistant tube, dilute it with 2 mL of methanol, then add 1 mL of carbon disulfide and potassium hydroxide (5.10 mg, 0.091 mmol). Seal the tube and heat under reflux at 70 °C for 12 h. Rotavapor to remove methanol and carbon disulfide. Purify by solid - phase extraction column, eluting the product spot with ethyl acetate / petroleum ether (3 / 1 - 2 / 1, v / v), and then rotavapor to dryness to obtain Compound 42 as a white solid product (about 15 mg, 0.04 mmol), with a yield of about 45%. 11H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.9, 1.5 Hz, 1H), 7.67 (s, 1H), 7.63 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.31 (ddd, J = 8.1, 7.3, 1.0 Hz, 1H), 7.19 - 7.15 (m, 1H), 6.80 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.71 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 176.19, 164.36, 160.47, 153.25, 148.81, 138.97, 135.62, 133.52, 128.75, 124.97, 119.18, 116.42, 115.03, 113.36, 112.71, 56.30, 56.18, 52.18.

[0123]

[0124] Synthesis of Compound 43: Compound 42 (100.00 mg, 0.269 mmol) was added to a 25 mL round-bottom flask and dissolved in 5 mL of methanol. Nickel chloride (104.40 mg, 0.806 mmol) was weighed and added to the above solution, and the mixture was stirred for 5 minutes. Subsequently, NaBH4 (91.43 mg, 2.42 mmol) was added. The solution changed from clear and transparent to black, and a large amount of bubbles were generated. After waiting for the bubbles to disappear, the reaction flask was sealed. Monitored by TLC, after about 30 minutes, the starting material spot disappeared, and then the reaction was stopped. Methanol was removed by rotary evaporation. 10 mL of water and 10 mL of ethyl acetate were added to the solid, and the aqueous phase was extracted 3 times with 10 mL of ethyl acetate. The organic phase was washed 2 times with 5 mL of saturated NaHCO3 solution and 1 time with 5 mL of saturated NaCl solution to remove water, and then dried by rotary evaporation. Purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (1 / 3, v / v, 1 - 3% triethylamine). Compound 43 was obtained as a transparent solid (30 mg, 0.088 mmol). The yield was approximately 32%. 1 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.79 (dd, J = 6.3, 1.6 Hz, 2H), 7.67 (s, 1H), 7.53 (ddd, J = 8.2, 6.1, 2.2 Hz, 1H), 6.84 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.68 (s, 3H). 1313C NMR (101 MHz, CDCl3) δ 164.68, 161.53, 153.10, 149.46, 148.25, 146.48, 134.66, 131.84, 127.78, 127.57, 127.25, 122.54, 120.11, 113.78, 112.30, 56.55, 56.52, 52.51.

[0125]

[0126] Compound 44 (synthesis process refers to 43): Synthesized with reference to Compound 12, the difference being that methyl iodide is replaced with ethyl iodide for the synthesis of the intermediate with Compound 11 Then, referring to the synthesis of Compound 43, Compound 44 was obtained as white (10 mg, 0.028 mmol), with a yield of approximately 27%. 1 1H NMR (400 MHz, CDCl3) δ 8.37 - 8.33 (m, 1H), 7.98 (s, 1H), 7.83 - 7.76 (m, 2H), 7.70 (s, 1H), 7.54 (ddd, J = 8.2, 6.6, 1.8 Hz, 1H), 6.84 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.95 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 164.36, 161.43, 152.88, 149.38, 148.12, 146.43, 134.59, 131.34, 127.59, 127.49, 127.08, 122.46, 120.55, 113.86, 112.05, 61.46, 56.43, 56.40, 13.58.

[0127] Example 6: This invention is a protection test of anthranilic acid derivatives on oxygen - glucose deprivation (OGD) cardiomyocytes.

[0128] 1. Sample preparation

[0129] The test samples were prepared into a 1.0 mg / mL solution with the solvent dimethyl sulfoxide (DMSO), and small amounts of the solution were respectively diluted to the required concentrations. For the cardiomyocyte protection experiment, the concentration of the test compound was 10 μM, and the positive drug diazoxide was 100 μM.

[0130] 2. Preparation of H9c2 cardiomyocytes

[0131] H9c2 cardiomyocytes (from ATCC) were cultured in complete high-glucose DMEM medium (containing 10% FBS and 1% PS), and placed in a constant temperature incubator with saturated humidity at 37°C and 5% CO2 for routine culture. The medium was changed every two days, and the cells were digested with EDTA trypsin. When performing oxygen-glucose deprivation / reoxygenation (OGD / R) treatment, H9c2 cells in the logarithmic phase with good growth status were digested with trypsin and seeded in 6-well plates at a density of 2×10 5 cells. The cells were incubated overnight in the incubator. After the cells were completely adherent, the complete culture medium of H9c2 cells was aspirated, and the cells were washed twice with PBS. Then, the medium was replaced with sugar-free DMEM medium, and the cells were cultured in an incubator at 37°C containing 95% N2 and 5% CO2 for 3 h. After the OGD was completed, the sugar-free medium was removed and replaced with high-glucose DMEM medium (containing 10% FBS and 1% PS), and the cells were continued to be cultured in a constant temperature incubator with saturated humidity at 5% CO2 and 37°C.

[0132] 3. Myocardial protection experiment

[0133] After H9c2 cells were treated with OGD (100 μL of sugar-free medium was added and the cells were placed in an anoxic device for 6 h of oxygen-glucose deprivation), the medium was replaced with 100 μL of complete medium containing drugs (10 μM of the test compound and 100 μM of the positive control drug diazoxide), and the cells were cultured in a normal incubator for 12 h. The original medium was discarded, and the prepared MTT working solution (prepared with complete medium, concentration 0.5 mg / mL) was added, 100 μL per well, and incubated at 37°C for 4 h. The MTT working solution was removed, and DMSO was added, 150 μL per well, and shaken in the dark on a shaker for 10 min. The absorbance of each well was measured at 570 nm using an enzyme-linked immunosorbent assay (ELISA) reader.

[0134] The myocardial cell protection activity was expressed as the increase in cell survival rate of the drug-administered group compared to the model group (cell survival rate % of the drug-administered group - cell survival rate % of the model group). The results are shown in Table 1:

[0135] Table 1 Myocardial protection activity of the compounds

[0136]

[0137] As can be seen from Table 1, all of the said derivatives could increase the survival rate of cardiomyocytes damaged by OGD / R to varying degrees.

Claims

1. o - amide benzoyl derivatives represented by Formula I - II: Among them, R1 is NHR6, CH3(CH2)4O-, CH3(CH2)5O- or one of the following groups: R6 is R'1, R'2, R'3 = -OCH3, H, F; R'4 = H, CH3; R2 is H or -OCH3; R3 is H, F or -OCH3; R4 is R5 is H, R7 is 2. Use of the anthranilic acid derivative according to Claim 1 in the preparation of a cardioprotective drug.

3. The application according to claim 2, wherein The drug further contains one or more pharmaceutically acceptable carriers or excipients.

4. The application according to claim 3, wherein The excipients include sustained - release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, adsorption carriers, surfactants or lubricants.

5. The application according to claim 3, characterized in that The carrier is at least one of microcapsules, microspheres, nanoparticles and liposomes.

6. The application according to Claim 3, wherein the drug is made into various dosage forms.

7. Use in the preparation of a myocardial protective drug.

8. The application according to claim 7, wherein The drug further contains one or more pharmaceutically acceptable carriers or excipients.

9. The application according to claim 8, wherein The carrier is at least one of microcapsules, microspheres, nanoparticles and liposomes; the excipients include sustained - release agents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, adsorption carriers, surfactants or lubricants.

10. The application according to claim 8, wherein The drug is made into various dosage forms.

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