Pentacyclic triterpene derivative and medical application thereof

Abstract

The invention discloses application of pentacyclic triterpenoid saponin and derivatives thereof in prevention and treatment of cardiac hypertrophy. Belongs to the field of pharmaceutical chemistry. The pentacyclic triterpene derivative or the pharmaceutically acceptable salt thereof is shown as a general formula (I): # imgabs0. The pentacyclic triterpene derivative disclosed by the invention has a relatively good binding effect on a potential intervention target GATA6 of myocardial hypertrophy, can be used for remarkably preventing and reversing in-vitro myocardial cell hypertrophy and in-vivo myocardial hypertrophy, and has a potential medicinal value.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and relates to a class of pentacyclic triterpene derivatives and uses thereof, and specifically relates to a class of pentacyclic triterpene derivatives and uses thereof in preparing drugs for preventing and treating hypertrophic cardiomyopathy. Background Art

[0002] Myocardial hypertrophy often occurs in a variety of heart diseases such as hypertension, valvular heart disease and myocardial infarction. It is a common pathological phenomenon in clinical practice. It is a compensatory mechanism for the heart when the load increases. It is also an independent predictor of increased mortality in patients with cardiovascular disease. With the progression of the disease, the hypertrophic myocardium gradually cannot resist the increased load due to factors such as increased oxygen consumption, decreased adrenergic receptor density, and weakened contractility. The cardiac output decreases, and the heart function decompensates and symptoms of congestive heart failure appear. It is also more prone to complications such as arrhythmias and morbidity. Therefore, myocardial hypertrophy and heart failure can be considered as two different stages of the same course of disease. The pathogenesis of myocardial hypertrophy involves complex signal pathway activation and pathological changes, which are not yet fully understood, and the clinical treatment effect is not ideal. Therefore, it is of great significance to clarify the pathological mechanism of myocardial hypertrophy and find new therapeutic targets and new drugs for prevention and treatment. Summary of the invention

[0003] Purpose of the invention: In response to the above problems, the present invention finds that GATA6 plays an important regulatory function in cardiomyocyte hypertrophy and can be used as a potential target for drug intervention, and provides a class of pentacyclic triterpene derivatives or pharmaceutically acceptable salts thereof, and their use in the preparation of drugs for the treatment of myocardial hypertrophy; another purpose of the present invention is to provide the use of the pentacyclic triterpene derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for the treatment of myocardial hypertrophy.

[0004] The technical solution of the present invention is: a class of pentacyclic triterpene derivatives or pharmaceutically acceptable salts thereof according to the present invention, the chemical structural formula of the derivative is shown in formula (I):

[0005]

[0006] Wherein, R1 is H or OH; R2 is -CH2OH or -COOH; R3 is H or OH;

[0007] R4 is

[0008]

[0009] Furthermore, the pentacyclic triterpenoid saponin compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0010]

[0011]

[0012]

[0013]

[0014]

[0015]

[0016]

[0017] One object of the present invention is to provide a potential therapeutic target for myocardial hypertrophy. The present invention finds that GATA6 plays an important regulatory function in cardiomyocyte hypertrophy and can be used as a potential intervention target for the treatment of myocardial hypertrophy. Another object of the present invention is to provide the use of the pentacyclic triterpene derivative or pharmaceutically acceptable salt, and its pharmaceutical composition in the preparation of a drug for preventing or treating myocardial hypertrophy.

[0018] The beneficial effect of the present invention is that the pentacyclic triterpene derivatives in the present invention have a good binding effect on GATA6, a potential intervention target for myocardial hypertrophy, and can significantly prevent and reverse myocardial cell hypertrophy in vitro and myocardial hypertrophy in vivo, and have potential medicinal value. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a schematic diagram of improving myocardial hypertrophy in mice by knocking down GATA6 in heart tissue in an embodiment of the present invention. DETAILED DESCRIPTION

[0020] Example 1, Synthesis of Compound 1-a:

[0021]

[0022] Compound 1 was purchased from a pharmaceutical technology company; 1 (100 mg, 0.15 mmol) was dissolved in methanol (2 mL), then NaOH solution (0.12 mL, 5 mol / L) was added, the temperature was raised to 80 ° C, and the reaction was allowed to proceed for 4 hours. After the reaction was completed as monitored by LC-MS, 2 mL of water was added to the reaction system, and the pH value of the mixed system was adjusted to 3 with HCl solution (2 mol / L), and a large amount of light yellow solid was precipitated. After suction filtration and drying, a light yellow solid 1a was obtained, with a yield of 90%. 1H NMR (500MHz, DMSO-d6) 1Hδ (ppm): 11.83 (s, 1H), 5.17 (t, J = 3.7Hz, 1H), 4.40 (t, J = 5.2Hz, 1H), 4.15 (d, J = 4.9Hz, 1 H),3.76(s,1H),3.45(dd,J=10.6,5.4Hz,1H),3.08(dd,J=10.5,5.0Hz,1H),2.37(s,1H),1.96–1.80(m,3H),1.69 (td,1H),1.64–1.57(m,3H),1.55–1.46(m,6H),1.40(dt,J=15.2,5.3Hz,3H),1.30(s,3H),1.28–1.24(m,2H),1.2 0–1.15m,(2H),1.15–1.11(m,2H),1.08(s,3H),0.88(s,3H),0.85(d,J=6.6Hz,3H),0.71(s,3H),0.55(s,3H).13C NMR(126MHz,DMSO-d6)δ(ppm):178.93,138.60,126.86,71.61(2C),70.4 1,64.51,53.18,46.88,46.71,46.45,41.83,41.39,41.13,39.28,38.00, 37.26,36.25,32.27,28.10,26.56,26.40,25.92,25.19,24.02,23.14,17 .59,16.62,16.27,15.47,12.61.ESI-MS(m / z)488.2[MH]-,490.7[M+H]+.

[0023] Example 2, Synthesis of Compound 2:

[0024]

[0025] Compound 1a (200 mg, 0.41 mmol) was dissolved in DMSO (2 mL), and HATU (172 mg, 0.45 mmol) and triethylamine (0.08 mL, 0.62 mmol) were added, and stirred at room temperature for 0.5 hours. Then piperazine (105 mg, 1.23 mmol) was added, and stirring continued for 2 hours at room temperature. After the reaction was completed by LC-MS monitoring, 5 mL of water was added to the reaction system, and a large amount of solid was precipitated. The mixture was filtered, and the filter cake was washed with water (5 mL × 2), and the crude product was dried to obtain a crude product, which was purified by column chromatography (CH2Cl2: MeOH = 40: 1) to obtain a pure white solid powder 2, with a yield of 80%. 1 H NMR(400MHz,C5D5N)δ(ppm):5.58(s,1H),5.18(s,1H),4.40–4.15(m,2H),3.86–3.63(m,5H),3.41–3.20(m,2H ),3.12–2.86(m,4H),1.69(s,3H),1.44(s,3H),1.14(d,J=6.8Hz,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H); 13 C NMR (126MHz, C5D5N) δ (ppm): 176.21, 140.65, 128.46, 74.08, 73.63, 68.46, 57.19, 50.06, 49.24, 48.39, 47.75, 47.26, 43.43, 42.82, 42.67, 40 .76,39.42,37.78,35.90,34.02,29.69,28.22,28.13,27.34,25.09,24.60,19.34,17.73,17.30,16.65,13.67; ESI-MS(m / z)602.1[M+HCOOH] - ,558.1[M+H] + .

[0026] Example 3, synthesis of compound 3:

[0027]

[0028] Compound 1a (200 mg, 0.41 mmol) was dissolved in DMSO (2 mL), and HATU (172 mg, 0.45 mmol) and triethylamine (0.08 mL, 0.62 mmol) were added, and stirred at room temperature for 0.5 hours. Then 1,4-diazacyclohexane (123 mg, 1.23 mmol) was added, and stirring continued for 2 hours at room temperature. After the reaction was completed by LC-MS monitoring, 5 mL of water was added to the reaction system, and a large amount of solid was precipitated. Filter by suction, wash the filter cake with water (5 mL × 2), dry to obtain the crude product, and purify by column chromatography (CH2Cl2: MeOH = 40: 1) to obtain pure white solid powder 3, yield: 70%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):5.10(s,1H),4.39(t,J=5.1Hz,1H),4.14(d,J=4.9Hz,1H),3.79(s,1H),3.56–3.37(m,5H),3.34(s,1H),3 .07(dd,J=10.5,1H),2.81(s,1H),2.63(s,1H),2.23(s,4H),2.14(s,3H),1.95–1.76(m,3H),1.65–1.55(m,3H),1.51(d,J=3.3Hz,1H),1. 49(s,2H),1.47-1.44(m,2H),1.39(d,J=12.7Hz,2H),1.28(s,3H),1.25(d,J=3.8Hz,1H),1.22(d,J=3.2Hz,1H),1.18–1.15(m,1H),1.15– 1.11(m,2H),1.09(s,3H),0.95–0.88(m,2H),0.87(s,3H),0.84(d,J=6.8Hz,3H),0.62(s,3H),0.54(s,3H).ESI-MS(m / z)616.2[M+HCOOH] - ,572.1[M+H] + .

[0029] Example 4: Synthesis of Compound 4:

[0030]

[0031] The reaction and post-treatment operations were performed such as replacing 3,1,4-diazacyclohexane with N-methylpiperazine (123 mg, 1.23 mmol) to obtain pure white solid powder 4 with a yield of 75%. 1H NMR(500MHz,DMSO-d6)δ(ppm):5.08(s,1H),4.41(s,1H),4.15(s,1H),3.77(s,1H),3.43(dd,J=11.6,5.0Hz,4H), 3.06(d,J=10.4Hz,1H),2.80–2.76(m,1H),2.66(s,2H),1.92(s,1H),1.88(t,J=5.3Hz,1H),1.86–1.77(m,2H),1.6 4–1.56(m,6H),1.52–1.44(m,6H),1.38(d,J=12.8Hz,3H),1.28(s,3H),1.26–1.19(m,3H),1.17–1.12(m,3H),1.1 0(s,1H),1.08(s,3H),0.86(s,3H),0.84(d,J=6.8Hz,5H),0.65(s,3H),0.53(s,3H).ESI-MS(m / z)616.2[M+HCOOH] - ,572.1[M+H] + .

[0032] Example 5, Synthesis of Compound 5:

[0033]

[0034] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with 4-amino-piperidine (123 mg, 1.23 mmol) to obtain pure white solid powder 5 with a yield of 80%. 1H NMR (500MHz, DMSO-d6) δ (ppm): 6.77 (d, J = 7.8Hz, 1H), 5.17 (d, J = 3.7Hz, 1H), 4.39 (s, 1H), 4.13 (d, J = 4.9Hz, 1H), 3.70 (s, 1H), 3.54–3.47 (m, 1H) ),3.47–3.39(m,2H),3.07(d,J=10.4Hz,1H),2.89(d,J=12.1Hz,2H),2 .44(s,2H),2.42–2.38(m,2H),1.94–1.84(m,2H),1.83-1.77(m,1H),1. 68–1.61(m,2H),1.61–1.54(m,4H),1.53(d,J=2.6Hz,1H),1.49(d,J=12.5Hz,5H),1.46(d,J=4.3Hz,1H),1.37(dd,J=12.7,5.1Hz,2H),1.28(s ,3H),1.27–1.23(m,3H),1.21-1.18(m,1H),1.13(d,J=13.1Hz,3H),1.0 8(s,3H),0.86(s,3H),0.83(d,J=6.7Hz,3H),0.65(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.22,139.40,127.08,72.43(2C),70.90,6 5.00,53.08,47.22,47.02,46.95,46.86,45.66,42.30(2C),41.74,41.55(2C) ),38.51,38.41,36.71,33.26,32.95,28.35,27.06,26.98,26.58,24.85,24 .48,23.65,18.05,17.24,16.77,15.95,13.11.ESI-MS(m / z)616.1[M+HCOOH] - ,572.1[M+H] + .

[0035] Example 6, Synthesis of Compound 6:

[0036]

[0037] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with N-methylpiperidin-4-amine (140 mg, 1.23 mmol) to obtain pure white solid powder 6 with a yield of 70%. 1H NMR (500MHz, DMSO-d6) δ (ppm): 6.77 (d, J = 7.7Hz, 1H), 5.16 (t, J = 3.7Hz, 1H), 4.38 (t,J=5.2Hz,1H),4.13(d,J=5.0Hz,1H),3.70(s,1H),3.45-3.40(m,3H),3.07(dd ,J=10.5,5.0Hz,1H),2.69(t,J=4.1Hz,1H),2.67(s,1H),2.45(s,1H),2.11(s,3H ),1.92-1.87(m,1H),1.85(s,1H),1.82(d,J=3.1Hz,1H),1.82–1.79(m,1H),1.64( d,J=4.9Hz,1H),1.59(d,J=4.4Hz,1H),1.57(s,2H),1.55(s,1H),1.51(d,J=7.4H z,3H),1.48(d,J=3.9Hz,2H),1.47–1.41(m,4H),1.40(d,J=3.8Hz,1H),1.35(d,J =4.4Hz,1H),1.28(s,3H),1.23(s,2H),1.15(t,J=3.2Hz,1H),1.12(s,1H),1.08( s,3H),0.86(s,3H),0.83(d,J=6.7Hz,5H),0.80(s,1H),0.64(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):175.94,138.87,126.59,71.91(2C),70.40,64.5 0,54.62,54.56,52.59,46.71,46.44,46.38,45.97,45.79,41.79,41.24,41.04 ,38.00,37.88,36.20,32.43,31.48,31.12,27.84,26.55,26.47,26.07,24.33, 23.98,23.14,17.54,16.68,16.25,15.44,12.59.ESI-MS(m / z)630.1[M+HCOOH] - ,586.1[M+H] + .

[0038] Example 7, Synthesis of Compound 7:

[0039]

[0040] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with piperidin-4-ylmethylamine (140 mg, 1.23 mmol) to obtain pure white solid powder 7 with a yield of 80%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.13(t,J=5.7Hz,1H),5.18(t,J=3.7Hz,1H),4.41(s,1H),4.16 (s,1H),3.74(s,1H),3.43(dd,J=11.4,4.8Hz,2H),3.07(d,J=10.4Hz,1H),2.92–2.88(m,2H), 2.83–2.80(m,1H),2.77–2.74(m,1H),2.43(s,1H),2.39–2.33(m,2H),1.92–1.87(m,1H),1.82 –1.78(m,1H),1.65(d,J=4.8Hz,1H),1.63(d,J=4.1Hz,1H),1.60(d,J=4.6Hz,1H),1.57(d,J=3 .7Hz,1H),1.56–1.54(m,1H),1.53–1.50(m,3H),1.49(s,1H),1.49–1.47(m,2H),1.47–1.45(m ,2H),1.44(d,J=4.2Hz,1H),1.39(d,J=4.3Hz,1H),1.37(s,1H),1.28(s,3H),1.24(t,J=3.6Hz ,1H),1.20(d,J=3.2Hz,1H),1.12(t,J=6.9Hz,2H),1.09(s,1H),1.08(s,3H),0.93(s,1H),0.9 0(s,1H),0.86(s,3H),0.83(d,J=6.7Hz,J=6.7Hz,4H),0.78(s,1H),0.62(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):178.22,140.47,128.13,73.40(2C),71.87,65. 98,54.23,48.18,48.09,47.93,47.12,46.58,43.28,42.71,42.49,39.58,39. 45,37.68(2C),37.17,33.85,32.26,29.32,28.01,27.93,27.56,26.10,25.51 ,24.60,19.03,18.11,17.73,16.88,14.07,1.54.ESI-MS(m / z)630.2[M+HCOOH]- ,586.1[M+H] + .

[0041] Example 8, Synthesis of Compound 8:

[0042]

[0043] Reaction and post-treatment operations such as replacing 3,1,4-diazacyclohexane with N 1 ,N 1 -dimethylethane-1,2-diamine (108 mg, 1.23 mmol) to obtain pure white solid powder 8, yield: 80%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):6.94(t,J=5.5Hz,1H),5.18(t,J=3.7Hz,1H),4.39(t,J=5.1Hz,1H),4.14(d,J=4.9Hz,1H),3.75(s,1H),3.45-3.41(m,1 H),3.10-3.05(m,2H),3.01–2.96(m,1H),2.54(dd,J=13.5,4.3Hz,1H),2.3 6(s,1H),2.23(t,J=6.9Hz,2H),2.12(s,5H),1.92–1.87(m,1H),1.86-1.82 (m,1H),1.65–1.61(m,1H),1.61–1.54(m,3H),1.53-1.51(m,2H),1.48(d,J =4.0Hz,1H),1.47–1.42(m,2H),1.40(s,2H),1.36(d,J=4.3Hz,1H),1.28(s ,3H),1.25–1.21(m,2H),1.14(s,1H),1.11(d,J=11.6Hz,3H),1.08(s,3H), 0.87(s,3H),0.83(d,J=6.7Hz,4H),0.80(s,1H),0.64(s,3H),0.53(s,3H). 13C NMR(126MHz,DMSO-d6)δ(ppm):176.54,138.60,126.68,71.73(2C),70.2 1,64.31,57.73(2C),52.78,46.53,46.38,46.25,45.01(4C),41.62,41.1 5,40.88,37.81,36.74,36.01,32.11,27.63,26.32,25.89,24.57,23.79 ,22.96,17.36,16.34,16.08,15.24,12.40.ESI-MS(m / z)604.1[M+HCOOH] - ,560.0[M+H] + .

[0044] Example 9, Synthesis of Compound 9:

[0045]

[0046] Reaction and post-treatment operations such as replacing 3,1,4-diazacyclohexane with N 1 -methylethane-1,2-diamine (91 mg, 1.23 mmol) to obtain pure white solid powder 9, yield: 75%. 11H NMR (500 MHz, MeOD) δ (ppm): 5.36 (t, J = 3.7 Hz, 1H), 3.61 (dd, J = 11.5, 4.6 Hz, 1H), 3.53 (d, J = 10.9 Hz, 1H), 3.29 (s, 1H), 3.19–3.14 (m, 1H), 2.69 (d, J = 4.6 Hz, 1H), 2.64 (t, J = 6.5 Hz, 3H), 2.47 (s, 1H), 2.38 (s, 3H), 2.02–1.99 (m, 1H), 1.97 (t, J = 3.6 Hz, 1H), 1.74 (d, J = 3.2 Hz, 1H), 1.73–1.71 (m, 1H), 1.70 (d, J = 3.7 Hz, 1H), 1.67 (t, J = 3.2 Hz, 2H), 1.65 (s, 1H), 1.63–1.61 (m, 1H), 1.60 (d, J = 1.9 Hz, 1H), 1.55 (d, J = 4.4 Hz, 1H), 1.52 (d, J = 4.1 Hz, 1H), 1.50–1.48 (m, 1H), 1.44 (s, 1H), 1.41 (s, 1H), 1.38 (d, J = 3.2 Hz, 1H), 1.35 (s, 3H), 1.27 (d, J = 3.0 Hz, 1H), 1.23 (d, J = 3.0 Hz, 1H), 1.22 (s, 1H), 1.21 (s, 3H), 1.18 (d, J = 2.2 Hz, 1H), 1.16 (d, J = 2.3 Hz, 1H), 1.01 (d, J = 3.6 Hz, 1H), 0.99 (s, 1H), 0.97 (s, 3H), 0.96 (s, 1H), 0.93 (d, J = 6.6 Hz, 4H), 0.75 (s, 3H), 0.71 (s, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ (ppm): 176.87, 138.86, 126.78, 71.91 (2C), 70.40, 64.50, 52.84, 50.52, 46.71, 46.59, 46.44, 41.80, 41.30, 41.03, 38.49, 38.00, 36.20, 35.78 (2C), 32.30, 27.84, 26.54, 26.48, 26.07, 24.68, 24.01, 23.14, 17.54, 16.49, 16.26, 15.41, 12.59. ESI-MS (m / z) 590.0 [M+HCOOH] - , 546.1 [M+H] + 。

[0047] Example 10, Synthesis of Compound 10:

[0048]

[0049] Reaction and post-treatment operations such as replacing 3,1,4-diazacyclohexane with N 1 -ethylethane-1,2-diamine (109 mg, 1.23 mmol) was added to obtain pure white solid powder 10 with a yield of 75%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.05(t,J=5.5Hz,1H),5.20(t,J=3.6Hz,1H),4.39( t,J=5.1Hz,1H),4.14(d,J=4.9Hz,1H),3.74(s,1H),3.45–3.41(m,2H),3.09–3.05( m,2H),3.00(dd,J=12.8,6.1Hz,1H),2.55–2.53(m,1H),2.52(s,1H),2.39(s,1H),1 .90(dd,J=6.6,3.5Hz,1H),1.84(dd,J=11.2,3.5Hz,1H),1.62–1.57(m,4H),1.55(s ,1H),1.53–1.51(m,2H),1.48(s,2H),1.46(t,J=5.1Hz,2H),1.42(s,1H),1.40(d,J =3.6Hz,1H),1.38(d,J=4.1Hz,1H),1.28(s,3H),1.27–1.25(m,1H),1.24(d,J=3.4H z,1H),1.21(d,J=3.3Hz,1H),1.14(s,1H),1.12(s,1H),1.10(s,1H),1.08(s,3H),0 .99(t,J=7.1Hz,4H),0.86(s,3H),0.83(d,J=6.8Hz,4H),0.63(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.91,138.87,126.77,71.92(2C),70.38, 64.49,52.82,48.10,46.70,46.61,46.43,43.10,41.80,41.29,41.03,38.7 5,38.00,36.19(2C),32.27,27.83,26.53,26.48,26.07,24.69,24.02,23. 12,17.53,16.49,16.26,15.39,15.00,12.59.ESI-MS(m / z)604.0[M+HCOOH] - ,560.0[M+H] +.

[0050] Example 11, Synthesis of Compound 11:

[0051]

[0052] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with 2-morpholinoethane-1-amine (160 mg, 1.23 mmol) to obtain pure white solid powder 11 with a yield of 80%. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 6.93 (t, J = 5.3Hz, 1H), 5.20 (t, J = 3.7Hz, 1H), 4.39 (t,J=5.1Hz,1H),4.14(d,J=4.9Hz,1H),3.75(s,1H),3.55(t,J=4.6Hz,5H),3.45 -3.41(m,1H),3.13-3.01(m,4H),2.54(dd,J=13.4,4.5Hz,1H),2.36(s,1H),2.33(t,J=4.7Hz,4H),2.31(s,1H),2.30(s,1H),2.28( s,1H),1.91(t,J=5.9Hz,1H),1.87–1.82(m,1H),1.61(s,1H),1.57(s,1H),1.56(d,J=2.9Hz,1H),1.53(d,J=2.9Hz,1H),1.51(s,1H ),1.49(s,1H),1.47–1.45(m,1H),1.40(d,J=4.5Hz,1H),1.37(d,J=4.1Hz,1H),1.28(s,3H),1.24(d,J=4.6Hz,1H),1.23–1.20(m,1 H),1.14(s,1H),1.12(s,1H),1.10(s,1H),1.08(s,3H),1.07(s,1H),0.86(s,3H),0.84(d,J=6.7Hz,4H),0.63(s,3H),0.53(s,3H). 13C NMR(126MHz,DMSO-d6)δ(ppm):176.74,138.85,126.81,71.95(2C),70.40, 66.24(3C),64.50,56.95,53.22(3C),52.92,46.72,46.62,46.43,41.82,41 .34,41.08,37.99,36.22(2),35.98,32.27,27.83,26.54,26.09,24.79,24. 01,23.16,17.55,16.54,16.29,15.44,12.61.ESI-MS(m / z)644.1[M+HCOOH] - ,600.2[M+H] + .

[0053] Example 12, Synthesis of Compound 12:

[0054]

[0055] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with ethane-1,2-diamine (74 mg, 1.23 mmol) to obtain pure white solid powder 12 with a yield of 80%. 1H NMR(500MHz,DMSO-d6)δ(ppm):7.04(t,J=5.5Hz,1H),5.20–5.18(m,1H),4.40(s, 1H),4.14(s,1H),3.45–3.42(m,2H),3.09–2.97(m,3H),2.91–2.85(m,1H),2.42( s,1H),1.93–1.86(m,1H),1.86–1.81(m,1H),1.62(d,J=4.4Hz,1H),1.60(s,1H), 1.58(d,J=3.9Hz,1H),1.56(d,J=4.0Hz,1H),1.53(d,J=3.0Hz,1H),1.51(s,1H), 1.48(d,J=3.9Hz,2H),1.47–1.45(m,2H),1.43(d,J=4.3Hz,1H),1.38(q,J=4.2,3 .5Hz,2H),1.28(s,3H),1.26(dd,J=6.6,3.2Hz,2H),1.24(d,J=3.6Hz,1H),1.21( d,J=3.2Hz,1H),1.15(d,J=3.3Hz,1H),1.12(s,1H),1.10(s,1H),1.08(s,3H),0. 86(s,3H),0.83(d,J=6.8Hz,5H),0.80(d,J=3.8Hz,1H),0.63(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.87,138.88,126.73,71.92(2C),70.40,64.49,52.75,46.72,46.59,46.43,42.52,41.80,41.29,41.13,41.02 ,38.07,37.99,36.20,32.31,27.86,26.54,26.49,26.09,24.64,24.03, 23.14,17.54,16.54,16.27,15.42,12.60.ESI-MS(m / z)576.0[M+HCOOH] - ,532.1[M+H] + .

[0056] Example 13, Synthesis of Compound 13:

[0057]

[0058] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with propane-1,3-diamine (91 mg, 1.23 mmol) to obtain pure white solid powder 13 with a yield of 80%. 1 H NMR(500MHz,DMSO-d6)δ(ppm):7.19(t,J=5.6Hz,1H),5.19(q,J=4.6,3.6Hz,1 H),4.39(s,1H),4.14(s,1H),3.72(s,1H),3.43(dd,J=10.9,5.1Hz,2H),3.07 (d,J=10.6Hz,1H),3.03–3.00(m,1H),3.00–2.96(m,1H),2.89(d,J=6.7Hz,1H ),2.42(s,1H),1.89(dd,J=6.3,3.5Hz,1H),1.85-1.82(m,1H),1.64(d,J=4.4 Hz,1H),1.59(d,2H),1.56–1.53(m,1H),1.51(s,2H),1.48(s,2H),1.46–1.43 (m,3H),1.43–1.40(m,3H),1.38(d,J=4.9Hz,2H),1.28(s,3H),1.25–1.22(m, 2H),1.21(d,J=3.1Hz,1H),1.15(s,1H),1.12(s,1H),1.10(s,1H),1.08(s,3H ),0.86(s,3H),0.83(d,J=6.9Hz,4H),0.80(s,1H),0.62(s,3H),0.53(s,3H). 13 C NMR (126MHz, DMSO-d6) δ (ppm): 176.73, 138.84, 126.73, 71.92 (3C), 70.40, 64.50, 52.71, 46.73, 46.51, 46.44, 41.80, 41.32, 40.99, 38.12, 37.9 9,36.68,36.21(2C),32.31,32.12,27.85,26.50,26.09,24.61,24.06, 23.13,17.55,16.49,16.27,15.42,12.59.ESI-MS(m / z)590.0[M+HCOOH] - ,546.1[M+H] + .

[0059] Example 14, Synthesis of Compound 14:

[0060]

[0061] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with butane-1,4-diamine (108 mg, 1.23 mmol) to obtain pure white solid powder 14 with a yield of 85%. 1 H NMR(500MHz,MeOD)δ(ppm):5.35(t,J=3.6Hz,1H),3.62(d,J=4.7Hz,1H),3.60(d,J =4.5Hz,1H),3.53(d,J=10.9Hz,1H),3.29(s,1H),3.14(t,J=6.4Hz,1H),3.09–3.06 (m,1H),2.71(t,J=6.8Hz,3H),2.67(d,J=9.7Hz,1H),2.47(s,1H),1.99(s,1H),1.9 6(d,J=3.3Hz,1H),1.74(d,J=3.4Hz,1H),1.71(d,J=4.7Hz,2H),1.68(d,J=4.4Hz,2 H),1.66(d,J=3.1Hz,1H),1.65(s,1H),1.62–1.61(m,1H),1.60(s,1H),1.55(s,1H ),1.52–1.50(m,4H),1.49(s,1H),1.44(s,2H),1.40(s,1H),1.35(s,3H),1.29(s,1 H),1.26(s,1H),1.23(s,1H),1.21(s,3H),1.18(s,1H),1.16(s,1H),1.01(d,J=3.6 Hz,1H),0.97(s,3H),0.96(s,1H),0.93(d,J=6.6Hz,4H),0.75(s,3H),0.71(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.58,138.90,126.68,71.92(2C),70.38, 64.49,52.69,46.72,46.47,46.43,41.80(2C),41.28,41.11,40.99,38.72 ,37.98,36.20(2C),32.32,30.17,27.85,26.49,26.37,26.08,24.60,24.0 4,23.12,17.54,16.50,16.26,15.41,12.59.ESI-MS(m / z)604.0[M+HCOOH] - ,560.1[M+H] + .

[0062] Example 15, Synthesis of Compound 15:

[0063]

[0064] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with 4-methylaminopyridine (132 mg, 1.23 mmol) to obtain pure white solid powder 15 with a yield of 75%. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.46–8.44 (m, 2H), 7.86 (t, J = 6.0Hz, 1H), 7.20 (d ,J=5.2Hz,2H),5.21–5.17(m,1H),4.40(t,J=5.1Hz,1H),4.23–4.17(m,2H),4.15 (d,J=5.0Hz,2H),3.79(s,1H),3.45-3.40(m,1H),3.07(dd,J=10.5,5.1Hz,1H),2 .58(td,J=13.4,4.5Hz,1H),2.46(s,1H),1.88(t,1H),1.68–1.64(m,2H),1.62(d ,J=2.7Hz,1H),1.60(d,J=4.3Hz,1H),1.58–1.55(m,1H),1.50(d,J=3.9Hz,2H),1 .47(t,J=4.9Hz,3H),1.44(d,J=5.2Hz,1H),1.37(d,J=12.5Hz,2H),1.29(s,3H), 1.27–1.25(m,1H),1.24(d,J=3.4Hz,1H),1.20–1.17(m,1H),1.14(d,J=3.2Hz,1H ),1.12(s,2H),1.09(s,3H),0.85(s,2H),0.84(s,4H),0.53(s,3H),0.51(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):177.08,149.22(2C),149.18,138.75,126.88,1 22.19(2C),71.92(2C),70.41,64.52,52.74,46.73,46.63,46.45,41.81,41.35 ,41.31,40.96,38.04,37.98,36.20,32.27,27.85,26.55,26.48,26.05,24.65, 24.12,23.13,17.55,16.36,16.27,15.40,12.61.ESI-MS(m / z)624.2[M+HCOOH] - ,580.1[M+H] + .

[0065] Example 16, Synthesis of Compound 16:

[0066]

[0067] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with pyridine-2-methylamine (133 mg, 1.23 mmol) to obtain pure white solid powder 16 with a yield of 80%. 1 H NMR (500MHz, DMSO-d6) δ (ppm): 8.43 (d, J = 2.2 Hz, 1H), 8.40 (dd, J = 4.7, 1.6 Hz, 1H), 7.79 (t, J=6.0Hz,1H),7.60(dt,J=7.9,2.1Hz,1H),7.30(dd,J=7.8,4.7Hz,1H),5.19(t,J=3.7Hz,1 H),4.38(t,J=5.1Hz,1H),4.18(t,J=5.2Hz,2H),4.14(d,J=4.9Hz,1H),3.76(s,1H),3.45- 3.40(m,2H),3.07(dd,1H),2.59–2.54(m,1H),2.45(s,1H),1.92–1.86(m,1H),1.80(dd,J= 11.1,3.6Hz,1H),1.65–1.62(m,2H),1.60(t,J=2.1Hz,1H),1.58(t,J=3.7Hz,1H),1.56–1. 54(m,1H),1.50(d,J=3.8Hz,1H),1.48(s,1H),1.47(s,2H),1.43(s,1H),1.41(d,J=4.2Hz, 1H),1.38(s,1H),1.36(s,1H),1.28(s,3H),1.24(d,J=3.0Hz,1H),1.19(s,1H),1.17(d,J= 3.1Hz,1H),1.11(s,1H),1.08(s,3H),0.84(s,2H),0.83(s,5H),0.53(s,3H),0.46(s,3H). 13C NMR(126MHz,DMSO-d6)δ(ppm):176.92,148.81,147.68,138.75,135.55,135.01, 126.85,123.17,71.92(2C),70.43,64.53,52.74,46.73,46.58,46.45,41.81,41 .31,40.96,39.98,39.24,37.99,36.20,32.27,27.83,26.56,26.48,26.04,24.6 3,24.10,23.12,17.54,16.30,16.26,15.40,12.61.ESI-MS(m / z)624.2[M+HCOOH] - ,580.1[M+H] + .

[0068] Example 17, Synthesis of Compound 17:

[0069]

[0070] The reaction and post-treatment operations were as follows: 3,1,4-diazacyclohexane was replaced with pyridin-2-ylmethylamine (133 mg, 1.23 mmol) to obtain pure white solid powder 17 with a yield of 85%. 1H NMR(500MHz,MeOD)δ(ppm):8.48(d,J=5.2Hz,1H),7.78(td,J=7.8,1.8Hz,1H),7.34(d,J=7.8Hz,1H),7.30–7.28(m,1H),5.39(t,J=3.7Hz,1H),4.40(s,2H),3.60(dd,J=11.6,4.5Hz,1H),3.52(d,J=10.8Hz,1H),2.72(td,J=13.6,4.5Hz,1H),2.48(s,1H),2.02(t,J=5.3Hz,1H),1.99(dd,J=6.9,3.7Hz,1H),1.92(dd,J=11.1,3.6Hz,1H),1.79–1.77(m,1H),1.76–1.74(m,1H),1.73(s,1H),1.72(d,J=2.4Hz,1H),1.70(s,1H),1.67(dd,J=8.2,4.0Hz,1H),1.64–1.61(m,2H),1.61–1.59(m,2H),1.57(d,J=4.1Hz,1H),1.55–1.53(m,1H),1.42(s,1H),1.38(d,J=5.7Hz,1H),1.35(s,3H),1.33(d,J=3.3Hz,1H),1.25(d,J=4.2Hz,1H),1.22(s,3H),1.20(d,J=3.0Hz,1H),1.16(d,J=2.2Hz,1H),1.14(s,1H),1.02(s,1H),0.99(d,J=4.2Hz,1H),0.97(d,J=4.7Hz,1H),0.94(d,J=6.6Hz,3H),0.90(s,3H),0.69(s,3H),0.57(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.98,158.84,148.48,138.69,136.37,127.04,121.79,120.96,71.93,70.39,64.49,54.85,52.93,46.71,46.61,46.42,44.30,41.79,41.30,40.97,37.97,37.89,36.16,32.20,27.82,26.53,26.48,26.07,24.78,24.07,23.11,17.51,16.27,16.14,15.37,12.57.ESI-MS(m / z)624.2[M+HCOOH] - ,580.1[M+H]+ .

[0071] Example 18, Synthesis of Compound Ast-a:

[0072]

[0073] The compound Ast was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd. 10 g of Ast was dissolved in 200 mL of MeOH, 12 mL of 5 N NaOH was added, refluxed at 80°C for 4 h, and then concentrated under reduced pressure, 200 mL of water was added, and 2 N HCl was slowly added dropwise to the system pH = 3 under stirring at room temperature, filtered, the filter cake was washed with a large amount of water, and dried to obtain a light yellow solid Ast-a with a yield of 90%. 1 HNMR (400MHz, CD3OD) δ (ppm): 5.24 (t, J = 3.6 Hz, 1H), 3.70 (ddd, J = 11.4, 9.6, 4 .5Hz,1H),3.51(d,J=11.1Hz,1H),3.36(d,J=9.6Hz,1H),3.27(d,J=11.1Hz,1 H),2.21(d,J=11.3Hz,1H),2.13–1.80(m,5H),1.77–1.23(m,11H),1.14(s,3H ),1.05(s,3H),0.97(s,3H),0.89(d,J=6.4Hz,3H),0.85(s,3H),0.70(s,3H); 13 C NMR(126MHz,MeOD)δ(ppm):181.59,139.75,126.63,78.10,69.64,66.22,54.28,48.95,48.10,47.98,44.10,43.34,40.75, 40.37,38.95,38.07,33.60,31.75,29.13,25.28,24.45,24.19,21.63,19.06,17.84,17.71,13.96; ESI-MS(m / z)488.0[MH] - ,490.1[M+H] + .

[0074] Example 19, Synthesis of Compound 18:

[0075]

[0076] Compound Ast-a (200 mg, 0.410 mmol) was dissolved in DMSO (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (172 mg, 0.451 mmol) and triethylamine (62.1 mg, 0.615 mmol) were added. After stirring at room temperature for 0.5 h, anhydrous piperazine (105.8 mg, 1.230 mmol) was added, and the mixture was heated and stirred at 60°C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, 5 mL of water was added, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed twice with water (5 mL × 2) and ethanol (2 mL × 2) and dried to obtain a white solid powder 18 with a yield of 79%. 1 H NMR (400MHz, CD3OD) δ (ppm): δ5.22 (t, J=3.8Hz, 1H), 3.80–3.61 (m, 5H), 3.51 ( d,J=11.2Hz,1H),3.35(d,J=9.6Hz,1H),3.26(d,J=11.2Hz,1H),2.95(br,4H), 2.40(d,J=11.1Hz,1H),2.29–2.16(m,1H),2.04–1.24(m,17H),1.14(s,3H),1. 04(s,3H),1.00–0.95(m,3H),0.91(d,J=6.4Hz,3H),0.77(s,3H),0.69(s,3H); 13 C NMR(126MHz,DMSO-d6)δ(ppm):173.93,138.85,124.22,75.55,67.44,63.90,47.54,47.06,46.95,46.47,46.05,45.79,42.50,4 1.71,38.26,37.31,33.49,32.18,30.05,27.69,23.62,23.01,21.14,17.39,16.87,16.55,13.80; ESI-MS(m / z)602.0[M+HCOOH] - ,557.9[M+H] + .

[0077] Example 20, Synthesis of Compound 19:

[0078]

[0079] The reaction and post-treatment were performed as in 18, except that piperazine was replaced by 1,4-diazacyclohexane (123.0 mg, 1.230 mmol) to obtain pure white solid powder 19 with a yield of 72%. 1H NMR (400MHz, DMSO-d6) δ (ppm): 5.09 (s, 1H), 4.41 (t, J = 5.2Hz, 1H), 4.23 (s, 1H), 4. 26–4.12(m,1H),4.18(s,1H),3.48(s,5H),3.28(s,1H),3.17(d,J=8.6Hz,1H),3.0 3(dd,J=10.5,3.8Hz,1H),2.89–2.57(m,4H),2.37(d,J=11.2Hz,1H),2.11–1.08(m ,20H),1.04(s,3H),0.92(s,6H),0.84(d,J=6.2Hz,3H),0.69(s,3H),0.54(s,3H); 13 C NMR(101MHz,DMSO-d6)δ(ppm):174.40,138.82,124.04,75.53,67.43,63.88,47.05,46.96,46.73,46.59,46.04,45.88,45.77,42.4 8,41.89,38.32,37.31,33.70,32.22,30.15,27.85,22.99,21.19,17.51,17.37,16.88,16.71,13.80; ESI-MS(m / z)616.1[M+HCOOH] - ,572.1[M+H] + .

[0080] Example 21, Synthesis of Compound 20:

[0081]

[0082] The reaction was carried out as in 18, except that piperazine was replaced by N-methylpiperazine (123.0 mg, 1.230 mmol) to give pure white solid powder 20 in a yield of 82%. 1H N R(400MHz,CD3OD)δ(ppm):5.23(t,J=3.6Hz,1H),3.89(br,4H),3.70(ddd,J=11.3,9 .6,4.5Hz,1H),3.51(d,J=11.1Hz,1H),3.36(d,J=9.6Hz,1H),3.26(d,J=11.1Hz,1H ),3.14(br,4H),2.84(s,3H),2.38(d,J=10.9Hz,1H),2.03–1.24(m,17H),1.14(s,3 H),1.04(s,3H),1.01–0.95(m,3H),0.92(d,J=6.4Hz,3H),0.76(s,3H),0.69(s,3H); 13 C NMR (126MHz, CD3OD) δ (ppm): 177.70, 139.99, 126.59, 78.13, 69.62, 66.25, 54.66, 50.03, 48.16, 47.99, 44.11, 43.87, 43.40, 40 .69,40.06,38.96,35.28,33.45,31.43,29.23,24.44,21.57,19.03,17.97,17.69,17.56,13.94; ESI-MS(m / z)615.9[M+HCOOH] - ,571.9[M+H] + .

[0083] Example 22, Synthesis of Compound 21:

[0084]

[0085] The reaction was carried out as in 18, except that piperazine was replaced by 4-dimethylaminopiperidine (175.0 mg, 1.230 mmol) to give pure white solid powder 21 in a yield of 77%. 1H NMR (500MHz, CD3OD) δ (ppm): 5.22 (s, 1H), 4.47 (d, J = 12.6Hz, 2H), 3.69 (ddd, J = 11 .7,9.6,4.6Hz,1H),3.51(d,J=11.0Hz,1H),3.36(d,J=9.6Hz,1H),3.26(d,J=11. 0Hz,1H),2.77(s,2H),2.49–2.38(m,2H),2.33(s,6H),2.26–1.23(m,23H),1.14( s,3H),1.04(s,3H),0.98(s,2H),0.91(d,J=6.4Hz,3H),0.79(s,3H),0.70(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):177.05,140.18,126.49,78.08,69.65,66.19,63.54,48.87,48.13,47.98,44.11,43.46,41.78,40.71,40.18 ,38.97,35.27,33.58,31.54,30.01,29.43,25.05,24.46,24.21,21.66,19.04,18.07,17.73,17.69,13.96; ESI-MS(m / z)644.0[M+HCOOH] - ,600.0[M+H] + .

[0086] Example 23, Synthesis of Compound 22:

[0087]

[0088] The reaction was carried out as in 18, except that piperazine was replaced by N-methylpiperidin-4-amine (140.0 mg, 1.230 mmol) to give pure white solid powder 22 in 80% yield. 1H NMR (400MHz, CD3OD) δ (ppm): 5.35 (t, J=3.6Hz, 1H), 3.71 (ddd, J=11.3, 9.6, 4.5Hz, 1 H),3.70–3.57(m,1H),3.52(d,J=11.1Hz,1H),3.38(d,J=9.6Hz,1H),3.28(d,J=11. 1Hz,1H),2.87(dd,J=12.4,4.5Hz,2H),2.29(s,3H),2.25–1.26(m,24H),1.16(s,3H ),1.06(s,3H),1.01–0.98(m,3H),0.93(d,J=6.5Hz,3H),0.84(s,3H),0.71(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):179.50,140.19,126.76,78.07,69.63,66.18,55.66,55.58,53.98,48.06,47.99,47.51,46.15,44.11,43.50,40.92 ,40.79,40.22,38.94,38.74,33.60,32.26,31.91,28.93,24.93,24.48, 24.06,21.60,19.01,18.27,17.70,13.97; ESI-MS(m / z)629.6[M+HCOOH] - ,586.6[M+H] + .

[0089] Example 24, Synthesis of Compound 23:

[0090]

[0091] The reaction was carried out as in step 18, except that piperazine was replaced by 4-aminopiperidine (123.0 mg, 1.230 mmol) to give pure white solid powder 23 in a yield of 75%. 1H NMR (400MHz, CD3OD) δ (ppm): 5.33 (t, J = 3.7 Hz, 1H), 3.79 (tt, J = 11.2, 4.3 Hz, 1H), 3.69 (ddd,J=11.3,9.6,4.5Hz,1H),3.50(d,J=11.1Hz,1H),3.35(d,J=9.6Hz,1H),3.29–3.1 7(m,3H),2.83(td,J=12.6,2.9Hz,2H),2.29–2.17(m,1H),2.13–1.22(m,22H),1.15(s ,3H),1.04(s,3H),1.00–0.96(m,3H),0.92(d,J=6.5Hz,3H),0.83(s,3H),0.69(s,3H); 13 C NMR(126MHz,CD3OD+CDCl3)δ(ppm):178.85,139.57,126.06,78.48,68.93,67.1 9,53.68,48.22,48.07,47.98,47.00,46.04,44.73,44.63,43.31,43.00,40.24 ,40.14,39.54,38.43,38.12,32.98,31.33,30.82,30.36,28.29,24.60,23.95, 23.75,21.42,18.58,17.92,17.55,17.47,13.48; ESI-MS(m / z)615.9[M+HCOOH] - ,571.9[M+H] + .

[0092] Example 25, Synthesis of Compound 24:

[0093]

[0094] The reaction was carried out as in step 18, except that piperazine was replaced by 2-aminomethylpiperidine (140.0 mg, 1.230 mmol) to give pure white solid powder 24 in a yield of 72%. 1H NMR (400MHz, CD3OD) δ (ppm): 5.35 (t, J = 3.7 Hz, 1H), 3.70 (ddd, J = 11.3, 9.5, 4. 5Hz,1H),3.50(d,J=11.1Hz,1H),3.36(d,J=9.6Hz,1H),3.26(d,J=11.1Hz,1H ),3.18–2.93(m,3H),2.69–2.50(m,2H),2.23–1.25(m,23H),1.15(s,3H),1.0 4(s,3H),0.99–0.96(m,3H),0.92(d,J=6.5Hz,3H),0.81(s,3H),0.69(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):180.62,140.25,126.79,78.06,69.61,66.16 ,54.09,48.07,47.97,45.38,44.93,44.13,43.43,40.89,40.78,40.26,39 .04,38.95,35.13,33.53,31.89,28.90,27.92,27.88,25.08,24.47,24.1 5,21.58,19.01,18.05,17.72,17.68,13.96; ESI-MS(m / z)630.0[M+HCOOH] - ,585.9[M+H] + .

[0095] Example 26, Synthesis of Compound 25:

[0096]

[0097] The reaction was carried out as in 18, except that piperazine was replaced by piperidin-4-ylmethylamine (140.0 mg, 1.230 mmol) to give pure white solid powder 25 in a yield of 70%. 1H NMR (400MHz, CD3OD) δ (ppm): 7.48 (t, J = 6.1 Hz, 1H), 5.35 (t, J = 3.2 Hz, 1H), 3.77–3. 60(m,1H),3.50(d,J=11.0Hz,1H),3.44–3.33(m,3H),3.26(d,J=11.0Hz,1H),3.05 (m,2H),2.99–2.84(m,2H),2.19(d,J=10.4Hz,1H),2.12–1.20(m,23H),1.14(s,3H ),1.04(s,3H),0.99–0.95(m,3H),0.92(d,J=6.2Hz,3H),0.79(s,3H),0.69(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):180.63,140.26,126.80,78.07,69.62,66.17 ,54.09,48.07,47.96,45.39,44.93,44.13,43.43,40.89,40.77,40.26,39 .04,38.95,35.13,33.53,31.89,28.90,27.92,27.88,25.08,24.46,24.1 5,21.58,19.01,18.05,17.72,17.68,13.96; ESI-MS(m / z)629.9[M+HCOOH] - ,585.9[M+H] + .

[0098] Example 27, Synthesis of Compound 26:

[0099]

[0100] The reaction was carried out as in 18, except that piperazine was replaced by 2-morpholinoethane-1-amine (159.8 mg, 1.230 mmol) to give pure white solid powder 26 in a yield of 75%. 1 HNMR(400MHz,CD3OD)δ(ppm):5.38(t,J=3.5Hz,1H),3.93–3.64(m,5H),3.52(d,J=11.2Hz,1H),3.37(d,J=9.5Hz,1H),3.29–3.15 (m,2H),2.49(m,6H),2.16–1.24(m,19H),1.17(s,3H),1.06(s,3H),1.00(s,3H),0.94(d,J=6.4Hz,3H),0.83(s,3H),0.71(s,3H); 13C NMR (126MHz, CD3OD) δ (ppm): 180.24, 140.32, 126.89, 78.08, 69.64, 67.87, 66.18, 58.19, 54.64, 54.39, 48.03, 44.13, 43.51, 40.88, 40.35 ,38.96,38.67,37.10,33.42,31.86,28.90,25.33,24.54,24.04,21.59,19.00,17.99,17.78,17.68,13.94; ESI-MS(m / z)645.6[M+HCOOH] - ,601.7[M+H] + .

[0101] Example 28, Synthesis of Compound 27:

[0102]

[0103] The reaction was carried out as in 18, except that piperazine was replaced by N 1 ,N 1 -dimethylethane-1,2-diamine (108.2 mg, 1.230 mmol) to obtain pure white solid powder 27 with a yield of 76%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.36 (t, J=3.5Hz, 1H), 3.72 (ddd, J=11.3, 9.6, 4.4Hz ,1H),3.52(d,J=11.1Hz,1H),3.38(d,J=9.6Hz,1H),3.28(d,J=11.1Hz,1H),3.19( dt,J=13.7,6.9Hz,1H),2.52–2.39(m,2H),2.31(s,6H),2.17–1.25(m,18H),1.16( s,3H),1.06(s,3H),1.00(s,3H),0.93(d,J=6.5Hz,3H),0.83(s,3H),0.71(s,3H); 13CNMR(101MHz,CD3OD)δ(ppm):180.30,140.10,126.99,78.04,69.63,66.13,58.89,54.20,48.04,47.97,45.48,44.12,43.45,40.88,40.82,4 0.32,38.93,38.62,38.02,33.45,31.88,28.89,25.25,24.50,24.08,2 1.59,19.00,17.98,17.76,17.67,13.96; ESI-MS(m / z)604.1[M+HCOOH] - ,560.0[M+H] + .

[0104] Example 29, Synthesis of Compound 28:

[0105]

[0106] The reaction was carried out as in 18, except that piperazine was replaced by N,N-dimethylpropylenediamine (108.2 mg, 1.230 mmol) to give pure white solid powder 28 in a yield of 79%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.33 (t, J=3.6Hz, 1H), 3.70 (ddd, J=11.3, 9.6, 4.4Hz, 1H) ,3.50(d,J=11.1Hz,1H),3.36(d,J=9.6Hz,1H),3.26(d,J=11.1Hz,1H),3.15(ddt,J=3 5.6,13.5,6.9Hz,2H),2.34(td,J=7.1,3.2Hz,2H),2.25(s,6H),2.18–1.23(m,21H),1 .14(s,3H),1.04(s,3H),0.98(s,3H),0.92(d,J=6.5Hz,3H),0.81(s,3H),0.69(s,3H); 13 C NMR (126MHz, CD3OD) δ (ppm): 178.39, 140.07, 126.31, 78.10, 69.65, 66.22, 56.86, 50.26, 49.83, 48.15, 47.99, 45.66, 44.12, 43.60, 40.76 ,40.23,38.98,37.90,35.10,33.56,31.54,29.25,24.44,21.62,19.04,18.01,17.92,17.86,17.68,13.95; ESI-MS(m / z)617.7[M+HCOOH]- ,574.7[M+H] + .

[0107] Example 30, Synthesis of Compound 29:

[0108]

[0109] The reaction was carried out as in 18, except that piperazine was replaced by N 1 -methylethane-1,2-diamine (91.0 mg, 1.230 mmol) to obtain pure white solid powder 29 with a yield of 69%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.35 (t, J = 3.6Hz, 1H), 3.70 (ddd, J = 11.4, 9.5, 4.5Hz, 1H), 3.50 (d, J = 11.1Hz, 1H), 3.36 (d, 9.5Hz 1H),3.29–3.12(m,3H),2.61(t,J=6.5Hz,2H),2.37(s,3H),2.24–1.19(m,19H),1.1 5(s,3H),1.04(s,3H),0.98(s,3H),0.92(d,J=6.4Hz,3H),0.81(s,3H),0.69(s,3H); 13 C NMR (101MHz, CD3OD) δ (ppm): 180.45, 140.22, 126.83, 78.06, 69.62, 66.16, 54.03, 51.51, 48.90, 48.05, 47.97, 44.12, 43.43, 40.86, 40.80, 40.27 ,39.78,38.93,38.70,35.92,33.47,31.88,28.90,25.14,24.48,24.13, 21.60,19.00,17.98,17.75,17.66,13.96; ESI-MS(m / z)590.1[M+HCOOH] - ,546.0[M+H] + .

[0110] Example 31, Synthesis of Compound 30:

[0111]

[0112] The reaction was carried out as in 18, except that piperazine was replaced by N-methylpropylenediamine (108.2 mg, 1.230 mmol) to give pure white solid powder 30 with a yield of 70%. 1H NMR (400MHz, CD3OD) δ (ppm): 5.34 (t, J = 3.6Hz, 1H), 3.69 (ddd, J = 11.3, 9.6, 4.5Hz, 1H), 3.50 (d, J = 11.1Hz, 1H), 3.35 (d, J = 9.6Hz, 1H), 3.28–3.08 (m, 3H),2.68(t,J=7.1Hz,2H),2.48(s,3H),2.23–1.24(m,20H),1.15(s,3H), 1.04(s,3H),0.98(s,3H),0.92(d,J=6.4Hz,3H),0.80(s,3H),0.69(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):180.79,

[0113] 140.07,126.90,78.06,69.64,66.15,54.03,48.92,48.04,47.96,44.12,43.40,40.88,40.78,40.31,38.99,38.94,3 7.91,35.09,33.45,31.87,28.87,25.10,24.47,24.14,21.58,19.00,17.99,17.74,17.65,13.94; ESI-MS(m / z)603.6

[0114] [M+HCOOH] - ,559.7[M+H] + .

[0115] Example 32, Synthesis of Compound 31:

[0116]

[0117] The reaction was carried out as in 18, except that piperazine was replaced by N 1 -ethylethane-1,2-diamine (108.2 mg, 1.230 mmol) was added to obtain pure white solid powder 31 with a yield of 72%. 1H NMR (400MHz, CD3OD) δ (ppm): 5.37 (t, J = 3.5 Hz, 1H), 3.71 (ddd, J = 11.3, 9.5, 4.5 Hz, 1H), 3.52 (d, J = 11.0 Hz, 1H), 3.44–3.35 (m, 2H), 3.31–3.22 (m, 2H), 2.89–2.73(m,4H),2.25–1.26(m,20H),1.21(t,J=7.2Hz,3H),1.17(s,3H), 1.06(s,3H),1.00(s,3H),0.94(d,J=6.5Hz,3H),0.82(s,3H),0.71(s,3H); 13 C NMR (101MHz, CD3OD) δ (ppm): 181.08, 140.03, 126.93, 78.05, 69.62, 66.15, 53.96, 48.90, 48.02, 47.94, 44.33, 44.11, 43.38, 40.86, 40.76, 40.24 ,39.06,38.92,38.67,33.39,31.83,28.86,25.12,24.44,24.13,21.58, 18.99,17.97,17.72,17.64,13.94,13.57; ESI-MS(m / z)604.1[M+HCOOH] - ,560.1[M+H] + .

[0118] Example 33, Synthesis of Compound 32:

[0119]

[0120] The reaction was carried out as in 18, except that piperazine was replaced by ethane-1,2-diamine (74.0 mg, 1.230 mmol) to give pure white solid powder 32 in a yield of 50%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.35 (t, J = 3.6 Hz, 1H), 3.69 (ddd, J = 11.3, 9.7, 4.4 Hz, 1H), 3.50 (d, J = 11.1 Hz, 1H), 3.35 (d, J = 9.7 Hz, 1H), 3.29–3. 16(m,3H),2.79(t,J=6.4Hz,2H),2.20–1.25(m,19H),1.15(s,3H),1.0 4(s,3H),0.98(s,3H),0.92(d,J=6.5Hz,3H),0.81(s,3H),0.69(s,3H); 13C NMR(101MHz,CD3OD)δ(ppm):181.09,140.08,126.91,78.07,69.62,66.17,54.01,4 8.92,48.04,47.95,44.12,43.39,41.31,41.09,40.87,40.76,40.26,38.93,38.74 33.43 31.85,28.88,25.12,24.46,24.15,21.59,19.01,17.97,17.74,17.65,13.95; ESI-MS(m / z)576.1[M+HCOOH] - ,532.1[M+H] + . ESI-MS (m / z) 576.1 [M+HCOOH] - ,532.1[M+H] + .

[0121] Example 34, Synthesis of Compound 33:

[0122]

[0123] The reaction was carried out as in 18, except that piperazine was replaced by 1,3-propylenediamine (91.0 mg, 1.230 mmol) to give pure white solid powder 33 in a yield of 44%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.36 (t, J = 3.6 Hz, 1H), 3.72 (ddd, J = 11.3, 9.5, 4.4 Hz, 1H), 3.52 (d, J = 11.1 Hz, 1H), 3.38 (d, J = 9.5 Hz, 1H), 3.29–3. 05(m,3H),2.66(t,J=6.9Hz,2H),2.32–1.23(m,21H),1.16(s,3H),1.0 6(s,3H),1.00(s,3H),0.93(d,J=6.5Hz,3H),0.82(s,3H),0.71(s,3H); 13C NMR(101MHz,CD3OD)δ(ppm):180.31,140.10,126.84,78.05,69.61,66.15,54.05,48.03,47.96,44.11,43.40,40.85,40.78,40.30,39.74,38 .93,38.89,37.83,33.47,32.95,31.89,28.89,25.11,24.46,24.16,21.62,19.00,17.96,17.77,17.68,13.97; ESI-MS(m / z)590.1[M+HCOOH] - ,546.1[M+H] + .

[0124] Example 35, Synthesis of Compound 34:

[0125]

[0126] The reaction was carried out as in 18, except that piperazine was replaced by butane-1,4-diamine (108.2 mg, 1.230 mmol) to give pure white solid powder 34 in a yield of 44%. 1 H NMR (400MHz, CD3OD) δ (ppm): 5.36 (t, J=3.7Hz, 1H), 3.71 (ddd, J=11.3, 9.6, 4.5Hz, 1H) ,3.52(d,J=11.1Hz,1H),3.37(d,J=9.6Hz,1H),3.28(d,J=11.1Hz,1H),3.14(ddt,J=3 3.2,13.5,6.5Hz,2H),2.70(t,J=6.1Hz,2H),2.22–1.48(m,24H),1.45–1.26(m,3H),1 .16(s,3H),1.06(s,3H),1.00(s,3H),0.93(d,J=6.7Hz,3H),0.82(s,3H),0.71(s,3H); 13 CNMR(126MHz,CD3OD)δ(ppm):180.14,140.21,126.83,78.14,69.63,66.29,54.13,48.12,47.97,44.11,43.44,41.88,40.90,40.81,40.31,3 8.96,38.79,33.50,31.91,30.37,28.92,27.66,25.17,24.48,24.13,2 1.60,19.03,18.00,17.75,17.69,13.94; ESI-MS(m / z)604.1[M+HCOOH]- ,560.1[M+H] + .

[0127] Example 36, Synthesis of Compound 35:

[0128]

[0129] The reaction was carried out as in step 18, except that piperazine was replaced by 4-methylaminopyridine (132.8 mg, 1.230 mmol) to give pure white solid powder 35 in a yield of 85%. 1 H NMR (400MHz, CD3OD) δ (ppm): 8.44 (d, J = 6.1 Hz, 2H), 7.34 ( d, J = 6.1 Hz, 2H), 5.34 ( t,J=3.7Hz,1H),4.48–4.24(m,1H),3.69(ddd,J=11.3,9.6,4.4Hz,1H),3.50(d,J =11.0Hz,1H),3.35(d,J=9.6Hz,1H),3.25(d,J=11.0Hz,1H),2.27–1.20(m,21H), 1.13(s,3H),1.05–0.96(m,6H),0.92(d,J=6.2Hz,3H),0.68(s,3H),0.58(s,3H); 13 C NMR (126MHz, CD3OD) δ (ppm): 180.32, 151.14, 149.90, 139.99, 126.94, 124. 37,78.12,69.64,66.25,54.22,48.93,48.77,48.10,47.96,44.10,43.37, 43.14,40.85,40.76,40.30,38.93,33.50,31.87,28.86,25.16,24.44,24. 19,21.57,18.99,17.89,17.72,17.67,13.93; ESI-MS(m / z)623.6[M+HCOOH] - ,579.7[M+H] + .

[0130] Example 37, Synthesis of Compound 36:

[0131]

[0132] The reaction was carried out as in step 18, except that piperazine was replaced by 3-methylaminopyridine (132.8 mg, 1.230 mmol) to afford pure white solid powder 36 in a yield of 79%. 1H NMR (400MHz, CD3OD) δ (ppm): 8.51 (s, 1H), 8.42 (d, J = 4.6Hz, 1H), 7.80 (dt, J = 7.8, 1.9H z,1H),7.40(dd,J=7.8,4.6Hz,1H),5.33(t,J=3.5Hz,1H),4.48–4.21(m,2H),3.79–3.6 2(m,1H),3.51(d,J=11.0Hz,1H),3.36(d,J=9.4,1H),3.26(d,J=11.0Hz,1H),2.25–1. 18(m,20H),1.13(s,3H),1.00(s,6H),0.93(d,J=6.2Hz,3H),0.70(s,3H),0.48(s,3H); 13 CNMR(101MHz,CD3OD)δ(ppm):180.23,149.88,148.53,139.92,138.14,137.0 7,126.90,125.12,78.06,69.64,66.14,54.24,48.88,48.03,47.96,44.10,43 .34,41.79,40.79,40.76,40.32,38.90,33.48,31.86,28.83,25.13,24.42,2 4.13,21.56,18.96,17.81,17.70,17.65,13.94; ESI-MS(m / z)623.6[M+HCOOH] - ,579.7[M+H] + .

[0133] Example 38, Synthesis of Compound 37:

[0134]

[0135] The reaction was carried out as in step 18, except that piperazine was replaced by 2-methylaminopyridine (132.8 mg, 1.230 mmol) to give pure white solid powder 37 in a yield of 78%. 1H NMR (400MHz, CD3OD) δ (ppm): 8.51 (d, J = 5.0Hz, 1H), 7.92 (t, J = 5.4Hz, 1H), 7.80 (m, 1H), 7.37 (d, J=9.0Hz,1H),7.32(dd,J=7.3,5.0Hz,1H),5.41(t,J=3.5Hz,1H),4.44(s,2H),3.70(ddd,J=11. 3,9.7,4.4Hz,1H),3.51(d,J=11.0Hz,1H),3.36(d,J=9.7Hz,1H),3.27(d,J=11.0Hz,1H),2.31– 1.22(m,21H),1.16(s,3H),1.03–0.98(m,6H),0.95(d,J=6.4Hz,3H),0.69(s,3H),0.60(s,3H); 13 C NMR(126MHz,CD3OD)δ(ppm):180.37,180.30,158.84,149.64,139.91,138.68,12 7.32,123.74,123.34,78.04,69.64,66.12,54.42,48.02,47.96,45.58,45.48,44 .11,43.38,40.86,40.83,40.34,38.89,38.64,33.39,31.89,28.87,25.38,24.4 4,24.12,21.58,18.96,17.75,17.63,17.59,13.92; ESI-MS(m / z)623.6[M+HCOOH] - ,579.7[M+H] + .

[0136] Example 39, Synthesis of Compound 38:

[0137]

[0138] Compound 2 (100 mg, 0.18 mmol) was dissolved in EA (2 mL), 1 mL of HCl-EA solution was slowly added dropwise at low temperature, and stirred for 0.5 hours to precipitate a large amount of white solid. After suction filtration and drying, a white solid 38 was obtained with a yield of 90%. 1HNMR(400MHz,C5D5N)δ(ppm):5.58(s,1H),5.18(s,1H),4.40–4.15(m,2H),3.86–3.63(m,5H),3.41–3.20(m,2 H),3.12–2.86(m,4H),1.69(s,3H),1.44(s,3H),1.14(d,J=6.8Hz,3H),1.12(s,3H),1.08(s,3H),1.05(s,3H); 13 C NMR (126MHz, C5D5N) δ (ppm): 176.21, 140.65, 128.46, 74.08, 73.63, 68.46, 57.19, 50.06, 49.24, 48.39, 47.75, 47.26, 43.43, 42.82, 42.67, 40 .76,39.42,37.78,35.90,34.02,29.69,28.22,28.13,27.34,25.09,24.60,19.34,17.73,17.30,16.65,13.67; ESI-MS(m / z)602.1[M+HCOOH] - ,558.1[M+H] + .

[0139] Example 40, Synthesis of Compound 39:

[0140]

[0141] Compound 5 (100 mg, 0.17 mmol) was dissolved in EA (2 mL), 1 mL of HCl-EA solution was slowly added dropwise at low temperature, and stirred for 0.5 hours to precipitate a large amount of white solid. After suction filtration and drying, a white solid 39 was obtained with a yield of 85%. 1HNMR(500MHz,DMSO-d6)δ(ppm):6.77(d,J=7.8Hz,1H),5.17(d,J=3.7Hz,1H),4.39(s,1H),4.13(d,J=4.9Hz,1H),3.70(s,1H),3.54–3.47(m,1 H),3.47–3.39(m,2H),3.07(d,J=10.4Hz,1H),2.89(d,J=12.1Hz,2H),2 .44(s,2H),2.42–2.38(m,2H),1.94–1.84(m,2H),1.83-1.77(m,1H),1. 68–1.61(m,2H),1.61–1.54(m,4H),1.53(d,J=2.6Hz,1H),1.49(d,J=12.5Hz,5H),1.46(d,J=4.3Hz,1H),1.37(dd,J=12.7,5.1Hz,2H),1.28(s ,3H),1.27–1.23(m,3H),1.21-1.18(m,1H),1.13(d,J=13.1Hz,3H),1.0 8(s,3H),0.86(s,3H),0.83(d,J=6.7Hz,3H),0.65(s,3H),0.53(s,3H). 13 C NMR(126MHz,DMSO-d6)δ(ppm):176.22,139.40,127.08,72.43(2C),70.90,6 5.00,53.08,47.22,47.02,46.95,46.86,45.66,42.30(2C),41.74,41.55(2C) ),38.51,38.41,36.71,33.26,32.95,28.35,27.06,26.98,26.58,24.85,24 .48,23.65,18.05,17.24,16.77,15.95,13.11.ESI-MS(m / z)616.1[M+HCOOH] - ,572.1[M+H] + .

[0142] Example 41, Synthesis of Compound 40:

[0143]

[0144] Compound 26 (100 mg, 0.17 mmol) was dissolved in EA (2 mL), 1 mL of HCl-EA solution was slowly added at low temperature, and the mixture was stirred for 0.5 hours to precipitate a large amount of white solid. After suction filtration and drying, a white solid 40 was obtained with a yield of 88%.1 HNMR (400MHz, CD3OD) δ (ppm): 5.35 (t, J = 3.7 Hz, 1H), 3.70 (ddd, J = 11.3, 9.5, 4 .5Hz,1H),3.50(d,J=11.1Hz,1H),3.36(d,J=9.6Hz,1H),3.26(d,J=11.1Hz,1 H),3.18–2.93(m,3H),2.69–2.50(m,2H),2.23–1.25(m,23H),1.15(s,3H),1. 04(s,3H),0.99–0.96(m,3H),0.92(d,J=6.5Hz,3H),0.81(s,3H),0.69(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):180.62,140.25,126.79,78.06,69.61,66.16 ,54.09,48.07,47.97,45.38,44.93,44.13,43.43,40.89,40.78,40.26,39 .04,38.95,35.13,33.53,31.89,28.90,27.92,27.88,25.08,24.47,24.1 5,21.58,19.01,18.05,17.72,17.68,13.96; ESI-MS(m / z)630.0[M+HCOOH] - ,585.9[M+H] + .

[0145] Example 42, Synthesis of Compound 41:

[0146]

[0147] Compound 27 (100 mg, 0.18 mmol) was dissolved in EA (2 mL), 1 mL of HCl-EA solution was slowly added dropwise at low temperature, and the mixture was stirred for 0.5 hours to precipitate a large amount of white solid. After filtration and drying, a white solid 41 was obtained with a yield of 92%. 1HNMR (400MHz, CD3OD) δ (ppm): 5.36 (t, J=3.5Hz, 1H), 3.72 (ddd, J=11.3, 9.6, 4.4Hz ,1H),3.52(d,J=11.1Hz,1H),3.38(d,J=9.6Hz,1H),3.28(d,J=11.1Hz,1H),3.19( dt,J=13.7,6.9Hz,1H),2.52–2.39(m,2H),2.31(s,6H),2.17–1.25(m,18H),1.16( s,3H),1.06(s,3H),1.00(s,3H),0.93(d,J=6.5Hz,3H),0.83(s,3H),0.71(s,3H); 13 C NMR(101MHz,CD3OD)δ(ppm):180.30,140.10,126.99,78.04,69.63,66.13,58.89,54.20,48.04,47.97,45.48,44.12,43.45,40.88,40.82,40 .32,38.93,38.62,38.02,33.45,31.88,28.89,25.25,24.50,24.08,21.59,19.00,17.98,17.76,17.67,13.96; ESI-MS(m / z)604.1[M+HCOOH] - ,560.0[M+H] + .

[0148] Example 43: Study confirming that GATA6 is a potential therapeutic target for myocardial hypertrophy

[0149] Experimental methods:

[0150] Cells: Extraction of primary myocardial cells from suckling rats: 1-3 days old suckling rats were disinfected by immersion in 75% alcohol; they were killed by dislocating the cervical vertebrae; the chest cavity was opened with curved forceps to expose the heart and the heart was quickly removed; the heart was placed in a pre-cooled culture medium containing antibiotics and the blood in the heart was squeezed out before the heart stopped beating; the heart was placed in another fresh culture medium and washed twice; the heart was carefully clamped with curved forceps and cut into 6-7 tissue blocks of the same size and placed in a clean culture medium; the above steps were repeated to extract heart tissues from 10-15 suckling rats; Add 5 mL of digestion solution (0.1% type II collagenase); digest for 3 min for the first time to remove residual blood cells; digest for 5 min for the second time, collect the digested cells and immediately transfer them to a culture medium containing 5 mL of 10% serum, gently invert and mix, and terminate the digestion; digest for the third time, the same as the previous step; digest for 6 min for the fourth time, collect the digested cells; digest for the fifth time, the same as the previous step; digest for 7 min for the sixth time, collect the digested cells; after all myocardial tissues are digested, all the collected cells are centrifuged; use 10% The cells were resuspended in FBS-containing DMEM medium and spread in two large dishes; the extracted cells were cultured in an incubator for 90 minutes; the upper suspended cells were collected by filtering through a 75 μM cell sieve; the filtrate was collected and transferred to a centrifuge tube, and 5-bromodeoxyuridine (BrdU final concentration was 100 μM) was added to inhibit the growth of fibroblasts; an in vitro angiotensin II (Ang II) stimulation-induced rat primary cardiomyocyte hypertrophy model was established, and the extracted primary cardiomyocytes were cultured for 24 hours, infected with virus solution, and replaced with serum-free culture medium, Ang II with a final concentration of 1 μM was added to the culture medium, and the model was established for 48 hours.

[0151] In vivo AAV transfection: The diluted AAV8 virus solution was restored to room temperature and injected into the mouse through the tail vein using a mouse intravenous visual tail injection fixture, and gently pressed to stop bleeding. The control group and model group mice were injected with control virus solution, and the GATA6 knockdown group was injected with GATA6 shRNA virus solution. Subsequent experiments can be performed after the expression is stable after 3 weeks of injection.

[0152] A myocardial hypertrophy model was established by mouse aortic arch stenosis (TAC): mice were anesthetized with 1% sodium pentobarbital and fixed in a supine position; hair was removed with flat-head scissors, disinfected with iodine, and placed on a 37°C constant temperature heating plate; the skin was incised along the upper edge of the sternum to the fourth rib; ophthalmic scissors were used to cut the sternum along the middle of the sternum to the second rib, and the aortic arch was exposed with precision ophthalmic forceps; the aortic arch was sutured with a 27G needle using 6-0 silk thread; at this time, the pulsation of the right common carotid artery of the mouse was observed to accelerate, indicating that the operation was successful; the needle was quickly withdrawn, and the chest was sutured layer by layer; iodine disinfection was performed; routine feeding was carried out for 4 weeks after the operation, and relevant indicators were tested.

[0153] Experimental results: The results are as attached Figure 1As shown in the results, in rat primary myocardial cells, overexpression of GATA6 can lead to further increase in the transcription levels of Nppa, Nppb and Myh7, marker genes of myocardial hypertrophy, stimulated by angiotensin II (Ang II), while knocking down GATA6 can significantly inhibit the expression of hypertrophy-related genes. A mouse model of cardiac-specific knockdown of GATA6 was constructed by in situ injection of adeno-associated virus for in vivo verification, and a myocardial hypertrophy model was established by aortic arch stenosis (TAC) surgery in mice. The results showed that compared with the control group, the heart-to-body ratio, heart-to-tibia length ratio and lung-to-body ratio of TAC mice were significantly increased, and knocking down GATA6 significantly inhibited the above values. In addition, knocking down GATA6 can improve the cardiac dysfunction, increased expression of hypertrophic genes and degree of fibrosis in mice caused by TAC surgery. The above results all indicate that GATA6 plays an important regulatory function in myocardial cell hypertrophy and can be used as a potential target for drug intervention.

[0154] Example 44, Study on the interaction between the compound and the target protein GATA6:

[0155] Experimental method: insert the CM5 chip into the instrument, maintain a constant flow rate at 25°C, and allow the HBS-EP buffer to continuously pass through the chip surface for about 5 minutes; examine the effects of the pH value, ionic strength, concentration and flow rate of the protein solution to be fixed on the results, and select appropriate fixation conditions based on the pre-adsorption of the target protein by analyzing the sensor graph; after the baseline is stable, start injecting a 1:1 ratio of N-hydroxysuccinimide / N-ethyl-N-(dimethylaminopropyl) and carbodiimide (GE Healthcare) mixture to flow through the chip surface to activate the carboxyl groups on it; inject 200 μL GATA6 protein solution is used to couple the amino groups on the protein surface with the activated carboxyl groups on the chip surface to fix the protein on the chip; a hydrochloric acid solution of ethanolamine is injected to block the residual activated carboxyl groups on the chip surface; a certain volume of HBS-EP solution is injected to wash away the non-covalently bound adsorbed conjugates and ethanolamine; after the conjugate is fixed on the chip surface, HBS-EP buffer is used as the working solution to flow through the system, and the blank channel is used as the control channel to eliminate nonspecific binding as much as possible; after the baseline is stable, different concentrations of 1-37 solution are injected to monitor the binding process in real time; data processing is performed using the processing software provided by the Biacore T200 instrument, and the reaction kinetics and affinity information of binding and dissociation are obtained according to the 1:1 Langmuir binding model.

[0156] Experimental results: As shown in Table 1, many compounds have strong affinity to GATA6, and their binding affinity Kd is <1 μM.

[0157] Table 1. Affinity of compounds for GATA6

[0158]

[0159]

[0160] Example 45: Study on the in vitro anti-cardiac hypertrophy effect of compounds 1 and 5

[0161] Experimental method: The primary experiment on suckling rats was the same as in Example 43.

[0162] Experimental results: As shown in Table 2, Ang II stimulation led to a significant increase in the transcription levels of myocardial hypertrophy marker genes Nppa, Nppb and Myh7; while 1 and 5 could inhibit the increase in the transcription levels of primary cardiomyocyte hypertrophy marker genes induced by Ang II in a concentration-dependent manner.

[0163] Table 2. Effects of compounds 1 and 5 on hypertrophic gene expression in primary neonatal rat cardiomyocytes

[0164]

[0165] Example 46: Study on the effect of preventive administration of compounds 1 and 5 on improving myocardial hypertrophy

[0166] Experimental methods: Male C57BL / 6 mice, 6-8 weeks old, weighing 18-20 g; animals were fed and watered freely and kept in an environment with a room temperature of 22±2°C and a humidity of 45±10%; after 7 days of adaptive feeding, they were used in subsequent experiments;

[0167] The method for establishing the mouse TAC model was the same as that in Example 43. 10 mg / kg concentration of 1 and 5 and 2 mg / kg concentration of the positive drug Enalapril were orally administered to the mice to investigate the improvement effects of compounds 1 and 5 on the myocardial hypertrophy model mice.

[0168] Experimental results: As shown in Table 3, compared with the Sham group, the heart weight to body weight ratio (HW / BW) and heart weight to tibia length ratio (HW / TL) values ​​of TAC mice were significantly increased, while oral administration of 1 and 5 significantly inhibited the above values ​​and the effect was better than that of the positive drug enalapril, indicating that compounds 1 and 5 can inhibit TAC-induced heart enlargement and weight gain in mice; the left ventricular myocardial tissue of each group of mice was taken for RT-qPCR detection, as shown in Table 4, the transcription level of myocardial hypertrophy marker genes in TAC group mice was significantly higher than that in Sham group, while oral administration of 1 and 5 inhibited the expression of transcription level of TAC-induced myocardial hypertrophy marker genes (Nppa, Nppb, Myh7).

[0169] Table 3. Effects of Compounds 1 and 5 on Heart Weight of TAC Mice (n=5)

[0170]

[0171] Table 4. Effects of Compounds 1 and 5 on the expression of cardiac hypertrophy genes in TAC mice (n=5)

[0172]

[0173] Example 47: Study on the effect of preventive administration of compounds 1 and 5 on improving myocardial hypertrophy

[0174] Experimental method: The method for establishing the mouse TAC model was the same as that in Example 43; compounds 1, 2, and 5 were orally administered to mice at concentrations of 1 and 10 mg / kg, and the improvement effects of the compounds on the myocardial hypertrophy model mice were investigated by cardiac ultrasound.

[0175] Experimental results: As shown in Table 5, compared with the Sham group, the left ventricular heart weight (LV) of TAC mice was significantly increased, and the left ventricular fraction shortening (FS) and left ventricular ejection fraction (EF) were significantly decreased, while oral administration of 1, 2, and 5 could significantly improve the cardiac dysfunction caused by TAC surgery.

[0176] Table 4. Effects of Compounds 1, 2, and 5 on cardiac function in TAC mice (n=5)

[0177]

[0178]

[0179] Example 48: Study on the effect of compound 1 on improving myocardial hypertrophy by in vivo therapeutic administration

[0180] Experimental method: The method for establishing the mouse TAC model was the same as that in Example 43; after the TAC model was established, the mice were orally administered 1 at a concentration of 10 mg / kg in the 2nd and 3rd weeks, respectively, and the positive drug Enalapril (Enalapril) was orally administered to the mice at a concentration of 2 mg / kg in the 2nd week to investigate the therapeutic effect of compound 1 on mice with myocardial hypertrophy model.

[0181] Experimental results: As shown in Table 6, compared with TAC mice, 2 weeks and 3 weeks of treatment with compound 1 can significantly inhibit the enlargement and weight gain of the mouse heart; the left ventricular myocardial tissue of each group of mice was taken for RT-qPCR detection. As shown in Table 7, the transcription level of myocardial hypertrophy marker genes in the TAC group was significantly higher than that in the Sham group, and oral treatment with 1 can inhibit the expression of TAC-induced myocardial hypertrophy (Nppa, Nppb, Myh7) marker gene transcription levels, and the effect is better than the positive drug enalapril.

[0182] Table 6. Effects of Compound 1 on the heart weight of TAC mice (n=5)

[0183]

[0184] Table 7. Effects of Compound 1 on the expression of cardiac hypertrophy genes in TAC mice (n=5)

[0185]

Claims

1. A pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof, characterized in that: The chemical structural formula of the pentacyclic triterpene derivative is shown in formula (I): Wherein: R1 is H or OH; R2 is -CH2OH or -COOH; R3 is H or OH; R4 is 2. The pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: in: R1 is H; R2 is -CH2OH; R3 is OH; R4 is 3. The pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: in: R1 is OH; R2 is -CH2OH; R3 is H; R4 is 4. A pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The pentacyclic triterpene derivative or its pharmaceutically acceptable salt is selected from the following compounds:

5. A pharmaceutical composition comprising a pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, and at least one pharmaceutically acceptable carrier, additive, adjuvant or excipient.

6. Use of a pentacyclic triterpene derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 in the preparation of a drug for preventing / treating myocardial hypertrophy.

7. Use of the pharmaceutical composition according to claim 5 in preparing a drug for preventing / treating myocardial hypertrophy.

8. The use according to claim 6, wherein the pentacyclic triterpene derivative has a binding effect on GATA6, a potential intervention target for myocardial hypertrophy.

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