Diamino acid-genipin derivative as well as preparation method and application thereof

Abstract

The invention discloses a double amino acid-genipin derivative as well as a preparation method and application thereof. The invention aims to provide a bis-amino acid-genipin derivative with neuroprotective activity. A first amino acid fragment is introduced through oxidation and amination of hemiacetal at the C-1 position of genipin, a second amino acid fragment is introduced through esterification at the C-10 position to obtain a series of brand-new genipin derivatives, and the genipin derivatives show good neuroprotective activity on an OGD / R induced HT22 nerve cell injury model and can be used for preparing neuroprotective drugs; the structural general formula of the double amino acid-genipin derivative is # imgabs0 #, relates to the field of medical technology and medicinal chemistry.

Description

Technical Field

[0001] The present invention relates to the fields of medical technology and pharmaceutical chemistry, and in particular to a diamino acid-genipin derivative. The present invention also relates to a preparation method and application of the diamino acid-genipin derivative. Background Art

[0002] Cerebral stroke, commonly known as "stroke", is a neurological disease, which is divided into ischemic and hemorrhagic stroke. Most of them are ischemic stroke, which has a high disability rate, mortality rate and recurrence rate. With the acceleration of population aging, the incidence of stroke in my country has increased year by year. The mechanism of neural damage after stroke is complex, mainly including ischemia-reperfusion injury, oxidative stress, and immune-inflammatory injury. Tissue prothrombin activator (Rt-PA), as a thrombolytic agent, was approved by the FDA for the treatment of stroke more than 20 years ago and is currently widely used worldwide. However, its clinical use has side effects such as a narrow treatment time window, possible intracranial hemorrhage and neurotoxicity. Edaravone was approved by Japan in 2001 for the treatment of acute ischemic stroke and is a free radical scavenger. Free radicals are reactive oxygen molecules produced during cell metabolism, which can damage cells. Edaravone can neutralize these free radicals, reduce oxidative stress, and thus protect nerve cells from further damage, but it will damage kidney function.

[0003] Ischemia-reperfusion (IR) is an important cause of death from ischemic stroke. In the hypoxic brain, the cessation of oxygen and glucose supply will lead to rapid depolarization of nerve cells, release of a large number of neurotransmitters, and cause nerve cell damage and death. Currently, occluded arteries can be recanalized by thrombolysis or thrombectomy. However, rapid restoration of blood flow in the ischemic area may further aggravate the damage to nerve cells and brain tissue. Finding effective neuroprotective drugs has important value and broad application prospects for the treatment of ischemia-reperfusion injury and stroke.

[0004] HT22 is a mouse hippocampal neural cell line that is commonly used in neuroscience research. It is derived from neuronal cells in the mouse hippocampus, has relatively stable characteristics, and is easy to culture and maintain under laboratory conditions. The HT22 cell line is widely used due to its research value in oxidative stress, neuroprotection, and neurodegenerative diseases. In addition, neurons in the hippocampus of the brain are vulnerable to cerebral ischemia-reperfusion and are commonly studied in the study of cerebral ischemia-reperfusion injury. Therefore, the HT22 cell line is often used to explore how different compounds protect neurons from cellular oxygen-glucose deprivation damage and their mechanism of action.

[0005] Oxygen-Glucose Deprivation / Reperfusion (OGD / R) is an important in vitro model that can simulate the process of ischemia-reperfusion injury in HT22 neuronal cells. In this model, neuronal cells first experience a period of anaerobic and glucose-free environment, which leads to energy metabolism disorders and impaired mitochondrial function, thereby producing a large amount of reactive oxygen species (ROS). Subsequently, when oxygen and glucose are resupplied, ROS further accumulate, exacerbating oxidative stress and ultimately leading to neuronal cell death. By measuring changes in lactate dehydrogenase (LDH), the integrity of the cell membrane and the degree of cell damage can be assessed. This model is widely used to study the pathological mechanism of ischemic brain injury and to evaluate the effects of neuroprotective drugs.

[0006] In recent years, more and more studies have shown that amino acids have a variety of physiological activities and functions. For example, glycine has anti-inflammatory, immune-regulating, and cell-protective effects. It can prevent ischemia / reperfusion injury in multiple tissues and organs such as liver, kidney, heart, intestine, and skeletal muscle, and reduce liver and kidney damage caused by liver and kidney toxins and drugs. Clinical experiments have shown that the use of glycine treatment has a significant improvement effect on ischemic stroke and can reduce the 30-day mortality rate of patients with ischemic stroke. The aromatic amino acid L-phenylalanine (L-Phe) has a selective and significant inhibition of the ionotropic glutamate receptors of excitatory synapses in rat or mouse hippocampal and cerebral cortical neuronal cultures, and can safely and effectively protect the brain when glutamate receptors are overactivated. At the same time, the brain contains amino acid transporters (large neutral amino acid transporter 1, LAT1), and drugs outside the blood-brain barrier (BBB) ​​can enter the brain through transporter-mediated means to exert their effects. The substrates of endogenous transporters, such as amino acids, combined with active drug molecules can greatly increase the probability of compounds passing through the blood-brain barrier.

[0007] Genipin is the aglycone of geniposide, which can be obtained by hydrolysis of geniposide by β-glucosidase and belongs to the class of terpenoid compounds. Genipin has a wide range of biological activities, such as neuroprotection, anti-cancer, hypoglycemic, anti-viral, and anti-anxiety. Genipin can also be used as a new type of natural cross-linking agent, which can react with proteins, gelatin, and chitosan to prepare biomaterials. However, the hemiacetal structure at the 1-position of genipin is unstable, which affects its drug development and application. At present, research on the development of new neuroprotective drugs by effectively combining amino acids with genipin is still very limited. Summary of the invention

[0008] One of the purposes of the present invention is to provide a diamino acid-genipin derivative having neuroprotective activity.

[0009] The second object of the present invention is to provide a method for preparing a diamino acid-genipin derivative.

[0010] The third object of the present invention is to provide the use of diamino acid-genipin derivatives in the preparation of neuroprotective drugs.

[0011] To this end, the first technical solution provided by the present invention is a diamino acid-genipin derivative having a general structural formula 1:

[0012] Formula 1 Wherein: R1 is one of hydrogen, methyl, and benzyl; R2 is one of hydrogen, methyl, benzyl, isopropyl, 2-methylpropyl, 2-(methylthio)ethyl, 2-methoxybenzyl, (benzyloxy)yl, (benzylthio)yl, 1-(benzyloxy)ethyl, and indole-3-methyl; R3 is one of hydrogen and tert-butyloxycarbonyl.

[0013] The second technical solution provided by the present invention is a method for preparing the above-mentioned diamino acid-genipin derivative, which comprises the following steps in sequence: Genipin is used as a starting material, and an intermediate 1 is obtained by an etherification reaction with tert-butyldimethylsilyl chloride. Intermediate 1 is subjected to an oxidation reaction to obtain intermediate 2. Intermediate 2 and amino acid tert-butyl ester hydrochloride are subjected to an amination reaction to obtain intermediate 3. Intermediate 3 is subjected to an esterification reaction with an amino acid compound, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain a diamino acid-genipin derivative 1. The synthetic route and its products are shown below: .

[0014] Furthermore, in the above-mentioned method for preparing the diamino acid-genipin derivative, the oxidation reaction is a Dess-Martin periodinane oxidation reaction.

[0015] Furthermore, in the above-mentioned preparation method of the diamino acid-genipin derivative, the amino acid tert-butyl ester hydrochloride is one of glycine tert-butyl ester hydrochloride, alanine tert-butyl ester hydrochloride, and phenylalanine tert-butyl ester hydrochloride, or any combination thereof.

[0016] Further, in the preparation method of the above-mentioned diamino acid-genipin derivative, the amino acid compound is one of N-(tert-butoxycarbonyl)-L-tryptophan, N-(tert-butoxycarbonyl)-L-methionine, N-(tert-butoxycarbonyl)-O-benzyl-L-threonine, N-(tert-butoxycarbonyl)-L-isoleucine, N-(tert-butoxycarbonyl)-D-alanine, N-(tert-butoxycarbonyl)-O-benzyl-L-serine, N-(tert-butoxycarbonyl)-S-benzyl-L-cysteine, N-(tert-butoxycarbonyl)-L-valine, N-(tert-butoxycarbonyl)-L-phenylalanine, N-(tert-butoxycarbonyl)glycine, N-tert-butoxycarbonyl-4-methoxy-L-phenylalanine or any combination thereof.

[0017] Furthermore, the method for preparing the above-mentioned bis-amino acid-genipin derivative further comprises deaminating the protecting group of the bis-amino acid-genipin derivative 1 by trifluoroacetic acid to obtain the bis-amino acid-genipin derivative 2; The synthetic route and its products are shown below:

[0018] .

[0019] The last technical solution of the present invention is the use of the above-mentioned diamino acid-genipin derivatives in the preparation of therapeutic neuroprotective drugs.

[0020] Compared with the prior art, the present invention has carried out multi-site modification on genipin, and introduced different amino acid combinations into the skeleton of the natural product, including oxidation of the hemiacetal at the C-1 position of genipin, introduction of the first amino acid fragment by amination, and introduction of the second amino acid by esterification at the C-10 position to obtain a series of new genipin derivatives, which showed good neuroprotective activity in the OGD / R-induced HT22 neuronal cell injury model, such as Figure 1OGD / R induced HT22 neuronal cell damage and reduced its survival rate to 58%. The cell survival rates of the positive control drug Eda at 1 and 10 μM were 72% and 76%, respectively, and the cell survival rates of the parent compound genipin (1) at 1 and 10 μM were 68% and 71%, respectively. The neuroprotective activity of 9 compounds 7a-7k and 10a-10k derived from compound 4 was significantly improved at a concentration of 1 μM. At a concentration of 10 μM, the neuroprotective activity of 7 compounds was significantly improved, among which the neuroprotective activity of compound 10i at 1 and 10 μM concentrations was better than that of the positive control drug edaravone (Eda). The neuroprotective activity of 10 compounds 8a-8k and 11a-11k derived from compound 5 was significantly improved at a concentration of 1 μM. At a concentration of 10 μM, the neuroprotective activity of 7 compounds was significantly improved. The neuroprotective activity of 10 compounds 9a-9k and 12a-12k derived from compound 6 was significantly improved at a concentration of 1 μM. At a concentration of 10 μM, the neuroprotective activity of 7 compounds was significantly improved, among which the survival rate of compound 9a at a concentration of 10 μM reached 85%, which was significantly better than the positive control drug Eda (72%). Further studies on compound 9a confirmed that this type of derivative can effectively restore the morphology of OGD / R-induced damaged neurons and reduce the levels of reactive oxygen species and lactate dehydrogenase. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a comparison chart of the protective activity of diamino acid-genipin derivatives 7a-7k and 10a-10k against OGD / R-induced HT-22 cell damage.

[0022] Figure 2 This is a comparative chart of the protective activities of the diamino acid-genipin derivatives 8a-8k and 11a-11k against OGD / R-induced HT-22 cell damage.

[0023] Figure 3 This is a comparison chart of the protective activities of the diamino acid-genipin derivatives 9a-9k and 12a-12k against OGD / R-induced HT-22 cell damage.

[0024] Figure 4 This is a screening diagram for the optimal concentration of diamino acid-genipin derivatives for their protective activity against OGD / R-induced HT-22 cell damage.

[0025] Figure 5 This is a graph showing the changes in lactate dehydrogenase content and morphological changes in HT-22 cell damage induced by OGD / R by a diamino acid-genipin derivative.

[0026] Figure 6This is a graph showing the changes in reactive oxygen content in HT-22 cell damage induced by OGD / R in response to the diamino acid-genipin derivative. DETAILED DESCRIPTION

[0027] The present invention is further explained below in conjunction with Examples and accompanying drawings, but the Examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art. Unless otherwise specified, the reagents and materials used in the present invention are commercially available.

[0028] Example 1 Synthesis of Compounds 7a-7k As shown in synthetic route 1, genipin is used as a starting material and reacted with tert-butyldimethylsilyl chloride in an N,N-dimethylformamide solution to generate compound 2, compound 2 is dissolved in dichloromethane and reacted with Dess-Martin periodinane to generate compound 3, compound 3 is dissolved in N,N-dimethylformamide and reacted with amino acid tert-butyl ester hydrochloride compounds to generate compound 4 or 5 or 6, and then the C-10 position of compound 4 or 5 or 6 is reacted with the corresponding amino acid compound under the conditions of 4-dimethoxypyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and dichloromethane solution to obtain one of compounds 7a-7k, 8a-8k, 9a-9k.

[0029] The synthetic route is as follows:

[0030] Synthetic route 1

[0031] Reaction conditions and reagents in synthetic route 1: (a) tert-butyldimethylsilyl chloride, N,N-dimethylformamide, room temperature; (b) Dess-Martin periodinane, in dichloromethane, room temperature. (c) Amino acid tert-butyl ester hydrochloride compounds, in N,N-dimethylformamide, heated at 110°C. (d) Amino acid compounds, 4-dimethoxypyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, in dichloromethane, room temperature.

[0032] The specific steps of each compound are as follows: Reaction conditions and reagents in synthetic route 1: (a) tert-butyldimethylsilyl chloride, N,N-dimethylformamide, room temperature; (b) Dess-Martin periodinane, dichloromethane, room temperature. (c) Amino acid tert-butyl ester hydrochloride compounds, N,N-dimethylformamide, heated at 110°C. (d) Amino acid compounds, 4-dimethoxypyridine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dichloromethane, room temperature.

[0033] The specific steps for each compound are as follows: (1) Synthesis of compound 2 0.88mmol of compound 1 genipin and 1.056mmol of tert-butyldimethylsilyl chloride were dissolved in 25.8mmol N , N - Dimethylformamide, stirred at room temperature, the reaction was continued for 1h; ethyl acetate and saturated brine were added to the reaction solution for extraction, the organic layer was collected, dried at room temperature and concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 2; (2) Synthesis of compound 3 0.34 mmol of compound 2 and 0.408 mmol of Dess-Martin periodinane were dissolved in dichloromethane, reacted at room temperature for 3 h, and then ethyl acetate and saturated brine were added for extraction. The organic layer was collected, dried at room temperature, and then concentrated. The concentrate was separated and purified by column chromatography to obtain compound 3; (3) Synthesis of compound 4 0.34 mmol of compound 3 and 1.02 mmol of glycine tert-butyl ester hydrochloride were dissolved in 25.8 mmol of N,N-dimethylformamide, heated at 110°C with stirring, reacted for 2 h, then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction, the organic layer was collected, dried at room temperature and concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 4; (4) Synthesis of compounds 7a-7k Compound 4 (100 mg, 0.34 mmol), 4-dimethoxypyridine (49 mg, 0.40 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.01 mmol) and a carboxylic acid compound (0.50 mmol) were dissolved in dichloromethane, reacted at room temperature for 2 h, and then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 7a-7k, respectively; Wherein: the carboxylic acid compounds used in the synthesis of 7a-7k are as follows: The synthesis of 7a uses N-(tert-butoxycarbonyl)glycine; the synthesis of 7b uses N-(tert-butoxycarbonyl)-D-alanine; the synthesis of 7c uses N-(tert-butoxycarbonyl)-L-valine; the synthesis of 7d uses N-(tert-butoxycarbonyl)-L-isoleucine; the synthesis of 7e uses N-(tert-butoxycarbonyl)-L-methionine; the synthesis of 7f uses N-(tert-butoxycarbonyl)-L-phenylalanine; the synthesis of 7g uses N-tert-butoxycarbonyl-4-methoxy-L-phenylalanine; the synthesis of 7h uses N-(tert-butoxycarbonyl)-O-benzyl-L-serine; the synthesis of 7i uses N-(tert-butoxycarbonyl)-S-benzyl-L-cysteine; the synthesis of 7j uses N-(tert-butoxycarbonyl)-O-benzyl-L-threonine; and the synthesis of 7k uses N-(tert-butoxycarbonyl)-L-tryptophan.

[0034] The structural formulas of compounds 7a-7k are shown in Table 1; the appearance and NMR spectrum data are shown below: Compound 7a: colorless oil (50%) 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H, H-3), 5.90 (s, 1H, H-7), 5.30 (s, 1H, -NH), 5.02 (s, 2H, H-10), 4.15 (d, J = 3.5Hz, 2H, -N-CH2), 3.94 (d, J = 5.2 Hz, 2H, -CH2-NHBoc), 3.76 (s, 3H, -COOCH3), 3.68 – 3.66 (m, 1H, H-9), 3.59 (m, 1H, H-5), 2.95 – 2.89 (m, 1H, H-6), 2.32 –2.25 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3), 1.45 (s, 9H, Boc). 13 C NMR (100MHz, CDCl3) δ 170.04, 168.99, 166.95, 166.79, 155.69, 137.84, 136.66, 130.57,110.57, 82.84, 79.99, 63.47, 51.66, 49.25, 48.41, 42.48, 40.00, 37.12, 28.32,28.32, 28.32, 28.04, 28.04, 28.04. HRMS (ESI, m / z) calcd for C 24 H 34N2O9Na,517.2162, [M+Na] + ; found, 517.2158.

[0035] Compound 7b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.05 (s, 1H, -NH), 5.00 (s, 2H, H-10), 4.33 (d, J = 7.0Hz, 1H, -CH-COOCH2), 4.15 (d, J = 3.1 Hz, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3),3.68 – 3.65 (m, 1H, H-9), 3.63 – 3.52 (m, 1H, H-5), 2.95 – 2.89 (m, 1H, H-6),2.33 – 2.23 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 1.40(d, J = 7.2 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ 173.00, 168.93,166.95, 166.80, 155.08, 137.83, 136.80, 130.08, 110.58, 82.81, 79.80, 63.48,55.74, 51.65, 49.25, 48.45, 40.06, 37.08, 28.34, 28.34, 28.34, 28.03, 28.03,28.03, 18.82. HRMS (ESI, m / z) calcd for C 25 H 36 N2O9Na, 531.2319, [M+Na] + ; found,531.2315.

[0036] Compound 7c: colorless oil (50%), 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3),5.90 (s, 1H, H-7), 5.05 (d, J = 8.0 Hz, 1H, -NH), 5.01 - 4.94 (m, 2H, H-10),4.29 - 4.19 (m, 1H, -CH-COOCH2), 4.18 – 4.08 (m, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.68 – 3.65 (m, 1H, H-9), 3.61 – 3.54 (m, 1H, H-5), 2.96 – 2.90 (m,1H, H-6), 2.35 – 2.23 (m, 1H, H-6), 2.15 (dd, J = 11.9, 6.5 Hz, 1H, -CH-(CH3)2), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 0.97 (d, J = 6.9 Hz,3H, -CH-CH3), 0.89 (d, J = 6.9 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ172.09, 168.94, 166.95, 166.81, 155.70, 137.85, 136.82, 130.45, 110.56,82.79, 79.72, 63.34, 58.59, 51.65, 49.28, 48.35, 40.06, 37.05, 31.39, 28.32,28.32, 28.32, 28.02, 28.02, 28.02, 19.04, 17.55.

[0037] Compound 7d: colorless oil (43%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.89 (s, 1H, H-7), 4.99 (s, 2H, H-10), 4.92 (d, J = 8.7 Hz, 1H, -NH), 4.33(d, J= 5.6 Hz, 1H, -CH-COOCH2), 4.22 – 4.06 (m, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.69 – 3.67 (m, 1H, H-9), 3.61 – 3.55 (m, 1H, H-5), 2.95 – 2.89 (m,1H, H-6), 2.38 – 2.21 (m, 1H, H-6), 1.72 – 1.57 (m, 2H, -CH2-CH-(CH3)2), 1.55– 1.47 (m, 1H, -CH-(CH3)2), 1.46 (s, 9H, -COOC(CH3)3), 1.43 (s, 9H, Boc), 0.95(s, 3H, -CH-CH3), 0.93 (d, J = 1.3 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ173.12, 168.95, 166.95, 166.80, 155.42, 137.84, 136.82, 130.06, 110.56,82.76, 79.77, 63.41, 52.17, 51.63, 49.24, 48.37, 41.86, 40.03, 37.08, 28.31,28.31, 28.31, 28.02, 28.02, 28.02, 24.79, 22.83, 21.96.

[0038] Compound 7e: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.90 (s, 1H, H-7), 5.16 (d, J = 7.7 Hz, 1H, -NH), 5.01 (s, 2H, H-10), 4.44(d, J = 5.0 Hz, 1H, -CH-COOCH2), 4.15 (s, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.69 – 3.66 (m, 1H, H-9), 3.62 – 3.55 (m, 1H, H-5), 2.96 – 2.90 (m, 1H, H-6),2.55 (t, J= 7.6 Hz, 2H, -S-CH2), 2.34 – 2.23 (m, 1H, H-6), 2.17 – 2.12 (m,1H, -CH-CH 2a ), 2.09 (s, 3H, -S-CH3), 2.01 – 1.88 (m, 1H, -CH-CH 2b ), 1.46 (s,9H, -COOC(CH3)3), 1.44 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.96, 168.88,166.94, 166.79, 155.35, 137.83, 136.62, 130.53, 110.57, 82.81, 80.00, 63.66,52.86, HRMS (ESI, m / z) calcd for C 27 H 40 N2O9SNa, 591.2353,[M+Na] + ; found, 591.2357.

[0039] Compound 7f: colorless oil (45%), 1 H NMR (400 MHz, CDCl3) δ 7.30 – 7.27 (m, 1H,H-3), 7.25 – 7.08 (m, 5H, -Ph), 5.81 (s, 1H, H-7), 5.01 – 4.93 (m, 3H,overlap, H-10, -NHBoc), 4.60 (d, J = 7.4 Hz, 1H, -CH-NHBoc), 4.22 – 4.08 (m,2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.62 – 3.43 (m, 2H, overlap, H-9, H-5), 3.10 (d, J= 5.5 Hz, 2H, -CH2-Ph), 2.92 – 2.86 (m, 1H, H-6), 2.34 – 2.18 (m,1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.59, 169.00, 166.96, 166.82, 155.08, 137.86, 136.60, 136.06,130.71, 129.40, 129.40, 128.54, 128.54, 126.95, 110.51, 82.80, 79.88, 63.58,54.49, 51.66, 49.23, 48.15, 39.98, 38.49, 37.08, 28.31, 28.31, 28.31, 28.03,28.03,28.03.

[0040] Compound 7g: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3),7.06 (d, J = 8.6 Hz, 2H, Ar-H), 6.81 (d, J = 8.6 Hz, 2H, Ar-H), 5.83 (s, 1H,H-7), 5.00 (d, J = 6.8 Hz, 2H, H-10), 4.94 (d, J = 13.4 Hz, 1H, -CH-COOCH2),4.56 (d, J = 7.7 Hz, 1H, -NH), 4.15 (s, 2H, -N-CH2), 3.77 (s, 3H, -COOCH3), 3.76 (s, 3H, -OCH3), 3.55 – 3.51 (m, 2H, overlap, H-9, H-5), 3.04 (d, J = 5.8Hz, 2H, -CH2-Ph), 2.96 – 2.85 (m, 1H, H-6), 2.33 – 2.21 (m, 1H, H-6), 1.45(s, 9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13C NMR (100 MHz, CDCl3) δ 171.66,169.00, 166.96, 166.81, 158.63, 155.11, 137.87, 136.66, 130.64, 130.40,130.40, 127.97, 113.95, 113.95, 110.49, 82.78, 79.84, 63.54, 55.21, 54.60,51.65, 49.26, 48.14, 39.96, 37.58, 37.11, 28.32, 28.32, 28.32, 28.03, 28.03,28.03.

[0041] Compound 7h: colorless oil (12%), 1 H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 4H,Ar-H), 7.26 – 7.23 (m, 1H, Ar-H), 7.12 (s, 1H, H-3), 5.84 (s, 1H, H-7), 5.41(d, J = 8.8 Hz, 1H, -O-CH2-CH), 5.13 – 4.97 (m, 2H, H-10), 4.51 (d, J = 5.4Hz, 2H, -CH2-Ph), 4.49 – 4.44 (m, 1H, -NH), 4.14 (s, 2H, -N-CH2), 3.92 (dd, J = 9.4, 3.0 Hz, 1H, -O-CH 2a -CH), 3.75 (s, 3H, -COOCH3), 3.70 (dd, J = 9.4, 3.0Hz, 1H, -O-CH 2b -CH), 3.60 – 3.58 (m, 1H, H-9), 3.55 – 3.46 (m, 1H, H-5), 2.88– 2.82 (m, 1H, H-6), 2.30 – 2.16 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.44(s, 9H, Boc). 13C NMR (100 MHz, CDCl3) δ 170.31, 168.96, 166.97, 166.81,155.50, 139.82, 137.81, 136.72, 129.90, 128.41, 128.41, 127.79, 127.64,127.64, 110.56, 82.79, 79.96, 73.36, 70.26, 63.71, 54.10, 51.63, 49.21,48.40, 39.99, 37.13, 28.33, 28.33, 28.33, 28.03, 28.03, 28.03. HRMS (ESI, m / z)calcd for C 32 H 42 N2O 10 Na, 637.2737, [M+Na] + ; found, 637.2794.

[0042] Compound 7i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.33 (m, 1H, Ar-H), 7.24 (m, 1H, Ar-H), 7.15 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.30 (d, J = 7.9Hz, 1H, -NH), 5.12 – 4.92 (m, 2H, H-10), 4.54 (d, J = 7.3 Hz, 1H, -CH-COOCH2), 4.15 (s, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.73 (s, 2H, -CH2-Ph), 3.61 (t, J = 8.5 Hz, 1H, H-9), 3.58 – 3.49 (m, 1H, H-5), 3.00 – 2.85 (m, 2H,-CH-CH2), 2.94 – 2.86 (m, 1H, H-6), 2.41 – 2.16 (m, 1H, H-6), 1.45 (s, 18H,overlap, -COOC(CH3) 3, Boc). 13C NMR (100 MHz, CDCl3) δ 171.74, 168.93, 166.95,166.81, 155.19, 139.11, 137.85, 136.53, 130.52, 128.98, 128.98, 128.58,128.58, 127.19, 110.54, 82.80, 80.15, 63.81, 53.21, 51.66, 49.23, 48.37,40.04, 37.08, 36.63, 33.73, 28.33, 28.33, 28.33, 28.04, 28.04, 28.04. HRMS(ESI, m / z) calcd for C 32 H 42 N2O9SNa, 653.2509, [M+Na] + ; found, 653.2519.

[0043] Compound 7j: colorless oil (53%), 1 H NMR (400 MHz, CDCl3) δ 7.34 – 7.28 (m, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.25 (d, J = 7.9 Hz, 1H, Ar-H), 7.12 (s, 1H, H-3), 5.84 (s, 1H, H-7), 5.31 (d, J = 9.6 Hz, 1H, -NH), 5.05 – 4.93 (m, 2H, H-10), 4.54 (d, J = 11.6 Hz, 1H, -O-CH), 4.47 – 4.31 (m, 2H, -O-CH2), 4.21 – 4.15(m, 1H, -CH-COOCH2), 4.13 (s, 2H, -N-CH2), 3.75 (s, 3H, -COOCH3), 3.61 – 3.58(m, 1H, H-9), 3.53 – 3.46 (m, 1H, H-5), 2.90 – 2.77 (m, 1H, H-6), 2.31 – 2.17(m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 1.26 (d, J = 6.3 Hz, 3H, -O-CH-CH3). 13C NMR (100 MHz, CDCl3) δ 170.78, 168.93, 166.96, 166.79,156.14, 137.97, 137.81, 136.74, 130.08, 128.33, 128.33, 127.66, 127.60,127.60, 110.53, 82.75, 79.81, 74.84, 70.98, 63.58, 58.27, 51.62, 49.22,48.39, 39.99, 37.07, 28.33, 28.33, 28.33, 28.02, 28.02, 28.02, 16.35.

[0044] Compound 7k: colorless oil (41%), 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H, -NH inindole), 7.66 (d, J = 6.7 Hz, 1H, Ar-H), 7.32 (d, J = 7.4 Hz, 1H, Ar-H), 7.14(s, 1H, H-3), 7.11 – 7.08(m, 2H, Ar-H), 6.92 (d, J = 2.2 Hz, 1H, -CH inpyrrole ring), 5.70 (s, 1H, H-7), 5.19 – 5.09 (m, 2H, H-10), 4.69 (s, 1H, -NHBoc), 4.63 (d, J = 12.7 Hz, 1H, -CH-COOCH2), 4.47 (d, J = 17.2 Hz, 1H, -N-CH 2a ), 3.86 (d, J = 17.3 Hz, 1H, -N-CH 2b ), 3.77 (s, 3H, -COOCH3), 3.33 (d, J =10.5 Hz, 1H, -CH-CH 2a ), 3.19 – 2.97 (m, 2H, overlap, H-9, H-5), 2.75 – 2.69(m, 1H, H-6), 2.58 (d, J = 10.1 Hz, 1H, -CH-CH 2b), 2.15 – 2.07 (m, 1H, H-6), 1.51 (s, 9H, -COOC(CH3)3), 1.45 (s, 9H, Boc). HRMS (ESI, m / z) calcd forC 33 H 41 N3O9Na, 646.2741, [M+Na] + ; found, 646.2746.

[0045] Table 1 Structural formula of 7a-7k

[0046] Example 2 Synthesis of Compounds 8a-8k (1) Synthesis of compound 5 0.34 mmol of compound 3 prepared in Example 1 and 1.02 mmol of tert-butyl propylamino acid hydrochloride were dissolved in 25.8 mmol of N,N-dimethylformamide, heated and stirred at 110° C., reacted for 2 h, and then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction. The organic layer was collected, dried at room temperature and concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 5; (2) Synthesis of compounds 8a-8k Compound 5 (100 mg, 0.34 mmol), 4-dimethoxypyridine (49 mg, 0.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.01 mmol) and a carboxylic acid compound (0.50 mmol) were dissolved in dichloromethane, reacted at room temperature for 2 h, and then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 8a-8k, respectively; Wherein: the carboxylic acid compounds used in the synthesis of 8a-8k are as follows: The synthesis of 8a uses N-(tert-butoxycarbonyl)glycine; the synthesis of 8b uses N-(tert-butoxycarbonyl)-D-alanine; the synthesis of 8c uses N-(tert-butoxycarbonyl)-L-valine; the synthesis of 8d uses N-(tert-butoxycarbonyl)-L-isoleucine; the synthesis of 8f uses N-(tert-butoxycarbonyl)-L-phenylalanine; the synthesis of 8e uses N-(tert-butoxycarbonyl)-L-methionine; the synthesis of 8g uses N-tert-butoxycarbonyl-4-methoxy-L-phenylalanine; the synthesis of 8h uses N-(tert-butoxycarbonyl)-O-benzyl-L-serine; the synthesis of 8i uses N-(tert-butoxycarbonyl)-S-benzyl-L-cysteine; the synthesis of 8j uses N-(tert-butoxycarbonyl)-O-benzyl-L-threonine; and the synthesis of 8k uses N-(tert-butoxycarbonyl)-L-tryptophan.

[0047] The structural formulas of compounds 8a-8k are shown in Table 2; the appearance and NMR spectrum data are shown below: Compound 8a: colorless oil (65%) 1 H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.89 (s, 1H, H-7), 5.01 (m, 3H, overlap, H-10, -NH), 4.99 – 4.93 (m, 1H, -N-CH), 3.95 (d, J = 5.4 Hz, 2H, -CH2-NHBoc), 3.76 (s, 3H, -COOCH3), 3.68 – 3.65(m, 1H, H-9), 3.61 – 3.50 (m, 1H, H-5), 2.95 – 2.89 (m, 1H, H-6), 2.28 – 2.14(m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 170.04, 169.80, 168.70, 166.87,155.68, 136.85, 134.96, 130.45, 110.65, 82.44, 79.99, 63.45, 53.00, 51.64,48.81, 42.46, 8.09, 36.47, 28.32, 28.32, 28.32, 27.93, 27.93, 27.93, 15.94.HRMS (ESI, m / z) calcd for C25 H 36 N2O9Na, 531.2319, [M+Na] + ; found, 531.2292.

[0048] Compound 8b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.87 (s, 1H, H-7), 5.07 (d, J = 5.5 Hz, 1H, -NH), 5.00 (s, 2H, H-10), 4.99 –4.93 (m, 1H, -N-CH), 4.41 – 4.28 (m, 1H, -CH-COOCH2), 3.76 (s, 3H, -COOCH3),3.68 – 3.65 (m, 1H, H-9), 3.60 - 3.53 (m, 1H, H-5), 2.95 - 2.90 (m, 1H, H-6), 2.30 - 2.15 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 18H,overlap, -COOC(CH3) 3, Boc), 1.40 (d, J = 7.2 Hz, 3H, -CH-CH3). 13 C NMR (100MHz, CDCl3) δ 172.97, 169.83, 168.66, 166.89, 155.11, 136.98, 134.94, 129.96,110.68, 82.43, 79.81, 63.45, 52.99, 51.64, 49.26, 48.87, 40.15, 36.44, 28.33,28.33, 28.33, 27.93, 27.93, 27.93, 18.79, 15.94. HRMS (ESI, m / z) calcd forC 26 H 38 N2O9K, 561.2214, [M+K] + ; found, 561.2180.

[0049] Compound 8c: colorless oil (51%), 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.89 (s, 1H, H-7), 5.05 (d, J = 8.4 Hz, 1H, -NH), 5.00 (s, 2H, H-10), 4.98 –4.91 (m, 1H, -N-CH), 4.24 (dd, J = 8.9, 4.6 Hz, 1H, -CH-COOCH2), 3.76 (s, 3H,-COOCH3), 3.68 – 3.65 (m, 1H, H-9), 3.61 – 3.48 (m, 1H, H-5), 2.96 – 2.89 (m,1H, H-6), 2.24 – 2.08 (m, 2H, overlap, H-6, -CH-(CH3)2), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 18H, overlap, -COOC(CH3) 3, Boc), 0.97 (d, J = 6.8 Hz,3H, -CH-CH3), 0.89 (d, J = 6.9 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ172.09, 169.84, 168.66, 166.89, 155.69, 137.00, 134.93, 130.31, 110.65,82.40, 79.72, 63.30, 62.71, 58.59,53.01,51.63,48.76,40.14,36.41,28.32,28.32,28.32,27.92,27.92,27.92,19.04,17.54,15.90. C 28 H 42 N2O9Na, 573.2788, [M+Na] + ; found, 573.2769.

[0050] Compound 8d: colorless oil (50%), 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.06 – 4.94 (m, 3H, overlap, H-10, -NH), 4.91 (d, J = 8.6Hz, 1H, -N-CH), 4.33 (dd, J = 14.0, 8.6 Hz, 1H, -CH-COOCH2), 3.76 (s, 3H, -COOCH3), 3.67 – 3.64 (m, 1H, H-9), 3.59 – 3.52 (m, 1H, H-5), 2.96 – 2.89 (m,1H, H-6), 2.25 – 2.16 (m, 1H, H-6), 1.77 – 1.70 (m, 1H, -CH-CH2), 1.66 – 1.50(m, 2H, -CH-CH2), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 0.94 (dd, J = 6.5, 1.5 Hz, 6H, -CH-(CH3)2). 13 C NMR(100 MHz, CDCl3) δ 173.15, 169.84, 168.68, 166.90, 155.42, 137.00, 134.95,129.95, 110.68, 82.41, 79.79, 63.41, 52.99, 52.17,51.63,48.79,41.88,40.14,36.45,28.32,28.32,28.32,27.93,27.93,27.93,24.80,22.84,21.97,15.94. m / z) calcd for C 29 H 44 N2O9Na, 587.2945, [M+Na] + ; found,587.2938.

[0051] Compound 8e: colorless oil (88%), 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.89 (s, 1H, H-7), 5.15 (d, J = 7.6 Hz, 1H, -NH), 5.00 (d, J = 6.5 Hz, 2H, H-10), 4.98 – 4.92 (m, 1H, -N-CH), 4.44 (d, J = 5.0 Hz, 1H, -CH-COOCH2), 3.76(s, 3H, -COOCH3), 3.69 – 3.66 (m, 1H, H-9), 3.60 – 3.53 (m, 1H, H-5), 3.16 –2.89 (m, 1H, H-6), 2.55 (t, J = 7.6 Hz, 2H, -S-CH2), 2.33 – 2.11 (m, 2H, -CH-CH2), 2.09 (s, 3H, -S-CH3), 2.03 – 1.86 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H,-N-CH-CH3), 1.44 (s, 18H, overlap, -COOC(CH3)3, Boc). 13 C NMR (100 MHz, CDCl3)δ 171.98, 169.79, 168.60, 166.87, 155.33, 136.81, 134.97, 130.38, 110.67,82.43, 80.00, 63.64, 53.06, 52.86, 51.65, 48.85, 40.19, 36.40, 32.32, 29.94,28.31, 28.31, 28.31, 27.93, 27.93, 27.93, 15.95, 15.49.

[0052] Compound 8f: colorless oil (45%), 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.27 (m, 2H,overlap, Ar-H, H-3), 7.23 (dd, J = 14.4, 7.4 Hz, 2H, Ar-H), 7.15 (d, J= 6.8Hz, 2H, Ar-H), 5.80 (s, 1H, H-7), 5.01 (d, J = 8.0 Hz, 1H, -NH), 4.97 (d, J =7.2 Hz, 2H, H-10), 4.94 (d, J = 4.3 Hz, 1H, -N-CH), 4.60 (dd, J = 13.5, 6.1Hz, 1H, -CH-COOCH2), 3.77 (s, 3H, -COOCH3), 3.57 – 3.41 (m, 2H, overlap, H-9,H-5), 3.09 (d, J = 5.3 Hz, 2H, -CH2-Ph), 2.98 – 2.81 (m, 1H, H-6), 2.26 –2.09 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.62, 169.84, 168.72,166.90, 155.09, 136.79, 136.04, 135.00, 130.60, 129.40, 129.40, 128.55,128.55, 126.96, 110.61, 82.42, 79.89, 63.56, 54.51, 53.02, 51.65, 48.54,40.08, 38.52, 36.43, 28.31, 28.31, 28.31, 27.93, 27.93, 27.93, 15.97. HRMS(ESI, m / z) calcd for C 32 H 42 N2O9Na, 621.2788, [M+Na] + ; found, 621.2827.

[0053] Compound 8g: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3),7.06 (d, J= 8.6 Hz, 2H, Ar-H), 6.82 (d, J = 8.6 Hz, 2H, Ar-H), 5.81 (s, 1H,H-7), 4.97 (s, 3H, overlap, H-10, -NH), 4.94 (d, J = 7.3 Hz, 1H, -N-CH), 4.56(d, J = 7.5 Hz, 1H, -CH-COOCH2), 3.77 (s, 3H, -COOCH3), 3.77 (s, 3H, -OCH3), 3.59 – 3.46 (m, 2H, overlap, H-9, H-5), 3.04 (d, J = 5.3 Hz, 2H, -CH2-Ph),2.93 – 2.87 (m, 1H, H-6), 2.27 – 2.13 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H,-N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.66, 169.82, 168.72, 166.90, 158.66, 155.11, 136.82, 135.00,130.50, 130.50, 130.40, 127.94, 113.96, 113.96, 110.64, 82.41, 79.88, 63.49,55.21, 54.59, 53.09, 51.65, 48.65, 40.11, 37.55, 36.44, 28.32, 28.32, 28.32,27.93, 27.93, 27.93, 15.94. HRMS (ESI, m / z) calcd for C 33 H 44 N2O 10 Na, 651.2894,[M+Na] + ; found, 651.2860.651.2860.

[0054] Compound 8h: colorless oil (12%), 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 4H,Ar-H), 7.27 – 7.22 (m, 2H, overlap, Ar-H, H-3), 5.83 (s, 1H, H-7), 5.42 (d, J = 8.7 Hz, 1H, -N-CH), 5.03 (s, 2H, H-10), 5.01 – 4.91 (m, 1H, -NH), 4.52 (t, J = 9.1 Hz, 2H, -CH2-Ph), 4.49 – 4.42 (m, 1H, -CH-COOCH2), 3.92 (dd, J = 9.3,2.9 Hz, 1H, -O-CH 2a -CH), 3.76 (s, 3H, -COOCH3), 3.70 (dd, J = 9.3, 3.1 Hz, 1H,-O-CH 2b -CH), 3.61 – 3.58 (m, 1H, H-9), 3.54 – 3.49 (m, 1H, H-5), 2.89 – 2.83(m, 1H, H-6), 2.30 – 2.02 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3),1.44 (s, 9H, -COOC(CH3)3), 1.43 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ170.30, 169.82, 168.67, 166.88, 155.49, 137.48, 136.85, 134.95, 129.75,128.42, 128.42, 127.81, 127.67, 127.67, 110.69, 82.40, 79.95, 73.37, 70.20,63.67, 54.09, 52.98, 51.62, 48.88, 40.12, 36.46, 28.33, 28.33, 28.33, 27.92,27.92, 27.92, 15.97. HRMS (ESI, m / z) calcd for C 33 H 44 N2O 10 Na, 651.2894, [M+Na]+ ;found, 647.2922.

[0055] Compound 8i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.4Hz, 4H, Ar-H), 7.27 (s, 1H, H-3), 7.25 -7.22 (m, 1H, Ar-H), 5.87 (s, 1H, H-7), 5.30 (d, J = 7.9 Hz, 1H, -NH), 5.01 (s, 2H, H-10), 4.96 (t, J = 7.4 Hz,1H, -N-CH), 4.54 (dd, J = 12.5, 5.4 Hz, 1H, -CH-COOCH2), 3.77 (s, 3H, -COOCH3), 3.73 (s, 2H, -CH2-Ph), 3.63 – 3.60 (m, 1H, H-9), 3.59 – 3.50 (m, 1H,H-5), 2.96 – 2.86 (m, 2H, -S-CH2-CH), 2.94 – 2.79 (m, 1H, H-6), 2.31 – 2.12(m, 1H, H-6), 1.47 (d, J = 7.6 Hz, 3H, -N-CH-CH3), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 170.78, 169.80, 168.65, 166.88,155.19, 137.71, 136.72, 134.99, 130.38, 128.98, 128.98, 128.58, 128.58,127.20, 110.65, 82.41, 80.10, 63.78, 53.19, 53.01, 51.65, 48.79, 40.15,36.62, 36.43, 33.70, 28.33, 28.33, 28.33, 27.94, 27.94, 27.94,15.97. HRMS(ESI, m / z) calcd for C 33 H 44N2O9SNa, 667.2665, [M+Na] + ; found, 667.2660.

[0056] Compound 8j: colorless oil (53%), 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 4H,Ar-H), 7.24 (s, 2H, Ar-H, H-3), 5.83 (s, 1H, H-7), 5.31 (d, J = 9.6 Hz, 1H, -NH), 5.03 (d, J = 13.8 Hz, 1H, -N-CH), 4.94 (dd, J = 13.0, 5.4 Hz, 2H, H-10),4.54 (d, J = 11.7 Hz, 1H, -O-CH-CH3), 4.43 – 4.29 (m, 2H, -O-CH2), 4.20 – 4.08(m, 1H, -CH-NHBoc), 3.76 (s, 3H, -COOCH3), 3.62 – 3.59 (m, 1H, H-9), 3.50 – 3.45 (m, 1H, H-5), 2.87 – 2.81 (m, 1H, H-6), 2.20 – 2.08 (m, 1H, H-6), 1.46(d, J = 7.7 Hz, 3H, -N-CH-CH3), 1.45 (s, 9H, -COOC(CH3)3), 1.43 (s, 9H, Boc), 1.27 (s, 3H, -O-CH-CH3). 13 C NMR (100 MHz, CDCl3) δ 170.78, 169.82, 168.64,166.89, 156.14, 137.94, 136.88, 134.95, 129.95, 128.34, 128.34, 127.69,127.65, 127.65, 110.66, 82.38, 79.82, 74.78, 70.98, 63.55, 58.27, 53.02,51.61, 48.87, 40.11, 36.41, 28.33, 28.33, 28.33, 27.92, 27.92, 27.92, 16.35,15.94.

[0057] Compound 8k: colorless oil (8%), 1 H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H, -NH inindole), 7.65 (d, J = 7.3 Hz, 1H, Ar-H), 7.31 (d, J = 7.3 Hz, 1H, Ar-H), 7.27(s, 1H, H-3), 7.14 - 7.07 (m, 2H, Ar-H), 6.91 (d, J = 2.0 Hz, 1H, -CH inpyrrole ring), 5.70 (s, 1H, H-7), 5.24 - 5.04 (m, 3H, overlap, -N-CH, H-10), 4.71 (d, J = 4.6 Hz, 1H, -NH), 4.63 (d, J = 12.7 Hz, 1H, -CH-COOCH2), 3.78(s, 3H, -COOCH3), 3.34 – 3.29 (m, 1H, H-9), 3.16 – 3.10 (m, 1H, H-5), 3.05 –2.98 (m, 1H, -CH 2a -CH-NHBoc), 2.75 – 2.68 (m, 1H, H-6), 2.56 (d, J = 10.6 Hz,1H, -CH 2b -CH-NHBoc), 2.12 - 1.96 (m, 1H, H-6), 1.50 (s, 9H, -COOC(CH3)3), 1.49– 1.46 (m, 3H, -N-CH-CH3), 1.45 (s, 9H, Boc). 13C NMR (100 MHz, CDCl3) δ172.41, 170.91, 169.34, 166.94, 155.08, 137.20, 136.23, 134.30, 130.77,127.39, 123.07, 121.91, 119.49, 118.98, 111.33, 110.11, 99.99, 83.05, 79.83,63.56, 54.28, 52.43, 51.67, 46.86, 39.51, 36.27, 29.40, 28.37, 28.37, 28.37,28.00, 28.00, 28.00, 15.97. HRMS (ESI, m / z) calcd for C 34 H 43 N3O9Na, 660.2897,[M+Na] + ; found, 660.2876.

[0058] Table 2 Compounds 8a-8k

[0059] Example 3 Synthesis of Compounds 9a-9k (1) Synthesis of compound 6 0.34 mmol of compound 3 prepared in Example 1 and 1.02 mmol of tert-butyl phenylalanine hydrochloride were dissolved in 25.8 mmol of N,N-dimethylformamide, heated and stirred at 110° C., reacted for 2 h, and then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction. The organic layer was collected, dried at room temperature and concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 6; (2) Synthesis of compounds 9a-9k Compound 6 (100 mg, 0.34 mmol), 4-dimethoxypyridine (49 mg, 0.42 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.01 mmol) and a carboxylic acid compound (0.50 mmol) were dissolved in dichloromethane, reacted at room temperature for 2 h, and then ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 9a-9k, respectively; Wherein: the carboxylic acid compounds used in compounds 9a-9k are as follows: The synthesis of 9a uses N-(tert-butoxycarbonyl)glycine; the synthesis of 9b uses N-(tert-butoxycarbonyl)-D-alanine; the synthesis of 9c uses N-(tert-butoxycarbonyl)-L-valine; the synthesis of 9d uses N-(tert-butoxycarbonyl)-L-isoleucine; the synthesis of 9f uses N-(tert-butoxycarbonyl)-L-phenylalanine; the synthesis of 9e uses N-(tert-butoxycarbonyl)-L-methionine; the synthesis of 9g uses N-tert-butoxycarbonyl-4-methoxy-L-phenylalanine; the synthesis of 9h uses N-(tert-butoxycarbonyl)-O-benzyl-L-serine; the synthesis of 9i uses N-(tert-butoxycarbonyl)-S-benzyl-L-cysteine; the synthesis of 9j uses N-(tert-butoxycarbonyl)-O-benzyl-L-threonine; and the synthesis of 9k uses N-(tert-butoxycarbonyl)-L-tryptophan.

[0060] The structural formulas of compounds 9a-9k are shown in Table 3; the appearance and NMR spectrum data are shown below: Compound 9a: colorless oil (65%), 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.16 (m, 4H,Ar-H), 7.11 (s, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.72 (s, 1H, H-7), 5.26 (dd, J = 11.1, 5.3 Hz, 1H, -N-CH-CH2-Ph), 5.00 (s, 1H, -NH), 4.78 (dd, J = 13.7 Hz,2H, H-10), 3.92 (d, J = 4.2 Hz, 2H, -CH2-NH), 3.75 (s, 3H, -COOCH3), 3.54 (d, J = 10.7 Hz, 1H, H-9), 3.46 -3.36 (m, 2H, -N-CH-CH2-Ph), 3.91 – 2.95 (m, 1H,H-5), 2.78 – 2.72 (m, 1H, H-6), 1.88 – 1.82 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.45 (s, 9H, Boc). 13C NMR (100 MHz, CDCl3) δ 169.96, 168.83, 168.51,166.80, 155.69, 136.52, 136.06, 135.32, 130.18, 128.98, 128.98, 128.54,128.54, 126.96, 110.54, 82.83, 79.98, 63.27, 57.78, 51.64, 48.57, 42.45,39.63, 36.34, 36.23, 28.32, 28.32, 28.32, 27.95, 27.95, 27.95.

[0061] Compound 9b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.15 (m, 1H,Ar-H), 7.11 (d, J = 1.5 Hz, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.71 (s, 1H, H-7), 5.27 (dd, J = 11.2, 5.4 Hz, 1H, -N-CH-CH2-Ph), 5.07 (d, J = 5.5 Hz, 1H, -NH),4.79 (d, J = 13.5 Hz, 1H, H-10), 4.71 (d, J = 13.5 Hz, 1H, H-10), 4.40 – 4.26 (m, 1H, -CH-COOCH2), 3.75 (s, 3H, -COOCH3), 3.55 (m, 1H, H-9), 3.47 – 3.33 (m,2H, -N-CH-CH2-Ph), 2.98 (m, 1H, H-5), 2.75 (m, 1H, H-6), 1.92 – 1.81 (m, 1H,H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 1.39 (d, J = 7.2 Hz, 3H, -CH-CH3). 1313C NMR (100 MHz, CDCl3) δ 172.89, 168.85, 168.45, 166.81, 155.11, 136.65, 136.06, 135.31, 129.73, 128.98, 128.98, 128.54, 128.54, 126.97, 110.55, 82.82, 79.79, 63.26, 57.75, 51.63, 49.22, 48.67, 39.68, 36.36, 36.21, 28.33, 28.33, 28.33, 27.96, 27.96, 27.96, 18.80。

[0062] Compound 9c: colorless oil (50%), 1 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.17 (m, 4H, Ar-H), 7.11 (d, J J = 1.7 Hz, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.73 (s, 1H, H-7), 5.26 (dd, J J = 11.2, 5.4 Hz, 1H, -N-CH-CH2-Ph), 5.04 (d, J J = 9.1 Hz, 1H, -NH), 4.80 (d, J J = 13.1 Hz, 1H, H-10), 4.71 (d, J J = 13.1 Hz, 1H, H-10), 4.22 (dd, J J = 9.0, 4.6 Hz, 1H, -CH-COOCH2), 3.75 (s, 3H, -COOCH3), 3.55 – 3.54 (m, 1H, H-9), 3.46 – 3.36 (m, 2H, -N-CH-CH2-Ph), 3.03 – 2.95 (m, 1H, H-5), 2.78 – 2.72 (m, 1H, H-6), 2.17 – 2.08 (m, 1H, -CH-(CH3)2), 1.91 – 1.82 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 0.96 (d, J J = 6.8 Hz, 3H, -CH-CH3), 0.88 (d, J= 6.9 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ 172.03, 168.87,168.47, 166.83, 155.71, 136.67, 136.07, 135.36, 130.10, 128.98, 128.98,128.54, 128.54, 126.98, 110.54, 82.81, 79.73, 63.16, 58.57, 57.83, 51.63,48.57, 39.68, 36.33, 36.21, 31.40, 28.33, 28.33, 28.33, 27.96, 27.96, 27.96,19.03, 17.55.

[0063] Compound 9d: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.16 (m, 4H,Ar-H), 7.11 (d, J = 1.5 Hz, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.71 (s, 1H, H-7), 5.26 (dd, J = 11.1, 5.4 Hz, 1H, -N-CH), 4.90 (d, J = 8.6 Hz, 1H, -NH), 4.75(q, J = 13.6 Hz, 2H, H-10), 4.31 (d, J = 5.5 Hz, 1H, -CH-COOCH2), 3.75 (s,3H, -COOCH3), 3.54 (d, J = 10.6 Hz, 1H, H-9), 3.48 – 3.33 (m, 2H, -N-CH-CH2-Ph), 3.02 – 2.95 (m, 1H, H-5), 2.78 – 2.72 (m, 1H, H-6), 1.92 – 1.81 (m, 1H,H-6), 1.74 – 1.66 (m, 2H, -CH2-CH-(CH3)2), 1.64 – 1.57 (m, 1H, -CH-(CH3)2), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc), 0.94 (dd, J= 6.5, 2.2 Hz, 6H, -CH-(CH3)2). 13 C NMR (100 MHz, CDCl3) δ 173.08, 168.87, 168.49, 166.83, 155.43,136.68, 136.07, 135.35, 129.74, 128.98, 128.98, 128.54, 128.54, 126.98,110.56, 82.80, 79.77, 63.24, 57.80, 52.13, 51.62, 48.59, 41.91, 39.66, 36.35,36.24, 28.33, 28.33, 28.33, 27.95, 27.95, 27.95, 24.79, 22.85, 21.97.

[0064] Compound 9e: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.17 (m, 4H,Ar-H), 7.11 (d, J = 1.4 Hz, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.72 (s, 1H, H-7), 5.26 (dd, J = 11.2, 5.3 Hz, 1H, -N-CH), 5.14 (d, J = 7.6 Hz, 1H, -NH), 4.75(dd, J = 13.1 Hz, 2H, H-10), 4.42 (d, J = 5.0 Hz, 1H, -CH-COOCH2), 3.75 (s,3H, -COOCH3), 3.56 (m, 1H, H-9), 3.47 – 3.36 (m, 2H, -N-CH-CH2-Ph), 3.01 –2.95 (m, 1H, H-5), 2.79 – 2.73 (m, 1H, H-6), 2.54 (dd, J = 12.6, 5.1 Hz, 2H,-S-CH2), 2.19 – 2.10 (m, 1H, H-6), 2.08 (s, 3H,-S-CH3), 195 – 1.84 (m, 2H, -S-CH2-CH2), 1.46 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc).13 C NMR (100 MHz, CDCl3) δ 171.90, 168.83, 168.39, 166.80, 155.34, 136.47, 136.06, 135.31,130.16, 128.99, 128.99, 128.54, 128.54, 126.98, 110.55, 82.83, 79.99, 63.46,57.79, 52.82, 51.64, 48.65, 39.74, 36.36, 36.16, 32.33, 29.93, 28.31, 28.31,28.31, 27.96, 27.96, 27.96, 15.48. HRMS (ESI, m / z) calcd for C 34 H 46 N2O9SK,697.2561, [M+K] + ; found, 697.2598.

[0065] Compound 9f: colorless oil (45%), 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, Ar-H), 7.26 – 7.16 (m, 6H, Ar-H), 7.16 – 7.10 (m, 3H, Ar-H), 7.09 (s, 1H, H-3), 5.64 (s, 1H, H-7), 5.28 (dd, J = 11.0, 5.4 Hz, 1H, -N-CH-CH2-Ph), 4.99 (d, J = 8.6Hz, 1H, -NH), 4.78 (d, J = 13.2 Hz, 1H, H-10), 4.69 (d, J = 13.2 Hz, 1H, H-10), 4.58 (d, J = 7.5 Hz, 1H, -CH-COOCH2), 3.76 (s, 3H, -COOCH3), 3.43 – 3.39(m, 1H, H-9), 3.37 (d, J= 5.3 Hz, 2H, -N-CH-CH2-Ph), 3.07 (s, 2H, -CH2-CH-NHBoc), 3.02 – 2.95 (m, 1H, H-5), 2.76 – 2.67 (m, 1H, H-6), 1.84 – 1.80 (m,1H, H-6), 1.46 (s, 9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.53, 168.89, 168.54, 166.82, 155.00, 136.48, 136.05, 135.34,130.32, 129.40, 128.98, 128.98, 128.98, 128.98, 128.54, 128.54, 128.54,128.54, 126.98, 126.98, 110.49, 82.82, 79.86, 63.39, 57.69, 54.46, 51.64,48.34, 39.56, 38.51, 36.41, 36.23, 28.31, 28.31, 28.31, 27.97, 27.97,27.97.HRMS (ESI, m / z) calcd for C 38 H 46 N2O9Na, 697.3101, [M+Na] + ; found,697.3135.

[0066] Compound 9g: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.15 (m, 4H,Ar-H), 7.11 (s, 1H, Ar-H), 7.09 (s, 1H, H-3), 7.05 (d, J = 8.5 Hz, 2H, Ar-H),6.81 (d, J = 8.6 Hz, 2H, Ar-H), 5.66 (s, 1H, H-7), 5.27 (dd, J = 11.1, 5.4Hz, 1H, -N-CH-CH2-Ph), 4.97 (d, J = 8.2 Hz, 1H, -NH), 4.79 (d, J= 13.3 Hz,1H, H-10), 4.70 (d, J = 13.3 Hz, 1H, H-10), 4.54 (d, J = 7.7 Hz, 1H, -CH-COOCH2), 3.76 (s, 3H, -COOCH3), 3.75 (s, 3H, -OCH3), 3.44 – 3.40 (m, 1H, H-9), 3.38 – 3.32 (m, 2H, -N-CH-CH2-Ph), 3.02 (s, 1H, -CH2-CH-NHBoc), 2.99 – 2.92(m, 1H, H-5), 2.75 – 2.69 (m, 1H, H-6), 1.86 – 1.80 (m, 1H, H-6), 1.45 (s,9H, -COOC(CH3)3), 1.41 (s, 9H, Boc). 13 C NMR (100 MHz, CDCl3) δ 171.58, 168.86,168.53, 166.82, 158.65, 155.14, 136.51, 136.07, 135.36, 130.39, 130.39,130.26, 128.98, 128.98, 128.54, 128.54, 127.95, 126.98, 113.94, 113.94,110.52, 82.81, 79.84, 63.32, 57.78, 55.21, 54.54, 51.63, 48.44, 39.60, 37.54,36.38, 36.24, 28.32, 28.32, 28.32, 27.96, 27.96, 27.96.

[0067] Compound 9h: colorless oil (12%), 1 H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 4H, Ar-H), 7.25 (s, 1H, Ar-H), 7.22 – 7.15 (m, 4H, Ar-H), 7.10 (d, J = 1.6 Hz,1H, Ar-H), 7.09 (s, 1H, H-3), 5.67 (s, 1H, H-7), 5.40 (d, J= 9.2 Hz, 1H, -NH), 5.31 – 5.24 (m, 1H, -CH-CH2-Ph), 4.84 (d, J = 14.0 Hz, 1H, H-10), 4.73(d, J = 14.0 Hz, 1H, H-10), 4.51 (d, J = 6.9 Hz, 2H, -O-CH2-Ph), 4.45 (d, J =9.2 Hz, 1H, -O-CH2-CH), 3.89 (dd, J = 9.2, 2.9 Hz, 1H, -O-CH 2a -CH), 3.75 (s,3H, -COOCH3), 3.69 (dd, J = 9.4, 3.2 Hz, 1H, -O-CH 2b -CH), 3.48 (m, 1H, H-9),3.41 – 3.33 (m, 2H, -CH-CH2-Ph), 3.01 – 2.94 (m, 1H, H-5), 2.72 - 2.65 (m,1H, H-6), 1.84 – 1.78 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H,Boc). 13 C NMR (100 MHz, CDCl3) δ 170.22, 168.86, 168.48, 166.81, 155.49,137.49, 136.54, 136.06, 135.31, 129.51, 128.98, 128.98, 128.53, 128.53,128.41, 128.41, 127.81, 127.81, 127.65, 126.96, 110.55, 82.79, 79.93, 73.36,70.19, 63.48, 57.70, 54.05, 51.60, 48.67, 39.63, 36.40, 36.23, 28.33, 28.33,28.33, 27.95, 27.95, 27.95. HRMS (ESI, m / z): calcd for C 39 H 48 N2O 10 Na, 727.3207,[M+Na] +; found, 727.3214.

[0068] Compound 9i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 4.3Hz, 4H, Ar-H), 7.24 – 7.13 (m, 5H, Ar-H), 7.10 (d, J = 1.5 Hz, 1H, Ar-H),7.08 (s, 1H, H-3), 5.70 (s, 1H, H-7), 5.29 – 5.25 (m, 2H, overlap, -NH, -N-CH), 4.81 (d, J = 13.4 Hz, 1H, H-10), 4.72 (d, J = 13.4 Hz, 1H, H-10), 4.52(d, J = 7.2 Hz, 1H, -CH-COOCH2), 3.75 (s, 3H, -COOCH3), 3.72 (s, 2H, -S-CH2-Ph), 3.51 – 3.48 (m, 1H, H-9), 3.44 – 3.36 (m, 2H, -N-CH-CH2-Ph), 3.01 – 2.94(m, 1H, H-5), 2.91 – 2.77 (m, 2H, -S-CH2-CH), 2.77 – 2.71 (m, 1H, H-6), 1.87– 1.81 (m, 1H, H-6), 1.45 (s, 18H, overlap, -COOC(CH3) 3, Boc). 13C NMR (100MHz, CDCl3) δ 170.70, 168.84, 168.43, 166.80, 155.19, 137.71, 136.39, 136.06,135.33, 130.14, 128.98, 128.98, 128.98, 128.98, 128.57, 128.57, 128.53,128.53, 127.18, 126.96, 110.52, 82.81, 80.08, 63.59, 57.71, 53.15, 51.63,48.59, 39.67, 36.61, 36.39, 36.21, 33.72, 28.33, 28.33, 28.33, 27.96, 27.96,27.96. HRMS (ESI, m / z) calcd for C 39 H 48 N2O9SNa, 743.2978, [M+Na] + ; found,743.2939.

[0069] Compound 9j: colorless oil (53%), 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.28 (m, 2H,Ar-H), 7.26 – 7.04 (m, 9H, Ar-H, H-3), 5.67 (s, 1H, H-7), 5.30 (d, J = 9.6Hz, 1H, -N-CH), 5.25 (dd, J = 11.1, 5.4 Hz, 1H, -NH), 4.74 (s, 2H, H-10), 4.53 (d, J = 11.6 Hz, 1H, -O-CH 2a ), 4.38 (d, J = 11.6 Hz, 1H, -O-CH 2b ), 4.32(dd, J= 9.6, 2.1 Hz, 1H, -CH-CH3), 4.16 – 4.12 (m, 1H, -CH-NHBoc), 3.74 (s,3H, -COOCH3), 3.50 – 3.48 (m, 1H, H-9), 3.41 – 3.27 (m, 2H, -O-CH2), 3.00 –2.94 (m, 1H, H-5), 2.70 – 2.64 (m, 1H, H-6), 1.91 – 1.75 (m, 1H, H-6), 1.45(s, 18H, -COOC(CH3) 3, Boc), 1.26 (s, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ170.72, 168.87, 168.47, 166.83, 156.16, 137.95, 136.57, 136.06, 135.33,129.70, 128.97, 128.97, 128.54, 128.54, 128.34, 128.34, 127.69, 127.62,126.97, 110.54, 82.79, 79.82, 74.79, 70.99, 63.38, 58.23, 57.77, 51.61,51.61, 48.68, 39.63, 36.36, 36.21, 28.33, 28.33, 28.33, 27.95, 27.95, 16.38.

[0070] Compound 9k: colorless oil (9%), 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H, -NH inindole), 7.62 (d, J = 7.5 Hz, 1H, Ar-H), 7.29 (d, J = 7.6 Hz, 1H, Ar-H), 7.24(s, 1H, Ar-H), 7.21 - 7.15 (m, 3H, Ar-H), 7.15 - 7.11 (m, 2H, Ar-H), 7.10 (s,1H, H-3), 7.07 (d, J = 5.6 Hz, 2H, Ar-H), 6.91 (d, J= 2.0 Hz, 1H, -CH inpyrrole ring), 5.53 (s, 1H, H-7), 5.42 (dd, J = 11.2, 5.5 Hz, 1H, -CH-CH2-Ph), 5.15 (d, J = 8.0 Hz, 1H, -NH), 4.96 (d, J = 12.4 Hz, 1H, H-10), 4.70 (d, J = 5.3 Hz, 1H, -CH-COOCH2), 4.47 (d, J = 12.4 Hz, 1H, H-10), 3.77 (s, 3H, -COOCH3), 3.45 – 3.40 (m, 1H, H-9), 3.35 – 3.24 (m, 1H, -N-CH-CH 2a -Ph), 3.15(dd, J = 14.2, 8.1 Hz, 1H, -N-CH-CH 2b -Ph), 3.00 – 2.89 (m, 2H, -CH2-CH-COO), 2.57 – 2.48 (m, 2H, overlap, H-5, H-6), 2.05 – 1.99(m, 1H, H-6), 1.51 (s, 9H, -COOC(CH3)3), 1.44 (s, 9H, Boc). HRMS (ESI, m / z) calcd for C 40 H 47 N3O9Na,736.3210, [M+Na] + ; found, 736.3210. Table 3 Structural formula of compounds 9a-9k

[0071] Example 4 Synthesis of Compounds 10a-10k As shown in Synthesis Scheme 2, 7a-7k prepared in Example 1 was used as the starting material and reacted with trifluoroacetic acid in a dichloromethane solution to generate compounds 10a-10k.

[0072]

[0073] Synthetic route 2

[0074] Reaction conditions and reagents in synthetic route 2: (e) trifluoroacetic acid, dichloromethane.

[0075] The specific steps are as follows: (1) Synthesis of compounds 10a-10k One of the compounds 7a-7k (0.34 mmol) and trifluoroacetic acid (6.4 mmol) were dissolved in dichloromethane, and the mixture was reacted at room temperature for 0.5 h. Ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 10a-10k, respectively. Among them: synthesis 10a uses 7a, synthesis 10b uses 7b, synthesis 10c uses 7c, synthesis 10d uses 7d, synthesis 10f uses 7f, synthesis 10e uses 7e, synthesis 10g uses 7g, synthesis 10h uses 7h, synthesis 10i uses 7i, synthesis 10j uses 7j, and synthesis 10k uses 7k.

[0076] The structural formulas of compounds 10a-10k are shown in Table 4; the appearance and NMR spectrum data are shown below: Compound 10a: colorless oil (65%), 1 H NMR (400 MHz, MeOD) δ 7.33 (s, 1H, H-3), 5.84 (s, 1H, H-7), 4.10 – 4.30 (m, 2H, H-10), 4.29 – 4.16 (m, 2H, -N-CH2), 3.75 (s, 3H, -COOCH3), 3.66 (d, J = 10.6 Hz, 2H, -CH2-NH2), 3.57 – 3.50 (m,2H, overlap, H-9, H-5), 2.97 – 2.72 (m, 1H, H-6), 2.34 – 2.11 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3).

[0077] Compound 10b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.05 – 4.89 (m, 2H, H-10), 4.27 – 4.09 (m, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.67 (d, J= 10.7 Hz, 1H,-CH-NH2), 3.59 - 3.57 (m, 2H,overlap, H-9, H-5), 2.96 - 2.90 (m, 1H, H-6), 2.39 - 2.23 (m, 1H, H-6), 1.46(s, 9H, -COOC(CH3)3), 1.36 (d, J = 7.0 Hz, 3H, -CH-CH3). 13 C NMR (100 MHz, CDCl3) δ 176.17, 168.94, 166.96, 166.80, 137.85, 137.10, 129.97, 110.55,82.82, 63.07, 51.65, 50.10, 49.59, 49.25, 48.48, 42.00, 37.12, 28.02, 28.02, 28.02, 20.65.

[0078] Compound 10c: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.90 (s, 1H, H-7), 5.10 – 4.89 (m, 2H, H-10), 4.34 – 4.01 (m, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.67 (d, J = 10.7 Hz, 1H, H-9), 3.61 - 3.54 (m, 1H, H-5), 3.32 (d, J = 4.9 Hz, 1H, -CH-NH2), 2.96 – 2.90 (m, 1H, H-6), 2.38 – 2.15(m, 1H, H-6), 2.09 – 2.01 (m, 1H, -CH-CH3), 1.46 (s, 9H, -COOC(CH3)3), 0.99(d, J = 6.9 Hz, 3H, -CH-CH3), 0.91 (d, J = 6.8 Hz, 3H, -CH-CH3). 13C NMR (100MHz, CDCl3) δ 175.23, 168.94, 166.96, 166.81, 137.87, 137.17, 130.27, 110.52,82.80, 62.92, 59.98, 51.65, 49.27, 48.39, 40.01, 37.11, 32.12, 28.02, 28.02,28.02, 19.37, 17.14.

[0079] Compound 10d: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.89 (s, 1H, H-7), 4.98 (s, 2H, H-10), 4.16 (q, J = 17.2 Hz, 2H, -N-CH2),3.76 (s, 3H, -COOCH3), 3.67- 3.66 (m, 1H, H-9), 3.62 - 3.55 (m, 1H, H-5),3.55 – 3.47 (m, 1H, -CH-NH2), 2.96 – 2.90 (m, 1H, H-6), 2.40 – 2.24 (m, 1H,H-6), 1.86 – 1.76 (m, 2H, -CH2-CH-CH3), 1.61 – 1.57 (m, 1H, -CH-CH3), 1.46 (s,9H, -COOC(CH3)3), 0.93 (dd, J = 8.0, 6.7 Hz, 6H, -CH-(CH3)2). 13 C NMR (100 MHz, CDCl3) δ 176.16, 168.96, 166.96, 166.80, 137.86, 137.11, 130.07, 110.55,82.81, 63.05, 52.92, 51.65, 49.25, 48.43, 43.98, 39.99, 37.14, 28.03, 28.03, 28.03, 24.77, 22.98, 21.87.

[0080] Compound 10e: colorless oil (88%), 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3), 5.89 (s, 1H, H-7), 4.99 (s, 2H, H-10), 4.17 (dd, J = 8.6, 3.7 Hz, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.69 – 3.55 (m, 3H, overlap, H-9, H-5, -CH-NH2), 2.96 – 2.90 (m, 1H, H-6), 2.64 (t, J = 7.4 Hz, 2H, -S-CH2), 2.38 – 2.26 (m,1H, H-6), 2.10 (s, 3H, -S-CH3), 2.07 – 1.98 (m, 1H, -S-CH2-CH 2a ), 1.86 – 1.81(m, 1H, -S-CH2-CH 2b ), 1.46 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 175.33, 168.91,166.95, 166.79, 137.85, 136.96, 130.34, 110.56, 82.84, 63.25, 53.39, 51.67,49.26, 48.49, 40.04, 37.11, 33.89, 30.48, 28.04, 28.04, 29.04, 15.41.

[0081] Compound 10f: colorless oil (45%), 1 H NMR (400 MHz, CDCl3) δ 7.31 - 7.27 (m, 2H,Ar-H), 7.24 - 7.17 (m, 3H, Ar-H), 7.15 (s, 1H, H-3), 5.81 (s, 1H, H-7), 5.03- 4.93 (m, 2H, H-10), 4.30 – 3.98 (m, 2H, -N-CH2), 3.81 – 3.77 (m, 1H, -CH-NH2), 3.76 (s, 3H, -COOCH3), 3.56 – 3.48 (m, 2H, overlap, H-9, H-5), 3.12 –3.08 (m, 1H, -CH 2a-Ph), 2.94 – 2.88 (m, 2H, overlap, H-6, -CH 2b -Ph), 2.36 –2.16 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3). 13 C NMR (100 MHz, CDCl3) δ174.59, 169.01, 166.97, 166.81, 137.86, 137.13, 136.92, 130.48, 129.35,129.35, 128.58, 128.58, 126.82, 110.52, 82.83, 63.21, 55.85, 51.66, 49.23,48.25, 41.02, 39.96, 37.13, 28.04, 28.04, 28.04.

[0082] Compound 10g: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H, H-3),7.12 (d, J = 8.6 Hz, 2H, Ar-H), 6.83 (d, J = 8.6 Hz, 2H, Ar-H), 5.82 (s, 1H,H-7), 5.04 - 4.92 (m, 2H, H-10), 4.16 (s, 2H, -N-CH2), 3.78 (s, 3H, -COOCH3), 3.76 (s, 3H, -OCH3), 3.74 – 3.69 (m, 1H, -CH-NH2), 3.56 – 3.53 (m, 2H,overlap, H-9, H-5), 3.10 – 2.98 (m, 1H, -CH 2a -Ph), 2.92 – 2.83 (m, 1H, H-6), 2.88 – 2.81 (m, 1H, -CH 2b -Ph), 2.30 – 2.20 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3). 13C NMR (100 MHz, CDCl3) δ 174.85, 169.01, 166.98, 166.82, 158.50,137.88, 137.00, 130.39, 130.34, 130.34, 129.12, 113.97, 113.97, 110.50,82.82, 63.15, 55.98, 55.23, 51.67, 49.25, 48.23, 40.19, 39.95, 37.16, 28.04,28.04, 28.04.

[0083] Compound 10h: colorless oil (12%), 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.32 (m,5H, Ar-H), 7.15 (d, J = 0.9 Hz, 1H, H-3), 5.86 (s, 1H, H-7), 5.03 (q, J =13.7 Hz, 2H, H-10), 4.61 – 4.46 (m, 2H, -CH2-Ph), 4.16 (s, 2H, -N-CH2), 3.86 –3.79 (m, 1H, -CH-NH2), 3.77 (s, 3H, -COOCH3), 3.75 – 3.49 (m, 4H, overlap, H-9, H-5, -O-CH2-CH), 2.92 – 2.85 (m, 1H, H-6), 2.29 – 2.23 (m, 1H, H-6), 1.47(s, 9H, -COOC(CH3)3).

[0084] Compound 10i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 6.9,4.4 Hz, 4H, Ar-H), 7.25 – 7.18 (m, 1H, Ar-H), 7.14 (d, J = 3.4 Hz, 1H, H-3),5.87 (s, 1H, H-7), 4.99 (q, J= 13.3 Hz, 2H, H-10), 4.35 – 4.05 (m, 2H, -N-CH2), 3.76 (s, 3H, -COOCH3), 3.74 (s, 2H, -CH2-Ph), 3.65 – 3.46 (m, 3H,overlap, H-9, H-5, -CH-NH2), 2.95 – 2.82 (m, 2H, overlap, H-6, -S-CH 2a -CH),2.72 – 2.62 (m, 1H, -S-CH 2b -CH), 2.33 – 2.23 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3). 13 C NMR (100 MHz, CDCl3) δ 173.55, 168.93, 166.95, 166.80, 137.93,137.86, 136.81, 130.37, 128.96, 128.96, 128.58, 128.58, 127.17, 110.54,82.82, 63.40, 54.14, 51.67, 49.23, 48.41, 40.02, 37.12, 36.63, 36.40, 28.04,28.04, 28.04.

[0085] Compound 10j: colorless oil (53%), 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m,4H, Ar-H), 7.25 (s, 1H, Ar-H), 7.12 (s, 1H, H-3), 5.85 (s, 1H, H-7), 5.08 –4.87 (m, 2H, H-10), 4.56 (t, J = 10.4 Hz, 1H, -O-CH 2a ), 4.46 – 4.36 (m, 1H, -O-CH 2b ), 4.15 (d, J = 13.4 Hz, 2H, -N-CH2), 4.07 – 3.93 (m, 1H, -O-CH), 3.75(s, 3H, -COOCH3), 3.61 (d, J= 10.7 Hz, 1H, -CH-COO), 3.55 – 3.40 (m, 2H,overlap, H-9, H-5), 2.88 – 2.82 (m, 1H, H-6), 2.26 – 2.20 (m, 1H, H-6), 1.45(s, 9H, -COOC(CH3)3).

[0086] Compound 10k: colorless oil (42%), 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H, -NHin indole), 7.62 (d, J = 7.5 Hz, 1H, Ar-H), 7.33 (d, J = 7.7 Hz, 1H, Ar-H),7.19 – 7.04 (m, 4H, Ar-H, H-3), 6.96(d, J = 1.9 Hz, 1H, -CH in pyrrole ring),5.72 (s, 1H, H-7), 5.15 (d, J = 12.9 Hz, 1H, H-10), 4.63 (d, J = 12.7 Hz, 1H,H-10), 4.45 (d, J = 17.3 Hz, 1H, -CH-NH2), 3.96 – 3.84 (m, 2H, -N-CH2), 3.78(s, 3H, -COOCH3), 3.28 – 3.03 (m, 3H, overlap, H-9, H-5, -CH 2a -CH-NH2), 2.82 –2.59 (m, 2H, overlap, -CH 2b -CH-NH2, H-6), 2.17 – 2.08 (m, 1H, H-6), 1.52 (s,9H, -COOC(CH3)3).

[0087] Table 4 Structural formula of compounds 10a-10k

[0088] Example 5 Synthesis of Compounds 11a-11k One of the compounds in Example 2 8a-8k (0.34 mmol) and trifluoroacetic acid (6.4 mmol) were dissolved in dichloromethane, and reacted at room temperature for 0.5 h. Ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 11a-11k respectively; Among them: synthesis 11a uses 8a, synthesis 11b uses 8b, synthesis 11c uses 8c, synthesis 11d uses 8d, synthesis 11f uses 8f, synthesis 11e uses 8e, synthesis 11g uses 8g, synthesis 11h uses 8h, synthesis 11i uses 8i, synthesis 11j uses 8j, and synthesis 11k uses 8k.

[0089] The structural formulas of compounds 11a-11k are shown in Table 5; the appearance and NMR spectrum data are shown below: Compound 11a: colorless oil (65%) 1 H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H, H-3), 5.77 (s, 1H, H-7), 5.01 – 4.82 (m, 2H, H-10), 4.36 – 4.16 (m, 1H, -N-CH), 3.70 (s, 3H, -COOCH3), 3.49 (ddd, J = 13.6, 9.8, 6.4 Hz, 2H, H-9, H-5), 2.93– 2.76 (m, 1H, H-6), 2.26 – 2.07 (m, 1H, H-6), 1.42 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.38 (s, 9H, -COOC(CH3)3).

[0090] Compound 11b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, H-3), 5.87 (s, 1H, H-7), 5.03 – 4.96 (m, 3H, overlap, H-10, -N-CH), 3.76 (s, 3H, -COOCH3), 3.67 (d, J= 10.8 Hz, 1H, -CH-NH2), 3.62 – 3.52 (m, 2H, overlap, H-9,H-5), 2.99 – 2.87 (m, 1H, H-6), 2.29 – 2.16 (m, 1H, H-6), 1.48 (d, J = 7.4Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3), 1.37 (s, 3H, NH2-CH-CH3). 13 13C NMR (100 MHz, CDCl3) δ 176.20, 169.85, 168.69, 166.89, 137.32, 134.92,129.89, 110.66, 82.46, 63.06, 52.92, 51.65, 50.13, 48.89, 40.09, 36.50,27.94, 27.94, 27.94, 20.68, 15.96。

[0091] Compound 11c: colorless oil (55%). 1 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, H-3),5.89 (s, 1H, H-7), 4.98 (q, J = 7.4 Hz, 3H, overlap, H-10, -N-CH), 3.76 (s,3H, -COOCH3), 3.68 – 3.65 (m, 1H, H-9), 3.60 – 3.49 (m, 1H, H-5), 3.32 (d, J = 4.9 Hz, 1H, -CH-CH-CH3), 2.96 – 2.90 (m, 1H, H-6), 2.28 – 2.16 (m, 1H, H-6), 2.10 – 2.00 (m, 1H, -CH-CH-CH3), 1.48 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44(s, 9H, -COOC(CH3)3), 0.99 (d, J = 6.9 Hz, 3H, -CH-CH-CH3), 0.91 (d, J = 6.8Hz, 3H, -CH-CH-CH3). 13C NMR (100 MHz, CDCl3) δ 175.18, 169.85, 168.67,166.89, 137.35, 134.93, 130.18, 110.61, 82.41, 62.89, 59.95, 52.95, 51.63, 48.80, 40.08, 36.46, 32.10, 27.91, 27.91, 27.91, 19.35, 17.12, 15.90.

[0092] Compound 11d: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.10 – 4.88 (m, 3H, overlap, H-10, -N-CH), 3.76 (d, J =7.1 Hz, 3H, -COOCH3), 3.66 (d, J = 10.7 Hz, 1H, -CH-NH2), 3.61 – 3.42 (m, 2H,overlap, H-9, H-5), 2.96 – 2.90 (m, 1H, H-6), 2.31 – 2.12 (m, 1H, H-6), 1.83– 1.75 (m, 2H, -CH2-CH-(CH3)2), 1.62 – 1.56 (m, 1H, -CH-(CH3)2), 1.48 (d, J =7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3), 0.95 – 0.91 (m, 6H, -CH-(CH3)2). 13 C NMR (100 MHz, CDCl3) δ 176.19, 169.81, 168.66, 166.86, 137.35,134.93, 129.91, 110.64, 82.40, 62.99, 52.93, 51.60, 48.84, 44.05, 40.07,36.51, 31.42, 27.91, 27.91, 27.91, 24.76, 22.96, 21.87, 15.92.

[0093] Compound 11e: colorless oil (88%), 11H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H, H-3), 5.88 (s, 1H, H-7), 5.07 – 4.89 (m, 3H, overlap, H-10, -N-CH), 3.76 (s, 3H, -COOCH3), 3.70 – 3.59 (m, 2H, overlap, H-9, H-5), 3.60 – 3.49 (m, 1H, -CH-NH2), 2.96 – 2.90 (m, 1H, H-6), 2.64 (t, J J = 7.3 Hz, 2H, -S-CH2), 2.30 – 2.18 (m, 1H, H-6), 2.09 (d, J J = 5.6 Hz, 3H, -S-CH3), 2.07 – 2.02 (m, 1H, -CH-CH 2a ), 1.83 (m, 1H, -CH-CH 2b ), 1.48 (d, J J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3).

[0094] Compound 11f: colorless oil (45%), 1 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.27 (m, 4H, Ar-H), 7.24 – 7.19 (m, 2H, Ar-H, H-3), 5.79 (s, 1H, H-7), 5.04 – 4.90 (m, 3H, overlap, H-10, -N-CH), 3.77 (s, 3H, -COOCH3), 3.75 – 3.69 (m, 1H, -CH-NH2), 3.54 – 3.51 (m, 2H, overlap, H-5, H-9), 3.11 – 3.07 (m, 1H, -CH 2a -Ph), 2.93 – 2.88 (m, 2H, overlap, H-6, -CH 2b -Ph), 2.26 – 2.11 (m, 1H, H-6), 1.47 (d, J J = 7.4 Hz, 3H, -N-CH-CH3), 1.44 (s, 9H, -COOC(CH3)3).

[0095] Compound 11g: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H, H-3),7.12 (d, J = 8.5 Hz, 2H, Ar-H), 6.83 (d, J = 8.5 Hz, 2H, Ar-H), 5.80 (s, 1H,H-7), 5.05 – 4.92 (m, 3H, overlap, H-10, -N-CH), 3.78 (s, 3H, -OCH3), 3.77(s, 3H, -COOCH3), 3.75 – 3.69 (m, 1H, -CH-NH2), 3.60 – 3.46 (m, 2H, overlap,H-9, H-5), 3.12 – 2.98 (m, 1H, -CH 2a -Ph), 2.95 – 2.80 (m, 2H, overlap, H-6, -CH 2b -Ph), 2.29 – 2.12 (m, 1H, H-6), 1.48 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.44(s, 9H, -COOC(CH3)3).

[0096] Compound 11h: colorless oil (12%), 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m,5H, Ar-H), 7.27 (d, J = 1.7 Hz, 1H, H-3), 5.83 (s, 1H, H-7), 5.08 – 4.89 (m,3H, overlap, H-10, -N-CH), 4.61 – 4.43 (m, 2H, -CH2-Ph), 3.80 – 3.78 (m, 1H,-CH-NH2), 3.76 (s, 3H, -COOCH3), 3.75 – 3.65 (m, 2H, overlap, H-9, H-5), 3.61(d, J = 10.8 Hz, 1H, -CH-CH 2a -O), 3.55 – 3.46 (m, 1H, -CH-CH 2b-O), 2.90 – 2.84(m, 1H, H-6), 2.26 – 2.12 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -N-CH-CH3),1.44 (s, 9H, -COOC(CH3)3). 13 C NMR (100 MHz, CDCl3) δ 173.37, 169.82, 168.69,166.87, 137.75, 137.09, 134.94, 129.84, 128.40, 128.40, 127.74, 127.69,127.69, 110.67, 82.41, 73.36, 72.00, 63.31, 54.99, 52.97, 51.63, 48.86,40.08, 36.48, 27.93, 27.93, 27.93, 15.97.

[0097] Compound 11i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.31 (m, 4H, Ar-H), 7.28 (m, 1H, Ar-H), 7.28 (s, 1H, H-3), 5.86 (s, 1H, H-7), 5.08 – 4.91 (m,3H, overlap, H-10, -N-CH-CH3), 3.77 (s, 3H, -COOCH3), 3.73 (d, J = 11.3 Hz,2H, -CH2-Ph), 3.70 – 3.62 (m, 1H, -CH-NH2), 3.62 – 3.47 (m, 2H, overlap, H-9,H-5), 2.94 – 2.91 (m, 1H, H-6), 2.89 – 2.82 (m, 1H, -S-CH 2a -CH), 2.73 – 2.68(m, 1H, -S-CH 2b -CH), 2.26–2.13 (m, 1H, H-6), 1.47 (d, J = 7.4 Hz, 3H, -CH-CH3), 1.44 (s, 9H, -COOC(CH3)3).

[0098] Compound 11j: colorless oil (53%), 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m,5H, Ar-H), 7.25 (s, 1H, H-3), 5.84 (s, 1H, H-7), 5.06 – 4.86 (m, 3H, overlap,H-10, -N-CH), 4.57 (d, J = 11.7 Hz, 1H, -CH 2a -Ph), 4.42 (d, J = 11.7 Hz, 1H, -CH 2b -Ph), 4.01 – 3.99 (m, 1H, -O-CH-CH3), 3.76 (s, 3H, -COOCH3), 3.62 (d, J =10.8 Hz, 1H, -CH-NH2), 3.55 – 3.47 (m, 1H, H-9), 3.45 – 3.44 (m, 1H, H-5), 2.88 – 2.82 (m, 1H, H-6), 2.25 – 2.08 (m, 1H, H-6), 1.46 (d, J = 7.4 Hz, 3H, -N-CH-CH3), 1.43 (s, 9H, -COOC(CH3)3), 1.32 – 1.30 (m, 3H, -O-CH-CH3). 13 C NMR(100 MHz, CDCl3) δ 173.85, 169.83, 168.68, 166.87, 138.28, 137.11, 134.93,130.13, 128.31, 28.31, 127.58, 127.58, 110.65, 82.40, 75.81, 70.96, 63.24,59.59, 52.97, 51.62, 48.83, 40.07, 36.45, 31.44, 27.92, 27.92, 27.92, 16.50,15.95.

[0099] Compound 11k: colorless oil (42%), 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H, -NHin indole), 7.62 (d, J= 7.2 Hz, 1H, Ar-H), 7.37 – 7.30 (m, 1H, Ar-H), 7.28(s, 1H, H-3), 7.17 – 7.06 (m, 2H, Ar-H), 6.94 (d, J = 2.2 Hz, 1H, -CH inpyrrole ring), 5.72 (s, 1H, H-7), 5.19 (d, J = 13.1 Hz, 1H, H-10), 5.09 (q, J = 7.5 Hz, 1H, -N-CH), 4.62 (d, J = 12.8 Hz, 1H, H-10), 3.89 (t, J = 7.0 Hz,1H, -CH-NH2), 3.78 (s, 3H, -COOCH3), 3.23 – 3.08 (m, 2H, overlap, H-9, H-5), 3.07 – 2.98 (m, 1H, -CH 2a -CH), 2.76 – 2.70 (m, 1H, H-6), 2.62 (d, J = 10.8 Hz,1H, -CH 2b -CH), 2.07 (m, 1H, H-6), 1.50 (s, 9H, -COOC(CH3)3), 1.48 (s, 3H, -N-CH-CH3). 13 C NMR (100 MHz, CDCl3) δ 175.60, 170.87, 169.27, 166.93, 137.56,136.31, 134.34, 130.60, 127.33, 123.07, 121.86, 119.39, 118.76, 111.43,111.03, 110.97, 83.03, 63.09, 55.37, 52.41, 51.66, 46.98, 39.54, 36.34,31.82, 28.00, 28.00, 28.00, 16.00.

[0100] Table 5 Compounds 11a-11k

[0101]

[0102] Example 6 Synthesis of Compounds 11a-11k One of the compounds 9a-9k of Example 3 (0.34 mmol) and trifluoroacetic acid (6.4 mmol) were dissolved in dichloromethane, and the mixture was reacted at room temperature for 0.5 h. Ethyl acetate and saturated brine (volume ratio 1:1) were added for extraction to obtain an organic layer, which was dried over anhydrous sodium sulfate at room temperature for 12 h and then concentrated. The concentrate was separated and purified by column chromatography to obtain one of the pure products 12a-12k, respectively. Among them: synthesis 12a uses 42a, synthesis 12b uses 42b, synthesis 12c uses 42c, synthesis 12d uses 42d, synthesis 12f uses 42f, synthesis 12e uses 42e, synthesis 12g uses 42g, synthesis 12h uses 42h, synthesis 12i uses 42i, synthesis 12j uses 42j, and synthesis 12k uses 42k.

[0103] The structures of compounds 12a-12k are shown in Table 6; the appearance and NMR spectrum data are shown below: Compound 12a: colorless oil (65%), 1 H NMR (400 MHz, CDCl3) δ 7.26 – 7.18 (m, 4H,Ar-H), 7.13 – 7.06 (m, 2H, Ar-H, H-3), 5.72 (s, 1H, H-7), 5.27 (dd, J = 11.1,5.4 Hz, 1H, -N-CH), 4.77 (q, J = 13.3 Hz, 2H, H-10), 3.75 (s, 3H, -COOCH3), 3.56 (d, J = 10.6 Hz, 1H, H-9), 3.48 – 3.33 (m, 4H, overlap, -CH2-Ph, -CH2-NH2), 2.98 (dd, J = 14.3, 11.3 Hz, 1H, H-5), 2.75 (dd, J = 16.2, 8.4 Hz, 1H,H-6), 1.89 (d, J = 2.2 Hz, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3). 13C NMR (100MHz, CDCl3) δ 173.82, 168.84, 168.54, 166.79, 136.89, 136.08, 135.32, 130.11,128.99, 128.99, 128.53, 128.53, 126.94, 110.53, 82.83, 62.89, 57.74, 51.63,48.54, 43.92, 39.61, 36.35, 36.25, 27.95, 27.95, 27.95. Compound 12b: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.15 (m, 4H,Ar-H), 7.14 – 7.05 (m, 2H, overlap, Ar-H, H-3), 5.71 (s, 1H, H-7), 5.30 -5.26 (m, 1H, -N-CH), 4.80 - 4.69 (m, 2H, H-10), 3.74 (s, 3H, -COOCH3), 3.63 –3.50 (m, 2H, H-9, -CH-NH2), 3.50 – 3.32 (m, 2H, overlap, H-5, -CH 2a -Ph), 3.02- 2.95 (m, 1H, -CH 2b -Ph), 2.78 – 2.72 (m, 1H, H-6), 2.06 – 1.92 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3), 1.37 – 1.33 (m, 3H, -CH-CH3).

[0104] Compound 12c: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.16 (m, 4H,Ar-H), 7.13 – 7.08 (m, 2H, Ar-H, H-3), 5.73 (s, 1H, H-7), 5.28 – 5.24 (m, 1H,-N-CH), 4.81 (d, J = 13.4 Hz, 1H, H-10), 4.72 (d, J = 13.4 Hz, 1H, H-10),3.75 (s, 3H, -COOCH3), 3.55 (d, J= 10.7 Hz, 1H, -CH-NH2), 3.46 – 3.36 (m, 2H,overlap, H-9, -CH 2a -Ph), 3.30 (d, J = 4.9 Hz, 1H, -CH 2b -Ph), 3.02 - 2.96 (m,1H, H-5), 2.78 – 2.72 (m, 1H, H-6), 2.11 – 1.99 (m, 1H, -CH-CH3), 1.94 – 1.80(m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3), 0.98 (d, J = 6.9 Hz, 3H, -CH-CH3),0.90 (d, J = 6.8 Hz, 3H, -CH-CH3).

[0105] Compound 12d: colorless oil (50%), 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.24 (m, 1H,Ar-H), 7.21 – 7.07 (m, 5H, Ar-H, H-3), 5.71 (s, 1H, H-7), 5.27 (dd, J = 11.1,5.4 Hz, 1H, -N-CH), 4.86 – 4.55 (m, 2H, H-10), 3.75 (s, 3H, -COOCH3), 3.57 –3.32 (m, 4H, -N-CH-CH2-Ph, H-9, -CH-NH2), 3.06 – 2.94 (m, 1H, H-5), 2.83 –2.66 (m, 1H, H-6), 1.91 – 1.82 (m, 1H, H-6), 1.74 (d, J = 6.3 Hz, 2H, -CH2-CH-(CH3)2), 1.61 – 1.54 (m, 1H, -CH-(CH3)2), 1.46 (s, 9H, -COOC(CH3)3), 0.93(t, J = 7.1 Hz, 6H, -CH-(CH3)2). 13C NMR (100 MHz, CDCl3) δ 176.10, 168.87,168.52, 166.81, 137.04, 136.08, 135.37, 129.81, 129.81, 128.98, 128.98,128.53, 126.95, 110.52, 82.82, 62.87, 57.78, 52.91, 51.62, 48.58, 44.01,39.59, 36.35, 36.30, 27.95, 27.95, 27.95, 24.77, 22.99, 21.88.

[0106] Compound 12e: colorless oil (88%), 1 H NMR (400 MHz, CDCl3) δ 7.25 – 7.17 (m,4H, Ar-H), 7.13 – 7.05 (m, 2H, Ar-H, H-3), 5.72 (s, 1H, H-7), 5.27 (dd, J =11.2, 5.4 Hz, 1H, -N-CH), 4.79 – 4.70 (m, 2H, H-10), 3.75 (s, 3H, -COOCH3), 3.63 – 3.54 (m, 2H, -CH-NH 2, -CH 2a -Ph), 3.47 – 3.27 (m, 2H, H-9, -CH 2b -Ph),3.02 - 2.95 (m, 1H, H-5), 2.79 - 2.73 (m, 1H, H-6), 2.63 (t, J = 7.4 Hz, 2H,-S-CH2), 2.09 (s, 3H, -S-CH3), 2.07 – 1.98 (m, 1H, -S-CH2-CH 2a ), 1.93 – 1.85(m, 1H, H-6), 1.83 – 1.73 (m, 1H, -S-CH2-CH 2b ), 1.46 (s, 9H, -COOC(CH3)3) Compound 12f: colorless oil (12%), 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.25 (m, 3H, Ar-H), 7.18 (m, 6H, Ar-H), 7.11 (d, J= 1.7 Hz, 1H, Ar-H), 7.09 (s, 1H, H-3), 5.64 (s, 1H, H-7), 5.29 (dd, J = 11.1, 5.5 Hz, 1H, -N-CH), 4.80 (d, J = 13.4Hz, 1H, H-10), 4.70 (d, J = 13.4 Hz, 1H, H-10), 3.75 (s, 3H, -COOCH3), 3.72(s, 1H, -CH-NH2), 3.40 (d, J = 5.5 Hz, 2H, -N-CH-CH2-Ph), 3.38 – 3.33 (m, 1H,H-9), 3.08 (dd, J = 13.6, 5.7 Hz, 1H, -CH 2a -CH-NH2), 2.98 (dd, J = 14.4, 11.1Hz, 1H, H-5), 2.88 (dd, J = 13.6, 7.6 Hz, 1H, -CH 2b -CH-NH2), 2.79 – 2.64 (m,1H, H-6), 1.90 – 1.74 (m, 1H, H-6), 1.46 (s, 9H, -COOC(CH3)3). 13 C NMR (100MHz, CDCl3) δ 174.61, 168.89, 168.57, 166.83, 137.19, 136.87, 136.07, 135.35,130.19, 129.34, 129.34, 128.99, 128.99, 128.57, 128.57, 128.54, 128.54,126.96, 126.80, 110.48, 82.84, 63.01, 57.67, 55.86, 51.64, 48.39, 41.11,39.54, 36.42, 36.29, 27.97, 27.97, 27.97.

[0107] Compound 12g: colorless oil (88%) 11H NMR (400 MHz, CDCl3) δ 7.25 – 7.16 (m, 4H, Ar-H), 7.11 - 7.09 (m, 4H, Ar-H, H-3), 6.88 – 6.77 (m, 2H, Ar-H), 5.65 (s, 1H, H-7), 5.27 (dd, J J = 11.1, 5.5 Hz, 1H, -N-CH), 4.82 – 4.69 (m, 2H, H-10), 3.77 (s, 3H, -OCH3), 3.75 (s, 3H, -COOCH3), 3.44 (t, J J = 7.4 Hz, 1H, -CH-NH2), 3.42– 3.32 (m, 2H, -N-CH-CH2-Ph), 3.04 – 2.98 (m, 2H, -CH 2a -CH-NH2, H-5), 2.86 – 2.81 (m, 1H, -CH 2b -CH-NH2), 2.76 – 2.70 (m, 1H, H-6), 1.90 – 1.79 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3).

[0108] Compound 12h: colorless oil (12%), 1 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.22 (m, 7H, Ar-H), 7.20 – 7.13 (m, 2H, Ar-H), 7.11 (s, 1H, H-3), 7.09 (s, 1H, Ar-H), 5.67 (s, 1H, H-7), 5.28 (dd, J J = 11.1, 5.4 Hz, 1H, -N-CH), 4.91 – 4.68 (m, 2H, H-10), 4.63 – 4.43 (m, 2H, -O-CH2-Ph), 3.75 (s, 3H, -COOCH3), 3.73 – 3.69 (m, 1H, -CH-COOCH2), 3.67 – 3.66 (m, 1H, -O-CH 2a -CH), 3.50 – 3.47 (m, 1H, H-9), 3.42 – 3.31 (m, 2H, -N-CH-CH2-Ph), 3.01 – 2.98 (m, 1H, -O-CH 2b-CH), 2.73 –2.67 (m, 1H, H-6), 2.02 – 2.01 (m, 1H, H-6), 1.45 (s, 1H, -COOC(CH3)3).

[0109] Compound 12i: colorless oil (51%), 1 H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m,4H, Ar-H), 7.25 – 7.16 (m, 5H, Ar-H), 7.10 (d, J = 6.5 Hz, 2H, Ar-H, H-3),5.69 (s, 1H, H-7), 5.28 (dd, J = 11.1, 5.4 Hz, 1H, -N-CH), 4.74 (q, J = 13.4Hz, 2H, H-10), 3.76 (s, 3H, -COOCH3), 3.73 (s, 2H, -S-CH2-Ph), 3.59 (dd, J =7.6, 4.6 Hz, 1H, -CH-NH2), 3.51 – 3.48 (m, 1H, H-9, N-CH-CH 2a -Ph), 3.44 – 3.36(m, 2H, H-9, -N-CH-CH 2b -Ph), 3.01 – 2.95 (m, 1H, H-5), 2.85 – 2.81 (m, 1H, -S-CH 2a -CH), 2.77 – 2.71 (m, 1H, H-6), 2.68 – 2.63 (m, 1H, -S-CH 2b -CH), 1.89 –1.83 (m, 1H, H-6), 1.45 (s, 9H, -COOC(CH3)3).

[0110] Compound 12j: colorless oil (53%), 1 H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m,3H, Ar-H), 7.23 – 7.08 (m, 8H, Ar-H, H-3), 5.68 (s, 1H, H-7), 5.25 (dd, J= 11.1, 5.4 Hz, 1H, -N-CH), 4.76 – 4.70 (m, 2H, H-10), 4.55 (t, J = 10.4 Hz, 1H, -O-CH 2a ), 4.12 – 4.33 (m, 1H, -O-CH 2b ), 3.98 (dd, J = 6.3, 3.6 Hz, 1H, -CH-NH2), 3.74 (s, 3H, -COOCH3), 3.50 (d, J = 10.5 Hz, 1H, -CH-NH2), 3.46 – 3.21 (m, 3H, overlap, H-9, -N-CH-CH2-Ph), 3.01 – 2.94 (m, 1H, overlap, H-5), 2.71 – 2.65 (m, 1H, H-6), 1.88 – 1.78 (m, 1H, H-6), 1.12 (s, 9H, -COOC(CH3)3), 1.35 – 1.29 (m, 3H, -CH-CH3).

[0111] Compound 12k: colorless oil (42%), 1 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H, -NH in indole), 7.60 (d, J = 7.5 Hz, 1H, Ar-H), 7.30 (d, J = 7.7 Hz, 2H, Ar-H), 7.23 – 7.09 (m, 7H, Ar-H), 7.06 (s, 1H, H-3), 6.95 (d, J = 2.1 Hz, 1H, -CH in pyrrole ring), 5.56 (s, 1H, H-7), 5.42 (dd, J = 11.2, 5.6 Hz, 1H, -N-CH), 5.00 (d, J = 12.9 Hz, 1H, H-10), 4.48 (d, J = 12.9 Hz, 1H, H-10), 3.87 (t, J= 6.9 Hz, 1H, -CH-NH2), 3.77 (s, 3H, -COOCH3), 3.45 – 3.40 (m, 1H, H-9), 3.14(d, J = 6.9 Hz, 2H, -CH2-Ph), 3.01 – 2.93 (m, 2H, -CH2-CH-NH2), 2.62 – 2.59(m, 1H, H-5), 2.57 – 2.51 (m, 1H, H-6), 1.68 – 1.59 (m, 1H, H-6), 1.50 (s,9H, -COOC(CH3)3). 13 C NMR (100 MHz, CDCl3) δ 175.34, 169.65, 169.01, 166.84,137.24, 136.31, 135.91, 134.89, 130.12, 128.89, 128.89, 128.52, 128.52,127.34, 126.98, 123.08, 121.89, 119.41, 118.77, 111.42, 111.01, 110.84,83.37, 62.99, 57.13, 55.26, 51.66, 46.96, 38.94, 36.32, 36.23, 31.59, 28.02,28.02, 28.02.

[0112] Table 6 Compounds 12a-12k

[0113]

[0114] In order to demonstrate the advantages of the technical solution provided by the present application, an embodiment of the technical solution provided by the present application is given below.

[0115] Experimental Example 1: Compound 9a was used to investigate the cell activity.

[0116] (1) Cultivation of HT22 cells HT22 cells were revived in a 37°C water bath for 3 minutes, placed in a 15 mL centrifuge tube, and centrifuged at room temperature with 10 mL of high-glucose medium containing 10% fetal bovine serum and 1% double-antibody (penicillin-streptomycin mixture 100×). After removal of the supernatant, the cells and complete medium were cultured in a 37°C, 5% carbon dioxide incubator. When the cells grow to about 80%, they can be passaged.

[0117] (2) Oxygen-glucose deprivation / reperfusion (OGD / R)-induced HT22 injury model 96-well plates were inoculated with 5000 HT22 cells per well. After 12 hours, the complete medium was aspirated and serum-free and sugar-free medium was added. The cells were hypoxic in a three-gas incubator for 12 hours. After reoxygenation, the model group was added with complete medium, and the drug treatment group was added with different concentrations of drug complete medium solutions. The cells were cultured in a 37°C incubator with 5% CO2 for 24 hours, and MTT was added to detect cell activity.

[0118] (3) Exploration of the optimal protective activity concentration of compound 9a In the preliminary screening of cell activity, it was found that compound 9a had good neuroprotective activity at a concentration of 10 μM, and it was concentration-dependent. In order to explore the relationship between the specific concentration and activity of 9a, 9a was set at concentrations of 1, 5, 10, and 20 μM to detect cell survival rate in the OGD / R model. The results are as follows: Figure 4 The cell survival rate of the model group was 58%. After treatment with 9a at concentrations of 1, 5, 10, and 20 μM, the cell survival rates were 71%, 93%, 85%, and 61%, respectively. The activity results showed that 9a had the best cell protection effect at 5 μM, and the cell survival rate increased by 35%.

[0119] (4) Determination of lactate dehydrogenase (LDH) content In order to determine the changes in LDH content in each group of cells, the cells were grouped and measured according to the instructions of the cell LDH detection kit (Bestbio, Shanghai, China). HT22 was seeded in a 96-well plate at a density of 5000 cells per well. After 12 hours of culture, the complete medium was aspirated and serum-free and sugar-free medium was added. The cells were hypoxic for 12 hours in a three-gas incubator, and the drug was added for 9a and reoxygenated for 24 hours. The LDH content was measured using the kit. From the observation of cell morphology, such as Figure 5 A shows that, unlike the normal group cells, most of the HT22 cells in OGD / R became round, indicating that the cells were damaged to a certain extent due to the lack of oxygen and glucose. Under the treatment of the compound, the cells recovered their stretched morphology and showed a normal state. At the same time, the LDH content was detected. The results are as follows Figure 5 As shown in B, it can be seen that the LDH release of cells in the normal group is 111%, while the LDH level in the cell supernatant of the OGD / R group is significantly increased (239%), which is about twice that of the normal cell group. Treatment with 9a at concentrations of 5 and 10 μM has a significant reduction effect, resulting in LDH release of 172% and 136%, respectively. From the results, it can be seen that compound 9a can restore OGD / R-induced neuronal cell damage.

[0120] (5) Determination of reactive oxygen species (ROS) content In order to determine the changes in ROS content in each group of cells, the cells were grouped and measured according to the instructions of the cell ROS detection kit (Meilunbio, Dalian, China). HT22 cells were seeded in a 12-well plate at a density of 100,000 cells per well. After 12 hours of culture, the complete medium was aspirated and serum-free and sugar-free medium was added. The cells were hypoxic for 12 hours in a three-gas incubator. After adding drugs for 9a and reoxygenating for 24 hours, ROS fluorescence images were observed and photographed using an inverted fluorescence microscope. Figure 6 A in; through Figure 6 In B, it can be seen that the fluorescence level of the normal group HT22 cells is 0.86. It can be seen that unlike the normal group cells, the ROS level of the OGD / R HT22 cells increased significantly after stimulation, and the fluorescence level was 3.97, which is about 4.6 times that of the normal group. After treatment with 5 and 10 μM 9a, the ROS level induced by OGD / R was significantly reduced, and was close to the normal cell group at 5 μM.

Claims

1. A diamino acid-genipin derivative, characterized in that: It has the general structural formula 1: ； Formula 1; in: R1 is one of hydrogen, methyl, and benzyl; R2 is one of hydrogen, methyl, benzyl, isopropyl, 2-methylpropyl, 2-(methylthio)ethyl, 2-methoxybenzyl, (benzyloxy)yl, (benzylthio)yl, 1-(benzyloxy)ethyl, and indole-3-methyl; R3 is either hydrogen or tert-butyloxycarbonyl.

2. The method for preparing the diamino acid-genipin derivative according to claim 1, characterized in that: The steps are as follows: Genipin is used as a starting material, and an intermediate 1 is obtained by an etherification reaction with tert-butyldimethylsilyl chloride. Intermediate 1 is subjected to an oxidation reaction to obtain intermediate 2. Intermediate 2 and amino acid tert-butyl ester hydrochloride are subjected to an amination reaction to obtain intermediate 3. Intermediate 3 is subjected to an esterification reaction with an amino acid compound, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to obtain a diamino acid-genipin derivative 1. The synthetic route and its products are shown below: 。 3. The method for preparing the bis-amino acid-genipin derivative according to claim 2, characterized in that: The oxidation reaction is a Dess-Martin periodinane oxidation reaction.

4. The method for preparing the bis-amino acid-genipin derivative according to claim 2, characterized in that: The amino acid tert-butyl ester hydrochloride is one of glycine tert-butyl ester hydrochloride, alanine tert-butyl ester hydrochloride, and phenylalanine tert-butyl ester hydrochloride or any combination thereof.

5. The method for preparing the bis-amino acid-genipin derivative according to claim 2, characterized in that: The amino acid compound is one of N-(tert-butoxycarbonyl)-L-tryptophan, N-(tert-butoxycarbonyl)-L-methionine, N-(tert-butoxycarbonyl)-O-benzyl-L-threonine, N-(tert-butoxycarbonyl)-L-isoleucine, N-(tert-butoxycarbonyl)-D-alanine, N-(tert-butoxycarbonyl)-O-benzyl-L-serine, N-(tert-butoxycarbonyl)-S-benzyl-L-cysteine, N-(tert-butoxycarbonyl)-L-valine, N-(tert-butoxycarbonyl)-L-phenylalanine, N-(tert-butoxycarbonyl)glycine, and N-tert-butoxycarbonyl-4-methoxy-L-phenylalanine, or any combination thereof.

6. The method for preparing the bis-amino acid-genipin derivative according to claim 2, characterized in that: The invention also includes removing the amino protecting group of the bis-amino acid-genipin derivative 1 by trifluoroacetic acid to obtain the bis-amino acid-genipin derivative 2; The synthetic route and its products are shown below: 。 7. Use of the diamino acid-genipin derivative according to claim 1 in the preparation of neuroprotective drugs.

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