Hirsutine alkaloid boronic acid derivatives, methods of making and using the same

Abstract

The application provides a Hirsutine alkaloid borate derivative, a preparation method and application thereof, and belongs to the technical field of medicines.The Hirsutine alkaloid borate derivative has a structural formula shown in formula (I) or formula (II).The application further provides a specific preparation method of the Hirsutine alkaloid borate derivative.Experiments prove that part of the Hirsutine alkaloid borate derivatives involved in the application have strong inhibitory effects on influenza virus (H1N1), and can be used for preparing medicines for preventing or treating influenza virus infection;part of the Hirsutine alkaloid borate derivatives involved in the application have strong inhibitory effects on Staphylococcus aureus and Escherichia coli, and can be used for preparing medicines for preventing or treating bacterial infection.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a Hirsutine alkaloid borate derivative, a preparation method and application thereof. BACKGROUND

[0002] Influenza virus causes respiratory tract infection, which usually presents as seasonal epidemic and intermittent pandemic, and not only seriously affects public health, but also brings heavy economic burden to the country and society. At present, the anti-influenza virus drugs approved for clinical use in China include two ion channel inhibitors: amantadine and rimantadine, and two neuraminidase inhibitors: oral oseltamivir and inhaled zanamivir. However, most influenza viruses have developed varying degrees of resistance to amantadine and oseltamivir. Recently, FDA approved baloxavir marboxil targeting viral polymerase. However, the clinical efficacy, drug resistance and cost are still concerned. In addition, the challenge of drug resistance problem also exists in antibacterial drugs. The abuse of antibiotics often produces a large number of bacteria with super strong drug resistance, such as VRE and MRSA. In the past 20 years, the number of antibiotics approved by FDA has shown a downward trend. Some new antibiotics are usually designed as "me too" drugs, which can easily make bacteria develop drug resistance in a very short time. In addition, the cost of research on new antibiotics and the limited method for identifying lead compounds have greatly reduced the interest of pharmaceutical companies in the research on new antibiotics. Therefore, it is of great significance to develop and reserve anti-influenza virus and antibacterial drugs with new mechanisms, new targets and new structures.

[0003] Boronic acid group is an important pharmacophore in boron-containing drugs. The presence of empty p-orbital of boron atom makes it have mild Lewis acidity and unique electrophilic characteristics. The hydroxyl group connected to boron can reversibly covalently bind with cis-diol structure, and can enhance the binding ability with key amino acids of target protein through water molecule-mediated hydrogen bond, thus reducing the risk of drug resistance. As a derivative of boronic acid, borazole has similar chemical properties as boronic acid. However, unlike boronic acid, borazole is more likely to form a stable tetrahedral structure in water due to the presence of five-membered ring strain, thus having stronger water solubility. In addition, the borazole structure also has stronger stability under physiological pH conditions. Currently, several boron-based drugs have been marketed, including Bortezomib and Ixazomib approved by FDA in 2003 and 2015 respectively for the treatment of multiple myeloma, Tavaborole approved by FDA in 2014 for the treatment of onychomycosis, Crisaborole approved by FDA in 2016 for the treatment of mild to moderate condyloma acuminatum, and Vabomere approved by FDA in 2017 as a new antibacterial drug β-lactamase inhibitor. Among them, boron atoms play a key role as pharmacophores, so the development of boron-based drugs has broad prospects.

[0004] Hirsutine is a rod-shaped floral monoterpene indole alkaloid isolated from Mitragyna hirsuta in 1965, which has strong central inhibition and vasodilation effects. In addition, Takayama et al. (1997) first described the inhibitory effect of Hirsutine and its synthetic derivatives on influenza A virus in vitro. They found that Hirsutine inhibited the replication of influenza A virus (H3N2) with SI (CC 50 / EC 50 ) = 58.8. Therefore, we selected this compound as the parent compound for boronization modification, expecting that the introduced boronic acid group could enhance the anti-influenza virus activity of the compound, because our previous studies showed that the phenylboronic acid group is an effective functional group for anti-viral activity. The derivatives designed and synthesized by Kai Zhu's group and Hiromitsu's group have good antihypertensive and anti-viral activities by retaining the tetraloop parent structure and introducing different substituents in the side chain. Therefore, we retained the tetraloop parent structure of Hirsutine and modified it with borazole and boronic acid at C-20 position with different connecting arms and connecting modes, in order to seek anti-viral candidate compounds with stronger activity, lower toxicity and better drug-likeness.

[0005] In addition, the boronic acid compounds have been proved to be good leucine-tRNA synthetase inhibitors and β-lactamase inhibitors, and have certain bacteriostatic ability, therefore, the synthesized benzoboronic acid derivatives are also subjected to antibacterial activity research. SUMMARY

[0006] The present application provides a Hirsutine alkaloid boronic acid derivative, a preparation method thereof and application thereof in preparation of antiviral and antibacterial drugs, and can be used for preparation of drugs for preventing or treating viral infection, or preparation of drugs for preventing or treating bacterial infection.

[0007] To solve the above technical problems, the present application provides a compound having a structure shown in formula (I) or formula (II) and a pharmaceutically acceptable salt form:

[0008]

[0009] (1) In the formula, R is selected from one of the following groups: wherein R3 is o-NHCO, m-NHCO, p-NHCO, o-NHCH2, m-NHCH2, p-NHCH2; or n = 1, 2, 3, 4, 5; or wherein n = 1, 2, 3, 4, 5, and R4 is H or CH3; or or or NH. R1 is substituted at any position on the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0010] (2) In formula (I), the boronic acid group and R2 are as follows: when the boronic acid group is at the C2 position of the benzene ring, R2 is substituted at the C3 or C4 position of the benzene ring and is selected from one of the following groups: OCH3, F, Cl; when the boronic acid group is at the C3 position of the benzene ring, R2 is substituted at the C4 or C5 position of the benzene ring and is selected from one of the following groups: CH3, OCH3, COOH, OH, F, Cl, Br; when the boronic acid group is at the C4 position of the benzene ring, R2 is substituted at the C2 or C3 position of the benzene ring and is selected from one of the following groups: CH3, CH2CH3, OCH3, F, Cl.

[0011] (3) In formula (II), R can be at any one of the C1, C2, C3 and C4 positions of the benzene ring of the boronic acid.

[0012] The pharmaceutically acceptable salt refers to the salt of the above-mentioned compound and inorganic acid, organic acid, alkali metal or alkaline earth metal, etc. These salts include (but not limited to): (1) the salt with inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; (2) the salt with organic acid, such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine (3) other salts, including the salt with alkali metal or alkaline earth metal (such as sodium, potassium, calcium or magnesium), ammonium salt or water-soluble amine salt (such as N-methylglucamine salt), lower alkanol ammonium salt and other pharmaceutically acceptable amine salt (such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, t-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salt formed by morpholine, piperazine, lysine, respectively), or other conventional "prodrugs".

[0013] The Hirsutine alkaloid boronic acid derivative of the present application can be prepared by the following method, which comprises the following steps:

[0014] First, the 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylic acid ethyl ester with or without substituent on the indole ring of the Hirsutine mother nucleus part is hydrolyzed by 5 equivalent of lithium hydroxide in the reaction solution of THF:H2O=1:2, and the pH is adjusted to about 3 by 2N hydrochloric acid to obtain the 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylic acid hydrochloride with or without substituent on the indole ring; then the amide compound and the Hirsutine alkaloid boronic acid derivative with R being NH are formed by condensation with amine compound using HATU as condensing agent under the condition of molar ratio 1:1.5; the amide compound is condensed with the benzoboronic acid compound with carboxyl or methylene bromo group or the substituted benzene boronic acid compound with carboxyl or methylene bromo group under the condition of molar ratio 1:1.5 to obtain the Hirsutine alkaloid boronic acid derivative except that R is NH.

[0015] The required 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylic acid ethyl ester with or without substituent on the indole ring has the structural formula shown in formula (III), and can be prepared according to the known method.

[0016]

[0017] In the formula, R1 is substituted at any position of the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0018] The application provides a kind of Hirsutine alkaloid boronic acid derivative with antiviral effect or antibacterial effect and its preparation method and application.It is proved by experiment that part of the boronic acid modified, benzene boronic acid modified Hirsutine alkaloid boronic acid derivative involved in the application has strong inhibitory effect on influenza virus, and has lower cytotoxicity, meets the characteristics of high efficiency and low toxicity of antiviral drugs, and can be used for preparing antiviral drugs;Part of the benzene boronic acid modified Hirsutine alkaloid derivative involved in the application has strong inhibitory effect on a variety of bacterial strains, and can be used for preparing antibacterial drugs. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 It is the reaction flow schematic diagram of example 1 of the application;

[0020] Figure 2 It is the reaction flow schematic diagram of example 2 and 5 of the application;

[0021] Figure 3 It is the reaction flow schematic diagram of example 3 and 6 of the application;

[0022] Figure 4 It is the reaction flow schematic diagram of example 4 and 7 of the application;

[0023] Figure 5 It is the structure schematic diagram of Hirsutine alkaloid boronic acid derivative of the application. DETAILED DESCRIPTION

[0024] The application modifies the partial mother ring of Hirsutine by different aromatic boronic acid compounds, boronic acid compounds and different connecting arms, aims to obtain the Hirsutine alkaloid boronic acid derivative of the application, and obtains part of the Hirsutine alkaloid boronic acid derivative with good in vitro anti-influenza virus activity and lower cytotoxicity by testing the virus, bacterial and cell level activity of part of the compounds, which can be applied in the field of antiviral drugs;Part of the Hirsutine alkaloid boronic acid derivative obtained has good in vitro antibacterial activity and lower cytotoxicity, and can be applied in the field of antibacterial drugs.

[0025] The application will be further described in detail in combination with examples.

[0026] Example 1, preparation of 1, 4, 6, 7, 12, 12b-hexahydroindolo [2, 3-a] quinolizine-3-carboxylic acid ethyl ester containing or not containing substituent on indole ring

[0027] This example is aimed at the preparation of the required Hirsutine moiety parent core starting material, whose synthesis is based on the synthetic procedure reported by Reymundo A. Villa et al. The preparation route is shown in the attached scheme. Figure 1

[0028] The ethyl 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine-3-carboxylate with or without substituents on the indole ring as described in this example has the following structure:

[0029]

[0030] R1is substituted at any position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0031] 1. Preparation of tert-butyl 2-formyl-1H-indole-1-carboxylate

[0032] Weigh 1H-indole-2-carboxaldehyde (1.0 g, 6.89 mmol, 1.0 eq) and DMAP (84.18 mg, 0.69 mmol, 0.1 eq) in a 100 mL round bottom flask, add 10 mL THF to dissolve, then add triethylamine (11.47 mL, 8.27 mmol, 1.2 eq), slowly drop the di-tert-butyl dicarbonate (18.04 g, 82.67 mmol, 1.2 eq) solution dissolved in 10 mL THF under ice bath, after adding, transfer to room temperature 25 °C for 12 h. After TLC detection of the complete reaction, evaporate the solvent under reduced pressure, extract with dichloromethane for 3 times, combine the organic phase, wash once with saturated NaCl, dry with anhydrous magnesium sulfate, and finally column chromatography (PE:EA = 80:1) to obtain 1.25 g of white solid, yield: 74%.

[0033] 2. Preparation of tert-butyl 2-(5-(ethoxycarbonyl)-1-((4-nitrophenyl)sulfonyl)-1,2,3,6- tetrahydropyridin-2-yl)-1H-indole-1-carboxylate

[0034] ​Take 2-formyl-lH-indole-l-carboxylate tert-butyl ester (1.3 g, 5.3 mmol, 1.0 eq) and NsNH2(1.17 g, 5.83 mmol, 1.1 eq) in a 100 mL three-necked flask, under N2protection, add 40 mL of anhydrous dichloromethane to dissolve, then add Ti(OEt)4(2.42 g, 10.6 mmol, 2.0 eq) to the reaction solution, react at room temperature for 5 h, after TLC detection of complete reaction, slowly drop PBu3(0.79 mL, 3.19 mmol, 0.6 eq), after 5 min, continue to add 2-methylbutyl-2,3-dienoate ethyl ester (0.76 mL, 6.36 mmol, 1.2 eq), react at room temperature for 12 h, after TLC detection of complete reaction, concentrate and evaporate the solvent under reduced pressure, extract with ethyl acetate three times, combine the organic phase, wash once with saturated NaCl, dry over anhydrous magnesium sulfate, and finally column chromatography (PE:EA=5:1) to obtain 2.81 g of yellow foam solid, yield: 96%.

[0035] 3. Preparation of 6-(lH-indol-2-yl)-l-((4-nitrophenyl)sulfonyl)-l,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester

[0036] Take 2-(5-(ethoxycarbonyl)-l-((4-nitrophenyl)sulfonyl)-l,2,3,6-tetrahydropyridin-2-yl)-lH-indole-l-carboxylate tert-butyl ester (1.97 g, 3.55 mmol, 1.0 eq) and 1.97 g of SiO2in a 100 mL round-bottom flask, add 20 mL of toluene, react under heating and reflux conditions for 5 h, after TLC detection of complete reaction, concentrate and evaporate the solvent under reduced pressure, column chromatography (PE:EA=2:1) to obtain 1.31 g of yellow solid, yield: 81%.

[0037] 4. Preparation of 6-(3-(2-hydroxyethyl)-lH-indol-2-yl)-l-((4-nitrophenyl)sulfonyl)-l,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester

[0038] Into a 100 mL three-necked flask, 6-(lH-indol-2-yl)-l-((4-nitrophenyl)sulfonyl)- 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester (1.28 g, 2.81 mmol, 1.0 eq) was weighed, N2-protected, 30 mL of anhydrous THF was added, and oxalyl chloride (0.71 mL, 8.43 mmol, 3.0 eq) was slowly added dropwise under ice-bath cooling. After the addition was completed, the reaction was transferred to room temperature (25 °C) and reacted for 12 h. After the reaction was completed by TLC detection, BH3-DMS (1.69 mL, 1.69 mmol, 6.0 eq) was slowly added dropwise under ice-bath cooling. After the addition was completed, the reaction was transferred to room temperature (25 °C) and reacted for 4 h. After the reaction was completed by TLC detection, saturated NaHCO3 solution was added to quench the reaction until no gas bubbles were generated. THF was removed by concentration under reduced pressure, and ethyl acetate was extracted three times. The organic phases were combined, washed once with saturated NaCl, dried over anhydrous MgSO4, and finally column chromatographed (PE:EA = 1:1) to obtain 0.95 g of a yellow solid, with a yield of 68%.

[0039] 5. Preparation of 6-(3-(2-hydroxyethyl)-lH-indol-2-yl)-l,2,5,6-tetrahydropyridine-3- carboxylic acid ethyl ester

[0040] Into a 100 mL round-bottom flask, 6-(3-(2-hydroxyethyl)-lH-indol-2-yl)-l-((4- nitrophenyl)sulfonyl)-l,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester (950 mg, 1.90 mmol, 1.0 eq), p-toluenethiol (283 mg, 2.28 mmol, 1.2 eq), and anhydrous potassium carbonate (789 mg, 5.71 mmol, 3.0 eq) were weighed, and 20 mL of acetonitrile was added to dissolve them. The reaction was performed at 50 °C for 3 h. After the reaction was completed by TLC detection, acetonitrile was evaporated by concentration under reduced pressure, and dichloromethane was extracted three times. The organic phases were combined, washed once with saturated NaCl, dried over anhydrous MgSO4, and column chromatographed (DCM:MeOH = 20:1) to obtain 0.45 g of a white solid, with a yield of 75%.

[0041] 6. Preparation of 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxylic acid ethyl ester (Compound III-1)

[0042] Triphenylphosphine (563 mg, 2.15 mmol, 1.5 eq) and imidazole (146 mg, 2.15 mmol, 1.5 eq) were weighed into a 100 mL three-necked flask. Under N2 protection, 10 mL of dichloromethane was added to dissolve the phosphine. Iodine (436 mg, 1.72 mmol, 2.0 eq) was added under ice bath conditions. After 5 min, ethyl 6-(3-(2-hydroxyethyl)-1H-indol-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid (450 mg, 1.43 mmol, 1.0 eq) was added. The mixture was transferred to room temperature (25 °C) and reacted for 1 h. After the reaction was confirmed to be complete by TLC, 2 mL of triethylamine, dichloromethane, and saturated NaHCO3 solution were added to the reaction solution for extraction three times. The organic phases were combined, washed once with saturated NaCl, dried over anhydrous magnesium sulfate, and finally purified by column chromatography (PE:EA = 5:1) to obtain 300 mg of white solid, yield: 71%. 1 H NMR (400MHz, CDCl3)7.73(br s,1H),7.42(d,J=7.7Hz,1H),7.26(d,J=7.7Hz,1H),7.16-7.08(m,2H),7.03(br s,1H),4.19(q,J=7.1Hz,2H),3.79(d,J=16.5Hz,1H),3.49(d,J=10.4Hz,1H),3.28-3.17 (m,2H),3.04-2.95(m,1H),2.82-2.67(m,3H),2.49-2.41(m,1H),1.29(t,J=7.1Hz,3H); 13 C NMR (100MHz, CDCl3)165.42,136.15,136.37,133.64,129.24,126.62,121.14,11 9.56,118.14,110.62,108.24,60.35,54.34,53.23,52.07,31.21,21.14,14.35.

[0043]

[0044] 7. Preparation of ethyl 10-methyl-1,4,6,7,12,12-hexahydroindolo[2,3-a]quinoline-3-carboxylate (compound III-2)

[0045] The preparation was carried out in the same manner as steps 1 to 6 of Example 1, with 5-methyl-1H-indole-2-carboxaldehyde as the starting material, yielding 3.61 g of white solid, with an overall yield of 18%. 1H NMR (400MHz, DMSO-d6) δ8.48 (s, 1H), 7.39-7.34 (m, 1H), 7.03-7.09 (d, J = 7.7Hz, 1H), 6.97-6.91(d,J=5.1Hz,1H),4.49-4.41(m,1H),4.23-4.15(q,J=7.1Hz,2H),3.90-3. 85(m,1H),3.77-3.68(m,1H),3.28-3.19(ddd,J=12.1,6.1,4.2Hz,1H),3.15-3.11(m ,1H),2.99-2.87(m,2H),2.73-2.65(m,1H),2.48-2.39(m,1H),1.30(t,J=7.1Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ167.23,139.53,135.99,132.80,130.19,126.27,125.84,120 .72,119.59,109.78,107.51,60.67,55.26,53.61,52.15,31.88,21.48,20.29,14.21.

[0046]

[0047] 8. Preparation of ethyl 10-bromo-1,4,6,7,12,12-hexahydroindolo[2,3-a]quinoline-3-carboxylate (compound III-3)

[0048] The preparation was carried out in the same manner as steps 1 to 6 of Example 1, with 5-bromo-1H-indole-2-carboxaldehyde as the starting material, yielding 3.01 g of white solid, with an overall yield of 17%. 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.56-7.49 (d, J = 2.7Hz, 1H), 7.39-7.32 (d d,J=7.3,2.4Hz,1H),7.21(s,1H),6.97-6.89(m,1H),4.49-4.41(m,1H),4.23-4 .15(q,J=7.1Hz,2H),3.90-3.81(m,1H),3.77-3.68(m,1H),3.28-3.17(m,1H), 3.15-3.08(m,1H),2.99-2.87(m,2H),2.73-2.48(m,2H),1.30(t,J=7.1Hz,3H). 13CNMR (100 MHz, DMSO-d6) δ 167.22, 139.54, 136.15, 132.75, 128.07, 127.04, 122.65, 120.78, 112.45, 112.33, 107.50, 60.70, 55.30, 53.72, 51.98, 31.64, 21.58, 14.21.

[0049]

[0050] Example 2, Preparation of Hirsutine alkaloid derivatives modified by carboxyphenylboronic acid compounds

[0051] This reaction example uses compound III as starting material, hydrolysis under the condition of lithium hydroxide, pH is adjusted to about 3 by 2N dilute hydrochloric acid, then condensed with single Boc protected aromatic diamine or aliphatic diamine, followed by de-Boc, the obtained intermediate is condensed with carboxyphenylboronic acid with or without substituent to obtain the Hirsutine alkaloid derivatives modified by carboxyphenylboronic acid compounds, the preparation route is shown as Figure 2

[0052] The Hirsutine alkaloid derivatives modified by carboxyphenylboronic acid compounds described in this example have the following structure shown in the formula:

[0053]

[0054] In the formula, R is selected from one of the following groups: wherein R3 is o-NHCO, m-NHCO, p-NHCO; or n = 1, 2, 3, 4, 5; or In the formula, R1 is substituted at any position on the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN. In the formula, the boronic acid group and R2 are as follows: when the boronic acid group is at the C2 position of the benzene ring, R2 is substituted at the C3 or C4 position of the benzene ring and is selected from one of the following groups: OCH3, F, Cl; when the boronic acid group is at the C3 position of the benzene ring, R2 is substituted at the C4 or C5 position of the benzene ring and is selected from one of the following groups: CH3, OCH3, COOH, OH, F, Cl, Br; when the boronic acid group is at the C4 position of the benzene ring, R2 is substituted at the C2 or C3 position of the benzene ring and is selected from one of the following groups: CH3, CH2CH3, OCH3, F, Cl.

[0055] 1, 1, 4, 6, 7, 12, 12b-hexahydroindolo[2, 3-a] quinoline-3-carboxylic acid hydrochloride

[0056] ​In 100 mL round bottom flask, add 1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxylic acid (3.21 g, 10.8 mmol, 1.0 eq), add 11 mL THF and 22 mL water, add LiOH-H2O (2.27 g, 54 mmol, 5.0 eq), stir at room temperature for 12 h, after TLC test reaction is complete, adjust to pH about 3 with 2N dilute hydrochloric acid, suction filtration and washed with 10 mL water three times, oven dried to give 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxylic acid hydrochloride 2.51 g, yield 76%.

[0057] 2, Preparation of (2-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide)phenyl)carbamic acid tert-butyl ester

[0058] In 100 mL round bottom flask, add 1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxylic acid (3.21 g, 10.8 mmol, 1.0 eq), add 11 mL THF and 22 mL water, add LiOH-H2O (2.27 g, 54 mmol, 5.0 eq), stir at room temperature for 12 h, after TLC test reaction is complete, adjust to pH about 3 with 2N dilute hydrochloric acid, suction filtration and washed with 10 mL water three times, oven dried to give 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxylic acid hydrochloride 2.51 g, yield 76%.

[0059] 3, Preparation of N-(2-aminophenyl)-1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxamide

[0060] In 100 mL round bottom flask, add 1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxylic acid (3.21 g, 10.8 mmol, 1.0 eq), add 11 mL THF and 22 mL water, add LiOH-H2O (2.27 g, 54 mmol, 5.0 eq), stir at room temperature for 12 h, after TLC test reaction is complete, adjust to pH about 3 with 2N dilute hydrochloric acid, suction filtration and washed with 10 mL water three times, oven dried to give 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxylic acid hydrochloride 2.51 g, yield 76%.

[0061] 4. Preparation of 3-((2-(l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamido)phenyl)carbamoyl)phenylboronic acid (Compound 1-1)

[0062] In a 100 mL single neck flask, add 3-carboxyphenylboronic acid (111 mg, 0.67 mmol, 1.2 eq) and HATU (255 mg, 0.67 mmol, 1.2 eq), followed by DMF 10 mL and DIPEA (292 μL, 1.68 mmol, 3.0 eq), after stirring for 10 min at room temperature, finally add N-(2-aminophenyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (200 mg, 0.56 mmol, 1.0 eq), stir at room temperature overnight. After TLC detection of the reaction is complete, add about 100 mL of water to the reaction, extract with ethyl acetate three times, wash with saturated NaCl once, column chromatography (DCM:MeOH=25:1) to get white solid 92 mg, yield 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.04 (s, 1H), 9.56 (s, 1H), 8.40 (s, 1H), 8.27 (s, 2H), 8.01 (ddt, J = 11.0, 7.8, 1.3 Hz, 2H), 7.70 - 7.59 (m, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.34 - 7.20 (m, 3H), 7.04 (t, J = 8.2 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.85 (br, 1H), 3.74 (d, J = 16.3 Hz, 1H), 3.49 (s, 1H), 3.24 - 3.12 (m, 2H), 2.92 (d, J = 18.2 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.67 - 2.54 (m, 2H), 2.29 - 2.16 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.49, 165.34, 137.94, 136.68, 135.37, 133.84, 133.80, 132.98, 131.89, 131.62, 129.55, 128.13, 126.92, 126.21, 126.04, 125.99, 125.83, 121.07, 118.88, 118.10, 111.46, 107.05, 55.00, 53.62, 52.08, 31.55, 21.65. HRMS (ESI) m / z: calcd for (C 29 H28 O4N4B + H) + 507.2198; found: 507.2184.

[0063]

[0064] 5. Preparation of 3-((3-(l,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxamido)phenyl)carbamoyl)phenylboronic acid (Compound I-2)

[0065] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 3 one of the starting materials was m-phenylenediamine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give 104 mg of a white solid in 73% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.22 (s, 1H), 9.80 (s, 1H), 8.28 (s, 1H), 8.20-8.15 (m, 3H), 7.94-7.86 (m, 2H), 7.45-7.31 (m, 4H), 7.26-7.18 (m, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.78 (br, 1H), 3.69 (d, J = 16.4 Hz, 1H), 3.43 (d, J = 11.4 Hz, 1H), 3.20-3.05 (m, 2H), 2.94-2.82 (m, 1H), 2.80-2.70 (m, 1H), 2.65-2.58 (m, 1H), 2.53 (td, J = 11.3, 3.8 Hz, 1H), 2.24-2.11 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.67, 165.62, 139.89, 139.78, 137.52, 136.69, 135.51, 134.79, 133.99, 133.50, 130.96, 129.71, 128.98, 127.85, 126.95, 121.06, 118.88, 118.12, 116.19, 113.08, 111.46, 107.07, 55.19, 53.74, 52.16, 31.47, 21.71. HRMS (ESI) m / z: calcd for (C 29 H 28 O4N4B + H) + 507.2198; found: 507.2183.

[0066]

[0067] 6. Preparation of 3-((4-(1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxamido)phenyl)carbamoyl)phenylboronic acid (Compound I-3)

[0068] Prepared in the same manner as in Example 2, steps 1-4, except that in step 3 one of the starting materials was p-phenylenediamine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give 94 mg of a white solid in 66% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.24 (s, 1H), 9.82 (s, 1H), 8.36 (s, 1H), 8.25 (s, 2H), 8.01 - 7.93 (m, 2H), 7.77 - 7.62 (m, 4H), 7.50 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.97 (t, J = 7.1 Hz, 1H), 6.83 (br, 1H), 3.78 (d, J = 16.4 Hz, 1H), 3.52 (s, 1H), 3.26 - 3.15 (m, 2H), 2.96 (d, J = 17.6 Hz, 1H), 2.91 - 2.77 (m, 1H), 2.74 - 2.59 (m, 2H), 2.32 - 2.20 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.43, 165.40, 137.47, 136.72, 135.51, 135.32, 134.81, 133.89, 133.62, 130.64, 129.60, 127.85, 126.97, 121.07, 121.03, 120.86, 118.88, 118.11, 111.46, 107.09, 55.21, 53.77, 52.17, 31.48, 21.72. HRMS (ESI) m / z: calcd for (C 29 H 28 O4N4B+H) + , 507.2198; found: 507.2190.

[0069]

[0070] 7. Preparation of 3-((2-(1,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxamido)ethyl)carbamoyl)phenylboronic acid (Compound I-4)

[0071] Prepared by the same method as for example 2, steps 1-4, except that in step 3 one of the starting materials was ethylenediamine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give a white solid, 76 mg, 59% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.53 (t, J = 5.4 Hz, 1H), 8.27 (s, 1H), 8.20 (s, 2H), 8.08 (t, J = 5.5 Hz, 1H), 7.92 (dd, J = 7.3, 1.5 Hz, 1H), 7.86 (dt, J = 8.0, 1.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.64 (br, 1H), 3.68 (d, J = 16.4 Hz, 1H), 3.40 - 3.28 (m, 5H), 3.20 - 3.05 (m, 2H), 2.90 - 2.77 (m, 2H), 2.71 - 2.57 (m, 2H), 2.24 - 2.11 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.56, 166.63, 137.16, 136.67, 135.47, 134.18, 133.60, 133.04, 129.60, 129.20, 127.74, 126.90, 121.07, 118.87, 118.10, 111.45, 106.99, 55.19, 53.74, 52.15, 39.59, 39.20, 31.29, 21.62. HRMS (ESI) m / z: calcd for (C 25 H 28 O4N4B+H) + ,459.2198; found: 459.2187.

[0072]

[0073] 8. Preparation of 3-((3-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamido)propyl)carbamoyl)phenylboronic acid (Compound I-5)

[0074] Prepared by the same method as for example 2, steps 1-4, except that in step 3 one of the starting materials was propylenediamine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give a white solid, 79 mg, 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.46 (t, J = 5.7 Hz, 1H), 8.26 (s, 1H), 8.21 (s, 2H), 8.02 (t, J = 5.8 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.31 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.65 (br, 1H), 3.71 (d, J = 16.0 Hz, 1H), 3.35 - 3.26 (m, 3H), 3.25 - 3.17 (m, 4H), 2.93 - 2.78 (m, 2H), 2.74 - 2.60 (m, 2H), 2.26 - 2.15 (m, 1H), 1.77 - 1.66 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 167.33, 166.28, 137.11, 136.70, 134.30, 133.47, 129.32, 129.12, 127.76, 126.84, 121.17, 118.93, 118.15, 111.50, 106.93, 55.23, 53.59, 52.11, 37.45, 37.03, 31.05, 29.75, 21.54. HRMS (ESI) m / z: calcd for (C 26 H 30 O4N4B+H) + , 473.2355; found: 473.2347.

[0075]

[0076] 9. Preparation of 3-((4-(l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamido)butyl)carbamoyl)phenylboronic acid (Compound I-6)

[0077] Prepared in the same manner as in Example 2, steps 1-4, except that in step 3 one of the starting materials was butanediamine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give a white solid, 82 mg, in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.44 (t, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 2H), 7.96 (t, J = 5.5 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.61 (br, 1H), 3.66 (d, J = 16.4 Hz, 1H), 3.44 (s, 1H), 3.33 - 3.23 (m, 2H), 3.18 - 3.03 (m, 4H), 2.91 - 2.74 (m, 2H), 2.66 (d, J = 15.8 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.23 - 2.10 (m, 1H), 1.61 - 1.44 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 167.20, 166.32, 137.03, 136.66, 135.54, 134.40, 133.50, 133.21, 129.20, 129.15, 127.70, 126.92, 121.04, 118.85, 118.09, 111.45, 106.99, 55.21, 53.84, 52.16, 39.42, 38.95, 31.30, 27.19, 21.66. HRMS (ESI) m / z: calcd for (C 27 H 32 O4N4B+H) + ,487.2511; found: 487.2502.

[0078]

[0079] 10. Preparation of 3-(4-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carbonyl)piperazine-1 -carbonyl)phenylboronic acid (Compound I-7)

[0080] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 3 one of the starting materials was piperazine and in step 4 one of the starting materials was m-carboxyphenylboronic acid, to give 88 mg of a white solid in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.18 (s, 2H), 7.83 (dt, J = 6.9, 1.6 Hz, 1H), 7.79 (s, 1H), 7.44 - 7.37 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.99 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 5.94 (br, 1H), 3.67 - 3.39 (m, 10H), 3.20 - 3.04 (m, 2H), 2.83 - 2.72 (m, 2H), 2.66 - 2.51 (m, 2H), 2.16 - 2.03 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 170.17, 168.90, 136.66, 135.80, 135.18, 134.89, 133.01, 132.62, 129.12, 127.98, 126.90, 126.09, 121.08, 118.88, 118.10, 111.48, 106.93, 55.20, 54.55, 51.92, 47.77, 42.22, 30.70, 21.54. HRMS (ESI) m / z: calcd for (C 27 H 30 O4N4B+H) + , 485.2355; found: 485.2347.

[0081]

[0082] Example 3, Preparation of Hirsutine alkaloid derivatives modified by benzyl phenyl boronic acid compounds

[0083] This reaction example uses compound III as the starting material, hydrolysis under the condition of lithium hydroxide, then adjust pH to about 3 with 2N dilute hydrochloric acid, then condense with single Boc protected aromatic diamine or aliphatic diamine, then de-Boc, the obtained intermediate and bromobenzyl phenyl boronic acid containing or not containing substituent group perform affinity substitution reaction to obtain the Hirsutine alkaloid derivatives modified by benzyl phenyl boronic acid compounds, the preparation route is as shown in Figure 3 .

[0084] The Hirsutine alkaloid derivatives modified by benzyl phenyl boronic acid compounds described in this example have the following structure as shown in the formula:

[0085]

[0086] wherein R is selected from one of the following groups: wherein R3is o-NHCH2, m-NHCH2, p-NHCH2; or wherein n = 1, 2, 3, 4, 5, R4is H or CH3; or wherein R1is substituted at any position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN. Wherein the boronic acid group is as follows: when the boronic acid group is at the C2 position on the phenyl ring, R2is substituted at the C3 or C4 position on the phenyl ring and is selected from one of the following groups: OCH3, F, Cl; when the boronic acid group is at the C3 position on the phenyl ring, R2is substituted at the C4 or C5 position on the phenyl ring and is selected from one of the following groups: CH3, OCH3, COOH, OH, F, Cl, Br; when the boronic acid group is at the C4 position on the phenyl ring, R2is substituted at the C2 or C3 position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, OCH3, F, Cl.

[0087] 1. Preparation of 3-(((2-(l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3- carboxamido)phenyl)amino)methyl)benzeneboronic acid (Compound I-8)

[0088] In a 100 mL single neck flask, N-(2-aminophenyl)-l,4,6,7,12,12b- hexahydroindolo[2,3-a]quinoline-3-carboxamide (151 mg, 0.42 mmol, 1.5 eq) prepared by the same procedure as in Example 2, steps 1-3, m-bromobenzylic boronic acid (60 mg, 0.28 mmol, 1.0 eq), anhydrous potassium carbonate (116 mg, 0.84 mmol, 3.0 eq) were added, followed by 5 mL of DMF and stirred at room temperature for 4 h. After the reaction was complete by TLC, the reaction was poured into about 100 mL of water and extracted with ethyl acetate three times, washed with saturated NaCl once and purified by column chromatography (DCM:MeOH = 25:1) to give 90 mg of white solid with a yield of 65%. 1H NMR (400 MHz, Chloroform-d) δ 9.54 (s, 1H), 8.45 (s, 1H), 7.99 (s, 1H), 7.71 (dt, J = 6.9, 2.0 Hz, 1H), 7.66 (tt, J = 2.0, 1.0 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.34 - 7.20 (m, 5H), 7.16 - 7.07 (m, 2H), 6.99 (td, J = 7.8, 1.3 Hz, 1H), 6.93 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 (t, J = 5.3 Hz, 1H), 4.62 (dt, J = 5.3, 0.8 Hz, 2H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.97 - 3.84 (m, 2H), 3.30 - 3.17 (m, 2H), 2.99 - 2.87 (m, 2H), 2.73 (dt, J = 14.1, 4.9 Hz, 1H), 2.48 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 169.35, 138.68, 138.10, 137.54, 137.16, 136.40, 133.98, 133.27, 133.21, 130.12, 128.81, 128.74, 126.79, 123.86, 123.85, 123.72, 121.98, 121.44, 120.39, 119.08, 115.91, 111.52, 108.04, 55.23, 53.45, 52.11, 48.81, 31.53, 21.77.

[0089]

[0090] 2,4-(((2-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-carboxamide)phenyl)amino)methyl)benzeneboronic acid (Compound 1-9) was prepared according to the procedure of Example 3 for 1 except that one of the starting materials was p-bromobenzylphenylboronic acid to give 85 mg of a white solid in 62% yield.

[0091] Prepared according to the procedure of Example 3 for 1 except that one of the starting materials was p-bromobenzylphenylboronic acid to give 85 mg of a white solid in 62% yield. 1H NMR(400MHz,Chloroform-d)δ9.54(s,1H),8.47(s,1H),7.65-7.61(m,2H),7.57-7.51(m,2H), 7.35-7.25(m,4H),7.23(td,J=7.4,2.8Hz,1H),7.17-7.09(m,2H),7.03-6.92(m,2H),6.07(t, J=5.3Hz,1H),4.56(dt,J=5.4,0.9Hz,2H),4.51(td,J=4.8,1.8Hz,1H),3.97-3.84(m,2H),3.2 7-3.19(m,2H),2.94-2.88(m,2H),2.75(dt,J=14.0,5.1Hz,1H),2.48(dt,J=14.1,4.9Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ169.25,141.47,138.32,137.44,136.46,134.69,134.42,133.29,130.16,127.67,126.79,12 3.86,123.85,123.72,121.98,121.44,120.39,119.17,115.91,111.52,108.14,55.12,53.65,52.01,49.34,31.63,21.83.

[0092]

[0093] 3. Preparation of 3-(((3-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide)phenyl)amino)methyl)phenylboronic acid (compound I-10)

[0094] The preparation was carried out according to the method of Example 3,1, except that the raw material was replaced with m-bromobenzylphenylboronic acid. The N-(3-aminophenyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide was prepared by the same method as in Examples 2,1-3, to obtain 87 mg of white solid, with a yield of 63%. 1H NMR (400 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.71 (dt, J = 6.9, 2.0 Hz, 1H), 7.66 (tt, J = 2.0, 1.0 Hz, 1H), 7.57 (dd, J = 6.9, 2.4 Hz, 1H), 7.45 (dd, J = 7.9, 2.2 Hz, 1H), 7.32 - 7.20 (m, 5H), 7.18 - 7.09 (m, 2H), 6.99 (t, J = 2.1 Hz, 1H), 6.70 (dd, J = 7.7, 2.1 Hz, 1H), 5.34 (t, J = 5.3 Hz, 1H), 4.56 (dt, J = 5.2, 0.8 Hz, 2H), 4.51 (td, J = 4.9, 1.7 Hz, 1H), 3.95 - 3.80 (m, 2H), 3.32 - 3.17 (m, 2H), 2.96 - 2.87 (m, 2H), 2.78 (dt, J = 14.0, 4.6 Hz, 1H), 2.47 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 169.62, 148.17, 139.56, 138.69, 137.69, 137.17, 136.48, 134.44, 133.27, 133.21, 128.91, 128.84, 128.45, 126.79, 123.86, 122.29, 120.45, 119.12, 117.66, 112.06, 111.62, 108.13, 105.24, 55.08, 53.55, 52.02, 48.68, 31.63, 21.79.

[0095]

[0096] 4. Preparation of 3-(((4-(l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3- carboxamido)phenyl)amino)methyl)benzeneboronic acid (Compound I-11)

[0097] Prepared according to the procedure of Example 3 for 1, except that the starting material was replaced with m-bromobenzylphenylboronic acid and N-(4- aminophenyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide was prepared according to the procedure of Example 2 for 1-3 to give a white solid 92 mg in 67% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 7.0 Hz, 2H), 8.03 (s, 1H), 7.74 - 7.64 (m, 2H), 7.54 (dd, J = 6.9, 2.4 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.32 - 7.20 (m, 3H), 7.16 - 7.07 (m, 2H), 6.76 - 6.70 (m, 2H), 5.06 (t, J = 5.3 Hz, 1H), 4.55 (dt, J = 5.4, 0.9 Hz, 2H), 4.46 (td, J = 4.9, 1.7 Hz, 1H), 3.97 - 3.88 (m, 2H), 3.34 - 3.19 (m, 2H), 2.96 - 2.89 (m, 2H), 2.71 (dt, J = 14.1, 4.9 Hz, 1H), 2.53 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 169.42, 142.06, 138.68, 137.68, 137.16, 136.40, 134.39, 133.27, 133.21, 133.19, 128.81, 128.74, 126.79, 123.86, 122.19, 121.82, 120.39, 119.08, 116.05, 111.52, 108.04, 55.11, 53.55, 52.07, 48.76, 31.63, 21.73.

[0098]

[0099] 5. Preparation of 3-(((2-(l,4,6,7,12,12b-hexahydroindolo[2,3- a]quinoline-3-carboxamido)ethyl)amino)methyl)benzeneboronic acid (Compound I-12)

[0100] Prepared according to the procedure of Example 3 for 1, except that the starting material was replaced with m-bromobenzylphenylboronic acid and N-(2-aminoethyl)-l,4,6,7,12,12b- hexahydroindolo[2,3-a]quinoline-3-carboxamide was prepared according to the procedure of Example 2 for 1-3 to give a white solid 88 mg in 71% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.99 (s, 1H), 7.75-7.67 (m, 2H), 7.54 (dd, J = 6.9, 2.4 Hz, 1H), 7.32-7.24 (m, 1H), 7.28-7.20 (m, 3H), 7.20 (t, J = 5.2 Hz, 1H), 7.13 (td, J = 7.0, 2.0 Hz, 1H), 7.03 (td, J = 4.9, 1.8 Hz, 1H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.99-3.88 (m, 4H), 3.79 (dq, J = 13.6, 1.1 Hz, 1H), 3.34-3.26 (m, 3H), 3.17 (dd, J = 11.9, 6.1 Hz, 1H), 2.99-2.91 (m, 3H), 2.94-2.87 (m, 1H), 2.73 (dt, J = 13.9, 4.8 Hz, 1H), 2.48 (dt, J = 13.9, 4.8 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 171.52, 138.35, 137.28, 136.84, 136.40, 133.84, 133.32, 133.27, 128.86, 128.78, 126.79, 123.86, 122.47, 120.39, 119.08, 111.52, 108.04, 55.07, 53.47, 52.12, 49.93, 48.01, 40.10, 31.61, 21.73.

[0101]

[0102] 6. Preparation of 3-(((3-(l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3- carboxamido)propyl)amino)methyl)benzeneboronic acid (Compound I-13)

[0103] Prepared according to the procedure of Example 3 for 1, except that the starting material was replaced with m-bromobenzylphenylboronic acid and N-(3-aminopropyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide was prepared according to the procedure of Example 2 for 1-3 to give a white solid 89 mg in 69% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.99 (s, 1H), 7.75-7.67 (m, 2H), 7.54 (dd, J = 6.9, 2.4 Hz, 1H), 7.29 (dd, J = 7.0, 2.1 Hz, 1H), 7.29-7.20 (m, 3H), 7.13 (td, J = 7.0, 2.0 Hz, 1H), 7.10-7.00 (m, 2H), 4.72 (d, J = 5.3 Hz, 1H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.95 (t, J = 0.8 Hz, 1H), 3.96-3.88 (m, 2H), 3.79 (dt, J = 13.6, 1.0 Hz, 1H), 3.30-3.13 (m, 4H), 2.99-2.87 (m, 2H), 2.86 (d, J = 5.2 Hz, 2H), 2.73 (dt, J = 13.9, 4.8 Hz, 1H), 2.48 (dt, J = 13.9, 4.8 Hz, 1H), 1.71-1.63 (m, 1H). 13 CNMR (100 MHz, Chloroform-d) δ 171.91, 138.34, 137.28, 136.57, 136.40, 133.84, 133.32, 133.27, 128.86, 128.78, 126.79, 123.86, 121.56, 120.39, 119.08, 111.52, 108.04, 55.06, 53.62, 52.12, 49.93, 45.98, 39.09, 31.61, 28.40, 21.53.

[0104]

[0105] Example 4, Preparation of Hirsutine Alkaloid Derivatives Modified by Aminobenzene Boronic Acid Compounds

[0106] This reaction example uses compound III as the starting material, hydrolysis is carried out under the condition of lithium hydroxide, then pH is adjusted to about 3 by 2N dilute hydrochloric acid, and then condensation reaction is carried out with aminobenzene boronic acid compounds to obtain the Hirsutine alkaloid derivatives modified by aminobenzene boronic acid compounds, and the preparation route is as shown in Figure 4 .

[0107] The Hirsutine alkaloid derivatives modified by aminobenzene boronic acid compounds described in this example have the structure as shown in the following formula:

[0108]

[0109] wherein R is NH. R1is substituted at any position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN. Where the boronic acid group is at the C2 position on the phenyl ring, R2is substituted at the C3 or C4 position on the phenyl ring and is selected from one of the following groups: OCH3, F, Cl; where the boronic acid group is at the C3 position on the phenyl ring, R2is substituted at the C4 or C5 position on the phenyl ring and is selected from one of the following groups: CH3, OCH3, COOH, OH, F, Cl, Br; where the boronic acid group is at the C4 position on the phenyl ring, R2is substituted at the C2 or C3 position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, OCH3, F, Cl.

[0110] 1. Preparation of 3-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide)phenylboronic acid (Compound 1-14)

[0111] Prepared in the same manner as described in Example 2, steps 1-2, except that one of the starting materials in step 2 was replaced with m-aminophenylboronic acid, to give 38 mg of a white solid in 36% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.72 (s, 1H), 7.93 (s, 1H), 7.73 (dd, J = 8.2, 2.3 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.01 (t, J = 8.2 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.80 (s, 1H), 3.72 (d, J = 16.3 Hz, 1H), 3.45 (d, J = 10.8 Hz, 1H), 3.20 - 3.06 (m, 2H), 2.96 - 2.86 (m, 1H), 2.85 - 2.72 (m, 1H), 2.68 - 2.61 (m, 1H), 2.56 (td, J = 11.3, 3.9 Hz, 1H), 2.27 - 2.14 (m, 1H). 13 CNMR (100 MHz, DMSO-d6) δ 165.47, 138.70, 136.69, 135.51, 133.50, 130.77, 129.71, 127.98, 126.95, 126.89, 122.75, 121.06, 118.87, 118.11, 111.45, 107.07, 55.18, 53.75, 52.15, 31.47, 21.56. HRMS (ESI) m / z: calcd for (C 22 H 23 O3N3B+H)+ Found: 388.1827; found: 388.1822.

[0112]

[0113] 2. Preparation of 3-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide)-5-methylbenzeneboronic acid (Compound I-15)

[0114] Prepared in the same manner as described in Example 2, Step 1-2, except that one of the starting materials in Step 2 was replaced with 3-amino-5-methylbenzeneboronic acid, to give 46 mg of a white solid in 41% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.64 (s, 1H), 8.47 (s, 2H), 7.82 (t, J = 2.2 Hz, 1H), 7.55 (dd, J = 7.0, 2.5 Hz, 1H), 7.44 (t, J = 2.5 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.21 (td, J = 7.0, 2.7 Hz, 1H), 7.16 - 7.09 (m, 2H), 4.51 (td, J = 5.2, 1.9 Hz, 1H), 3.96 - 3.80 (m, 2H), 3.23 - 3.19 (m, 1H), 3.11 (ddd, J = 12.1, 6.3, 4.1 Hz, 1H), 2.95 - 2.89 (m, 2H), 2.73 (dt, J = 14.1, 4.8 Hz, 1H), 2.50 - 2.45 (m, 1H), 2.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.56, 139.89, 139.22, 138.11, 137.25, 136.25, 133.51, 128.43, 126.75, 121.90, 121.76, 121.43, 121.21, 119.20, 117.85, 110.85, 107.73, 55.18, 53.60, 52.08, 31.75, 21.11, 19.80.

[0115]

[0116] 3. Preparation of 4-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide)-3-methylbenzeneboronic acid (Compound I-16)

[0117] Prepared by the same method as for example 2, steps 1-2, except that one of the starting materials in step 2 was replaced with 4-amino-3-methoxyphenylboronic acid to give a white solid, 49 mg, 42% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.45 (s, 1H), 8.04 (s, 2H), 7.59-7.51 (m, 3H), 7.38 (d, J = 9.1 Hz, 1H), 7.29 (dd, J = 7.0, 2.1 Hz, 1H), 7.25 (td, J = 7.3, 2.5 Hz, 1H), 7.14-7.05 (m, 2H), 4.50 (td, J = 5.2, 1.8 Hz, 1H), 3.95 (dq, J = 13.5, 0.9 Hz, 1H), 3.83 (dq, J = 13.6, 1.1 Hz, 1H), 3.27-3.21 (m, 2H), 2.97-2.85 (m, 2H), 2.72 (dt, J = 14.1, 5.2 Hz, 1H), 2.46 (dt, J = 14.1, 4.9 Hz, 1H). 13 CNMR (100 MHz, Chloroform-d) δ 168.77, 140.39, 137.47, 136.35, 135.11, 133.79, 133.50, 133.33, 126.71, 126.15, 121.75, 120.52, 119.97, 119.21, 117.92, 110.87, 107.70, 55.16, 53.37, 52.02, 31.60, 21.64, 18.02.

[0118]

[0119] Preparation of 4,4-(1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide)-3-methoxyphenylboronic acid (Compound I-17)

[0120] Prepared by the same method as for example 2, steps 1-2, except that one of the starting materials in step 2 was replaced with 4-amino-3-methoxyphenylboronic acid to give a white solid, 49 mg, 42% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.45 (s, 1H), 7.75 (s, 2H), 7.56-7.50 (m, 2H), 7.47-7.40 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (td, J = 7.2, 2.6 Hz, 1H), 7.16-7.07 (m, 2H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.97 (dt, J = 13.5, 1.0 Hz, 1H), 3.89 (s, 2H), 3.84 (dt, J = 13.6, 1.0 Hz, 1H), 3.30-3.17 (m, 2H), 2.99-2.87 (m, 2H), 2.73 (dt, J = 14.1, 4.9 Hz, 1H), 2.48 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 167.83, 147.62, 137.43, 136.31, 134.06, 133.74, 132.14, 128.89, 126.73, 121.74, 121.62, 119.23, 117.88, 117.56, 116.85, 110.90, 107.71, 55.19, 53.46, 51.97, 48.09, 31.47, 20.99.

[0121]

[0122] The reaction example uses compound III as the starting material, hydrolysis is carried out under the condition of lithium hydroxide, then pH is adjusted to about 3 by 2N dilute hydrochloric acid, then condensed with mono-Boc protected aromatic diamine or aliphatic diamine, then de-Boc, the obtained intermediate is condensed with carboxybenzoborole to obtain the carboxybenzoborole modified Hirsutine alkaloid derivative, the preparation route is as shown in Figure 2

[0123] The carboxybenzoborole modified Hirsutine alkaloid derivative described in this example has the structure as shown in the following formula:

[0124]

[0125] In the formula, R can be any position on the benzoborole phenyl ring, and is selected from one of the following groups: wherein R2 is o-NHCO, m-NHCO, p-NHCO; or n = 1, 2, 3, 4, 5; or​ wherein R1is substituted at any position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0126] 1. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-7- ylcarboxamide)phenyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-1)

[0127] Prepared in the same manner as in Example 2, steps 1-4, except that in step 4 one of the starting materials was 7-carboxybenzoborole, to give 101 mg of a white solid in 35% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.40 (s, 1H), 9.43 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.51 (dd, J = 7.6, 2.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.28 - 7.13 (m, 3H), 6.96 (t, J = 7.6 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.73 (br, 1H), 5.05 (s, 2H), 3.63 (d, J = 16.3 Hz, 1H), 3.37 (d, J = 13.1 Hz, 1H), 3.12 - 3.01 (m, 2H), 2.81 (d, J = 18.4 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.64 - 2.54 (m, 1H), 2.54 - 2.45 (m, 1H), 2.12 (t, J = 14.2 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.20, 165.31, 155.18, 136.92, 136.67, 136.52, 135.39, 133.06, 132.45, 131.59, 127.55, 126.90, 126.62, 126.53, 125.81, 125.62, 125.57, 121.07, 118.86, 118.10, 111.45, 107.01, 70.80, 55.01, 53.61, 52.10, 31.51, 21.65. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + , 519.2198; found: 519.2188.

[0128]

[0129] 2. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-6-ylcarboxamide)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-2)

[0130] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 4 one of the starting materials was 6-carboxybenzoborole, to give 101 mg of a white solid in 35% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.08 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 8.37 (s, 1H), 8.08 (dd, J = 8.0, 1.8 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.62 - 7.57 (m, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.34 - 7.24 (m, 3H), 7.04 (t, J = 6.9 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.84 (br, 1H), 5.09 (s, 2H), 3.74 (d, J = 16.3 Hz, 1H), 3.48 (d, J = 9.4 Hz, 1H), 3.24 - 3.11 (m, 2H), 2.98 - 2.85 (m, 1H), 2.85 - 2.74 (m, 1H), 2.67 (dd, J = 15.1, 3.6 Hz, 1H), 2.58 (td, J = 11.3, 3.9 Hz, 1H), 2.29 - 2.15 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.21, 165.43, 158.06, 136.67, 135.39, 133.53, 133.02, 131.88, 131.71, 131.65, 130.53, 130.27, 126.92, 126.34, 126.06, 125.87, 122.15, 121.06, 118.87, 118.10, 111.45, 107.05, 70.52, 55.00, 53.65, 52.09, 31.57, 21.67. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2185.

[0131]

[0132] 3. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborol-5-ylcarboxamide)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-3)

[0133] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 4 one of the starting materials was 5-carboxybenzoborole, to give 112 mg of a white solid in 39% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.10 (s, 1H), 9.58 (s, 1H), 9.44 (s, 1H), 7.98 (s, 1H), 7.97-7.86 (m, 2H), 7.65 (m, 1H), 7.64-7.55 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.34-7.22 (m, 3H), 7.04 (t, J = 7.0 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.85 (bs, 1H), 5.10 (s, 2H), 3.75 (d, J = 16.3 Hz, 1H), 3.54-3.47 (d, J = 12 Hz 1H), 3.24-3.12 (m, 2H), 2.93 (m, 1H), 2.88-2.75 (m, 1H), 2.72-2.55 (m, 2H), 2.30-2.17 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.17, 165.49, 154.68, 136.86, 136.72, 135.46, 133.08, 131.96, 131.78, 131.60, 131.22, 126.97, 126.66, 126.33, 126.18, 125.93, 121.12, 121.09, 118.92, 118.16, 111.51, 107.10, 70.49, 55.08, 53.75, 52.18, 31.65, 21.75. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2190.

[0134]

[0135] 4. Preparation of N-(3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-7-ylformamido)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-4)

[0136] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was the mono-Boc protected m-phenylenediamine and in step 4 one of the starting materials was 7-carboxybenzoborole, to give 94 mg of white solid in 32% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.75 (s, 1H), 9.91 (s, 1H), 8.30 (s, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.49 (dd, J = 7.9, 2.1 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.86 (br, 1H), 5.12 (s, 2H), 3.77 (d, J = 16.4 Hz, 1H), 3.50 (dd, J = 10.6, 3.4 Hz, 2H), 3.25 - 3.12 (m, 2H), 3.02 - 2.90 (m, 1H), 2.88 - 2.78 (m, 1H), 2.73 - 2.66 (m, 1H), 2.60 (td, J = 11.3, 3.9 Hz, 1H), 2.33 - 2.19 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.33, 165.66, 155.03, 139.94, 139.41, 137.39, 136.69, 135.53, 133.49, 131.45, 131.05, 129.13, 128.07, 126.95, 125.31, 121.05, 118.87, 118.11, 116.55, 116.21, 113.15, 111.46, 107.08, 70.72, 55.18, 53.75, 52.16, 31.48, 21.72. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2189.

[0137]

[0138] 5. Preparation of N-(3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-6-ylformamido)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-5)

[0139] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was the mono-Boc protected m-phenylenediamine and in step 4 one of the starting materials was 6-carboxybenzoborole, to give 130 mg of a white solid in 46% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.32 (s, 1H), 9.84 (s, 1H), 9.36 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.03 (dd, J = 8.0, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 8.0, 2.1 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.30 - 7.23 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.81 (br, 1H), 5.05 (s, 2H), 3.73 (d, J = 16.2 Hz, 1H), 3.46 (d, J = 12.4 Hz, 1H), 3.19 - 3.10 (m, 2H), 2.96 - 2.88 (m, 1H), 2.84 - 2.75 (m, 1H), 2.68 - 2.62 (m, 1H), 2.57 (td, J = 11.2, 3.9 Hz, 1H), 2.29 - 2.15 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.45, 165.70, 157.71, 139.95, 139.87, 136.77, 135.59, 134.53, 133.59, 131.03, 130.72, 130.63, 129.07, 127.02, 121.92, 121.13, 118.94, 118.18, 116.29, 116.25, 113.16, 111.52, 107.15, 70.56, 55.25, 53.81, 52.22, 31.54, 21.78. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2185.

[0140]

[0141] 6. Preparation of N-(3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-5-ylcarboxamide)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-6)

[0142] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was the mono-Boc protected m-phenylenediamine and in step 4 one of the starting materials was 5-carboxybenzoborole, to give 120 mg of a white solid in 41% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.30 (s, 1H), 9.81 (s, 1H), 9.34 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.28 - 7.17 (m, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.78 (br, 1H), 5.02 (s, 2H), 3.69 (d, J = 16.4 Hz, 1H), 3.42 (d, J = 10.6 Hz, 1H), 3.20 - 3.05 (m, 2H), 2.88 (d, J = 17.7 Hz, 1H), 2.81 - 2.70 (m, 1H), 2.61 (d, J = 14.3 Hz, 1H), 2.57 - 2.47 (m, 1H), 2.18 (t, J = 14.5 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.19, 165.63, 154.41, 139.82, 139.73, 137.59, 136.69, 135.53, 133.51, 130.98, 130.92, 129.02, 126.95, 126.84, 121.09, 121.06, 118.87, 118.11, 116.35, 116.21, 113.11, 111.45, 107.08, 70.46, 55.19, 53.74, 52.16, 31.48, 21.72. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2189.

[0143]

[0144] 7. Preparation of N-(4-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-6-ylcarboxamide)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-7)

[0145] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected p-phenylenediamine and in step 4 one of the starting materials was 6-carboxybenzoborole, to give 101 mg of a white solid in 35% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.23 (s, 1H), 9.74 (s, 1H), 9.32 (s, 1H), 8.25 (s, 1H), 7.98 (dd, J = 8.0, 1.7 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.62 - 7.57 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 8.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.76 (br, 1H), 5.01 (s, 2H), 3.68 (d, J = 18.0 Hz, 1H), 3.41 (d, J = 12.9 Hz, 1H), 3.17 - 3.03 (m, 2H), 2.91 - 2.84 (m, 1H), 2.81 - 2.71 (m, 1H), 2.65 - 2.58 (m, 1H), 2.53 (td, J = 11.2, 3.9 Hz, 1H), 2.23 - 2.14 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 166.10, 165.41, 157.58, 136.69, 135.54, 135.35, 135.27, 134.46, 133.62, 130.68, 130.54, 130.47, 126.95, 121.87, 121.05, 121.02, 120.91, 120.85, 118.87, 118.11, 111.45, 107.08, 70.49, 55.19, 53.77, 52.16, 31.48, 21.72. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2191.

[0146]

[0147] 8. Preparation of N-(4-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxol-5-ylcarboxamide)phenyl)- 1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-8)

[0148] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected p-phenylenediamine and in step 4 one of the starting materials was 5-carboxybenzoborole, to give 97 mg of white solid in 33% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.33 (s, 1H), 9.84 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 9.1 Hz, 2H), 7.69 (d, J = 9.1 Hz, 2H), 7.41 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.84 (br, 1H), 5.10 (s, 2H), 3.78 (d, J = 16.4 Hz, 1H), 3.55-3.32 (m, 2H), 3.25-3.18 (m, 1H), 3.03-2.91 (m, 1H), 2.89-2.78 (m, 1H), 2.73-2.67 (m, 1H), 2.62 (td, J = 11.2, 3.8 Hz, 1H), 2.31-2.20 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 165.94, 165.40, 154.43, 137.63, 136.70, 135.49, 135.44, 135.13, 133.55, 130.94, 130.71, 126.94, 126.76, 121.08, 121.00, 120.86, 118.88, 118.12, 111.46, 107.06, 70.46, 55.20, 53.73, 52.15, 31.44, 21.54. HRMS (ESI) m / z: calcd for (C 30 H 28 O4N4B+H) + ,519.2198; found: 519.2191.

[0149]

[0150] 9. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-7- carboxamido)ethyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-9)

[0151] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected ethylenediamine and in step 4 one of the starting materials was 7-carboxybenzoborole, to give 111 mg of a white solid in 42% yield. 1 H NMR (400 MHz, CD3OD) δ 7.76 (dd, J = 6.7, 1.9 Hz, 1H), 7.44 (dd, J = 7.8, 1.0 Hz, 1H), 7.37 - 7.28 (m, 3H), 7.11 (ddt, J = 8.1, 7.0, 1.0 Hz, 1H), 7.01 (ddt, J = 8.0, 7.1, 0.9 Hz, 1H), 6.91 (br, 1H), 4.93 (s, 2H), 4.30 - 4.18 (m, 2H), 3.73 (d, J = 16.4 Hz, 1H), 3.66 (dd, J = 11.7, 5.1 Hz, 1H), 3.58 - 3.47 (m, 4H), 3.23 (td, J = 11.7, 4.6 Hz, 1H), 3.17 - 3.03 (m, 2H), 2.95 (dd, J = 15.9, 4.4 Hz, 1H), 2.56 - 2.46 (m, 1H). 13 C NMR (100 MHz, CD3OD) δ 171.15, 166.53, 149.92, 137.25, 135.26, 130.06, 129.97, 129.48, 127.74, 126.14, 125.47, 124.59, 121.87, 119.14, 117.74, 110.99, 106.21, 68.67, 55.79, 52.16, 51.78, 39.63, 39.32, 29.04, 19.49. HRMS (ESI) m / z: calcd for (C 26 H 28 O4N4B+H) + , 471.2198; found: 417.2187.

[0152]

[0153] 10. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-6- carboxamido)ethyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-10)

[0154] Prepared by the same method as in example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected ethylenediamine and in step 4 one of the starting materials was 6-carboxybenzoborole to give a white solid 156 mg in 59% yield. 1 H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.89 (dd, J = 8.0, 1.7 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.06 (ddd, J = 8.2, 7.1, 1.3 Hz, 1H), 6.98 (td, J = 7.5, 1.0 Hz, 1H), 6.72 (br, 1H), 5.06 (s, 2H), 3.84-3.75 (m, 1H), 3.69-3.59 (m, 1H), 3.58-3.48 (m, 4H), 3.35-3.31 (m, 1H), 3.29-3.24 (m, 1H), 3.05-2.85 (m, 2H), 2.84-2.71 (m, 2H), 2.42-2.29 (m, 1H). 13 CNMR (100 MHz, CD3OD) δ 169.52, 167.76, 156.93, 136.96, 133.04, 132.78, 131.50, 130.17, 129.28, 128.67, 126.56, 121.03, 121.00, 118.59, 117.41, 110.64, 106.68, 70.63, 55.20, 52.70, 52.11, 39.39, 39.16, 30.17, 20.47. HRMS (ESI) m / z: calcd for (C 26 H 28 O4N4B+H) + , 471.2198; found: 417.2188.

[0155]

[0156] 11. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-5- ylcarbamoyl)ethyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-11)

[0157] Prepared by the same method as in example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected ethylenediamine and in step 4 one of the starting materials was 5-carboxybenzoborole to give a white solid 156 mg in 59% yield. 1H NMR (400 MHz, CD3OD) δ 7.78-7.66 (m, 3H), 7.39 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.06 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.98 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.71 (br, 1H), 5.07 (s, 2H), 3.84-3.75 (m, 1H), 3.69-3.62 (m, 1H), 3.58-3.47 (m, 4H), 3.35-3.31 (m, 1H), 3.30-3.24 (m, 1H), 3.05-2.86 (m, 2H), 2.83-2.71 (m, 2H), 2.43-2.30 (m, 1H). 13 C NMR (100 MHz, CD3OD) δ 169.41, 167.77, 153.61, 136.97, 136.09, 132.78, 131.52, 130.17, 129.91, 126.57, 125.55, 121.00, 119.66, 118.58, 117.40, 110.63, 106.69, 70.59, 55.21, 52.70, 52.11, 39.45, 39.12, 30.19, 20.48. HRMS (ESI) m / z: calcd for (C 26 H 28 O4N4B+H) + , 471.2198; found: 417.2191.

[0158]

[0159] 12. Preparation of N-(2-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-4- carboxamido)ethyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-12)

[0160] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected ethylenediamine and in step 4 one of the starting materials was 4-carboxybenzoborole to give 131 mg of white solid in 50% yield. 1H NMR (400 MHz, CD3OD) δ 7.81 - 7.73 (m, 2H), 7.44 - 7.32 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.05 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.97 (td, J = 7.4, 1.1 Hz, 1H), 6.70 (br, 1H), 5.32 (s, 2H), 3.80 - 3.71 (m, 1H), 3.58 - 3.43 (m, 5H), 3.28 - 3.13 (m, 2H), 3.01 - 2.82 (m, 2H), 2.77 - 2.61 (m, 2H), 2.41 - 2.27 (m, 1H). 13 C NMR (100 MHz, CD3OD) δ 168.77, 167.75, 153.69, 136.93, 132.93, 131.56, 130.25, 128.43, 128.04, 127.08, 126.60, 120.98, 118.59, 117.43, 110.67, 106.71, 71.92, 55.11, 52.72, 52.07, 39.25, 30.22, 20.52. HRMS (ESI) m / z: calcd for (C 26 H 28 O4N4B+H) + , 471.2198; found: 417.2188.

[0161]

[0162] 13. Preparation of N-(3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-6- carboxamido)propyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-13)

[0163] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected propylenediamine and in step 4 one of the starting materials was 6-carboxybenzoborole, to give 134 mg of a white solid in 49% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.58 (t, J = 5.7 Hz, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.04 (t, J = 5.7 Hz, 1H), 7.93 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.62 (br, 1H), 5.00 (s, 2H), 3.61 (d, J = 16.4 Hz, 1H), 3.37 (d, J = 11.7 Hz, 1H), 3.31 - 3.22 (m, 2H), 3.19 - 3.07 (m, 3H), 3.00 (d, J = 16.5 Hz, 1H), 2.87 - 2.71 (m, 2H), 2.61 (d, J = 16.9 Hz, 1H), 2.54 - 2.48 (m, 1H), 2.11 (t, J = 14.6 Hz, 1H). 1.73 - 1.61 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 167.01, 166.42, 157.14, 136.68, 135.62, 134.05, 133.20, 130.18, 130.12, 129.94, 129.41, 126.92, 121.70, 120.97, 118.80, 118.05, 111.46, 106.95, 70.41, 55.21, 53.87, 52.18, 37.43, 36.94, 31.40, 29.65, 21.71. HRMS (ESI) m / z: calcd for (C 27 H 30 O4N4B+H) + ,485.2355; found: 485.2343.

[0164]

[0165] 14. Preparation of N-(3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-5- carboxamido)propyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-14)

[0166] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected propylenediamine and in step 4 one of the starting materials was 5-carboxybenzoborole to give 126 mg of a white solid in 46% yield.1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.65 (t, J = 5.5 Hz, 1H), 8.21 (s, 1H), 8.06 (t, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.03 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 6.95 (td, J = 7.4, 1.1 Hz, 1H), 6.65 (br, 1H), 5.04 (s, 2H), 3.66 (d, J = 16.4 Hz, 1H), 3.44 (d, J = 13.1 Hz, 1H), 3.35 - 3.26 (m, 2H), 3.24 - 3.12 (m, 3H), 3.09 - 3.02 (m, 1H), 2.92 - 2.76 (m, 2H), 2.69 - 2.63 (m, 1H), 2.56 (td, J = 11.3, 4.0 Hz, 1H), 2.23 - 2.09 (m, 1H), 1.77 - 1.65 (m, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.82, 166.40, 154.40, 137.20, 136.68, 135.53, 133.14, 130.90, 129.41, 126.91, 126.25, 121.00, 120.57, 118.82, 118.06, 111.46, 106.95, 70.38, 55.21, 53.83, 52.16, 37.48, 36.94, 31.35, 29.61, 21.66. HRMS (ESI) m / z: calcd for (C 27 H 30 O4N4B+H) + ,485.2355; found: 485.2343.

[0167]

[0168] 15. Preparation of N-(4-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-6- carboxamido)butyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-15)

[0169] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected butanediamine and in step 4 one of the starting materials was 6-carboxybenzoborole to give 150 mg of white solid in 53% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.27 (s, 1H), 8.46 (t, J = 5.6 Hz, 1H), 8.18 (s, 1H), 7.96 - 7.85 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.99 (ddd, J = 8.1, 7.0, 1.3 Hz, 1H), 6.91 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.56 (br, 1H), 4.99 (s, 2H), 3.60 (d, J = 16.8 Hz, 1H), 3.36 (d, J = 10.1 Hz, 1H), 3.29 - 3.20 (m, 2H), 3.15 - 3.07 (m, 3H), 3.04 - 2.95 (m, 1H), 2.83 - 2.71 (m, 2H), 2.65 - 2.58 (m, 1H), 2.55 - 2.47 (m, 1H), 2.16 - 2.06 (m, 1H), 1.55 - 1.42 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 166.93, 166.33, 157.09, 136.66, 135.62, 134.15, 133.28, 130.12, 129.97, 129.18, 126.93, 121.67, 121.00, 118.83, 118.07, 111.43, 107.00, 70.43, 55.20, 53.89, 52.17, 39.47, 38.94, 31.36, 27.21, 27.16, 21.71. HRMS (ESI) m / z: calcd for (C 28 H 32 O4N4B+H) + , 499.2511; found: 499.2501.

[0170]

[0171] 16. Preparation of N-(4-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborolan-5- carboxamido)butyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-16)

[0172] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was mono-Boc protected butanediamine and in step 4 one of the starting materials was 5-carboxybenzoborole to give 121 mg of a white solid in 43% yield. 1H NMR (400 MHz, CD3OD) δ 7.77-7.68 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.06 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 6.98 (td, J = 7.5, 1.0 Hz, 1H), 6.69 (br, 1H), 5.06 (s, 2H), 3.83-3.74 (m, 1H), 3.68-3.60 (m, 1H), 3.45-3.37 (m, 2H), 3.32-3.28 (m, 4H), 3.06-2.85 (m, 2H), 2.83-2.70 (m, 2H), 2.43-2.29 (m, 1H), 1.73-1.57 (m, 4H). 13 C NMR (100 MHz, CD3OD) δ 169.01, 167.39, 153.57, 136.97, 136.30, 132.84, 131.67, 129.90, 129.78, 126.58, 125.49, 120.99, 119.60, 118.58, 117.40, 110.64, 106.70, 70.56, 55.22, 52.77, 52.12, 39.29, 38.83, 30.18, 26.53, 26.51, 20.50. HRMS (ESI) m / z: calcd for (C 28 H 32 O4N4B+H) + , 499.2511; found: 499.2497.

[0173]

[0174] 17. Preparation of (1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-yl)(4-(1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-carbonyl)piperazin-1-yl)methanone (Compound II-17)

[0175] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was a mono-Boc protected piperazine and in step 4 one of the starting materials was 7-carboxybenzoborole to give 131 mg of a white solid in 47% yield. 1HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.01 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.97 (br, 1H), 5.04 (s, 2H), 3.71-3.45 (m, 8H), 3.23-3.07 (m, 4H), 2.85-2.76 (m, 2H), 2.70-2.53 (m, 2H), 2.20-2.09 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 169.24, 168.90, 154.66, 139.36, 136.66, 131.52, 127.91, 126.90, 126.05, 125.21, 122.49, 121.07, 118.87, 118.10, 111.48, 106.93, 70.43, 55.17, 54.53, 51.89, 47.24, 41.90, 30.70, 21.54. HRMS (ESI) m / z: calcd for (C 28 H 30 O4N4B+H) + ,497.2355; found: 497.2344.

[0176]

[0177] 18. Preparation of (1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-yl)(4-(1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)piperazin-1-yl)methanone (Compound II-18)

[0178] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was a mono-Boc protected piperazine and in step 4 one of the starting materials was 6-carboxybenzoborole to give 158 mg of a white solid in 57% yield. 1HNMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.36 (s, 1H), 7.79 (s, 1H), 7.54 (dd, J = 7.9, 1.6 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.98 (br, 1H), 5.04 (s, 2H), 3.71 - 3.43 (m, 10H), 3.18 - 3.08 (m, 2H), 2.87 - 2.74 (m, 2H), 2.66 (dd, J = 15.0, 3.9 Hz, 1H), 2.58 - 2.51 (m, 1H), 2.14 (t, J = 14.2 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 170.02, 168.96, 155.75, 136.68, 135.53, 134.76, 132.74, 131.06, 130.01, 129.72, 126.95, 126.09, 122.01, 121.02, 118.85, 118.07, 111.47, 106.97, 70.45, 55.20, 54.64, 51.94, 47.73, 42.38, 30.79, 21.64. HRMS (ESI) m / z: calcd for (C 28 H 30 O4N4B+H) + ,497.2355; found: 497.2344.

[0179]

[0180] 19. Preparation of (1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-yl)(4-(1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-ylcarbonyl)piperazin-1-yl)methanone (Compound II-19)

[0181] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was a mono-Boc protected piperazine and in step 4 one of the starting materials was 5-carboxybenzoborole, to give 154 mg of a white solid in 55% yield. 1HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.93 (br, 1H), 4.99 (s, 2H), 3.65-3.31 (m, 10H), 3.15-3.03 (m, 2H), 2.82-2.69 (m, 2H), 2.66-2.57 (m, 1H), 2.54-2.48 (m, 1H), 2.15-2.03 (m, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 169.73, 168.95, 154.49, 138.20, 136.66, 135.57, 132.77, 131.08, 126.94, 126.06, 126.01, 121.01, 120.45, 118.83, 118.07, 111.46, 106.96, 70.41, 55.18, 54.66, 51.93, 47.57, 42.17, 30.81, 21.64. HRMS (ESI) m / z: calcd for (C 28 H 30 O4N4B+H) + , 497.2355; found: 497.2343.

[0182]

[0183] 20. Preparation of (1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-yl)(4-(1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-carbonyl)piperazin-1-yl)methanone (Compound II-20)

[0184] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was a mono-Boc protected piperazine and in step 4 one of the starting materials was 4-carboxybenzoborole, to give 116 mg of a white solid in 41% yield. 1HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.85 (dd, J = 6.2, 2.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.98 (br, 1H), 5.03 (s, 2H), 3.74-3.33 (m, 10H), 3.21-3.07 (m, 2H), 2.87-2.75 (m, 2H), 2.66 (d, J = 14.6 Hz, 1H), 2.59-2.53 (m, 1H), 2.16 (t, J = 14.3 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6) δ 168.95, 168.29, 151.93, 136.67, 135.55, 132.74, 132.18, 129.64, 128.95, 127.53, 126.95, 126.08, 121.02, 118.85, 118.08, 111.46, 106.98, 69.56, 55.18, 54.64, 51.93, 47.29, 42.08, 30.80, 21.55. HRMS (ESI) m / z: calcd for (C 28 H 30 O4N4B+H) + , 497.2355; found: 497.2341.

[0185]

[0186] 21. Preparation of (1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolin-3-yl)((S)-4-(1- hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-methylpiperazin-1-yl)methanone (Compound II-21)

[0187] Prepared in the same manner as described in Example 2, steps 1-4, except that in step 2 one of the starting materials was the mono-Boc protected (S)-2-methylpiperazine and in step 4 one of the starting materials was 6-carboxybenzoborole to give 123 mg of a white solid in 43% yield. 1H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.53-7.38 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.09 (s, 1H), 5.07 (s, 2H), 4.78-4.33 (m, 2H), 4.15-4.00 (m, 2H), 3.81-3.66 (m, 2H), 3.58 (d, J = 16.6 Hz, 1H), 3.50-3.37 (m, 2H), 3.24-3.13 (m, 1H), 3.10-2.94 (m, 4H), 2.86 (d, J = 12.4 Hz, 1H), 2.41 (t, J = 14.8 Hz, 1H), 1.35-1.23 (m, 3H). 13 C NMR (100 MHz, CD3OD) δ 172.61, 168.78, 155.57, 137.12, 133.79, 131.24, 130.58, 130.42, 129.11, 128.44, 126.36, 125.98, 121.55, 121.49, 118.95, 117.65, 110.90, 106.44, 70.80, 60.23, 55.58, 54.44, 52.87, 51.96, 45.98, 42.42, 29.01, 19.93, 14.50. HRMS (ESI) m / z: calcd for (C 29 H 32 O4N4B+H) + , 511.2511; found: 511.2502.

[0188]

[0189] The reaction example uses compound III as the starting material, hydrolysis is carried out under the condition of lithium hydroxide, then pH is adjusted to about 3 by 2N dilute hydrochloric acid, then the obtained intermediate is condensed with mono-Boc protected aromatic diamine or aliphatic diamine, then Boc is removed, and the obtained intermediate is condensed with bromobenzylbenzoborole to obtain the benzylbenzoborole modified Hirsutine alkaloid derivative, and the preparation route is as shown in Figure 3 .

[0190] The benzylbenzoborole modified Hirsutine alkaloid derivative described in the example has the following structure:

[0191]

[0192] wherein R can be at any position on the benzoboroxole phenyl ring and is selected from one of the following groups: wherein R2is o-NHCH2, m-NHCH2, p-NHCH2; or wherein n = 1, 2, 3, 4, 5, R3is H or CH3; or wherein R1is substituted at any position on the phenyl ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0193] 1. Preparation of N-(2-(((1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborol-6-yl)methyl)amino)phenyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-22)

[0194] Prepared in the same manner as for Step 1 of Example 3, except that the starting material was replaced with 6-bromomethylbenzoboroxole, to give 61 mg of a white solid in 43% yield. 1 H NMR (400 MHz, Chloroform-d) δ 9.56 (s, 1H), 8.43 (s, 1H), 7.56 - 7.48 (m, 2H), 7.43 (dt, J=1.6, 0.8 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.25 (td, J=7.2, 2.6 Hz, 1H), 7.15 - 7.05 (m, 3H), 7.01 (td, J=7.9, 1.4 Hz, 1H), 6.93 (dd, J=8.0, 1.3 Hz, 1H), 6.38 (s, 1H), 6.31 (t, J=5.3 Hz, 1H), 5.21 (d, J=0.9 Hz, 2H), 4.64 (dt, J=5.5, 1.1 Hz, 2H), 4.52 (td, J=4.9, 1.7 Hz, 1H), 4.01 (dq, J=13.3, 1.1 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.26 - 3.14 (m, 2H), 3.01 - 2.89 (m, 2H), 2.75 (dt, J=14.1, 5.1 Hz, 1H), 2.51 (dt, J=14.1, 4.9 Hz, 1H). 13CNMR (100 MHz, Chloroform-d) δ 168.16, 142.74, 141.39, 141.22, 137.80, 137.28, 136.31, 133.74, 130.90, 130.48, 128.67, 126.73, 124.89, 122.31, 122.25, 121.74, 121.28, 121.01, 119.23, 117.88, 115.03, 110.90, 107.71, 68.13, 55.07, 53.55, 52.12, 48.06, 31.70, 21.72.

[0195]

[0196] 2. Preparation of N-(2-(((l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborol-5- yl)methyl)amino)phenyl)-l,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3- carboxamide (Compound II-23)

[0197] Prepared in the same manner as the procedure for 1 of Example 3, except that the starting material was replaced with 5-bromomethylbenzoborole, to give 62 mg of white solid, yield 44%.

[0198] 1 H NMR (400 MHz, Chloroform-d) δ 9.54 (s, 1H), 8.47 (s, 1H), 7.56 - 7.48 (m, 2H), 7.41 - 7.22 (m, 4H), 7.15 - 7.06 (m, 3H), 6.99 - 6.92 (m, 2H), 6.59 - 6.54 (m, 2H), 5.11 (d, J = 1.1 Hz, 2H), 4.62 (dt, J = 5.3, 0.9 Hz, 2H), 4.53 (td, J = 4.9, 1.7 Hz, 1H), 3.95 - 3.83 (m, 2H), 3.27 - 3.14 (m, 2H), 2.97 - 2.89 (m, 2H), 2.74 (dt, J = 14.1, 4.8 Hz, 1H), 2.48 (dt, J = 14.1, 4.9 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ 168.18, 143.61, 142.71, 139.16, 137.73, 137.31, 136.31, 133.74, 130.91, 130.52, 126.75, 125.94, 123.63, 122.31, 122.25, 121.77, 121.32, 121.03, 119.23, 117.85, 115.01, 110.90, 107.71, 68.15, 55.06, 53.58, 52.13, 48.06, 31.60, 21.64.

[0199]

[0200] 3. Preparation of N-(2-(((1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborol-5-yl)methyl)amino)ethyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-24)

[0201] Prepared in the same manner as in Step 1 of Example 3, except that the starting material was replaced with 5-bromomethylbenzoborole and N-(2-aminoethyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide prepared in the same manner as in Steps 1-3 of Example 2, to give a white solid 61 mg, yield 48%. 1 H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.53 (dd, J = 7.2, 2.4 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.31 (dd, J = 7.1, 2.2 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.15 (td, J = 7.1, 2.2 Hz, 1H), 7.08 - 7.00 (m, 2H), 6.58 (s, 1H), 5.12 (d, J = 0.7 Hz, 2H), 4.53 (td, J = 5.1, 1.8 Hz, 1H), 4.00 - 3.95 (m, 1H), 3.95 - 3.88 (m, 3H), 3.79 (dt, J = 13.6, 4.1 Hz, 1H), 3.32 - 3.18 (m, 2H), 2.99 - 2.89 (m, 3H), 2.94 - 2.87 (m, 1H), 2.73 (dt, J = 13.9, 4.8 Hz, 1H), 2.48 (dt, J = 13.9, 4.8 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ 170.76, 143.21, 142.65, 139.19, 136.58, 136.29, 133.74, 131.07, 126.73, 126.04, 123.13, 121.84, 121.74, 119.23, 117.92, 110.93, 107.70, 68.13, 55.05, 53.62, 52.16, 48.17, 47.70, 39.47, 31.55, 21.67.

[0202]

[0203] 4. Preparation of N-(2-(((1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborol-6-yl)methyl)amino)ethyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-25)

[0204] Prepared in the same manner as in Step 1 of Example 3, except that the starting material was replaced with 6-bromomethylbenzoborole and N-(2-aminoethyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide prepared in the same manner as in Steps 1-3 of Example 2, to give a white solid 60 mg, yield 47%. 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.54 (dd, J = 6.9, 2.4 Hz, 1H), 7.40 (dt, J = 2.0, 0.9 Hz, 1H), 7.32 - 7.17 (m, 3H), 7.16 - 7.08 (m, 2H), 7.08 - 7.00 (m, 2H), 6.41 (s, 1H), 5.22 (d, J = 1.0 Hz, 2H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.96 (s, 2H), 3.99 - 3.92 (m, 1H), 3.91 (dt, J = 13.5, 4.5 Hz, 1H), 3.79 (dt, J = 13.6, 4.5 Hz, 1H), 3.33 - 3.29 (m, 1H), 3.32 - 3.24 (m, 2H), 3.16 (ddd, J = 12.1, 6.2, 4.0 Hz, 1H), 2.99 - 2.87 (m, 4H), 2.73 (dt, J = 13.9, 4.8 Hz, 1H), 2.48 (dt, J = 13.9, 4.8 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ 170.86, 142.23, 141.42, 141.27, 136.60, 136.34, 133.74, 131.45, 128.73, 126.73, 124.81, 121.82, 121.73, 119.23, 117.91, 110.92, 107.71, 68.13, 55.24, 53.71, 52.16, 48.17, 47.71, 39.47, 31.52, 21.54.

[0205]

[0206] 5. Preparation of N-(3-(((1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborol-6-yl)methyl)amino)propyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-26)

[0207] Prepared in the same manner as in Step 1 of Example 3, except that the starting material was replaced with 6-bromomethylbenzoborole and N-(3-aminopropyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide prepared in the same manner as in Steps 1-3 of Example 2, to give 47 mg of a white solid, yield 43%. 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.44 (dd, J = 6.7, 2.5 Hz, 1H), 7.40 (dt, J = 2.3, 1.1 Hz, 1H), 7.35 (dd, J = 7.0, 2.1 Hz, 1H), 7.26 - 7.24 (m, 1H), 7.16 - 7.01 (m, 5H), 6.45 (s, 1H), 5.26 (d, J = 1.2 Hz, 2H), 4.82 (d, J = 5.2 Hz, 1H), 4.55 (td, J = 5.1, 1.9 Hz, 1H), 4.04 (dt, J = 5.6, 1.1 Hz, 2H), 3.97 - 3.82 (m, 2H), 3.31 (ddd, J = 11.8, 5.7, 4.1 Hz, 1H), 3.20 - 3.11 (m, 3H), 2.93 - 2.80 (m, 4H), 2.72 (dt, J = 14.0, 4.8 Hz, 1H), 2.52 (dt, J = 13.9, 4.7 Hz, 1H), 1.71 - 1.69 (m, 1H). 13C NMR (100 MHz, Chloroform-d) δ 171.17, 142.32, 141.46, 141.22, 136.61, 136.39, 133.73, 131.45, 128.72, 126.75, 124.79, 121.72, 120.79, 119.23, 117.93, 110.92, 107.74, 68.13, 55.14, 53.63, 52.06, 48.37, 45.14, 39.12, 31.55, 28.17, 21.71.

[0208]

[0209] 6. Preparation of N-(3-(((1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborol-5-yl)methyl)amino)propyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-27)

[0210] Prepared in the same manner as in Step 1 of Example 3, except that the starting material was replaced with 5-bromomethylbenzoborole and N-(3-aminopropyl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide prepared in the same manner as in Steps 1-3 of Example 2, to give a white solid 61 mg, yield 47%. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.48 (dd, J = 7.3, 2.3 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.31 (dd, J = 6.8, 2.5 Hz, 1H), 7.28 (td, J = 7.2, 2.6 Hz, 1H), 7.23 (td, J = 7.0, 2.3 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.68 (s, 1H), 5.10 (d, J = 5.9 Hz, 2H), 4.62 (d, J = 5.5 Hz, 1H), 4.44 (td, J = 4.7, 1.5 Hz, 1H), 3.95 - 3.85 (m, 3H), 3.82 (dt, J = 13.8, 5.4 Hz, 1H), 3.28 (ddd, J = 12.5, 5.9, 4.4 Hz, 1H), 3.20 - 3.09 (m, 3H), 2.99 - 2.80 (m, 4H), 2.75 (dt, J = 14.2, 4.6 Hz, 1H), 2.43 (dt, J = 13.9, 4.8 Hz, 1H), 1.71 - 1.69 (m, 1H). 13C NMR (100 MHz, Chloroform-d) δ 171.04, 143.22, 142.65, 139.19, 136.55, 136.36, 133.74, 131.08, 126.73, 126.27, 123.02, 121.84, 120.86, 119.27, 117.97, 110.87, 107.71, 68.13, 55.13, 53.64, 52.06, 48.39, 45.16, 39.10, 31.42, 28.19, 21.89.

[0211]

[0212] Example 7, Preparation of Amino-benzoboroxole-modified Hirsutine alkaloid derivatives This reaction example uses compound III as starting material, hydrolysis under the condition of lithium hydroxide, pH is adjusted to about 3 by 2N dilute hydrochloric acid, then amino-benzoboroxole compound condensation reaction, to obtain the amino-benzoboroxole-modified Hirsutine alkaloid derivatives, preparation route as shown in Figure 4

[0213] The amino-benzoboroxole-modified Hirsutine alkaloid derivatives described in this example are shown in the following formula:

[0214]

[0215] In the formula, R is NH; R1 is substituted at any position on the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

[0216] 1. Preparation of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]dioxaborolan-6-yl)-1,4,6,7,12,12b-hexahydroindolo[2,3-a]quinoline-3-carboxamide (compound II-28)

[0217] Prepared in the same way as in Example 4, 1, except that one of the starting materials was replaced with 6-aminobenzoboroxole, to obtain white solid 79 mg, yield 71%. 1 ​H NMR (400 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.55 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 7.1, 2.5 Hz, 1H), 7.32 - 7.24 (m, 3H), 7.16 - 7.09 (m, 2H), 6.68 (s, 1H), 5.20 (d, J = 1.0 Hz, 2H), 4.47 (td, J = 5.1, 1.9 Hz, 1H), 3.98 - 3.86 (m, 2H), 3.30 - 3.21 (m, 2H), 2.99 - 2.93 (m, 2H), 2.73 (dt, J = 14.0, 5.2 Hz, 1H), 2.48 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 168.78, 142.16, 139.78, 137.61, 137.47, 136.31, 133.84, 126.83, 125.36, 122.13, 121.84, 120.88, 120.81, 119.20, 117.98, 110.99, 107.71, 68.25, 55.15, 53.68, 52.04, 31.47, 21.62.

[0218]

[0219] 2. Preparation of N-(l-hydroxy-l,3-dihydrobenzo[c][l,2]dioxaborol-5-yl)-l,4,6,7,12,12b- hexahydroindolo[2,3-a]quinoline-3-carboxamide (Compound II-29)

[0220] Prepared in the same manner as Example 4, 1 except that one of the starting materials was replaced with 5-aminobenzoborole to give a white solid 77 mg, 69% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.45 (s, 1H), 7.88 (dt, J = 1.9, 0.9 Hz, 1H), 7.54 (dd, J = 6.9, 2.4 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.23 (td, J = 7.2, 2.6 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.58 (s, 1H), 5.10 (d, J = 1.0 Hz, 2H), 4.49 (td, J = 4.9, 1.7 Hz, 1H), 3.97 - 3.84 (m, 2H), 3.28 - 3.16 (m, 2H), 2.99 - 2.87 (m, 2H), 2.73 (dt, J = 14.1, 4.9 Hz, 1H), 2.48 (dt, J = 14.1, 4.9 Hz, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 168.59, 142.39, 141.44, 137.47, 136.31, 135.95, 133.74, 132.31, 126.73, 121.74, 120.76, 119.23, 118.02, 117.88, 115.39, 110.90, 107.71, 67.17, 55.06, 53.38, 52.12, 31.58, 21.59.

[0221]

[0222] Example 8, Anti-viral activity of Hirsutine alkaloid boronic acid derivatives

[0223] In this example, some of the Hirsutine alkaloid boronic acid derivatives synthesized above were selected to evaluate their anti-influenza virus H1N1 activity. The screening concentration was 30 μM, the cell line was MDCK cells, the screening method was CPE inhibition experiment, and the evaluation standard was the inhibition rate of virus-induced cytopathic effect (CPE) or the protection rate of cells as the index. Ribavirin with broad-spectrum anti-viral activity was selected as the positive control drug. The results are shown in Table 1. Most of the test compounds showed certain anti-influenza virus activity. Among them, Hirsutine derivatives I-4, II-2, II-10 and II-18 had 50.4%, 72.7%, 56.2% and 53.9% inhibition rates against the virus, respectively, and had good ability to inhibit virus growth.

[0224]

[0225] Table 1 Inhibition rate of Hirsutine derivatives on virus (H1N1)

[0226]

[0227]

[0228] Example 9, Cytotoxicity of Hirsutine alkaloid boronic acid derivatives

[0229] We selected four compounds which had more than 50% inhibition rate at the initial screening concentration of 30 μM, and determined their cytotoxicity to 293T, MDCK and A549 cells to evaluate their therapeutic index (SI). The experimental results are shown in Tables 2 and 3:

[0230] Table 2 Cytotoxicity of compounds to 293T human embryonic kidney cells and A549 cells

[0231]

[0232] Table 3 Cytotoxicity of compounds to MDCK cells

[0233]

[0234] From the above experimental results, it was found that the compounds had essentially no cytotoxicity (CC 50 >500 μM) to MDCK cells; for A549 cells, the boronic acid-modified Hirsutine derivatives II-2, II-10 and II-18 all showed lower cytotoxicity (IC 50 >150 μM). For 293T cells, the boronic acid-modified Hirsutine derivatives II-2, II-10 and II-18 also all showed lower cytotoxicity, except that the IC 50 value of II-2 was about 70 μM, and the IC 50 values of II-18 and II-10 were both greater than 300 μM. In combination with the initial screening results of antiviral activity and cytotoxicity data, it was found that the introduction of a boronic acid group on the phenyl ring connected by a carbonyl group not only enhanced the anti-influenza virus activity of the compounds, but also reduced their cytotoxicity to cells, and had potential research value from the perspective of antiviral drugs.

[0235] Example 10, Study on antibacterial activity of Hirsutine alkaloid boronic acid derivatives

[0236] The current study shows that boron-containing compounds have antibacterial activity, and there are some drugs that have been successfully applied in clinical. Therefore, we tested the antibacterial activity of some synthetic benzoboroxole derivatives. We screened several common pathogenic bacteria such as Staphylococcus aureus and Escherichia coli, selected 18 synthesized benzoboroxole derivatives, set four concentration gradients: 32 μM, 16 μM, 8 μM and 4 μM to determine the minimum inhibitory concentration MIC value of bacteria in 96-well plates. Two blank control groups: MHB medium control group (200 μL MHB) and bacteria-MHB medium control group (100 μL bacteria and 100 μL MHB medium). After incubation at 37°C for 12-18 h, the absorbance at 600 nm was determined by a microplate reader. The evaluation standard is the ratio of absorbance at each concentration gradient to that of the MHB medium control group. When the ratio is close to 1, it means that the compound inhibits the growth of bacteria at this concentration. Conversely, when the ratio is much greater than 1, it means that the compound cannot inhibit the growth of bacteria at this concentration.

[0237] Table 4 Minimum inhibitory concentration (MIC value) determination of benzoboroxole derivatives

[0238]

[0239]

[0240] The above experimental results show that, compared with Escherichia coli, benzoboroxole derivatives have a certain inhibitory effect on Staphylococcus aureus. Among them, the compounds with aromatic diamine as the connecting arm have stronger antibacterial activity than the compounds with aliphatic diamine as the connecting arm. And the compounds II-5, II-6, II-7, II-8 with m-phenylenediamine and p-phenylenediamine as the connecting arm (MIC values are 4-8, 4-8, 8-16 and ≤4 μM, respectively) have stronger antibacterial activity than the compounds II-1, II-2, II-3 with o-phenylenediamine as the connecting arm (MIC values are all greater than 32 μM). In addition, the position of boron atom in the boron structure also affects the antibacterial activity. The derivative II-8 with boron atom at the para position of the carbonyl group (MIC ≤4 μM) has better antibacterial activity against Staphylococcus aureus than the derivatives II-4, II-5 and II-7 with boron atom at the ortho and meta positions of the carbonyl group (MIC values are >32, 4-8 and 8-16 μM, respectively). Among them, the derivative II-8 with p-phenylenediamine as the connecting arm and boron atom at the para position of the carbonyl group has a minimum inhibitory concentration MIC value of Staphylococcus aureus less than or equal to 4 μM, which has further research value.

Claims

1. A boronic acid derivative of hirsutine alkaloid, characterized in that, having the structural formula of formula (I) or formula (II): wherein R is selected from one of the following groups: wherein R3is o-NHCO, m-NHCO, p-NHCO, o-NHCH2, m-NHCH2, p-NHCH2; or n = 1, 2, 3, 4, 5; or wherein n = 1, 2, 3, 4, 5, R4is H or CH3; or or or NH; R1is substituted at any position on the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN; In formula (I), the boronic acid group and R2are as follows: when the boronic acid group is at the C2position of the benzene ring, R2is substituted at the C3or C4position of the benzene ring and is selected from one of the following groups: OCH3, F, Cl; when the boronic acid group is at the C3position of the benzene ring, R2is substituted at the C4or C5position of the benzene ring and is selected from one of the following groups: CH3, OCH3, COOH, OH, F, Cl, Br; when the boronic acid group is at the C4position of the benzene ring, R2is substituted at the C2or C3position of the benzene ring and is selected from one of the following groups: CH3, CH2CH3, OCH3, F, Cl; In formula (II), R can be at the C1, C2, C3, C4position of the benzene ring of benzoboroxole.

2. A boronic acid derivative of hirsutine alkaloid characterized in that, selected from any one of the following:

3. The process for the preparation of Hirsutine alkaloid boronic acid derivatives as claimed in claim 1 wherein, comprising the following steps: First, ethyl 1, 4, 6, 7, 12, 12b-hexahydroindolo[2, 3-a] quinolizine-3-carboxylate with or without substituents on the indole ring of the Hirsutine parent nucleus is hydrolyzed by 5 equivalent of lithium hydroxide in a reaction solution of THF: H2O at 1:2, and the pH is adjusted to about 3 by 2N hydrochloric acid to obtain 1, 4, 6, 7, 12, 12b-hexahydroindolo[2, 3-a] quinolizine-3-carboxylic acid hydrochloride with or without substituents on the indole ring; then, the amide compound and the Hirsutine alkaloid boronic acid derivative of claim 1 in which R is NH are formed by condensation with amine compounds using HATU as the condensing agent under the condition of a molar ratio of 1:1.5; the amide compound is condensed with benzoboroxole compounds with carboxyl or methylene bromo groups and substituted phenylboronic acid compounds with carboxyl or methylene bromo groups under the condition of a molar ratio of 1:1.5 to obtain the Hirsutine alkaloid boronic acid derivative of claim 1 except that R is NH.

4. The production method according to claim 3, characterized by, The ethyl 1, 4, 6, 7, 12, 12b-hexahydroindolo[2, 3-a] quinolizine-3-carboxylate with or without substituents on the indole ring has the structural formula of formula (III): R1is substituted at any position on the benzene ring and is selected from one of the following groups: CH3, CH2CH3, F, Cl, Br, CN.

5. Use of the Hirsutine alkaloid boronic acid derivative of any one of claims 1-2 in the preparation of a medicament for preventing and / or treating influenza A virus infection and influenza B virus infection.

6. Use of the Hirsutine alkaloid boronic acid derivative of any one of claims 1-2 in the preparation of a medicament for preventing and / or treating Staphylococcus aureus infection, Escherichia coli infection and Pseudomonas aeruginosa infection.

Images