Deuterated panaxydol alkaloid compounds, synthesis and uses thereof

Abstract

The application belongs to the technical field of medicine, and discloses deuterated pan-epimedin alkaloid compounds, synthesis and purposes thereof, specifically discloses deuterated pan-epimedin alkaloid quaternary ammonium salt compounds, tertiary amine type deuterated pan-epimedin alkaloid compounds, 8-imine tertiary amine type deuterated pan-epimedin alkaloid compounds and purposes of preparing medicines thereof. Specifically, the application discloses compounds as shown in general formula I, II and III, pharmaceutical compositions, preparation methods and purposes thereof. The compound has significant anti-inflammatory activity and can be used for treating ulcerative colitis. The physical and chemical properties and pharmacological action intensity of the compound are superior to those of a positive control drug and related compounds, and the compound can be used for preparing anti-inflammatory drugs. The application has significant application value in preparing medicines for preventing, relieving and / or treating ulcerative colitis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to deuterium-substituted bioactive berberine-type alkaloids and their physiologically acceptable salts, their preparation methods, pharmaceutical compositions, and their uses in the preparation of drugs. Specifically, the deuterium-substituted berberine-type alkaloids include quaternary ammonium salts of berberine-type alkaloids, dihydroberberine-type tertiary amine compounds, and 8-imino-substituted tertiary amine compounds of berberine-type alkaloids. Specific uses include the application of the compounds of this invention and their pharmaceutical compositions in the preparation of drugs for the prevention, relief, and / or treatment of ulcerative colitis. Background Technology

[0002] Ulcerative colitis (UC) is an inflammatory bowel disease that causes persistent mucosal inflammation from the rectum to the proximal colon. It is characterized by complex clinical manifestations, difficulty in diagnosis, and a high recurrence rate. Most UC patients experience symptoms such as rectal bleeding, diarrhea and / or increased bowel frequency (more than three times daily), urgency, abdominal pain, and even fecal incontinence, significantly impacting their lives. Long-term illness can lead to serious complications, including the risk of developing colorectal cancer (JAMA vol. 331, 8(2024): 716.). The incidence of UC has been increasing globally for many years (Lancet (London, England) vol. 402, 10401(2023): 571-584.). While there is a lack of nationwide statistics on UC in my country and related studies are scattered, they have shown a rapid growth trend (Gastroenterological Association vol. 21, 13(2023): 3379-3386.e29.).

[0003] The etiology of ulcerative colitis involves multiple factors, including genetics, immunity, environment, and gut microbiota. Treatment outcomes vary among patients due to individual differences, and there is currently no cure. While existing treatments can improve symptoms and induce and maintain remission, they cannot completely cure the disease (Nature Reviews Drug Discovery 2024, 23(7), 546-562). Currently, research on the treatment of this disease both domestically and internationally focuses on biologics for severe cases. For mild and moderate ulcerative colitis, only 5-aminosalicylic acid derivatives are first-line drugs; however, these drugs have side effects such as nausea, vomiting, indigestion, anorexia, and headache. Therefore, there is a clear market demand for safer and more effective drugs for the treatment of mild or moderate ulcerative colitis.

[0004] Berberine-type alkaloids, which naturally exist in nature, are an important class of natural organic compounds. They mainly include berberine hydrochloride, berberine hydrochloride, palmatine hydrochloride, isoferberine hydrochloride, epiberberine hydrochloride, and cypermethrin hydrochloride, etc., and their structures are shown in Formula 1.

[0005]

[0006] In recent years, there have been numerous reports on the use of berberine-type alkaloid quaternary ammonium salts in the treatment of ulcerative colitis. For example, studies on berberine have shown that it can inhibit the production of interleukin-8 (IL-8) in colonic epithelial cells, block the expression of Toll-like receptor 4 (TLR4), and reduce the phosphorylation level of nuclear factor-κB (NF-κB) p65 protein, thereby effectively improving the symptoms of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice (European Journal of Pharmacology 2010, 648(1-3), 162-170); it can also regulate endoplasmic reticulum stress, protect Caco-2 cells from IFN-γ / TNF-α-induced apoptosis, and improve the survival of intestinal mucosal cells in inflammatory bowel disease (IBD). 2011, 35(3), 841-849); It can significantly reduce the mRNA levels of Th17-related cytokines IL-17 and transcription factor ROR-γt, inhibit the mRNA expression of genes related to the STAT3 signaling pathway (TNF-α, IL-6, IL-23) and the phosphorylation of STAT3, thereby significantly improving the symptoms of chronic colitis in mice induced by dextran sulfate sodium (DSS) (Pharmacological Research 2016, 110, 227-239); It can dose-dependently alleviate the symptoms of colitis in rats induced by DSS (The Journal of Pharmacology and Experimental Therapeutics 2018, 366(2), 332-340). Studies on berberine have shown that it can dose-dependently alleviate clinical symptoms such as weight loss, diarrhea, and hematochezia induced by DSS in mice. Its mechanism of action may be related to the inhibition of IκBα phosphorylation and the translocation of NF-κB p65 from the cytoplasm to the nucleus (European Journal of Pharmacology 2021, 896. DOI:10.1016 / j.ejphar.2021.173912.). It can also upregulate TSC1 expression by promoting m6A modification of TSC1 mRNA mediated by methyltransferase-like protein 14 (METTL14), inhibiting the mitogen-activated protein kinase (MEK) / extracellular regulated protein kinase (ERK) signaling pathway, blocking M1 polarization, enhancing mTOR-dependent c / EBPβ pathway, and promoting M2 polarization, thereby improving DSS-induced ulceration and potentially becoming a new treatment option for ulcerative colitis (Phytomedicine). 2024,122.DOI:10.1016 / j.phymed.2023.155153.).The above experimental results demonstrate that berberine alkaloids can effectively treat ulcerative colitis and are a valuable lead compound for developing related drugs. At the same time, the continuous discovery of its mechanism of action in treating ulcerative colitis provides a powerful tool for the early design and later activity verification of drug development.

[0007] Many derivatives of berberine-type alkaloids have been disclosed, such as oxidized berberine, oxidized berberine, oxidized palmatine, oxidized berberine, dihydroberberine, and dihydroberberine, which also have certain activity in the treatment of ulcerative colitis. Berberine (BBR), oxidized berberine (OBB), and dihydroberberine (DHBB) all possess anti-inflammatory activity, with the potency of OBB > BBR > DHBB. OBB exhibits significant anti-inflammatory effects, possibly related to the inhibition of the NF-κB signaling pathway (Phytomedicine 2019, 52, 272-283). Palmatine (PAL) and 8-oxidized palmatine (OPAL) both have protective effects against DSS-induced experimental ulcerative colitis in mice, with OPAL showing superior efficacy compared to PAL, similar to the positive control drug mesalazine (MSZ). Its mechanism may involve inhibiting NLRP3 inflammasome activation and activating the Nrf2 signaling pathway, thereby improving inflammatory and oxidative stress states (Biomedicine & Pharmacotherapy 2022, 153). In in vivo experiments, oxidized berberine can improve TNBS-induced colitis in rats (Phytomedicine: international journal of phytotherapy and...). phytopharmacologyvol.116(2023):154899).

[0008] In our medicinal chemistry research on berberine, we synthesized a large class of deuterium-substituted berberine-type alkaloids and their physiologically acceptable salts. These deuterium-substituted berberine-type alkaloids include quaternary ammonium salts of berberine-type alkaloids, dihydroberberine-type tertiary amine compounds, and 8-imino-substituted tertiary amine compounds of berberine-type alkaloids. We also discovered that these deuterium-substituted berberine-type alkaloids and their physiologically acceptable salts possess significant anti-inflammatory activity, particularly against ulcerative colitis, including activity at both the cell and animal experimental levels. They hold great potential for developing new drugs to treat ulcerative colitis. Summary of the Invention

[0009] The technical problem solved by this invention is to improve the metabolic properties of non-deuterated berberine compounds by preparing deuterated-substituted berberine compounds, thereby improving the drug-likeness of the compounds. This invention provides deuterated-substituted berberine-type alkaloid compounds or physiologically acceptable salts thereof, their preparation methods, pharmaceutical compositions, and their use in the preparation of drugs for the prevention, relief, and / or treatment of ulcerative colitis. These deuterated-substituted berberine-type alkaloid compounds include quaternary ammonium salts of berberine-type alkaloids, dihydroberberine-type tertiary amine compounds, and 8-imino-substituted tertiary amine compounds of berberine-type alkaloids. The half-life of these compounds in liver microsomes is significantly improved compared to the disclosed non-deuterated compounds. These compounds exhibit significant anti-inflammatory activity, particularly anti-ulcerative colitis activity. This invention significantly improves the pharmaceutical properties of quaternary ammonium salt compounds of the berberine type alkaloids, and has significant application value in the preparation of drugs for the prevention, relief and / or treatment of inflammatory diseases, especially for the treatment of ulcerative colitis.

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0011] The first aspect of the present invention provides deuterium-substituted quaternary ammonium salts of alkaloids of the genus *Pyrrosinone* as shown in general formula I, tertiary amine deuterium-substituted alkaloids of the genus *Pyrrosinone* as shown in general formula II, and 8-imine tertiary amine deuterium-substituted alkaloids of the genus *Pyrrosinone* including compounds 16-49 as shown in general formula III.

[0012] The second aspect of the present invention provides methods for preparing deuterium-substituted quaternary ammonium salts of pan-berberine alkaloids as shown in general formula I and tertiary amine-type deuterium-substituted pan-berberine alkaloids as shown in general formula II.

[0013] A third aspect of the present invention provides product compositions of deuterium-substituted quaternary ammonium salts of alkaloids of the genus *Pyrrosinone* as shown in general formula I, tertiary amine deuterium-substituted alkaloids of the genus *Pyrrosinone* as shown in general formula II, and 8-imine tertiary amine deuterium-substituted alkaloids of the genus *Pyrrosinone* comprising compounds 16-49 as shown in general formula III, said products comprising pharmaceuticals.

[0014] The fourth aspect of this invention provides the use of deuterium-substituted quaternary ammonium salts of alkaloids of the genus *berberine* as shown in general formula I, tertiary amine deuterium-substituted alkaloids of the genus *berberine* as shown in general formula II, and 8-imine tertiary amine deuterium-substituted alkaloids of the genus *berberine* including compounds 16-49 as shown in general formula III, in the preparation of medicaments for the prevention, relief, and / or treatment of ulcerative colitis.

[0015] The chemical structures of the deuterium-substituted pan-berberine alkaloid quaternary ammonium salts as shown in general formula I, the tertiary amine-type deuterium-substituted pan-berberine alkaloids as shown in general formula II, and the 8-imine tertiary amine-type deuterium-substituted pan-berberine alkaloids including compounds 16-49 as shown in general formula III are as follows:

[0016]

[0017] In general formula I

[0018] When R2 and R3 are bonded to form a deuterated alkylene dioxy group:

[0019] R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano;

[0020] R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group;

[0021] R 13 It is independently selected from H, D, alkyl, or trideuterated methyl;

[0022] X A ˉ Selected from monovalent inorganic or organic acid radicals;

[0023] When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group:

[0024] R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

[0025] R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano;

[0026] R 13 It is independently selected from H, D, alkyl, or trideuterated methyl;

[0027] X A ˉ Selected from monovalent inorganic or organic acid radicals;

[0028] When R 13 When independently selected from D:

[0029] R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

[0030] R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano;

[0031] R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group;

[0032] X A ˉ Selected from monovalent inorganic or organic acid radicals.

[0033] In general formula II,

[0034] Represents a single or double bond;

[0035] When R2 and R3 are bonded to form a deuterated alkylene dioxy group:

[0036] Selected from single bonds, R8 is independently selected from H, D, OH, trichloromethyl, tribromomethyl, trifluoromethyl, methyl ketone, or Selected from double bonds, R8 is selected from O, dichloromethylene, or dibromomethylene;

[0037] R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group;

[0038] R 13 It is independently selected from H, D, methyl, or trideuterated methyl;

[0039] When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group:

[0040] R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

[0041] Selected from single bonds, R8 is independently selected from H, D, OH, trichloromethyl, tribromomethyl, trifluoromethyl, methyl ketone, or Selected from double bonds, R8 is selected from O, dichloromethylene, or dibromomethylene;

[0042] R 13 It is independently selected from H, D, methyl or trideuterated methyl.

[0043] Formula III represents the specific compounds included in number 16-49.

[0044] The most preferred compounds of this invention are selected from the following group of compounds:

[0045] Deuterated pan-flavonoid alkaloid quaternary ammonium salts represented by general formula I:

[0046] Tertiary amine-type deuterated pan-flavonoid alkaloids represented by general formula II:

[0047] The 8-imine tertiary amine type deuterated pan-flavonoid alkaloid compound represented by general formula III:

[0048]

[0049]

[0050] The second aspect of this invention provides a method for preparing the compound of this invention:

[0051] The deuterated pan-berberine alkaloid derivatives involved in this invention can be prepared via the following synthetic route (see experimental examples for specific synthetic conditions):

[0052] (1) The 13-deuterated pan-flavonoid alkaloid quaternary ammonium salt compound of the present invention can be prepared by the following synthetic route:

[0053]

[0054] Weigh a certain amount of quaternary ammonium salt compounds of the berberine-type alkaloids and add them to 20-40 times their volume of a strong alkaline solution (the strong alkaline is selected from potassium hydroxide or sodium hydroxide, and the concentration of the alkaline is selected from 10%-20%). Stir at room temperature until the quaternary ammonium salt compounds of the berberine-type alkaloids are evenly dispersed in the strong alkaline solution. Then add 0.5-10 equivalents of methyl ketone (methyl ketone is selected from acetone, 2-butanone, acetophenone, etc.), stir at room temperature for 2-5 hours, filter, wash the filter cake with water until neutral, and dry the filter cake. Add the obtained filter cake to 20-40 times its volume of tetrahydrofuran solution and stir. Add 1-3 equivalents of deuterated acid (deuterated acid is selected from deuterated hydrochloric acid, deuterated sulfuric acid, deuterated acetic acid, etc.), heat under reflux for 2-6 hours, filter, and obtain quaternary ammonium salt compounds of the 13-position deuterated berberine-type alkaloids.

[0055] (2) The pan-flavonoid alkaloid quaternary ammonium salts of the present invention, which are substituted with dideuterium-methylenedioxy rings, can be prepared by the following synthetic route:

[0056]

[0057] Specifically, the method for synthesizing pan-berberine-type alkaloid quaternary ammonium salts substituted with a ring-A deuterated methylenedioxy group according to the present invention includes the following 7 steps:

[0058] 1) Take a certain amount of N-methylpyrrolidone and add 1-3 equivalents of anhydrous potassium carbonate and 1%-10% of benzyltriethylammonium chloride (TEBA). Stir and heat to 100-120℃ under Ar protection for later use. Weigh a certain amount of 3,4-dihydroxybenzaldehyde (M2-1), dissolve it in N-methylpyrrolidone, add 1-20 equivalents of deuterated dichloromethane or deuterated dibromomethane and mix evenly. Then add it dropwise to the above high-temperature system. The addition should be completed within 1-2 hours. Then keep the reaction at the temperature for 1-3 hours to obtain 3,4-deuterated methylenedioxybenzaldehyde (M2-2).

[0059] 2) Dissolve the above-mentioned 3,4-deuterated methylenedioxybenzaldehyde (M2-2) in glacial acetic acid, add 1-5 equivalents of nitromethane and ammonium acetate, heat at 70-90℃ for 2-4 hours, cool, then add 3-5 times the volume of ice water and stir. A solid precipitates out, and filter to obtain needle-shaped yellowish-brown powder, β-nitro-3,4-deuterated methylenedioxystyrene (M2-3);

[0060] 3) Dissolve β-nitro-3,4-deuterium-methylenedioxystyrene (M2-3) in anhydrous tetrahydrofuran, and add it dropwise to a tetrahydrofuran solution of boron trifluoride ether and sodium borohydride cooled in an ice-salt bath, wherein the amount of boron trifluoride ether and sodium borohydride is 1-5 equivalents. After the addition is complete, react at 70°C for 2-4 hours, then add 2-5 times the volume of cold water to the system and stir, then add 2-5 times the volume of 1%-10% dilute hydrochloric acid, and then heat to 80°C and stir for 2-4 hours. After the reaction is complete, remove the tetrahydrofuran, then add 0.5-1 times the volume of ether for extraction, leaving the aqueous layer. Adjust the pH to 12 with a 1-5N strong base (selected from potassium hydroxide and sodium hydroxide), and then extract with ether to remove the solvent, to obtain a white solid, namely 3,4-deuterium-methylenedioxyphenylethylamine (M2);

[0061] 4) The above-mentioned deuterated phenylethylamine (M2) and substituted benzaldehyde (M1) are added to a reaction solvent (such as dichloromethane, methanol, ethanol, etc.), followed by the addition of an acid-binding agent (such as triethylamine, N,N-diisopropylethylamine, pyridine, etc.) and a drying agent (anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, etc.). The mixture is stirred at 40-50°C to prepare a Schiff base. After 3-4 hours of reaction, the reaction is stopped. The reaction mixture is filtered, and the solvent in the filtrate is removed until a paste is obtained. Then, an alcohol solvent (such as...) is added. Dissolve in methanol or ethanol, add a reducing agent (such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc.) and carry out a reduction reaction at 50-60℃ to prepare a secondary amine intermediate. After the reaction is complete, add water, remove the alcohol organic solvent, and extract with ethyl acetate, etc. Remove the organic solvent layer to obtain a paste. Dissolve the paste with a small amount of tetrahydrofuran by stirring, add 1-5% of inorganic dilute acid (such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) until a white precipitate is formed. Filter the reaction mixture to obtain a white powder filter cake M.

[0062] 5) Anhydrous copper sulfate, sodium chloride and glyoxal were added to a mixed solvent of formic acid and phosphoric acid to carry out the intramolecular ring and pre-reaction steps. Then, the above intermediate M was added and the reaction continued until the reaction was completed. The reaction mixture was filtered, the filter cake was washed with water until neutral and dried to obtain copper salt intermediate M-1 of deuterated pan-flavonoid quaternary ammonium salt.

[0063] 6) Add M-1 to an inorganic strong base solution (optionally 0.5-3M sodium hydroxide, potassium hydroxide, or calcium hydroxide) and stir at room temperature. Then add 1.0-10.0 equivalents of methyl ketone reagent (optionally acetone, 2-butanone, 2-pentanone, 2-hexanone, etc.) to react and prepare the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate. Stir at room temperature for 4-6 hours. After the reaction is complete, filter the reaction mixture to obtain a filter cake. Wash the filter cake with water until neutral and dry to obtain the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate M-2.

[0064] 7) Add the M-2 obtained from filtration in step 6) to the reaction solvent tetrahydrofuran, then stir the mixture until it is evenly dispersed, add 1.0-5.0 equivalents of organic acid (such as benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, etc.) to react and prepare the organic acid type quaternary ammonium salt of deuterated pan-corydaline alkaloids. Heat and stir for 4-5 hours until the reaction is completed and then cool. Filter the reaction mixture to obtain a filter cake. Recrystallize the filter cake with a mixed solvent of ethanol and water to obtain the organic acid type quaternary ammonium salt T of deuterated pan-corydaline alkaloids.

[0065] (3) The D-cyclic dideuterated methylenedioxy-substituted pan-berberine-type alkaloid quaternary ammonium salts of the present invention can be prepared by the following synthetic route:

[0066]

[0067] Specifically, the synthetic route for the pan-berberine-type alkaloid quaternary ammonium salt compounds substituted with D-ring dideuterated methylenedioxy in this invention includes the following five steps:

[0068] 1) Take a certain amount of N-methylpyrrolidone and add 1-3 equivalents of anhydrous potassium carbonate and 1%-10% of benzyltriethylammonium chloride (TEBA). Stir and heat to 100-120℃ under Ar protection for later use. Weigh a certain amount of 2,3-dihydroxybenzaldehyde (M1-1), dissolve it in N-methylpyrrolidone, add 1-20 equivalents of deuterated dichloromethane or deuterated dibromomethane and mix evenly. Then add it dropwise to the above high-temperature system. The addition should be completed within 1-2 hours. Then keep the reaction at the temperature for 1-3 hours to obtain 2,3-dideuterated methylenedioxybenzaldehyde (M1).

[0069] 2) Add the above-mentioned deuterated methylenedioxybenzaldehyde (M1) and substituted phenylethylamine (M2) to a reaction solvent (such as dichloromethane, methanol, ethanol, etc.), followed by an acid-binding agent (such as triethylamine, N,N-diisopropylethylamine, pyridine, etc.) and a drying agent (anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride). Stir the reaction at 40-50°C to prepare a Schiff base. Stop the reaction after 3-4 hours, filter the reaction mixture, remove the solvent from the filtrate to obtain a paste, and then add an alcohol solvent ( The intermediate is prepared by dissolving the intermediate in methanol or ethanol, adding a reducing agent (such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc.) and carrying out a reduction reaction at 50-60℃. After the reaction is completed, water is added, the alcohol organic solvent is removed, and the intermediate is extracted with ethyl acetate, etc. The organic solvent layer is removed to obtain a paste. The paste is dissolved in a small amount of tetrahydrofuran by stirring, and 1-5% inorganic dilute acid (such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) is added until a white precipitate is formed. The reaction mixture is filtered to obtain a white powder filter cake M.

[0070] 3) Anhydrous copper sulfate, sodium chloride and glyoxal were added to a mixed solvent of formic acid and phosphoric acid to carry out the intramolecular ring and step pre-reaction. Then, the above intermediate M was added and the reaction continued until the reaction was completed. The reaction mixture was filtered, the filter cake was washed with water until neutral and dried to obtain copper salt intermediate M-1 of deuterated pan-flavonoid quaternary ammonium salt.

[0071] 4) Add M-1 to an inorganic strong base solution (optionally 0.5-3M sodium hydroxide, potassium hydroxide, or calcium hydroxide) and stir at room temperature. Then add 1.0-10.0 equivalents of methyl ketone reagent (optionally acetone, 2-butanone, 2-pentanone, 2-hexanone, etc.) to react and prepare the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate. Stir at room temperature for 4-6 hours. After the reaction is complete, filter the reaction mixture to obtain a filter cake. Wash the filter cake with water until neutral and dry to obtain the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate M-2.

[0072] 5) Add the M-2 obtained from filtration in step 4) to the reaction solvent tetrahydrofuran, then stir the mixture until it is evenly dispersed, add 1.0-5.0 equivalents of organic acid (such as benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, etc.) to react and prepare the organic acid type quaternary ammonium salt of deuterated pan-coryne alkaloids. Heat and stir for 4-5 hours until the reaction is completed and then cool. Filter the reaction mixture to obtain a filter cake. Recrystallize the filter cake with a mixed solvent of ethanol and water to obtain the organic acid type quaternary ammonium salt T of deuterated pan-coryne alkaloids.

[0073] (4) The pan-flavonoid alkaloid quaternary ammonium salts of the present invention, which are substituted with dideuterium-methylenedioxy rings of A and D, can be prepared by the following synthetic route:

[0074]

[0075] Specifically, the synthetic route for the pan-berberine-type alkaloid quaternary ammonium salt compounds of A and D cyclodeuterated methylenedioxy groups of this invention includes the following 8 steps:

[0076] 1) Take N-methylpyrrolidone, add anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA), stir and heat under Ar protection for later use; weigh 3,4-dihydroxybenzaldehyde (M2-1), dissolve it in N-methylpyrrolidone, add deuterated dichloromethane, add the above prepared system, keep warm and react to obtain 2,3-deuterated methylenedioxybenzaldehyde (M2-2);

[0077] 2) Dissolve M2-2 in glacial acetic acid, add nitromethane and ammonium acetate, heat at 70-90℃ to react, and after the reaction is complete, add water and filter to obtain β-nitro-3,4-deuterated methylenedioxystyrene (M2-3);

[0078] 3) Dissolve M2-3 in tetrahydrofuran and add it dropwise to a tetrahydrofuran solution of boron trifluoride diethyl ether and sodium borohydride in an ice-salt bath under argon protection. Heat the mixture and react. After the reaction is complete, add water to the reaction system, then add dilute acid, heat and stir. Remove the tetrahydrofuran and extract with diethyl ether, leaving the aqueous layer. Adjust the pH to 12 and extract with diethyl ether. Remove the organic layer and remove the solvent to obtain 3,4-deuterium dioxyphenylethylamine (M2).

[0079] 4) Take N-methylpyrrolidone and add anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA), stir and heat under Ar protection for later use; weigh 2,3-dihydroxybenzaldehyde (M1-1), dissolve N-methylpyrrolidone and add deuterated dichloromethane, add to the above prepared system, keep warm and react to obtain 2,3-deuterated methylenedioxybenzaldehyde (M1);

[0080] 5) Add the above-mentioned deuterated methylenedioxybenzaldehyde (M1) and substituted phenylethylamine (M2) to a reaction solvent (such as dichloromethane, methanol, ethanol, etc.), followed by an acid-binding agent (such as triethylamine, N,N-diisopropylethylamine, pyridine, etc.) and a drying agent (anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride). Stir the reaction at 40-50°C to prepare a Schiff base. Stop the reaction after 3-4 hours, filter the reaction mixture, remove the solvent from the filtrate to obtain a paste, and then add an alcohol solvent ( The intermediate is prepared by dissolving the intermediate in methanol or ethanol, adding a reducing agent (such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride, etc.) and carrying out a reduction reaction at 50-60℃. After the reaction is completed, water is added, the alcohol organic solvent is removed, and the intermediate is extracted with ethyl acetate, etc. The organic solvent layer is removed to obtain a paste. The paste is dissolved in a small amount of tetrahydrofuran by stirring, and 1-5% inorganic dilute acid (such as hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) is added until a white precipitate is formed. The reaction mixture is filtered to obtain a white powder filter cake M.

[0081] 6) Anhydrous copper sulfate, sodium chloride and glyoxal were added to a mixed solvent of formic acid and phosphoric acid to carry out the intramolecular ring and pre-reaction steps. Then, the above intermediate M was added and the reaction continued until the reaction was completed. The reaction mixture was filtered, the filter cake was washed with water until neutral and dried to obtain copper salt intermediate M-1 of deuterated pan-flavonoid quaternary ammonium salt.

[0082] 7) Add M-1 to an inorganic strong base solution (optionally 0.5-3M sodium hydroxide, potassium hydroxide, or calcium hydroxide) and stir at room temperature. Then add 1.0-10.0 equivalents of methyl ketone reagent (optionally acetone, 2-butanone, 2-pentanone, 2-hexanone, etc.) to react and prepare the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate. Stir at room temperature for 4-6 hours. After the reaction is complete, filter the reaction mixture to obtain a filter cake. Wash the filter cake with water until neutral and dry to obtain the 8-methyl ketone-substituted dihydro-type deuterated pan-copper alkaloid tertiary amine intermediate M-2.

[0083] 8) Add the M-2 obtained from filtration in step 4) to the reaction solvent tetrahydrofuran, then stir the mixture until it is evenly dispersed, add 1.0-5.0 equivalents of organic acid (such as benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, etc.) to react and prepare the organic acid type quaternary ammonium salt of deuterated pan-corydaline alkaloids. Heat and stir for 4-5 hours until the reaction is completed and then cool. Filter the reaction mixture to obtain a filter cake. Recrystallize the filter cake with a mixed solvent of ethanol and water to obtain the organic acid type quaternary ammonium salt T of deuterated pan-corydaline alkaloids.

[0084] (5) The tertiary amine-type deuterated dihydropanaxanine-type alkaloid compound of the present invention can be prepared by the following synthetic route:

[0085]

[0086] Specifically, the synthetic route of the tertiary amine type deuterated dihydropan-copperine alkaloid compound of the present invention includes the following steps: weigh the deuterated pan-copperine alkaloid quaternary ammonium salt compound, add an appropriate amount of organic solvent (the organic solvent is selected from methanol, ethanol or tetrahydrofuran) until fully dispersed, place it in an ice bath and stir, add 0.5-2.0 equivalents of anhydrous potassium carbonate, and then dissolve 0.5-1.1 equivalents of sodium borohydride in 1-5% strong base solution (the strong base is selected from sodium hydroxide or potassium hydroxide) and add it dropwise to the above ice bath. After the addition is complete, remove the ice bath and stir at room temperature for 2-4 hours, then filter, wash the filter cake with water, 30% alcohol solution and 80% alcohol solution in turn, and then recrystallize to obtain yellow crystals (the alcohol is selected from methanol or ethanol).

[0087] (6) The 8-methyl ketone-substituted tertiary amine deuterated pan-flavonoid alkaloid compound of the present invention can be prepared by the following synthetic route:

[0088]

[0089] Specifically, the synthetic route of the 8-methyl ketone-substituted tertiary amine deuterated berberine alkaloid compound of the present invention includes the following steps: weighing the deuterated berberine alkaloid quaternary ammonium salt compound, adding an appropriate amount of 1-5N strong base solution (the strong base is selected from sodium hydroxide or potassium hydroxide), stirring at room temperature until fully dispersed, adding methyl ketone reagent (methyl ketone reagent is selected from acetone, 2-butanone, 2-pentanone, 2-hexanone, etc.), stirring at room temperature for 2-6 hours after addition, filtering, washing the filter cake with water until neutral, recrystallizing with acetone to obtain the 8-methyl ketone-substituted tertiary amine deuterated berberine alkaloid compound.

[0090] A third aspect of the invention also relates to pharmaceutical compositions using the compounds described in the first aspect of the invention as active ingredients. These pharmaceutical compositions can be prepared according to their known methods. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compounds of the invention in their pharmaceutical compositions is typically 0.1-99.9% (w / w).

[0091] The compounds of this invention, or pharmaceutical compositions containing the compounds of this invention, can be administered in unit doses, primarily via the digestive tract, such as oral administration, enteral administration, etc. However, non-enteric administration is also acceptable, such as intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lungs and respiratory tract, vagina, application to the skin, etc. In the treatment of ulcerative colitis, a significant advantage is that they can be formulated into ordinary tablets for direct oral administration without special processing, making them very convenient to use. Various other routes and methods of administration can also be employed.

[0092] Oral administration or other routes of administration may also utilize other dosage forms, including various liquid, solid, or semi-solid dosage forms prepared using new technologies. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including O / W, W / O, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, creams, gels, and pastes, etc.

[0093] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0094] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the relevant art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0095] To formulate the drug delivery unit into capsules, the compound of the present invention can be mixed with a diluent and a gliding agent, and the mixture can be placed directly into hard or soft capsules; alternatively, the compound of the present invention can be first formed into granules or microspheres with a diluent, a binder, and a disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and gliding agents used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0096] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used pharmaceutical solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochlorides, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0097] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0098] To achieve pharmaceutical purposes and enhance therapeutic effects, the drugs (compounds) or pharmaceutical compositions of the present invention may be administered and used in any known method of administration and application.

[0099] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the severity of ulcerative colitis to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-500 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-40 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the progress of treatment, as well as the administration regimen including the use of other treatment methods.

[0100] The compounds or product compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0101] The fourth aspect of this invention provides the use of the aforementioned deuterated berberine quaternary ammonium salt compounds in the preparation of drugs for the prevention, relief, and / or treatment of inflammation, particularly ulcerative colitis. The compounds of this invention, or their physiologically acceptable salts, exhibit significantly higher activity at the cellular and animal levels than their undeuterated counterparts and significantly higher than positive control drugs, making them highly valuable deuterated berberine-type alkaloids for the treatment of inflammation. In in vitro cytotoxicity experiments, most of the above compounds did not exhibit cytotoxicity (see experimental examples).

[0102] Beneficial technical effects

[0103] This invention relates to deuterium-substituted bioactive berberine-type alkaloid quaternary ammonium salt compounds, methods for synthesizing deuterium-substituted bioactive berberine-type alkaloid quaternary ammonium salt compounds from commercially available raw materials, related derivatives synthesized using deuterium-substituted bioactive berberine-type alkaloid quaternary ammonium salt compounds as substrates and their synthetic methods, as well as the anti-inflammatory activity of the compounds of this invention, particularly their pharmacological activity in the treatment of ulcerative colitis. Pharmacological activity experiments on the compounds of this invention demonstrated their ability to inhibit NO release, and this bioactivity was superior to that of non-deuterated forms (such as berberine hydrochloride). Among the compounds of this invention, the tertiary amine type deuterated berberine alkaloids, the 8-monosubstituted tertiary amine type deuterated berberine alkaloids, and the 8-imine tertiary amine type deuterated berberine alkaloids all showed superior inhibitory effects on nitric oxide (NO) release compared to deuterated berberine alkaloid quaternary ammonium salts (see experimental examples). Compound 11 reached near-micromolar levels, and compounds 20 and 30 showed IC50 values ​​of [missing information]. 50All compounds reached micromolar levels and exhibited low toxicity, making them suitable for further in vivo anti-inflammatory activity assays. Animal experiments demonstrated that these compounds were highly effective in treating ulcerative colitis (see experimental examples). The examples show that compounds 11, 20, and 30, at a dose of 200 mg / kg, were more effective than the positive control drug sulfasalazine (SASP) at a dose of 500 mg / kg in reducing weight in mice with DSS-induced acute ulcerative colitis. The positive control drug SASP did not significantly improve fecal hemorrhage in mice, while the compounds of this invention significantly improved occult blood caused by acute ulcerative colitis in mice. After dissection of the mice, the degree of colorectal contracture in each group was examined. The experimental examples show that, compared with the normal control group, the colorectal contracture in the model group was significantly shorter and more contracted, with a statistically significant difference (p < 0.001). Compounds 11, 20, and 30 significantly improved colorectal contracture, with therapeutic effects superior to those of the positive control drug SASP at a dose of 500 mg / kg (**, p<0.01). Notably, compounds 11 and 30 showed statistically significant differences in efficacy compared to their non-deuterated forms, dihydroberberine (11-ND) and N-dihydroberberine-8-ylidene o-acetoxybenzamide (30-ND) (*, p<0.05), and the deuterated form exhibited superior activity, indicating that deuteration enhanced efficacy.

[0104] The compound of this invention introduces deuterium into the structure of berberine-type alkaloids. Its anti-inflammatory effects in vitro and in vivo are significantly improved compared to undeuterated berberine-type alkaloids. Furthermore, the core structure was modified, and the results showed that the biological activity was further significantly enhanced. This is a new discovery with substantial progress. Attached Figure Description

[0105] Figure 1 Effects of positive control drugs sulfasalazine, undeuterated dihydroberberine (11-ND), undeuterated N-dihydroberberine-8-yl o-acetoxybenzamide (30-ND), and compounds 11, 20, and 30 of this invention on the body weight of mice with a model of acute ulcerative colitis induced by sodium dextran sulfate.

[0106] Figure 2 Effects of positive control drugs sulfasalazine, undeuterated dihydroberberine (11-ND), undeuterated N-dihydroberberine-8-yl o-acetoxybenzamide (30-ND), and compounds 11, 20, and 30 of this invention on fecal occult blood in a mouse model of acute ulcerative colitis induced by sodium dextran sulfate.

[0107] Figure 3The effects of positive control drugs sulfasalazine, undeuterated dihydroberberine (11-ND), undeuterated N-dihydroberberine-8-yl o-acetoxybenzamide (30-ND), and compounds 11, 20, and 30 of this invention on rectal bleeding at the end of experiments in mice with a dextran sulfate-induced acute ulcerative colitis model.

[0108] Figure 4 Effects of positive control drugs sulfasalazine, undeuterated dihydroberberine (11-ND), undeuterated N-dihydroberberine-8-yl o-acetoxybenzamide (30-ND), and compounds 11, 20, and 30 of this invention on colorectal length at the end of experiments in mice with a dextran sulfate-induced acute ulcerative colitis model.

[0109] Figure 5 Representative colorectal images at the end of experiments using the positive control drug sulfasalazine, undeuterated dihydroberberine (11-ND), undeuterated N-dihydroberberine-8-yl-o-acetoxybenzamide (30-ND), and compounds 11, 20, and 30 of this invention in mice with a model of acute ulcerative colitis induced by sodium dextran sulfate. Detailed Implementation

[0110] The specific embodiments of the present invention are not intended to limit the invention in any way.

[0111] The preparation process and structural identification data of the active compounds of this invention are provided, wherein the compound numbers correspond to the specific compound numbers in the content of this invention.

[0112] I. Examples of Compound Preparation of the Invention

[0113] Example (1) Preparation process and structural identification data of compound 1

[0114] 1.0 g (2.80 mmol) of berberine hydrochloride was weighed into a reaction flask, and 15.0 mL of 5N NaOH was added. Stirring was then started, and 2.0 mL (27.20 mmol) of acetone was added dropwise. The mixture was stirred at room temperature for 4 h. TLC analysis showed that the reaction proceeds were complete. The reaction solution was filtered, and the filter cake was washed with water until neutral and dried to obtain a yellow solid. The solid was then added to 30.0 mL of tetrahydrofuran and stirred. 20% (w / w) deuterated hydrochloric acid (1.12 mL, 7.17 mmol) was diluted in 5.0 mL of heavy water and added dropwise to the solution. The system gradually turned yellow. The mixture was stirred and refluxed at 80 °C for 6 h. After cooling, the mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran to obtain 0.91 g of the yellow solid of compound 1, with a total yield of 90.8%. 1H NMR (400MHz, DMSO-d6) δ9.96(s,1H,ArH),8.04(d,J=8.8Hz,1H,ArH),7.83(d,J=8.8Hz,1H,ArH),7.79(s, 1H,ArH),7.08(s,1H,ArH),6.54(s,2H,OCH2O),6.17(s,2H,OCH2O),4.88(t,J=4.4Hz,J=12.0Hz,2H,ArCH2 CH2 N),3.19(t,J=4.4Hz,J=12.0Hz,2H,Ar CH2 CH2N). ESI-MS (m / z): 321.1 [M-Cl] + .

[0115] Example (2) Preparation process and structural identification data of compound 2

[0116] In 150.0 mL of N-methylpyrrolidone, 31.5 g (227.73 mmol) of anhydrous potassium carbonate and 0.1 g of benzyltriethylammonium chloride (TEBA) were added, and the mixture was stirred and heated to 120 °C under argon protection. 2,3-Dihydroxybenzaldehyde (21.0 g, 151.82 mmol) and 24.22 mL (379.55 mmol) of deuterated dichloromethane were added to 80.0 mL of N-methylpyrrolidone dropwise, and the mixture was kept at this temperature for 2 hours after the addition was complete. After the reaction was completed, twice the volume of water was added and stirred. The mixture was extracted with 500 ml of ethyl acetate. The combined organic layers were washed with saturated brine, and the organic layers were separated and dried with anhydrous sodium sulfate. After filtering off the drying agent, the solvent was removed under reduced pressure to obtain a brown paste. The paste was extracted multiple times with petroleum ether, and the solvent was removed to obtain a white powder, 2,3-deuterated methylenedioxybenzaldehyde. After drying, 9.42 g (61.87 mmol) was obtained, with a yield of 40.78%.

[0117] The above product was added to 300.0 mL of dichloromethane solvent, followed by the addition of 10.0 mL (74.24 mmol) of piperoethylamine, 8.6 mL (61.87 mmol) of triethylamine, and 11.2 g (92.81 mmol) of anhydrous magnesium sulfate. The mixture was refluxed at 40 °C for 4 hours. After filtration, the solvent was removed from the filtrate, yielding a brownish-yellow paste. 120.0 mL of methanol was added to the paste, and 7.02 g (1...) of sodium borohydride was added in portions with stirring. 85.60 mmol), after addition, stirred at 40 °C for 3 h, quenched with 100.0 ml of water to remove most of the methanol, then extracted twice with 400.0 ml of ethyl acetate, combined organic layers were rotary evaporated under reduced pressure to remove the solvent, then dissolved in 40.0 ml of tetrahydrofuran, and 220.0 mL of dilute hydrochloric acid (2 mol / L) was added dropwise with stirring to precipitate a white or off-white solid, which was dried and weighed to obtain 19.0 g (54.0 mmol), yield 87.28%.

[0118] 12.9 mL (112.5 mmol) of glyoxal, 26.94 g (168.75 mmol) of anhydrous copper sulfate, and 19.72 g (337.50 mmol) of sodium chloride were added to 300.0 mL of formic acid solution and stirred. 15.0 mL of phosphoric acid was then added, and the mixture was stirred at 50 °C for 30 min. Then, 19.0 g of the white or off-white solid powder obtained in the previous step was added. The temperature was raised to 90 °C, and the reaction was stirred for 3 h. The reaction was stopped, and the mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of water and added to 345.0 mL of sodium hydroxide solution (5.0 mol / L). 73.0 mL of acetone was then added dropwise. After stirring at room temperature for 4 hours, the mixture was filtered. The filter cake was washed with water until neutral and dried. The filter cake was then added to 500.0 mL of tetrahydrofuran. Then, 32.1 g (168.75 mmol) of p-toluenesulfonic acid was dissolved in 50.0 mL of tetrahydrofuran and added to the above system in portions. The mixture was refluxed and stirred at 80 °C for 4 hours and then filtered to obtain a brownish-yellow filter cake. The filter cake was recrystallized from 60% ethanol solution to obtain brownish-yellow crystals. After drying, 13.2 g of the crystals were weighed and added to 300 mL of tetrahydrofuran. 10.0 mL of concentrated hydrochloric acid was added and the mixture was refluxed at 80 °C for 2 hours. After cooling, the mixture was filtered to obtain compound 2. The yellow crystals were dried and weighed to obtain 13.2 g, with a yield of 68.32%. 1 H NMR (400MHz, DMSO-d6) δ9.96(s,1H,ArH),8.97(s,1H,ArH),8.04(d,J=8.8Hz,1H,ArH),7.83(d,J=8 .8Hz,1H,ArH),7.79(s,1H,ArH),7.08(s,1H,ArH),6.17(s,2H,OCH2O),4.89(t,J=6.2Hz,2H,ArCH2C H 2N), 3.20(t, J = 6.2 Hz, 2H, ArC H2CH2N).ESI-MS(m / z):322.1[M-Cl] + .

[0119] Example (3) Preparation process and structural identification data of compound 3

[0120] 26.0 mL of N-methylpyrrolidone was added to 4.2 g (30.00 mmol) of anhydrous potassium carbonate and 0.3 g of benzyltriethylammonium chloride (TEBA), and stirred. The mixture was heated to 110 °C under argon protection. 27.6 g (20.00 mmol) of 3,4-dihydroxybenzaldehyde and 3.2 mL of deuterated dichloromethane (50.00 mmol) were dissolved in 12.0 mL of N-methylpyrrolidone. This solution was then slowly added dropwise to the prepared 110 °C solution over 2 hours. The mixture was kept at this temperature and reacted for another 2 hours. After cooling, 80.0 mL of water was added, and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.44 g (16.02 mmol) of 3,4-deuterated methylenedioxybenzaldehyde, with a yield of 79.9%.

[0121] The above product was added to 15.0 mL of glacial acetic acid, and then 2.6 mL (48.05 mmol) of nitromethane and 3.09 g (40.05 mmol) of ammonium acetate were added while stirring. The temperature was gradually raised to 90 °C and the reaction was maintained at this temperature for 5 h. After cooling, the mixture was filtered and washed with water to obtain brownish-yellow needle-like crystals. After drying, 2.624 g (13.7 mmol) of β-nitro-3,4-deuterated methylenedioxystyrene was obtained, with a yield of 84.0%.

[0122] Add 40.0 mL of ultra-dry tetrahydrofuran to a three-necked flask and stir in an ice-salt bath. Add 2.585 g of NaBH4 in portions to the solution. Under argon (Ar) protection, dilute 21.14 mL (82.2 mmol) of BF3·Et2O with 40.0 mL of ultra-dry tetrahydrofuran and add it dropwise to the above system. After the addition is complete, stir at room temperature for 15 min. Dissolve 2.624 g (13.7 mmol) of the product obtained in the previous step in 40.0 mL of ultra-dry tetrahydrofuran and add it dropwise to the above system under Ar protection. After the addition is complete, stir at 70 °C for 5 h. Add 210.0 mL of water dropwise to the reaction system, then add 210.0 mL of 1M hydrochloric acid and heat to 80 °C and stir for 2 h. Cool, remove tetrahydrofuran under reduced pressure, extract three times with 100.0 mL of diethyl ether, retain the aqueous layer, and stir with 5N... The pH was adjusted to 12 with NaOH, and then extracted with diethyl ether to remove the solvent, yielding a white solid, namely deuterated piperoethylamine, weighing 1.5 g (9.00 mmol), with a yield of 65.0%.

[0123] Take 15.0 mL of dichloromethane, and add 1.5 g of the above product, 1.6 g (10.80 mmol) of 2,3-methyleneoxybenzaldehyde, 1.269 mL (9.00 mmol) of triethylamine, and 1.625 g (13.5 mmol) of anhydrous magnesium sulfate sequentially. Stir the reaction at 30 °C for 5 h, filter, remove the solvent, add 45.0 mL of methanol, and then add 1.022 g (27.00 mmol) of NaBH4 in portions. Heat to 40 °C and stir for 2 h, quench with 50.0 mL of water, extract with ethyl acetate, remove the solvent, and obtain a paste. Dissolve in 15.0 mL of tetrahydrofuran, add 150.0 mL of 2N hydrochloric acid while stirring, and a white solid precipitates. Filter, dry, and weigh to obtain 1.916 g, yield 63.03%.

[0124] 1.3 mL (11.34 mmol) of glyoxal, 2.716 g (17.02 mmol) of anhydrous copper sulfate, and 1.989 g (34.03 mmol) of sodium chloride were added to 40.0 mL of formic acid solution and stirred. 2.0 mL of phosphoric acid was then added, and the mixture was stirred at 50 °C for 30 minutes. Then, 1.916 g (5.67 mmol) of the white solid powder obtained in the previous step was added. The mixture was heated to 90 °C and stirred for 3 hours. The reaction was stopped, and the mixture was cooled to room temperature and filtered. The filter cake was washed with a small amount of water and added to 37.0 mL of sodium hydroxide solution (5 mol / L). 11.5 mL of acetone was added dropwise, and the mixture was cooled to room temperature. After stirring for 4 hours, the mixture was filtered. The filter cake was washed with water until neutral and dried. The filter cake was then added to 60.0 mL of tetrahydrofuran. Then, 3.5 g (17.02 mmol) of p-toluenesulfonic acid was dissolved in 10.0 mL of tetrahydrofuran and added to the above system. The mixture was refluxed and stirred at 70 °C for 4 hours, and then filtered to obtain a brownish-yellow filter cake. The filter cake was recrystallized from 60% ethanol solution to obtain brownish-yellow crystals. After drying, 2.3 g of the crystals were weighed, with a yield of 82.1%. The crystals were added to 90.0 mL of tetrahydrofuran and 2.0 mL of concentrated hydrochloric acid. The mixture was stirred at 80 °C for 2 hours, cooled, filtered, and dried to obtain 1.66 g of compound 3, with a yield of 99.76%. 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H,ArH),8.98(s,1H,ArH),8.04(d,J=8.8Hz,1H,ArH),7.83(d,J=8 .8Hz,1H,ArH),7.79(s,1H,ArH),7.08(s,1H,ArH),6.53(s,2H,OCH2O),4.89(t,J=6.4Hz,2H,ArCH2 CH2 N), 3.20(t, J = 6.4 Hz, 2H, Ar CH2 CH2N). ESI-MS (m / z): 322.1 [M-Cl] + .

[0125] Example (4) Preparation process and structural identification data of compound 4

[0126] Take 10.0 mL of dichloromethane, add 0.319 g (2.1 mmol) of 2,3-deuterated methylenedioxybenzaldehyde, 0.351 g (2.1 mmol) of 3,4-deuterated methylenedioxyphenylethylamine, 0.3 mL (2.1 mmol) of triethylamine, and 0.379 g (3.15 mmol) of anhydrous magnesium sulfate. Stir at 30-40 °C for 4 h. The reaction is complete as detected by TLC. Filter to remove dichloromethane, add 10.0 mL of methanol and stir to dissolve. Add 0.27 g (6.3 mmol) of sodium borohydride, maintain at 40 °C and continue stirring. After 2 h, quench the reaction with 10.0 mL of water. Remove methanol, extract with ethyl acetate to remove solvent, add 3.0 mL of tetrahydrofuran and stir to dissolve, then add 28.0 mL of 2N hydrochloric acid. A large amount of white solid appears. Filter, wash the filter cake with a small amount of water, dry, and weigh 0.298 g, yield 41.79%.

[0127] 0.2 mL (1.76 mmol) of glyoxal, 0.422 g (2.64 mmol) of anhydrous copper sulfate, and 0.309 g (5.28 mmol) of sodium chloride were added to 5.0 mL of formic acid solution and stirred. Then, 250.0 μL of phosphoric acid was added and the mixture was stirred at 50 °C for 30 min. Next, 0.298 g (0.88 mmol) of the white or off-white solid powder obtained in the previous step was added. The mixture was heated to 90 °C and stirred for 3 h. The reaction was then stopped, cooled to room temperature, and filtered. The filter cake was washed with a small amount of water and added to 4.0 mL of sodium hydroxide solution (5.0 mol / L). Adding... 0.85 mL of acetone was added, stirred at room temperature for 4 h, and then filtered. The filter cake was washed with water until neutral, dried, and added to 10.0 mL of tetrahydrofuran. Then, 0.502 g (2.64 mmol) of p-toluenesulfonic acid was added to the above system, refluxed at 80 °C for 4 h, and filtered to obtain a brownish-yellow filter cake. The filter cake was recrystallized from 60% ethanol solution to obtain brownish-yellow crystals, which were dried and weighed to 0.268 g. These crystals were added to 300 mL of tetrahydrofuran, and 10.0 mL of concentrated hydrochloric acid was added. The mixture was refluxed at 80 °C for 2 h, cooled, and filtered to obtain compound 4, which was yellow and dried to 0.19 g, with a yield of 25.16%. 1H NMR(400MHz,DMSO-d6)δ9.95(s,1H,ArH),8.96(s,1H,ArH),8.04(d,J=8.8Hz,1H,ArH),7 .83(d,J=8.8Hz,1H,ArH),7.79(s,1H,ArH),7.08(s,1H,ArH),4.88(t,J=6.0Hz,2H,ArCH2 CH2 N), 3.20(t, J = 6.0 Hz, 2H, Ar CH2CH2N).ESI-MS(m / z):324.35[M-Cl] + .

[0128] Example (5) Preparation process and structural identification data of compound 5

[0129] 100.0 mg (0.28 mmol) of compound 2 was added to a reaction flask, followed by 1.5 mL of 5N NaOH. 0.2 mL (2.72 mmol) of acetone was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was filtered, and the filter cake was washed with water until neutral. The solution was then dried to obtain a brownish-yellow powder. The solid was then added to 3.0 mL of tetrahydrofuran with stirring. 20% deuterated hydrochloric acid (0.12 mL, 0.72 mmol) was diluted in 1.0 mL of heavy water and added dropwise to the solution. The system gradually turned yellow. The mixture was refluxed at 80 °C for 6 hours with stirring. After cooling, the mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran to obtain 92 mg of the yellow solid of compound 5, with a total yield of 91.7%. 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H,ArH),8.03(d,J=8.8Hz,1H,ArH),7.83(d,J=8.8Hz,1H ,ArH),7.79(s,1H,ArH),7.08(s,1H,ArH),6.17(s,2H,OCH2O),4.89(t,J=6.4Hz,2H,ArCH2 CH2 N), 3.20(t, J = 6.4 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):323.11[M-Cl] + .

[0130] Example (6) Preparation process and structural identification data of compound 6

[0131] 100.0 mg (0.28 mmol) of compound 3 was added to a reaction flask, followed by 1.5 mL of 5N NaOH. 0.2 mL (2.72 mmol) of acetone was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was filtered, and the filter cake was washed with water until neutral. The solution was then dried to obtain a brownish-yellow powder. The solid was then added to 3.0 mL of tetrahydrofuran with stirring. 20% deuterated hydrochloric acid (0.12 mL, 0.72 mmol) was diluted in 1.0 mL of heavy water and added dropwise to the solution. The system gradually turned yellow. The mixture was refluxed at 80 °C for 6 hours with stirring. After cooling, the mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran to obtain 91.7 mg of a yellow solid of compound 6, with a total yield of 91.4%. 1H NMR (400MHz, DMSO-d6) δ9.97(s,1H,ArH),8.03(d,J=8.8Hz,1H,ArH),7.83(d,J=8.8Hz,1H ,ArH),7.78(s,1H,ArH),7.07(s,1H,ArH),6.53(s,2H,OCH2O),4.89(t,J=6.0Hz,2H,ArCH2 CH2 N), 3.20(t, J = 6.1 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):323.11[M-Cl] + .

[0132] Example (7) Preparation process and structural identification data of compound 7

[0133] 139.0 mg (0.38 mmol) of compound 4 was added to a reaction flask, followed by 1.5 mL of 5N NaOH. Acetone (0.28 mL, 3.80 mmol) was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was filtered, and the filter cake was washed with water until neutral. The solution was then dried to obtain a brownish-yellow powder. The solid was then added to 3.0 mL of tetrahydrofuran with stirring. 20% deuterated hydrochloric acid (0.12 mL, 0.72 mmol) was diluted in 1.0 mL of heavy water and added dropwise to the solution. The system gradually turned yellow. The mixture was refluxed at 80 °C for 6 hours with stirring. After cooling, the mixture was filtered, and the filter cake was washed with a small amount of tetrahydrofuran to obtain 123.4 mg of yellow solid compound 7, with a total yield of 90.0%. 1 H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H, ArH), 8.03 (d, J=8.8Hz, 1H, ArH), 7.83 (d, J= 8.8Hz,1H,ArH),7.79(s,1H,ArH),7.08(s,1H,ArH),4.89(t,J=6.4Hz,2H,ArCH2 CH2 N), 3.20(t, J = 6.4 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):325.12.[M-Cl] + .

[0134] Example (8) Preparation process and structural identification data of compound 8

[0135] Add 15.0 mL of 5N KOH to a reaction flask, stir and heat to 50 °C. Weigh 2.31 g (7.0 mmol) of potassium ferricyanide and add it to the above solution, then stir until the potassium ferricyanide is completely dissolved. If it is not completely dissolved, the temperature can be increased to 70-90 °C. Then, add 500.0 mg (1.4 mmol) of compound 2 in portions to the reaction flask, heat to 110 °C and stir under reflux for 6 h until the reactants react completely. Filter the reaction solution, wash the filter cake with water until neutral, then dry, and filter hot through chloroform and methanol to obtain a loose, yellowish-brown powder. Add 5.0 mL of phosphorus oxychloride to the above powder, reflux and stir at 110 °C for 2 h, then filter. Wash the filter cake with chloroform and ether successively, and after vacuum drying, weigh 256.4 mg of red powder, with a yield of 46.7%. 1 H NMR (400MHz, DMSO-d6) δ7.42(s,1H,ArH),7.29(d,J=8.4Hz,1H,ArH),7.10(d,J=8.4Hz,1H ,ArH),7.07(s,1H,ArH),6.87(s,1H,ArH),6.03(s,2H,OCH2O),4.04(t,J=6.4Hz,2H,ArCH2 CH2 N), 2.81(t, J = 6.4 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):356.07.[M-Cl] + Example (9) Preparation process and structural identification data of compound 9

[0136] 100.0 mg (0.255 mmol) of compound 8 was added to 20.0 mL of toluene, and 20.0 mg (0.255 mmol) of piperazine was added with stirring at room temperature. The mixture was stirred at room temperature for 4 h under argon protection. The reaction was detected by TLC after it was complete. 3.0 mL of diethyl ether was added to the system, followed by 1.0 mL of 4 M dioxane hydrochloride solution. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The mixture was stirred with 20.0 mL of chloroform for 2 h, filtered, and the filter cake was dissolved in a small amount of methanol. The white impurities were removed by filtration, and an orange-yellow solid was obtained. 28.2 mg was obtained after drying, with a yield of 25.0%. 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H,ArH),7.96(d,J=8.4Hz,1H,ArH),7.81(d,J=8.4Hz,1H ,ArH),7.59(s,1H,ArH),7.13(s,1H,ArH),6.15(s,2H,OCH2O),4.60(t,J=6.4Hz,2H,ArCH2 CH2N),3.79(s,4H,piperazinyl),3.38(s,5H,piperazinyl),3.13(t,J=6.4Hz,2H,Ar CH2 CH2N).ESI-MS(m / z):406.17.[M-Cl] + Example (10): Preparation process and structural identification data of compound 10

[0137] 100.0 mg (0.255 mmol) of compound 8 was added to 20.0 mL of toluene, and 56.0 mg (0.637 mmol) of piperazine was added with stirring at room temperature. The mixture was stirred at room temperature for 4 h under argon protection. The reaction was detected by TLC after it was complete. 3.0 mL of diethyl ether was added to the system, followed by 1.0 mL of 4 M dioxane hydrochloride solution. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in 20.0 mL of water and stirred for 2 h. The white impurities were removed by filtration, and an orange-yellow filtrate was obtained. The filtrate was lyophilized and weighed to obtain 11.3 mg, with a yield of 10.0%. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H,ArH),7.92(d,J=8.4Hz,1H,ArH),7.76(d,J=8.4Hz,1H ,ArH),7.54(s,1H,ArH),7.12(s,1H,ArH),6.15(s,2H,OCH2O),4.55(t,J=6.4Hz,2H,ArCH2 CH2 N),3.89(t,J=4.4Hz,4H,morpholino),3.58(t,J=4.4Hz,4H,morpholino),3.10(t,J=6.4Hz,2H,Ar CH2 CH2N).ESI-MS(m / z):407.16.[M-Cl] + Example (11) Preparation process and structural identification data of compound 11

[0138] 100.0 mg (0.279 mmol) of compound 2 was added to 4.0 mL of anhydrous methanol, followed by 78.0 mg (0.558 mmol) of anhydrous potassium carbonate. The mixture was placed in an ice bath and stirred. 10.0 mg (0.279 mmol) of NaBH4 was dissolved in 0.8 mL of 5% NaOH and added dropwise to the above system. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was detected by TLC and the mixture was filtered. The filter cake was washed with 30.0% ethanol and 80.0% ethanol, respectively, and then recrystallized from ethanol. After drying, 31.0 mg of the product was obtained, with a yield of 34.4%. 1H NMR (400MHz, DMSO-d6) δ7.29(s,1H,ArH),6.76(s,1H,ArH),6.69(d,J=8.0Hz,1H,ArH),6.47(d,J=8. 0Hz,1H,ArH),6.09(s,1H,ArH),6.00(s,2H,OCH2O),4.16(s,2H,NCH2Ar),3.05(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.79(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):324.11.[M+H] + .

[0139] Example (12) Preparation process and structural identification data of compound 12

[0140] Compound 2 (100.0 mg g, 0.279 mmol) was weighed into a reaction flask, 15.0 mL of 5N NaOH was added, and stirring was started. Acetone (2.0 mL, 27.20 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 h. The reaction was confirmed by TLC to be complete. The reaction solution was filtered, and the filter cake was washed with water until neutral. After drying, a yellow solid was obtained. The solid was recrystallized from acetone to obtain a light yellow, shiny, loose powder, weighing 46.2 g, with a yield of 43.6%. 1 H NMR (400MHz, DMSO-d6) δ7.25(s,1H,ArH),6.76(s,1H,ArH),6.72(d,J=8.0Hz,1H,ArH),6.50(d,J=8.0Hz,1H ,ArH),6.03(s,1H,ArH),6.00(d,J=3.2Hz,2H,OCH2O),5.09(t,J=6.0Hz,1H,NCHAr),3.31–3.13(m,2H,ArCH2 CH2 N),2.92(dd,J=14.4,6.0Hz,1H,NCH CH2 CO), 2.83–2.64 (m, 2H, Ar) CH2 CH2N), 2.49–2.43 (m, 1H, NCH) CH2 CO),2.03(s,3H,CH3).ESI-MS(m / z):322.10.[M+H] + .

[0141] Example (13) Preparation process and structural identification data of compound 13

[0142] Add 137.0 mL of 5N KOH to a reaction flask, stir and heat to 50 °C. Weigh 21.0 g (63.6 mmol) of potassium ferricyanide and add it to the above solution, then stir until the potassium ferricyanide is completely dissolved. If it is not completely dissolved, the temperature can be increased to 70-90 °C. Then, add 4.55 g (12.7 mmol) of compound 2 in portions to the reaction flask, heat to 110 °C and stir under reflux for 6 h until the reactants are completely reacted. Filter the reaction solution, wash the filter cake with water until neutral, then dry, filter hot through chloroform, and then filter hot through methanol to obtain a loose, yellowish-brown powder. Dry and weigh 2.0 g, yield 46.6%. 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H,ArH),7.34(d,J=8.4Hz,1H,ArH),7.15(d,J=8.4Hz,1 H,ArH),7.11(s,1H,ArH),6.92(s,1H,ArH),6.07(s,2H,OCH2O),4.12–4.04(m,2H,ArCH2C H 2N), 2.86(t, J = 6.0 Hz, 2H, ArC H 2CH2N).ESI-MS(m / z):338.10.[M+H] + .

[0143] Example (14) Preparation process and structural identification data of compound 14

[0144] 1.0 g of compound 2 was dissolved in 50.0 mL of a mixed solvent of chloroform and 95% ethanol (chloroform: 95% ethanol = 3:1), followed by the addition of 6.0 mL of concentrated ammonia. The mixture was heated to 50 °C and stirred for 48 h. The reaction was observed to be complete by TLC. The organic layer of the reaction mixture was separated using a separatory funnel, washed with water and saturated brine, and dried overnight with anhydrous sodium sulfate. The next day, the mixture was filtered to remove the organic solvent, yielding a foamy, golden-yellow solid with a loose texture, weighing 1.06 g, with a yield of 86.0%. 1 H NMR (400MHz, DMSO-d6) δ7.34(s,1H,ArH),6.95(d,J=8.0Hz,1H,ArH),6.78(s,1H,ArH),6.70(d,J=8.0H z,1H,ArH),6.38(s,1H,ArH),6.01-5.99(m,2H,OCH2O),5.59(s,1H,CHCCl3),3.82-3.76(m,1H,ArCH2C H 2N), 3.65–3.59 (m, 1H, ArCH2C) H 2N), 3.30-3.21(m, 1H, ArC H 2CH2N), 2.72-2.66 (m, 1H, ArC)H 2CH2N).ESI-MS(m / z):440.02.[M+H] + .

[0145] Example (15) Preparation process and structural identification data of compound 15

[0146] 200.0 mg (0.453 mmol) of compound 14 was weighed and dissolved in 4.0 mL of a mixed solvent of tert-butanol and dimethyl sulfoxide (tert-butanol: dimethyl sulfoxide = 1:1). 152.5 mg (1.359 mmol) of potassium tert-butoxide was added, and the mixture was stirred and heated to 80 °C. The reaction was allowed to proceed for 1.5 h, and TLC was used to determine the end of the reaction. The mixture was then cooled to room temperature, and cold water was added and stirred until the product precipitated completely. The mixture was filtered, and the filter cake was washed with water until neutral. After drying, 159.3 mg of a yellow solid was obtained, with a yield of 87.0%. 1 H NMR (400MHz, DMSO-d6) δ7.43 (s, 1H, ArH), 7.00 (d, J = 8.0Hz, 1H, ArH), 6.81 (s, 1H, ArH), 6. 76(d,J=8.0Hz,1H,ArH),6.65(s,1H,ArH),6.03(s,2H,OCH2O),3.60(t,J=6.0Hz,2H,ArCH2 CH2 N), 3.01(brs,2H,Ar CH2 CH2N).ESI-MS(m / z):404.04.[M+H] + .

[0147] Example (16) Preparation process and structural identification data of compound 16

[0148] 1.0 g (2.55 mmol) of compound 8 was weighed and added to a three-necked flask. 35.0 mL of anhydrous toluene was added and stirred. Dry ammonia gas was introduced and the reaction was carried out at room temperature for 3 h. The system changed from red to orange and finally to yellow-green. The reaction was completed. Toluene was removed, and the mixture was dissolved in 300.0 mL of a mixed solution of chloroform and methanol (chloroform:methanol = 10:1). The solution was washed with saturated sodium bicarbonate, dried over saturated brine and anhydrous magnesium sulfate, filtered, and the solvent was removed to obtain 561.0 mg of yellow-green solid, with a yield of 65.4%. 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H,ArH),7.74(s,1H,NH),7.67(d,J=8.4Hz,1H,ArH),7.52(s,1H, ArH),7.43(d,J=8.4Hz,1H,ArH),6.99(s,1H,ArH),6.11(s,2H,OCH2O),4.22(t,J=6.0Hz,2H,ArCH2 CH2N), 3.04(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):337.11.[M+H] + Example (17) Preparation process and structural identification data of compound 17

[0149] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 27.0 μL (0.36 mmol) of acetyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to pale yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate to remove the solvent, yielding a yellow crude solid. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 29.0 mg of yellow solid, with a yield of 25.6%. 1 HNMR(400MHz,DMSO-d6)δ7.52(s,1H,ArH),7.48–7.42(m,2H,ArH),7.27(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.22(s,2H,ArCH2 CH2 N), 2.90(t, J = 6.2 Hz, 2H, Ar CH2 CH2N),2.07(s,3H,CH3).ESI-MS(m / z):379.12.[M+H] + .

[0150] Example (18) Preparation process and structural identification data of compound 18

[0151] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 33.0 μL (0.36 mmol) of propionyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to pale yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate to remove the solvent, yielding a yellow crude solid. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 30.0 mg of yellow solid, with a yield of 26.7%. 1HNMR(400MHz,DMSO-d6)δ7.52(s,1H,ArH),7.47–7.40(m,2H,ArH),7.26(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.20(s,2H,ArCH2 CH2 N), 2.89(t, J = 6.4 Hz, 2H, Ar CH2 CH2N), 2.38 (q, J = 7.6 Hz, 2H, CO) CH2 CH3),1.08(t,J=7.6Hz,3H,COCH2 CH3 ESI-MS (m / z): 393.14. [M+H] + .

[0152] Example (19) Preparation process and structural identification data of compound 19

[0153] Weigh 150.0 mg (0.45 mmol) of compound 16 into a flask, add 15.0 mL of chloroform, place in an ice bath, and then add 125.0 μL (0.90 mmol) of triethylamine and stir. Dilute 56.0 μL (0.54 mmol) of butyryl chloride in 5.0 mL of chloroform and add it dropwise to the above system. After the addition is complete, remove the ice bath and react at a constant temperature for 3 h. The system changes from yellow-green to yellow. The reaction is complete when detected by TLC. Wash the reaction solution twice with 1% HCl and twice with saturated brine. Separate the organic layer, dry it with anhydrous magnesium sulfate, remove the solvent, and obtain a yellow solid crude product. Purify by silica gel column chromatography [v / v = 20:1 (dichloromethane: methanol)] to obtain 75.0 mg of yellow solid, yield 41.0%. 1 HNMR(400MHz,DMSO-d6)δ7.53(s,1H,ArH),7.48–7.42(m,2H,ArH),7.28(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.20(s,2H,ArCH2 CH2 N), 2.90(t, J = 6.1 Hz, 2H, Ar CH2 CH2N), 2.34(t, J=7.6Hz, 2H, CO CH2 CH2CH3),1.67-1.5(m,J=7.2Hz,2H COCH2 CH2 CH3),0.96(t,J=7.2Hz,3H,COCH2CH2 CH3 ESI-MS (m / z): 407.15. [M+H] + .

[0154] Example (20) Preparation process and structural identification data of compound 20

[0155] 150.0 mg (0.45 mmol) of compound 16 was weighed and added to a flask. 15.0 mL of chloroform was added and the flask was placed in an ice bath. 125.0 μL (0.90 mmol) of triethylamine was then added and stirred. 64.0 μL (0.54 mmol) of pentanoyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 109.0 mg of yellow solid, with a yield of 57.6%. 1 H NMR (400MHz, DMSO-d6) δ7.52(s,1H,ArH),7.47-7.43(m,2H,ArH),7.27(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.19(s,2H,ArCH2 CH2 N), 2.90(t, J = 6.0 Hz, 2H, Ar CH2 CH2N), 2.36(t, J=7.6Hz, 2H, CO CH2 CH2CH2CH3),1.59(p,J=7.6Hz,2H,COCH2 CH2 CH2CH3),1.39(tq,J=14.8,7.6Hz,2H,COCH2CH2 CH2 CH3),0.91(t,J=7.6Hz,3H,COCH2CH2CH2 CH3 ESI-MS (m / z): 421.17. [M+H] + .

[0156] Example (21) Preparation process and structural identification data of compound 21

[0157] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 54.0 μL (0.36 mmol) of hexanoyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate to remove the solvent, yielding a yellow crude solid. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 50.0 mg of yellow solid, with a yield of 38.4%. 1 HNMR(400MHz,DMSO-d6)δ7.51(s,1H,ArH),7.27-7.25(m,2H,ArH),7.26(d,J=8.0Hz,1H,ArH),6.94(s,1H,ArH),6.08(s,2H,OCH2O),4.19(brs,2H,ArCH2 CH2 N), 2.89(t, J = 6.0 Hz, 2H, Ar CH2 CH2N), 2.35 (t, J = 7.6 Hz, 2H, CO CH2 CH2CH2CH2CH3),1.61(t,J=7.6Hz,2H,COCH2 CH2 CH2CH2CH3),1.35-1.31(m,4H,COCH2CH2 CH2CH2 CH 3 ),0.90(t,J=6.8Hz,3H,COCH2CH2CH2CH2 CH3 ESI-MS (m / z): 435.18. [M+H] + .

[0158] Example (22) Preparation process and structural identification data of compound 22

[0159] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 34.0 μL (0.36 mmol) of cyclopropionyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 30.0 mg of yellow solid, with a yield of 24.7%.

[0160] 1 H NMR(400MHz,Methylene Chloride-d2)δ7.26(d,J=8.4Hz,1H,ArH),7.18(d,J=8.4Hz,3H,ArH),6.69(s,1H,ArH),5.95(s,2H,OCH2O),4.34–4.24(m,2H,ArCH2 CH2 N), 2.87(t, J = 6.4 Hz, 2H, Ar CH2 CH2N),1.67(tt,J=8.4,4.4Hz,1H,cyclopropyl),0.91(p,J=3.6Hz,2H,cyclopropyl),0.72(dt,J=7.1,3.6Hz,2H,cyclopropyl).ESI-MS(m / z):405.14.[M+H] + .

[0161] Example (23) Preparation process and structural identification data of compound 23

[0162] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 41.0 μL (0.36 mmol) of cyclobutyryl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 60.0 mg of yellow solid, with a yield of 47.8%. 1 HNMR(400MHz,DMSO-d6)δ7.53(s,1H,ArH),7.46–7.43(m,2H,ArH),7.27(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.19(brs,2H,ArCH2 CH2 N),3.25–3.12(m,1H,cyclobutyl),2.90(t,J=6.0Hz,2H,Ar CH2 CH2N),2.33-2.24(m,2H,cyclobutyl),2.15-2.04(m,2H,cyclobutyl),1.94-1.75(m,2H,cyclobutyl).ESI-MS(m / z):419.16.[M+H]+ .

[0163] Example (24) Preparation process and structural identification data of compound 24

[0164] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 46.0 μL (0.36 mmol) of cyclopentanoyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 29.0 mg of yellow solid, with a yield of 22.4%. 1 HNMR(400MHz,DMSO-d6)δ7.52(s,1H,ArH),7.45-7.43(m,2H,ArH),7.26(d,J=8.4Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.18(brs,2H,ArCH2 CH2 N), 2.90(t, J = 6.4 Hz, 2H, Ar CH2 CH2N),2.80(p,J=8.0Hz,1H,cyclopentyl),1.89-1.82(m,4H,cyclopentyl),1.68–1.51(m,4H,cyclopentyl).ESI-MS(m / z):433.17.[M+H] + .

[0165] Example (25) Preparation process and structural identification data of compound 25

[0166] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 50.0 μL (0.36 mmol) of cyclohexanoyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 71.0 mg of yellow solid, with a yield of 53.0%. 1HNMR(400MHz,Methylene Chloride-d2)δ7.23-7.22(m,2H,ArH),7.14(d,J=8.4Hz,1H,ArH),7.01(s,1H,ArH),6.73(s,1H,ArH),6.02(s,2H,OCH2O),4.29–4.25(m,2H,ArCH2 CH2 N), 2.90(t, J = 6.4 Hz, 2H, Ar CH2 CH2N),2.42–2.31(m,1H,COCH),2.09–2.02(m,2H,cyclohexyl),1.83-1.78(m,2H,cyclohexyl ),1.72–1.65(m,2H,cyclohexyl),1.41–1.22(m,4H,cyclohexyl).ESI-MS(m / z):447.19.[M+H] + Example (26): Preparation process and structural identification data of compound 26

[0167] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 45.0 μL (0.36 mmol) of tetrahydropyran-4-carboxylic chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 72.0 mg of yellow solid, with a yield of 53.5%. 1 H NMR(400MHz,Methylene Chloride-d2)δ7.23(d,J=7.6Hz,1H,ArH),7.23-7.20(m,3H,ArH),6.70(s,1H,ArH),6.73(s,1H,ArH),5.96(s,2H,OCH2O),4.29(brs,2H,ArCH2 CH2 N),3.96–3.92(m,2H,tetrahydropyranyl),3.44-3.38(m,2H,tetrahydropyranyl)2.90(t,J=6.4Hz,2H,Ar CH2CH2N),2.56–2.48(m,1H,tetrahydropyranyl),1.90–1.75(m,4H,tetrahydropyranyl).ESI-MS(m / z):449.17.[M+H] + .

[0168] Example (27) Preparation process and structural identification data of compound 27

[0169] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 41.0 μL (0.36 mmol) of tetrahydrofuran-2-carboxyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 15.0 mg of yellow solid, with a yield of 11.3%. 1 H NMR (400MHz, DMSO-d6) δ7.53(s,1H,ArH),7.50(s,1H,ArH),7.47(d,J=8.4Hz,1H,ArH),7.29(d,J=8.4Hz,1H, ArH),6.95(s,1H,ArH),6.09(s,2H,OCH2O),4.38(t,J=6.8Hz,1H,tetrahydrofuranyl),4.18(brs,2H,ArCH2 CH2 N),3.75-3.66(m,2H,tetrahydrofuranyl),2.91(t,J=6.2Hz,2H,Ar CH2 CH2N),2.11(q,J=7.6Hz,2H,tetrahydrofuranyl),1.92–1.71(m,2H,tetrahydrofuranyl).ESI-MS(m / z):435.15.[M+H] + .

[0170] Example (28) Preparation process and structural identification data of compound 28

[0171] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 38.0 μL (0.36 mmol) of furanoyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and the reaction was considered complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 88.0 mg of yellow solid, with a yield of 68.2%. 1 HNMR(400MHz,DMSO-d6)δ7.73(d,J=1.6Hz,1H,ArH),7.62(s,1H,ArH),7.56(s,1H,ArH),7.50(d,J=8.4Hz,1H,ArH), 7.35(d,J=8.4Hz,1H,ArH),7.00–6.96(m,2H,ArH),6.57-6.56(m,1H,ArH),6.10(s,2H,OCH2O),4.32(brs,2H,ArCH2 CH2 N), 2.94(t, J = 6.4 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):431.12.[M+H] + Example (29): Preparation process and structural identification data of compound 29

[0172] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 45.0 μL (0.36 mmol) of 2-thiophenecarboxyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate to remove the solvent, yielding a yellow crude solid. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 28.0 mg of yellow solid, with a yield of 27.5%. 1H NMR(400MHz,Methylene Chloride-d2)δ7.29–7.21(m,2H,ArH),7.21–7.14(m,2H,ArH),7.08(s,1H,ArH), 6.98–6.92(m,2H,ArH),6.73(s,1H,ArH),6.02(s,2H,OCH2O),4.36(brs,2H,ArCH2 CH2 N),3.99(s,2H,COCH2),2.90(t,J=6.4Hz,2H,Ar CH2 CH2N).ESI-MS(m / z):461.11.[M+H] + .

[0173] Example (30) Preparation process and structural identification data of compound 30

[0174] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 58.0 μL (0.36 mmol) of o-acetylsalicylic acid chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 3 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 72.0 mg of yellow solid, with a yield of 48.1%. 1 H NMR(400MHz,DMSO-d6)δ8.17(dd,J=7.6,2.0Hz,1H,ArH),7.64(s,1H,ArH),7.56(s,1H,ArH),7.54–7.44(m,2H,Ar H),7.39–7.28(m,2H,ArH),7.10(d,J=8.0Hz,1H,ArH),6.97(s,1H,ArH),6.10(s,2H,OCH2O),4.28(brs,2H,ArCH2 CH2 N), 2.94(t, J = 6.4 Hz, 2H, Ar CH2 CH2N),2.17(s,3H,COCH3).ESI-MS(m / z):499.14.[M+H] + .

[0175] Example (31) Preparation process and structural identification data of compound 31

[0176] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 40.0 μL (0.36 mmol) of isobutyryl chloride was added dropwise to 5.0 mL of chloroform and diluted. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 50.0 mg of yellow solid, with a yield of 41.0%. 1 HNMR(400MHz,DMSO-d6)δ7.53(s,1H,ArH),7.45(d,J=8.0Hz,2H,ArH),7.28(d,J=8.0Hz,1H,ArH),6.94(s,1H,ArH),6.09(s,2H,OCH2O),4.20(brs,2H,ArCH2 CH2 N), 2.91(t, J = 6.0 Hz, 2H, Ar CH2 CH2N), 2.61–2.51 (m, 1H, CO) CH (CH3)CH3), 1.17(s, 3H, COCH( CH3 )CH3),1.15(s,3H,COCH( CH3 )CH3).ESI-MS(m / z):407.16.[M+H] + .

[0177] Example (32) Preparation process and structural identification data of compound 32

[0178] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 50.0 μL (0.36 mmol) of isovaleryl chloride was added dropwise to 5.0 mL of chloroform and diluted. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 29.0 mg of yellow solid, with a yield of 23.0%. 1HNMR(400MHz,DMSO-d6)δ7.52(s,1H,ArH),7.44(d,J=7.9Hz,2H,ArH),7.28(d,J=8.4Hz,1H,ArH),6.93(s,1H,ArH),6.09(s,2H,OCH2O),4.20(s,2HArCH2 CH2 N), 2.91(t, J = 6.0 Hz, 2H, Ar CH2 CH2N), 2.61(d,2H,CO) CH2 CH(CH3)CH3),2.32(m,1H,COCH2 CH (CH3)CH3), 1.17(s, 3H, COCH2CH( CH3 )CH3),1.15(s,3H,COCH2CH(CH3) CH3 ESI-MS (m / z): 421.17. [M+H] + .

[0179] Example (33) Preparation process and structural identification data of compound 33

[0180] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 48.0 μL (0.36 mmol) of 3-chloropropionyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 47.0 mg of yellow solid, with a yield of 40.1%. 1 HNMR(400MHz,DMSO-d6)δ8.44(s,1H,ArH),7.84(d,J=8.4Hz,1H),7.71-7.67(m,2H,ArH),7.04(s,1H,ArH),6.61(dd,J=17.0,10.4Hz,1H,CO CH CH2),6.33(d,J=17.0Hz,1H,COCH CH2 ),6.14(s,2H,OCH2O),5.89(d,J=10.4Hz,1H,COCH CH2 ),4.52(brs,2H,ArCH2 CH2 N), 3.05(t, J = 6.0 Hz, 2H, Ar CH2CH2N).ESI-MS(m / z):391.12.[M+H] + .

[0181] Example (34) Preparation process and structural identification data of compound 34

[0182] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 42.0 μL (0.36 mmol) of 4-bromobutylyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and an orange-yellow crude solid was obtained. The crude solid was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 46.0 mg of yellow solid, with a yield of 37.9%. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H,ArH),7.84(d,J=8.4Hz,1H),7.68(d,J=7.2Hz,2H,ArH),7.04(s,1H,ArH),6.33(dd,J=17.0,10.4Hz,1H,CO CH2 CH CH2),6.14(d,J=17.0Hz,1H,COCH2CH CH2 ),6.14(s,2H,OCH2O),5.89(d,J=10.4Hz,1H,COCH2CH CH2 ),4.52(s,2H,ArCH2 CH2 N), 3.05(m, 4H, Ar CH2 CH2N,CO CH2 CHCH2).ESI-MS(m / z):405.14.[M+H] + .

[0183] Example (35) Preparation process and structural identification data of compound 35

[0184] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 49.0 μL (0.36 mmol) of 5-chloropentanoyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and an orange-yellow crude solid was obtained. The crude solid was purified by silica gel column chromatography [v / v = 20:1 (dichloromethane:methanol)] to obtain 15.0 mg of yellow solid, with a yield of 11.0%. 1 H NMR (400MHz, Methanol-d4) δ7.65(s,1H,ArH),7.50–7.41(m,3H,ArH),6.84(s,1H,ArH),6.04(s,2H,OCH2O),3.65(d,J=6.0Hz,2H,ArCH2 CH2 N), 3.00(brs,2H,Ar CH2 CH2N), 2.50(brs, 2H, COCH2CH2CH2 CH2 Cl), 1.94–1.90 (m, 4H, CO) CH2CH2 CH2CH2Cl),1.30-1.29(m,2H,COCH2CH2 CH2 CH2Cl).ESI-MS(m / z):455.13.[M+H] + .

[0185] Example (36) Preparation process and structural identification data of compound 36

[0186] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 40.0 μL (0.36 mmol) of methoxyacetyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and an orange-yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 35.0 mg of orange-yellow solid, with a yield of 28.6%. 1H NMR (400MHz, Chloroform-d) δ7.48 (s, 1H, ArH), 7.40 (d, J = 6.8Hz, 1H, ArH), 7.35 (d, J = 6. 8Hz,1H,ArH),7.29(s,1H,ArH),6.78(s,1H,ArH),6.06(s,2H,OCH2O),4.53(s,2H,ArCH2 CH2 N), 4.20(s, 1H, CO CH2 OCH3), 3.53(s, 3H, COCH2O CH3 ), 3.00(d, J = 7.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):409.14.[M+H] + .

[0187] Example (37) Preparation process and structural identification data of compound 37

[0188] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 42.0 μL (0.36 mmol) of ethoxyacetyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and an orange-yellow crude solid was obtained. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 46.0 mg of yellow solid, with a yield of 33.9%. 1 H NMR (400MHz, DMSO-d6) δ7.54(s,1H,ArH),7.52(s,1H,ArH),7.48(d,J=8.4Hz,1H,ArH ),7.31(d,J=8.4Hz,1H,ArH),6.95(s,1H,ArH),6.09(s,2H,OCH2O),4.24(s,2H,ArCH2 CH2 N), 4.02(s, 2H, CO CH2 O), 3.49(q, J = 7.2 Hz, 2H, O CH2 CH3), 2.91(t, J = 6.4 Hz, 2H, Ar CH2 CH2N),1.02(t,J=7.2Hz,3H,OCH2 CH3 ESI-MS (m / z): 423.14. [M+H] + .

[0189] Example (38) Preparation process and structural identification data of compound 38

[0190] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 51.0 μL (0.36 mmol) of 2-(2-methaneoxyethoxy)acetyl chloride was diluted in 5.0 mL of chloroform and added dropwise to the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was detected by TLC and found to be complete. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 46.0 mg of yellow solid, with a yield of 33.9%. 1 H NMR(400MHz,DMSO-d6)δ7.54 -7.53(m,2H,ArH),7.48(d,J=8.4Hz,1H,ArH),7.30(d,J=8.4Hz,1H,ArH),6.95(s,1H,ArH),6.09(s,2H,OCH2O),4.24(brs,2H,ArCH2 CH2 N),4.07(s,2H,COCH2O),3.61(t,J=5.2,4.4Hz,2H,O CH2 CH2OCH3),3.38(t,J=5.2,4.4Hz,2H,OCH2 CH2 OCH3),3.20(s,3H,OCH3),2.91(t,J=6.2Hz,2H,Ar CH2 CH2N).ESI-MS(m / z):453.16.[M+H] + Example (39): Preparation process and structural identification data of compound 39

[0191] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 38.7 μL (0.36 mmol) of acetoxyacetyl chloride was added to 5.0 mL of chloroform and diluted dropwise into the above system. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 63.0 mg of yellow solid, with a yield of 48.1%. 1H NMR (400MHz, DMSO-d6) δ7.62(s,1H,ArH),7.55(s,1H,ArH),7.51(d,J=8.4Hz,1H,ArH),7.34(d,J =8.4Hz,1H,ArH),6.96(s,1H,ArH),6.10(s,2H,OCH2O),4.67(s,2H,COCH2O),4.26(brs,2H,ArCH2 CH2 N), 2.92(t, J = 6.2 Hz, 2H, Ar CH2 CH2N),2.05(s,3H,COCH3).ESI-MS(m / z):437.13.[M+H] + .

[0192] Example (40) Preparation process and structural identification data of compound 40

[0193] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 35.0 μL (0.36 mmol) of oxaloyl chloride monomethyl ester was added dropwise to 5.0 mL of chloroform and diluted. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 70.0 mg of yellow solid, with a yield of 55.2%. 1 H NMR (400MHz, DMSO-d6) δ7.81(s,1H,ArH),7.60-7.58(m,2H,ArH),7.42(d,J=8.4Hz,1H,ArH),6.98(s,1H,ArH),6.11(s,2H,OCH2O),4.36(brs,2H,ArCH2 CH2 N),3.69(s,3H,OCH3),2.96(t,J=6.2Hz,2H,Ar CH2 CH2N).ESI-MS(m / z):423.11.[M+H] + .

[0194] Example (41) Preparation process and structural identification data of compound 41

[0195] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 42.0 μL (0.36 mmol) of oxaloyl chloride monoethyl ester was added dropwise to 5.0 mL of chloroform for dilution. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate to remove the solvent, yielding a yellow crude solid. The crude solid was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 48.0 mg of yellow solid, with a yield of 36.7%. 1 H NMR(400MHz,Chloroform-d)δ7.34-7.32(m,2H,ArH),7.24(s,1H,ArH),7.22(s,1H,ArH),6.73(s,1H,ArH),6.04(s,2H,OCH2O),4.53(s,2H,ArCH2 CH2 N), 4.37(q, J = 7.2 Hz, 2H, COO CH2 CH3), 2.96(t, J = 6.2 Hz, 2H, Ar CH2 CH2N),1.40(t,J=7.2Hz,3H,COOCH2 CH3 ESI-MS (m / z): 437.13. [M+H] + .

[0196] Example (42) Preparation process and structural identification data of compound 42

[0197] 100.0 mg (0.30 mmol) of compound 16 was weighed and added to a flask. 10.0 mL of chloroform was added and the flask was placed in an ice bath. 84.0 μL (0.60 mmol) of triethylamine was then added and stirred. 48.0 μL (0.36 mmol) of ethyl chloroformate was added dropwise to 5.0 mL of chloroform and diluted. After the addition was complete, the ice bath was removed and the reaction was carried out at a constant temperature for 5 h. The system changed from yellow-green to yellow. The reaction was stopped by TLC. The reaction solution was washed twice with 1% HCl and twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed, and a yellow solid crude product was obtained. The crude product was purified by silica gel column chromatography [v / v = 30:1 (dichloromethane:methanol)] to obtain 14.0 mg of yellow solid, with a yield of 10.4%. 1H NMR (400MHz, DMSO-d6) δ7.60(s,1H,ArH),7.54(s,1H,ArH),7.51(d,J=8.4Hz,1H,ArH ),7.33(d,J=8.4Hz,1H,ArH),6.95(s,1H,ArH),6.09(s,2H,OCH2O),4.29(s,2H,ArCH2 CH2 N), 4.10(q, J = 7.2 Hz, 2H, O CH2 CH3),3.39(s,2H,COCH2CO),2.92(t,J=6.2Hz,2H,Ar CH2 CH2N),1.21(t,J=7.2Hz,3H,OCH2 CH3 ESI-MS (m / z): 451.14. [M+H] + .

[0198] Example (43) Preparation process and structural identification data of compound 43

[0199] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 46.5 μL (0.51 mmol) of aniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 10:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 20:1 (chloroform:methanol)] to obtain 14.0 mg of yellow solid, with a yield of 11.3%. 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H,ArH),7.18-7.14(m,3H,ArH),7.06-7.03(m,1H,ArH),6.89(s,2H, ArH),6.84-6.81(m,1H,ArH),6.65-6.63(m,2H,ArH),6.07(s,2H,OCH2O),3.91(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.84(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):413.15.[M+H] + .

[0200] Example (44) Preparation process and structural identification data of compound 44

[0201] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 46.5 μL (0.51 mmol) of p-toluidine was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 10:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 20:1 (chloroform:methanol)] to obtain 52.0 mg of yellow solid, with a yield of 40.6%. 1 H NMR (400MHz, DMSO-d6) δ7.44(s,1H,ArH),7.14(d,J=8.4Hz,1H,ArH),7.00(d,J=8.4Hz,1H,ArH),6.97-6.95(m,2H,A rH),6.87(s,1H,ArH),6.82(s,1H,ArH),6.52(d,J=8.0Hz,2H,ArH),6.06(s,2H,OCH2O),3.84(t,J=5.8Hz,2H,ArCH2 CH2 N), 2.81(t, J = 5.9 Hz, 2H, Ar CH2 CH2N),2.21(s,3H,ArCH3).ESI-MS(m / z):427.15.[M+H] + .

[0202] Example (45) Preparation process and structural identification data of compound 45

[0203] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 62.8 mg (0.51 mmol) of p-methoxyaniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 10:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 20:1 (chloroform:methanol)] to obtain a yellow solid of 81.0 mg, with a yield of 71.8%. 1 H NMR (400MHz, DMSO-d6) δ7.44(s,1H,ArH),7.12(d,J=8.0Hz,1H,ArH),6.98(d,J=8.0Hz,1H,ArH),6.87(s,1H,ArH),6.7 9(s,1H,ArH),6.75(d,J=8.8Hz,2H,ArH),6.56(d,J=8.8Hz,2H,ArH),6.06(s,2H,OCH2O),3.85(t,J=6.0Hz,2H,ArCH2C H 2N),3.68(s,3H,OCH3),2.82(t,J=6.1Hz,2H,ArC H 2CH2N).ESI-MS(m / z):443.16.[M+H] + .

[0204] Example (46) Preparation process and structural identification data of compound 46

[0205] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 78.2 mg (0.51 mmol) of 3,4-dimethoxyaniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 20:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 20:1 (chloroform:methanol)] to obtain 20.0 mg of yellow solid, with a yield of 16.6%. 1H NMR(400MHz,DMSO-d6)δ7.98(d,J=8.4Hz,1H,ArH),7.45(s,1H,ArH),7.26(d,J=8.4Hz,1H,ArH),7.20–7.01(m, 2H,ArH),6.88(s,1H,ArH),6.76(d,J=8.4Hz,1H,ArH),6.40(s,1H,ArH),6.07(s,2H,OCH2O),3.85(s,2H,ArCH2C H 2N),3.68(s,3H,OCH3),3.64(s,3H,OCH3),2.82(t,J=6.0Hz,2H,ArC H 2CH2N).ESI-MS(m / z):473.17.[M+H] + .

[0206] Example (47) Preparation process and structural identification data of compound 47

[0207] 100.0 mg (0.265 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 114 mg (0.663 mmol) of p-bromoaniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 20:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 20:1 (chloroform:methanol)] to obtain 40.0 mg of yellow solid, with a yield of 30.7%. 1 H NMR (400MHz, DMSO-d6) δ7.46(s,1H,ArH),7.29(d,J=8.4Hz,2H,ArH),7.19(d,J=8.0Hz,1H,ArH),7.0 5(d,J=8.0Hz,1H,ArH),6.91(s,1H,ArH),6.89(s,1H,ArH),6.57(d,J=8.4Hz,2H,ArH),6.07(s,2H,OC H 2O),3.94(t,J=6.0Hz,2H,ArCH2C H2 N), 2.88–2.81 (m, 2H, ArC) H2 CH2N).ESI-MS(m / z):491.06.[M+H] + .

[0208] Example (48) Preparation process and structural identification data of compound 48

[0209] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 81.3 mg (0.64 mmol) of p-chloroaniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane hydrochloride solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 20:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 30:1 (chloroform:methanol)] to obtain 35.0 mg of yellow solid, with a yield of 30.7%. 1 H NMR (400MHz, DMSO-d6) δ7.46(s,1H,ArH),7.20(d,J=8.4Hz,1H,ArH),7.17(d,J=8.4Hz,2H,ArH),7.06(d,J=8.4Hz,1H ,ArH),6.93(s,1H,ArH),6.89(s,1H,ArH),6.63(d,J=8.4Hz,2H,ArH),6.07(s,2H,OCH2O),3.95(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.85(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):447.11.[M+H] + .

[0210] Example (49) Preparation process and structural identification data of compound 49

[0211] 100.0 mg (0.255 mmol) of compound 8 was weighed and added to a flask. 20.0 mL of toluene was added and stirred. 140.0 mg (0.64 mmol) of p-iodoaniline was added to the above system. The reaction was carried out at room temperature for 6 h under argon protection. The system remained red and turbid. 3.0 mL of diethyl ether was added to the reaction system and stirred. Then 1.0 mL of 4M dioxane solution was added. A large amount of orange-red flocculent matter was present in the system. The mixture was filtered, and the filter cake was light red. The filter cake was dissolved in a mixed solvent of chloroform and methanol (V chloroform:V methanol = 20:1). The mixture was extracted with 1.0% NaHCO3 solution. The organic phase was washed twice with saturated brine. The organic layer was separated and dried with anhydrous magnesium sulfate. The solvent was removed to obtain a red solid crude product. The crude product was purified by silica gel column chromatography [v / v = 30:1 (chloroform:methanol)] to obtain 38.0 mg of yellow solid, with a yield of 27.7%. 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=8.4Hz,1H,ArH),7.45-7.43(m,3H,ArH),7.26(d,J=8.4Hz,1H,ArH),7.19(d,J=8.4Hz,1H,ArH), 7.05(d,J=8.4Hz,1H,ArH),6.89(d,J=6.0Hz,2H,ArH),6.45(d,J=8.1Hz,2H,ArH),6.07(s,2H,OCH2O),3.93(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.84(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):539.04.[M+H] + .

[0212] Example (50) Preparation process and structural identification data of compound 50

[0213] 100.0 mg (0.279 mmol) of compound 3 was added to 4.0 mL of anhydrous methanol, followed by 78.0 mg (0.558 mmol) of anhydrous potassium carbonate. The mixture was placed in an ice bath and stirred. 10.0 mg (0.279 mmol) of NaBH4 was dissolved in 0.8 mL of 5% NaOH and added dropwise to the above system. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was detected by TLC and the mixture was filtered. The filter cake was washed with 30.0% ethanol and 80.0% ethanol, respectively, and then recrystallized from ethanol. After drying, 31.0 mg of the product was obtained, with a yield of 34.4%. 1H NMR (400MHz, DMSO-d6) δ7.29(s,1H,ArH),6.76(s,1H,ArH),6.69(d,J=8.0Hz,1H,ArH),6.47(d,J=8. 0Hz,1H,ArH),6.09(s,1H,ArH),6.53(s,2H,OCH2O),4.16(s,2H,NCH2Ar),3.05(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.79(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):324.11.[M+H] + Example (51): Preparation process and structural identification data of compound 51

[0214] 100.0 mg (0.278 mmol) of compound 4 was added to 4.0 mL of anhydrous methanol, followed by 78.0 mg (0.556 mmol) of anhydrous potassium carbonate. The mixture was placed in an ice bath and stirred. 10.0 mg (0.278 mmol) of NaBH4 was dissolved in 0.8 mL of 5% NaOH and added dropwise to the above system. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction was detected by TLC and the mixture was filtered. The filter cake was washed with 30.0% ethanol and 80.0% ethanol, respectively, and then recrystallized from ethanol. After drying, 31.0 mg of the product was obtained, with a yield of 34.4%. 1 H NMR(400MHz,DMSO-d6)δ7.29(s,1H,ArH),6.76(s,1H,ArH),6.69(d,J=8.0Hz,1H,ArH),6.4 7(d,J=8.0Hz,1H,ArH),6.09(s,1H,ArH),4.16(s,2H,NCH2Ar),3.05(t,J=6.0Hz,2H,ArCH2 CH2 N), 2.79(t, J = 6.0 Hz, 2H, Ar CH2 CH2N).ESI-MS(m / z):326.12.[M+H] + .

[0215] II. Toxicological and pharmacodynamic evaluation examples of the compounds of this invention

[0216] Experimental Example 1: Toxicity Evaluation of the Inhibitory Activity of the Compounds of the Present Invention on RAW264.7 Cell Growth – CCK-8 Assay for the Effect of the Compounds of the Present Invention on RAW264.7 Cell Viability

[0217] RAW 264.7 cells in the logarithmic growth phase were collected, the original culture medium was discarded, and fresh DMEM culture medium was added. The cells were gently pipetted to mix thoroughly. 10 μL of the cell mixture was placed in a cell counter to detect the cell concentration. The cells were then diluted with culture medium to control the cell count at 5 × 10⁻⁶ cells / mL. 5 Cells / mL, after being thoroughly mixed by pipetting, are seeded into 96-well plates at a volume of 100 μL per well. The wells are filled with PBS around the edges to prevent the "edge effect." The plates are then incubated at 37°C with 5% CO2. After 24 hours of incubation, cell morphology and adhesion are observed. If everything is normal, 10 mM of the compound stock solution and the positive control drug (YSHLJ, berberine hydrochloride) are diluted with culture medium to the appropriate concentration and added to each 96-well plate at a volume of 100 μL. At least three replicates are set up for each drug concentration. A blank group (containing only culture medium) and a normal cell control group are also included. The plates are then incubated for further incubation. After 24 hours of drug treatment, 10 μL of CCK-8 solution is added to each well. The plates are incubated for 3 hours, and the absorbance (OD value) is measured at 450 nm using a microplate reader. The calculation formula is as follows:

[0218] Cell viability (%) = [(OD value of drug administration wells - OD value of blank wells) / (OD value of control wells - OD value of blank wells)] x 100%

[0219] The experimental results are shown in Table 1.

[0220] Table 1. Effects of different concentrations of the compounds of the present invention on the cell viability of RAW264.7 cells.

[0221]

[0222]

[0223] As can be seen from Table 1 above, the compounds of the present invention do not have obvious cytotoxicity to normal RAW264.7 cells, and the survival rate is above 90%. Furthermore, the cell survival rate does not decrease significantly with increasing concentration.

[0224] Experimental Example 2: Evaluation of the inhibitory effect of the compound of the present invention on excessive NO secretion levels in an LPS-stimulated RAW 264.7 cell inflammation model (ICP-C) 50 )

[0225] In this experiment, the Griess method was used to detect the inhibitory effect of the compounds of this invention on the excessive production of nitric oxide (NO) in an LPS-stimulated RAW264.7 cell inflammation model.

[0226] Take the initial solution of the compound and dilute it with culture medium to prepare a working solution with a specific final effective concentration.

[0227] Take RAW264.7 cells that are in good growth condition and in the logarithmic growth phase, add an appropriate amount of culture medium, gently pipette to prepare a cell suspension, and adjust the cell density of the cell suspension to 6 × 10⁻⁶. 5 Cells were seeded at a density of 100 μl / mL in 96-well cell culture plates. The plates were incubated overnight in a 5% CO2 incubator at 37°C until complete cell adhesion was observed, indicating good cell morphology. Experimental groups were set up in the 96-well plates, including groups treated with the compounds of this invention, LPS-stimulated model groups, and normal cell control groups. The cell culture supernatant was discarded, and working solutions of the compounds of this invention at specific final action concentrations were added to each group to prepare intervention cell suspensions containing the compounds of this invention, with a volume of 100 μl per well. The LPS-stimulated model groups and normal cell control groups were treated with the corresponding amounts of culture medium. After pre-incubating the 96-well plates in a cell culture incubator for 2 hours, LPS stimulation was added to each group treated with the compounds of this invention and the model groups at a concentration of 0.5 μg / mL. The 96-well plates were placed in a cell culture incubator and cultured for 24 hours. Afterward, 50 μL of supernatant was collected from each well and added to a new 96-well plate. Following the procedure outlined in the NO detection kit instructions, 50 μL of Griess A was added, followed by 50 μL of Griess B after 1 min. The reaction was continued for 15 min, and the OD value was measured at 540 nm using a microplate reader. Based on a pre-established standard curve using NaNO2, the concentration of sodium nitrite in the samples was calculated, and the NO content in the cell culture medium of each group was calculated. The nitric oxide release inhibition rate was calculated by substituting the NO content values ​​into the following formula. Each compound was performed independently at least three times.

[0228] Nitric oxide release inhibition rate = [(NO amount in model group - NO release in treatment group) / (NO amount in model group - NO release in blank group)] × 100%

[0229] The inhibition rate values ​​of NO release at different concentrations obtained from the above three independent experiments were summarized and imported into Prism software for processing to obtain the experimental results of the compounds of this invention (see Table 2).

[0230] Table 2. Inhibitory effect of the compounds of this invention on NO release in LPS-stimulated RAW264.7 cells.

[0231]

[0232]

[0233] As can be seen from Table 2, the compounds of the present invention generally exhibit a stronger inhibitory effect on the release of nitric oxide in LPS-stimulated RAW264.7 cells than non-deuterated coptisine hydrochloride, wherein the deuterated dihydropalmatrubine compounds have a stronger inhibitory effect on the release of nitric oxide in LPS-stimulated RAW264.7 cells than the quaternary ammonium salt compounds of palmatrubine. The IC of Compounds 20, 30, and 33 of the present invention 50 can reach the micromolar level. Experimental Example 3: In vivo activity evaluation of the compounds of the present invention in animal experiments for anti-ulcerative colitis

[0234] (1) Materials and methods

[0235] 1) Animals: C57BL / 6J mice, male, with a body weight range of 22-25g.

[0236] 2) Grouping: This experiment is divided into a normal control group, a dextran sulfate sodium model group, a positive drug sulfasalazine group, a dihydrocoptisine (11-ND) group, an N-dihydrocoptisine-8-ylidene-o-acetoxybenzamide (30-ND) group, and administration groups of Compounds 11, 20 and 30 of the present invention. The mice are randomly grouped, with 7 mice in each group.

[0237] 3) Administration dosage and frequency: The administration dosage for the positive drug sulfasalazine administration group is 500mg / kg; the administration dosages for the dihydrocoptisine (11-ND) group, the N-dihydrocoptisine-8-ylidene-o-acetoxybenzamide (30-ND) group, and the administration groups of Compounds 11, 20 and 30 of the present invention are all 200mg / kg; administration is performed once a day for 8 days.

[0238] 4) Experimental method: C57BL / 6J mice are acclimatized and reared for one week in an SPF-grade animal room (Laboratory Animal Use License No.: SYXK(Jing)2014-0023), then randomly grouped according to the experimental design. Mice in the model group and each compound administration group are modeled daily with dextran sulfate sodium (MP, CA9011-18-1, US) according to the literature method (J. Med. Chem., 2015, 58, 7557-7571). The normal control group and the model group are administered by gavage with 0.5% sodium carboxymethyl cellulose aqueous solution once a day. The sulfasalazine group, each compound of the present invention, the dihydrocoptisine (11-ND) control experimental group, and the N-dihydrocoptisine-8-ylidene-o-acetoxybenzamide (30-ND) control experimental group are administered by gavage once a day according to the experimental design protocol. Sulfasalazine, each compound of the present invention and the control compounds are respectively prepared with 0.5% sodium carboxymethyl cellulose aqueous solution at the administration dosages specified in the experimental protocol.

[0239] After modeling, the drugs were administered continuously for 8 days until the animals in the model group showed obvious typical symptoms of ulcerative colitis, such as lethargy, reduced activity, weight loss, loose stools, and bloody stools. The experiment was terminated at that time, and the animals in each group were sacrificed. Various relevant evaluation indicators of ulcerative colitis were tested (see the experimental results section) to comprehensively evaluate the anti-ulcerative colitis pharmacodynamic activity of each group.

[0240] (2) Experimental Results

[0241] Compounds 11, 20, and 30 of this invention exhibit significant therapeutic effects in vivo on an acute C57BL / 6J mouse ulcerative colitis model induced by sodium dextran sulfate, which are superior to other comparative compounds (11-ND, 30-ND); the results of each evaluation index are as follows.

[0242] 1) Compounds 11, 20, and 30 of the present invention can effectively reduce the decrease in body weight in a mouse model of acute C57BL / 6J ulcerative colitis induced by sodium dextran sulfate (see Table 3).

[0243] Table 3. The effect of the compounds of this invention on reducing body weight in mice with ulcerative colitis.

[0244]

[0245] Note: ### p<0.001, ## p<0.01, # p<0.05, compared with the normal control group; *** p<0.001, ** p<0.01, * p<0.05, compared with the model group. Positive drug: sulfasalazine; 11-ND: dihydroberberine; 30-ND: N-dihydroberberine-8-methylenediamine o-acetoxybenzamide. a p<0.05, comparison between group 11 and group 11-ND; b p<0.05, comparison between group 30 and group 30-ND.

[0246] As shown in Table 3, compared with the initial body weight of each group of animals, at the end of the experiment, the body weight of the normal control group increased by +4.43% (increase is positive, decrease is negative), while the body weight of the model group decreased by -20.51%. ### p<0.001 (compared to the normal control group), consistent with the trend of ulcerative colitis model, indicating successful model establishment. The weight loss rates of animals in the compound 11, 20, and 30 administration groups at a dose of 200 mg / kg were -7.47% (p<0.001, compared to the normal control group). *** p<0.001, compared with the model group), -7.76% ( *** p<0.001, compared with the model group), -4.88% (*** p<0.001 (compared to the model group), the weight change rates of animals in the control groups 11-ND and 30-ND at a dose of 200 mg / kg were -10.51% (p<0.001). * p<0.05, compared with the model group), -7.10% ( *** p < 0.001 (compared to the model group). Therefore, compounds 11, 20, and 30 of the present invention, as well as comparative compounds 11-ND and 30-ND, can all slow down or significantly slow down the decrease in body weight of model animals, showing statistically significant differences compared to the model group. It is particularly noteworthy that compound 11 of the present invention, compared to comparative compound 11-ND... * p<0.05, compared with the comparative compound 30-ND, the compound of the present invention 30. * p<0.05 indicates that the deuterated berberine compound in this invention has a better therapeutic effect on ulcerative colitis than the undeuterated berberine compound.

[0247] 2) Compounds 11, 20, and 30 of this invention can effectively alleviate colorectal contracture in a model of acute C57BL / 6J mouse ulcerative colitis induced by sodium dextran sulfate (see Table 4).

[0248] Table 4. Improvement of colorectal spasm in mice with ulcerative colitis by the compounds of the present invention.

[0249]

[0250]

[0251] Note: ### p<0.001, ## p<0.01, # p<0.05, compared with the normal control group; *** p<0.001, ** p<0.01,

[0252] * p<0.05, compared with the model group. Positive drug: sulfasalazine; 11-ND: dihydroberberine; 30-ND: N-dihydroberberine-8-methylenediamine o-acetoxybenzamide. a p<0.05, comparison between group 11 and group 11-ND; b p<0.05, comparison between group 30 and group 30-ND.

[0253] As shown in Table 4, the colon and rectum length in the normal group was approximately 6.8 cm. Compared to the normal group, the percentage of colon and rectum contracture in the model group was 29.7%, a significant difference, indicating successful model establishment. At a dosage of 200 mg / kg, the percentage of colon and rectum contracture in the animal groups treated with compounds 11, 20, and 30 of this invention was -10.74% (…). *** p<0.001, compared with the model group), 12.79% ( *** p<0.001, compared with the model group), -3.97% ( *** p<0.001 (compared to the model group), the percentage of colorectal contracture in the control groups 11-ND and 30-ND at a dose of 200 mg / kg was 18.53% (p<0.001, compared to the model group). * p<0.05, compared with the model group), 9.24% ( *** p < 0.001 (compared to the model group). Therefore, compounds 11, 20, and 30 of the present invention, as well as comparative compounds 11-ND and 30-ND, can alleviate or significantly alleviate the spasms of the colon and rectum in model animals, showing statistically significant differences compared to the model group. It is particularly noteworthy that compound 11 of the present invention, compared to comparative compound 11-ND... * p<0.05, compared with the comparative compound 30-ND, the compound of the present invention 30. * p<0.05 indicates that the deuterated berberine compound in this invention has a better therapeutic effect on ulcerative colitis than the undeuterated berberine compound.

[0254] from Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 As can be seen, compounds 11, 20, and 30 of the present invention, at a dosage of 200 mg / kg, showed similar trends in improving fecal occult blood, disease activity index (DAI), and hematochezia in mice with DSS-induced acute ulcerative colitis as the aforementioned animal weight and colonic and rectal contracture indices. From the beginning to the end of the experiment, the fecal occult blood and disease activity index (DAI) scores of the model mice treated with compounds 11, 20, and 30 showed significant improvement compared to the model group. All compounds were superior to the positive control drug. Compound 11 of the present invention was superior to the control compound 11-ND, and compound 30 of the present invention was superior to the control compound 30-ND, indicating that the deuterated berberine compounds of the present invention have a superior therapeutic effect on ulcerative colitis compared to the undeuterated berberine compounds.

[0255] Experimental Example 4: In vitro metabolism experiment of the compound of the present invention

[0256] (1) Experimental materials: Phase I metabolic stability kit (IPHASE), compound of the present invention, 0.1M PBS buffer, acetonitrile (chromatographic grade), centrifuge tubes, sterile pipette tips.

[0257] (2) Experimental apparatus: constant temperature water bath, centrifuge, pipette, shaker

[0258] (3) Experimental methods:

[0259] 1) Thaw the kit components in an ice bath and use on ice.

[0260] 2) Preparation of the incubation system:

[0261]

[0262] The concentration of liver microsomal protein used was 0.5 mg / mL, and the final concentration of the test substance (the compound of the present invention) was 1 μmol.

[0263] 3) Add 160 μL of pre-incubation solution B to a centrifuge tube containing 10 μmol of pre-incubation solution A, mix by blowing three times, and immediately place it in a 37°C water bath for incubation and timing. Set up five sampling points at 0, 15, 30, 45, and 60 minutes.

[0264] 4) Take samples at the set incubation time points and add the stop solution (the stop solution is pre-cooled acetonitrile, acetonitrile:incubation system volume = 4:1).

[0265] 5) Control Groups: To ensure the validity of the experiment, a positive control group, a negative control group, and a blank control group were set up. The system configuration was the same as that of the experimental group. In the positive control group, the test substance was replaced with a positive substrate (testosterone) to assess whether the incubation system was working properly. In the negative control group, incubation solution A was not added; PBS was used instead, which theoretically does not metabolize. In the blank control group, only a solution containing the test substance and PBS was added to assess the stability of the test substance itself.

[0266] 6) Data processing: Peak area was used as the calculation data. The in vitro half-life of the compound was determined by calculating the percentage of each time point relative to the initial concentration using a regression curve. The zero-time concentration of the test substance was taken as 100%, and the remaining percentage was obtained by comparing the concentrations at each non-zero time point with the zero-time concentration. The natural logarithm of the substrate remaining percentage at each time point was linearly regressed against the incubation time to obtain the slope K. Elimination half-life = -0.693 / K

[0267] (4) Experimental results: see Table 5

[0268] Table 5 Results of rat liver microsomal metabolism experiments on the compounds of the present invention at a concentration of 1 μmol.

[0269]

[0270] As shown in Table 5, the metabolic half-life of berberine hydrochloride in mouse liver microsomes in vitro is 11.89 minutes. In comparison, the half-lives of compounds 2 and 4 of the present invention are 19.74 minutes and 20.32 minutes, respectively, which is twice as long. This indicates that the modification of the compounds of the present invention based on berberine hydrochloride improves its metabolic stability through deuteration, thereby enhancing its efficacy.

Claims

1. Deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivatives as shown in general formula I: When R2 and R3 are bonded to form a deuterated alkylene dioxy group: R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano; R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group; R 13 It is independently selected from H, D, alkyl, or trideuterated methyl; X A ˉ Selected from monovalent inorganic or organic acid radicals; When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group: R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group. R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano; R 13 It is independently selected from H, D, alkyl, or trideuterated methyl; X A ˉ Selected from monovalent inorganic or organic acid radicals; When R 13 When independently selected from D: R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group. R8 is independently selected from H, D, alkyl, trideuterated methyl, halogen, and cyano; R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group; X A ˉ Selected from monovalent inorganic or organic acid radicals.

2. The deuterium-substituted pan-berberine alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The C1-C4 alkoxy groups are independently selected from methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

3. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The alkylene dioxy group is independently selected from methylenedioxy, ethylenedioxy, propylenedioxy, and butylenedioxy.

4. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The deuterated alkylene dioxy group is independently selected from dideuterated methylene dioxy group.

5. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The alkyl group includes C1-C12 straight-chain or branched alkyl groups, C3-C8 monocyclic cycloalkyl groups, and C5-C8 monocyclic heterocyclic alkyl groups containing heteroatoms.

6. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The halogens are independently selected from fluorine, chlorine, bromine, and iodine.

7. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 5, characterized in that, The heteroatoms are independently selected from oxygen and nitrogen.

8. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The monovalent inorganic acid anions are independently selected from halogen anions, bisulfate anions, bicarbonate anions, dihydrogen phosphate anions, hypohalite anions, halide anions, halide anions, perhalite anions, and nitrate anions.

9. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to claim 1, characterized in that, The monovalent organic acid anions are independently selected from formate, acetate, propionate, benzoate, p-hydroxybenzoate, salicylate, protocatechuic acid, ferulic acid, isoflavone, urobilinate, cinnamic acid, p-hydroxycinnamic acid, caffeic acid, phenylacetic acid, scopolamine, gallic acid, veratrite, piperate, 3,4,5-trimethoxybenzoate, bromelain, shikimate, (S)-lactate, (R)-lactate, (±)-lactate, (2R,3R)-(+)-hydrotartrate, (2S,3S)-(-)- Dihydrotartrate, (±)-tartrate, furanoate, dihydrocitrate, dihydrocitrate, maleate, fumarate, L-malate, D-malate, (dl)-malate, oxalate, carotene, succinate, glutarate, adipate, heptaate, succinate, azelaate, sebacic acid, benzenesulfonate, gluconate, ascorbate, aminosulfonate, p-toluenesulfonate, methanesulfonate, ethanesulfonate, 2-naphthalenesulfonate, dichloroacetate, or difluoroacetate.

10. The deuterium-substituted pan-berberine-type alkaloid quaternary ammonium salt derivative according to any one of claims 1-9, characterized in that, The compounds are selected from the following group of compounds:

11. A method for synthesizing quaternary ammonium salts of 13-position deuterated pan-berberine alkaloids, characterized in that, The synthetic method used to prepare the 13-deuterated berberine-type alkaloid quaternary ammonium salt compound is as follows: weigh the berberine-type alkaloid quaternary ammonium salt compound, add sodium hydroxide solution and stir, then add acetone, react at room temperature, filter after the reaction is complete, wash the filter cake with water until neutral, dry the filter cake, add the obtained filter cake to tetrahydrofuran and stir, add deuterated hydrochloric acid, heat to reflux, filter after the reaction is complete to obtain the 13-deuterated berberine-type alkaloid quaternary ammonium salt compound.

12. A synthetic method for preparing deuterated substituted pan-berberine alkaloid quaternary ammonium salt derivatives with R2 and R3 linked to form a dideuterated methylenedioxy group, as shown in Formula IV: N-methylpyrrolidone was added to anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA) and stirred and heated under Ar protection for later use. 3,4-Dihydroxybenzaldehyde was weighed, dissolved in N-methylpyrrolidone, and then dideuterated dichloromethane was added to the above-mentioned prepared system. The reaction was kept at a constant temperature to obtain M2-2. M2-2 was dissolved in glacial acetic acid, and nitromethane and ammonium acetate were added. The reaction was heated until the reaction was complete, and water was added and filtered to obtain M2-3. M2-3 was dissolved in tetrahydrofuran and added dropwise to a tetrahydrofuran solution of boron trifluoride diethyl ether and sodium borohydride in an ice-salt bath under argon protection. The reaction was heated until the reaction was complete, water was added to the reaction system, followed by dilute hydrochloric acid. The system was heated and stirred until the reaction was complete. The tetrahydrofuran was removed after the reaction was complete, and the system was extracted with an organic solvent, leaving an aqueous layer. The pH was adjusted to 12, and the aqueous layer was extracted with an organic solvent. The solvent was removed from the organic layer to obtain M2. M2 reacted with substituted benzaldehyde M1 to prepare an ammonium salt to obtain M. Copper sulfate, sodium chloride, and glyoxal were added to a mixed solvent of formic acid and phosphoric acid for a pre-reaction. Then, M was added, and the reaction continued until completion. The reaction mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain intermediate M-1. M-1 was added to an inorganic strong base solution and stirred until uniformly dispersed. Methyl ketone reagent was added to react until completion. The reaction mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain intermediate M-2. M-2 was added to a reaction solvent and stirred until uniformly dispersed. Acid was added to react until completion. The reaction mixture was filtered to obtain a filter cake, which is the quaternary ammonium salt T of the pan-corydaline alkaloid. R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group.

13. The method for preparing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 12, characterized in that, The organic solvent is independently selected from ethyl acetate, dichloromethane, chloroform, and diethyl ether.

14. The method for preparing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 12, characterized in that, The inorganic strong base is independently selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide.

15. The method for preparing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 12, characterized in that, The methyl ketone reagent is independently selected from acetone, 2-butanone, 2-pentanone, and 2-hexanone.

16. The method for preparing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 12, characterized in that, The acid is independently selected from inorganic acids or organic acids.

17. The method for preparing a deuterated substituted pan-berberine alkaloid quaternary ammonium salt derivative with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 16 and claim 12, characterized in that, The inorganic acid is independently selected from inorganic acids corresponding to the inorganic acid anions in claim 8.

18. The method for synthesizing a deuterated pan-berberine alkaloid quaternary ammonium salt derivative with R2 and R3 linked to form a dideuterated methylenedioxy group according to claim 16, characterized in that... The organic acid is independently selected from organic acids corresponding to the organic acid anions in claim 8.

19. Prepare R9 and R as shown in Formula V. 10 Synthetic methods for deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group: N-methylpyrrolidone was added to anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA), and stirred and heated under Ar protection for later use. 2,3-Dihydroxybenzaldehyde was weighed, dissolved in N-methylpyrrolidone, and then dideuterated dichloromethane was added. This was then added to the prepared system, and the reaction was maintained at this temperature to obtain M1. M1 reacted with substituted phenylethylamine M2 to prepare an ammonium salt, yielding M. Copper sulfate, sodium chloride, and glyoxal were added to a mixed solvent of formic acid and phosphoric acid for a pre-reaction, followed by the addition of M, and the reaction continued until... After the reaction was completed, the reaction mixture was filtered, the filter cake was washed with water until neutral and dried to obtain intermediate M-1; M-1 was added to an inorganic strong base solution and stirred until evenly dispersed, methyl ketone reagent was added to carry out the reaction until the reaction was completed, the reaction mixture was filtered, the filter cake was washed with water until neutral and dried to obtain intermediate M-2; M-2 was added to the reaction solvent and stirred until evenly dispersed, acid was added to carry out the reaction until the reaction was completed, the reaction mixture was filtered to obtain filter cake, which is the quaternary ammonium salt T of the pan-coprenine type alkaloid. R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

20. The preparation of R9 and R according to claim 19 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The inorganic strong base is independently selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide.

21. The preparation of R9 and R according to claim 19 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The methyl ketone reagent is independently selected from acetone, 2-butanone, 2-pentanone, and 2-hexanone.

22. The preparation of R9 and R according to claim 19 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The acid is independently selected from inorganic acids or organic acids.

23. The preparation of R9 and R according to claim 22 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The inorganic acid is independently selected from inorganic acids corresponding to the inorganic acid anions in claim 8.

24. The preparation of R9 and R according to claim 22 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The organic acid is independently selected from organic acids corresponding to the organic acid anions in claim 8.

25. Preparation as shown in Formula VI: R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 Synthetic methods for deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group: N-methylpyrrolidone was added to anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA) and stirred and heated under Ar protection for later use. 3,4-Dihydroxybenzaldehyde was weighed, dissolved in N-methylpyrrolidone, and then dideuterated dichloromethane was added to the prepared system. The reaction was maintained at a certain temperature to obtain M2-2. M2-2 was dissolved in glacial acetic acid, and nitromethane and ammonium acetate were added. The reaction was heated until complete, and the mixture was filtered with water to obtain M2-3. M2-3 was dissolved in tetrahydrofuran and added dropwise under argon protection to a tetrahydrofuran solution of boron trifluoride diethyl ether and sodium borohydride in an ice-salt bath. The reaction was heated. After the reaction is complete, water is added to the reaction system, followed by dilute hydrochloric acid. The mixture is heated and stirred until the reaction is complete. After removing tetrahydrofuran, the mixture is extracted with an organic solvent, leaving an aqueous layer. The pH is adjusted to 12, and the mixture is extracted with an organic solvent. The organic layer is removed to obtain M2. N-methylpyrrolidone is added to anhydrous potassium carbonate and benzyltriethylammonium bromide (TEBA), and stirred and heated under Ar protection for later use. 2,3-Dihydroxybenzaldehyde is weighed, N-methylpyrrolidone is dissolved, and dideuterated dichloromethane is added. The mixture is then added to the above-mentioned prepared system, and the reaction is maintained at a certain temperature to obtain M1. M1 reacts with M2 to prepare an ammonium salt to obtain M. Copper sulfate, sodium chloride, and glyoxal were added to a mixed solvent of formic acid and phosphoric acid for a pre-reaction. Then, M was added, and the reaction continued until completion. The reaction mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain intermediate M-1. M-1 was added to an inorganic strong base solution and stirred until uniformly dispersed. Methyl ketone reagent was added to react until completion. The reaction mixture was filtered, and the filter cake was washed with water until neutral and dried to obtain intermediate M-2. M-2 was added to a reaction solvent and stirred until uniformly dispersed. Acid was added to react until completion. The reaction mixture was filtered to obtain a filter cake, which is the quaternary ammonium salt T of the pan-corydaline alkaloid.

26. According to claim 25, R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The organic solvent is independently selected from ethyl acetate, dichloromethane, chloroform, and diethyl ether.

27. According to claim 25, R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The inorganic strong base is independently selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide.

28. According to claim 25, R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The methyl ketone reagent is independently selected from acetone, 2-butanone, 2-pentanone, and 2-hexanone.

29. The preparation according to claim 25, wherein R2 and R3 are linked to form a dideuterated methylenedioxy group and R9 and R 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The acid is independently selected from inorganic acids or organic acids.

30. According to claim 29, R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The acid is independently selected from inorganic acids or organic acids, and the inorganic acid is independently selected from inorganic acids corresponding to the inorganic acid anions in claim 8.

31. According to claim 29, R2 and R3 are linked to form a dideuterated methylenedioxy group, and R9 and R... 10 A method for synthesizing deuterated pan-berberine-type alkaloid quaternary ammonium salt derivatives linked to a dideuterated methylenedioxy group, characterized in that... The acid is independently selected from inorganic acids or organic acids, and the organic acid is independently selected from organic acids corresponding to the organic acid anions in claim 8.

32. A pharmaceutical composition, characterized in that, The product contains an effective dose of any one of the deuterated quaternary ammonium salt derivatives of the pan-berberine alkaloids according to claims 1-31 and a pharmaceutically acceptable carrier or excipient.

33. The use of the deuterium-substituted quaternary ammonium salt derivative of any one of claims 1-10 or the pharmaceutical composition of claim 32 in the preparation of a medicament for the prevention, relief and / or treatment of inflammatory diseases.

34. In the application of claim 33, the inflammation is selected from ulcerative colitis.

35. Tertiary amine-type deuterated pan-berberine alkaloids as shown in general formula II and their physiologically acceptable salts: Represents a single or double bond; When R2 and R3 are bonded to form a deuterated alkylene dioxy group: Selected from single bonds, R8 is independently selected from H, D, OH, trichloromethyl, tribromomethyl, trifluoromethyl, alkylmethyl, or Selected from double bonds, R8 is selected from O, dichloromethylene, or dibromomethylene; R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group; R 13 It is independently selected from H, D, methyl, or trideuterated methyl; When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group: R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group. Selected from single bonds, R8 is independently selected from H, D, OH, trichloromethyl, tribromomethyl, trifluoromethyl, alkylmethyl, or Selected from double bonds, R8 is independently selected from O, dichloromethylene, and dibromomethylene; R 13 It is independently selected from H, D, methyl, or trideuterated methyl.

36. The tertiary amine-type deuterated pan-berberine alkaloid compound and its physiologically acceptable salt according to claim 35, characterized in that, The C1-C4 alkoxy groups are independently selected from methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

37. The tertiary amine-type deuterated pan-berberine alkaloid compound and its physiologically acceptable salt according to claim 35, characterized in that, The alkylene dioxy group is independently selected from methylenedioxy, ethylenedioxy, propylenedioxy, and butylenedioxy.

38. The tertiary amine-type deuterated pan-berberine alkaloid compound and its physiologically acceptable salt according to claim 35, characterized in that, The deuterated alkylene dioxy group is independently selected from dideuterated methylene dioxy group.

39. The tertiary amine-type deuterated pan-berberine alkaloid compound and its physiologically acceptable salt according to claim 35, characterized in that, The alkylmethyl group is independently selected from acetylmethyl, propionylmethyl, butyrylmethyl, and butyrylmethyl.

40. The tertiary amine-type deuterated pan-berberine alkaloid compound and its physiologically acceptable salt according to any one of claims 35-39, characterized in that, The compounds are selected from the following group of compounds:

41. A synthetic method for preparing deuterated dihydropan-fenestrated amine alkaloids, as shown in Formula VII: Weigh out the deuterated pan-coryne alkaloid quaternary ammonium salt compound, add an organic solvent, place in an ice bath and stir, add anhydrous potassium carbonate and stir, then dissolve sodium borohydride (1.0 equiv) in a strong alkaline solution and add it dropwise to the system. After the addition is complete, remove the ice bath and stir at a constant temperature until the reaction is complete. Filter to obtain the deuterated dihydropan-coryne tertiary amine alkaloid compound. When R2 and R3 are bonded to form a deuterated alkylene dioxy group: R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group; When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group: R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

42. The method for synthesizing tertiary amine-type deuterated pan-berberine alkaloids according to claim 41, characterized in that, The organic solvent is independently selected from methanol, ethanol, and tetrahydrofuran.

43. The method for synthesizing tertiary amine-type deuterated pan-berberine alkaloids according to claim 41, characterized in that, The strong base is independently selected from sodium hydroxide and potassium hydroxide.

44. A synthetic method for preparing 8-acetone-substituted tertiary amine deuterated pan-berberine alkaloids, as shown in Formula VIII: Weigh out a quaternary ammonium salt of berberine-type alkaloids, add sodium hydroxide solution and stir, then add acetone reagent and stir at room temperature. After the reaction is complete, filter to obtain an 8-acetone-substituted tertiary amine deuterated berberine-type alkaloid compound; when R2 and R3 are connected to form a deuterated alkylene dioxy group: R9, R 10 R 11 Each is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The linkage becomes an alkylene dioxy group and R 11 Independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, and ... 10 With R 11 The linkage forms an alkylene dioxy group, or R9 is independently selected from H, OH, C1-C4 alkoxy, trideuteroxy, and R... 10 With R 11 It is linked to form a deuterated alkylene dioxy group; When R9 and R 10 The R group is linked to become a deuterated alkylene dioxy group. 11 When R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy, or when R9 is independently selected from H, OH, C1-C4 alkoxy, or trideuterated methoxy and R 10 With R 11 When linked to a deuterated alkylene dioxy group: R2 and R3 are each independently selected from H, OH, C1-C4 alkoxy, trideuterated methoxy, or R2 and R3 are connected to form an alkylene dioxy group, or R2 and R3 are connected to form a deuterated alkylene dioxy group.

45. A pharmaceutical composition, characterized in that, The tertiary amine-type deuterated pan-berberine alkaloid compound containing an effective dose of any one of claims 35-44, and its physiologically acceptable salt and pharmaceutically acceptable carrier or excipient.

46. ​​The use of the tertiary amine-type deuterated berberine-type alkaloid compound of any one of claims 35-40 and its physiologically acceptable salt, or the pharmaceutical composition of claim 45, in the preparation of a medicament for the prevention, relief, and / or treatment of inflammatory diseases.

47. In the application of claim 46, the inflammation is selected from ulcerative colitis.

48. 8-imine tertiary amine deuterated pan-berberine alkaloids of Formula III, comprising compounds 16-49, and their physiologically acceptable salts:

49. A pharmaceutical composition, characterized in that, The effective dose of the 8-imine tertiary amine type deuterated pan-berberine alkaloid compound of claim 48, and its physiologically acceptable salts and pharmaceutically acceptable carriers or excipients.

50. The use of a physiologically acceptable salt of the 8-imine tertiary amine deuterated berberine alkaloid compound of claim 48 or the pharmaceutical composition of claim 49 in the preparation of a medicament for the prevention, relief and / or treatment of ulcerative colitis.

Images