Isoquinoline medicine and application thereof in improvement or treatment of fungal infection

Abstract

The invention relates to the technical field of small molecule drugs, in particular to an isoquinoline drug and application thereof to improvement or treatment of fungal infection. The isoquinoline medicine has good bacteriostatic activity on candida albicans, further research and observation of the compound have an inhibition effect on adhesion, hypha formation, biofilm formation, pathogenicity and the like of the candida albicans, and the result shows that the 10, 13-substituted berberine derivative can be used for preventing and / or treating fungal infection, especially candida albicans infection.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule drugs, and in particular to an isoquinoline drug and application thereof in improving or treating fungal infection. Background Art

[0002] In recent years, the continuous expansion of patients with malignant tumors and HIV-infected people, coupled with the widespread use of immunosuppressive drugs, has led to a significant increase in invasive fungal infections. Among many opportunistic pathogens, Candida, especially Candida albicans (CA), has become the pathogen with the highest clinical detection rate. It is worth noting that CA not only has a strong tissue invasion ability, but its increasingly severe drug resistance trend also makes the deep infection caused by the bacteria present a high mortality rate, which poses a new challenge to clinical antifungal treatment.

[0003] Currently, the first-line antifungal drugs in clinical practice mainly include three categories: azoles (fluconazole, etc.), polyenes (amphotericin B, etc.) and echinocandins (caspofungin, etc.). However, the frequent occurrence of CA-resistant mutants caused by long-term drug exposure has significantly weakened the clinical efficacy of these traditional drugs. In addition, the above-mentioned drugs generally have treatment limitations, which may induce adverse reactions such as gastrointestinal reactions, allergic syndrome, liver and kidney damage, and have neurological side effects such as headache and fever, which seriously affect patients' treatment compliance.

[0004] In response to this clinical dilemma, the development of antifungal preparations with novel mechanisms of action has become a key breakthrough in solving the problem of drug resistance. Summary of the invention

[0005] The present invention aims to solve one of the technical problems in the related art to at least a certain extent. To this end, one object of the present invention is to provide a compound, a product containing the compound and its use, the compound has good antibacterial activity against Candida albicans, and further studies and observations show that the compound has an inhibitory effect on the adhesion, hyphae formation, biofilm formation, pathogenicity, etc. of Candida albicans, indicating that the 10,13-substituted berberine derivatives of the present invention can be used to prevent and / or treat fungal infections, especially Candida albicans infections.

[0006] To this end, the first aspect of the present invention provides a compound, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt of the compound represented by the general formula (I):

[0007] R 1 , R 2 Each independently selected from -(CH 2 ) m R 3 、-(CH2 ) n -CN, unsubstituted C 2 -C 10 Alkenyl, unsubstituted C 2 -C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C 1 -C 10 alkyl; m=1, n=1~5, R 3 is unsubstituted or substituted with at least one R b Substituted phenyl; R a For -NH 2 ; R b Select from -NO 2 , halogen, C 1 Alkoxy, C 1 alkyl, And R 1 , R 2 Not at the same time unsubstituted C 1 -C 10 alkyl.

[0008] The current clinical antifungal treatment system mainly relies on four major types of drugs: azoles, polyenes, echinocandins, and flucytosine. However, the application of drugs is significantly limited: although polyene drugs such as nystatin have a strong killing effect, they have defects such as low bioavailability (<5%) and obvious nephrotoxicity; and the problem of drug resistance caused by long-term antifungal treatment is becoming increasingly serious, especially the dynamic regulation mechanism of virulence factors such as biofilm formation and hyphae differentiation, which significantly enhances the tissue invasiveness and drug tolerance of pathogens. These factors together lead to the clinical dilemma of diminishing efficacy of existing treatment options.

[0009] Recent studies have found that berberine (BBR), an active ingredient in traditional Chinese medicine, exhibits unique antifungal properties. Its mechanism of action involves: 1) inhibiting mycelial differentiation and biofilm formation; 2) upregulating the expression of genes related to cell wall β-1,3-glucan and chitin synthesis; 3) interfering with the quorum sensing system to reduce the secretion of virulence factors. However, due to its high minimum inhibitory concentration (MIC=16μg / ml) and poor pharmacokinetic properties, BBR has not yet reached the clinical transformation standard.

[0010] Based on the above background, this study focuses on the field of berberine structure optimization. Through computer-aided drug design and structure-activity relationship analysis, key pharmacophores such as the C-10, 13 hydroxyl group and the C-13 methoxy group of the parent nucleus are modified in a targeted manner. The goal is to obtain innovative derivatives with the following advantages: 1) the antibacterial activity is 5-10 times higher than that of the parent; 2) breaking through the existing drug resistance mechanism; 3) improving solubility and tissue permeability; 4) reducing host cell toxicity. Finally, the inventors screened and obtained the compounds shown in the general structural formula (I), and found that the compounds have good antibacterial activity against Candida albicans. Further studies and observations showed that the compounds have inhibitory effects on the adhesion, hyphae formation, biofilm formation, pathogenicity, etc. of Candida albicans, indicating that the 10, 13-substituted berberine derivatives of the present invention can be used to prevent and / or treat fungal infections, especially Candida albicans infections. Therefore, the 10, 13-substituted berberine derivatives of the present invention can be used to prepare drugs for preventing and / or treating infectious diseases caused by Candida albicans.

[0011] According to an embodiment of the present invention, the compound is selected from one of the following structures:

[0012]

[0013]

[0014]

[0015] .

[0017] The second aspect of the present invention provides a medicine. According to an embodiment of the present invention, the medicine comprises the compound described in the first aspect, and the medicine is used to improve or treat Candida albicans infection.

[0018] According to an embodiment of the present invention, the drug further includes a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier, diluent or excipient.

[0019] The compounds provided by the present invention are used to prepare medicines in various dosage forms, which are administered to subjects in a therapeutically effective amount. After being absorbed by the subjects, the medicines can treat or improve fungal infections.

[0020] According to an embodiment of the present invention, the medicine further comprises one or more other therapeutic agents, wherein the other therapeutic agents have similar functions to the compounds of the present invention and can be used to treat or improve fungal infections.

[0021] The present invention relates to suitable pharmaceutically acceptable salts of the compounds represented by general formula (I) or (I), including but not limited to hydrochloride, hydrobromide, sulfate or hydrogensulfate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate or p-toluenesulfonate. According to the foregoing, any compound of the present invention mentioned herein includes its pharmaceutically acceptable salt, solvate or combination thereof.

[0022] In addition to the pharmaceutically acceptable salts of the compounds of the present invention, the present invention also includes other salts which may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used for the identification, characterization or purification of the compounds of the present invention.

[0023] The third aspect of the present invention provides use of the compound of the first aspect in preparing a medicament. According to an embodiment of the present invention, the medicament is used to improve or treat Candida albicans infection.

[0024] The innovatively developed antifungal compounds, 10,13-substituted berberine derivatives, exhibit multiple advantages: they do not primarily kill Candida albicans, but rather exert their effects by inhibiting the adhesion and pathogenicity of Candida albicans; the 10,13-substituted berberine derivatives of the present invention are expected to be used in combination with other first-line antifungal drugs, thereby producing a synergistic effect against drug-resistant Candida albicans.

[0025] The antifungal compound 10,13-substituted berberine derivative of the present invention can target and inhibit CA biofilm formation. More importantly, the compound exhibits excellent safety characteristics while exerting significant antifungal activity and has no significant toxic effects on host cells. These characteristics make it have important transformation value in the field of anti-CA infection drug research and development, and provide a new solution for dealing with fungal infections.

[0026] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which: Figure 1 The effects of BBR and compound 23 on the thickness of Candida albicans biofilm detected by CLSM were shown; Figure 2 The effects on the tongue mucosa of mice with oropharyngeal candidiasis after treatment with BBR or compound 23 are shown; Figure 3The effects of BBR or compound 23 treatment on the oral fungal load in mice with oropharyngeal candidiasis are shown; Figure 4 shows the results of HE staining of tongue tissues of mice with oropharyngeal candidiasis after treatment with BBR or compound 23; Figure 5 The effects of drugs on the tongue mucosal surface of mice with oropharyngeal candidiasis after treatment with BBR or compound 23 were observed by SEM; Figure 6 The results show that BBR or compound 23 treatment can significantly reduce the expression of BBR in the tongue tissue of mice with oropharyngeal candidiasis. S100a8 Effects on gene expression; Figure 7 Shown is the effect of BBR or compound 23 treatment on EGFR protein expression in tongue tissue of mice with oropharyngeal candidiasis. DETAILED DESCRIPTION

[0028] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0029] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0030] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0031] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0032] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0033] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0034] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0035] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed by Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include, but are not limited to, salts of primary, secondary or tertiary amines, including naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzylpenicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or polyamine resins. organic salts derived from inorganic and organic acids include, but are not limited to, organic salts formed from sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid.

[0036] The term "drug" refers to a mixture of one or more compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a drug is to facilitate the administration of the compound to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0037] The term "C 1 -C 10“Alkyl” is understood as meaning a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; “C 1 -C 6 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0038] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Non-limiting examples of the types of the term "excipient" include binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesion. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol, or corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinyl pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants and the like excipients commonly used in pharmaceutical preparations.

[0039] Candida albicans is a resident commensal microorganism of the human body, widely present in the mucosal systems of the skin, oral cavity, digestive tract, urogenital tract, etc. of healthy people. This pathogen often manifests as asymptomatic colonization or superficial infection in individuals with healthy immune function, but it can cause systemic infection with a mortality rate of up to 40% in immunocompromised groups (such as patients undergoing chemotherapy for hematological tumors, solid organ transplant recipients, and HIV / AIDS patients). It is an important pathogen causing fungemia, disseminated infection, and intensive care unit-related sepsis.

[0040] Based on this, the purpose of the present invention is to provide a class of 10,13-disubstituted berberine derivatives and their preparation methods and applications. Through the rational design and modification of BBR, candidate drugs with improved activity, new mechanism, low resistance and good safety are obtained.

[0041] According to a specific embodiment of the present invention, the present invention provides a compound, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt of the compound represented by general formula (I):

[0042] R 1 , R 2 Each independently selected from -(CH 2 ) m R 3 、-(CH 2 ) n -CN, unsubstituted C 2 -C 10 Alkenyl, unsubstituted C 2 -C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C 1 -C 10 alkyl; m=1, n=1~5, R 3 is unsubstituted or substituted with at least one R b Substituted phenyl; R a For -NH 2 ; R b Select from -NO 2 , halogen, C 1 Alkoxy, C 1 alkyl, And R 1 , R 2 Not at the same time unsubstituted C 1 -C 10 Alkyl. Halogen is fluorine, chlorine, bromine or iodine.

[0043] It should be noted that m is 1, and n can be 1, 2, 3, 4, or 5. For example, n is 1-3, 1-4, or 1-5.

[0044] According to a specific embodiment of the present invention, the present invention provides a method for preparing a 10,13-substituted berberine derivative, comprising the following steps:

[0045] (M-2), anhydrous acetonitrile, potassium carbonate and the first raw material were reacted at 60-70 °C, and the reaction progress was monitored by TLC. After the reaction was complete, it was cooled until the solid was completely precipitated, filtered, and the filtrate was mixed with silica gel, and dichloromethane and methanol were used as mobile phases. The yellow intermediate (M-3) was purified by Flash fast column chromatography to obtain the yellow intermediate. The intermediate obtained above was reacted with anhydrous acetonitrile, sodium hydrogen and the second raw material at 70-90 °C, and the reaction progress was monitored by TLC. After the reaction was complete, the hydrochloric acid methanol solution was neutralized and mixed with silica gel, and dichloromethane and methanol were also used as mobile phases. Purification was performed by Flash fast column chromatography to obtain a yellow final product. According to a specific embodiment of the present invention, the present invention provides the use of the above-mentioned 10,13-substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation, prevention and / or treatment of microbial infection products.

[0046] Further, the microorganism is Candida albicans.

[0047] According to a specific embodiment of the present invention, the present invention provides the use of the above-mentioned 10,13-substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation, prevention and / or treatment of antibacterial drugs.

[0048] The beneficial effects of the present invention are: The present invention provides a class of 10,13-substituted berberine derivatives and their preparation methods and applications. In the preliminary work, compounds with high efficiency, low toxicity and low resistance were screened in a targeted manner. Compared with the minimum inhibitory concentration (MIC) of BBR, the 10,13-substituted berberine derivatives prepared by the method of the present invention showed more promising antibacterial activity against Candida albicans. Then, Candida albicans was used as the test object to investigate the effects of 10,13-substituted berberine derivatives on the formation of Candida albicans hyphae and biofilm. The purpose was to further affect the invasion of Candida albicans by detecting the interference of 10,13-substituted berberine derivatives on the formation factors of Candida albicans virulence. The results showed that 10,13-substituted berberine derivatives had a good inhibitory effect on the formation of Candida albicans hyphae. Moreover, 10,13-substituted berberine derivatives themselves have low toxicity and do not affect the normal growth of human cells and Candida albicans. They inhibit the adhesion and pathogenicity of Candida albicans and are therefore not prone to drug resistance. This has great application prospects in the development of new antifungal drugs, especially in the development of drugs against Candida albicans infections.

[0049] Therefore, the use of 10,13-substituted berberine derivatives in the preparation of drugs for resisting Candida albicans infection, and in the preparation, prevention and / or treatment of infectious diseases caused by Candida albicans, should be within the scope of protection of the present invention.

[0050] The scheme of the present disclosure will be explained below in conjunction with the examples. Those skilled in the art will appreciate that the following examples are only used to illustrate the present disclosure and should not be considered to limit the scope of the present disclosure. Where specific techniques or conditions are not indicated in the examples, the techniques or conditions described in the literature in this area or the product instructions are used. Where the manufacturers of reagents or instruments are not indicated, they are all conventional products that can be obtained commercially.

[0051] Example 1 Synthesis of 13-((E)-but-2-en-1-yl)-10-(((E)-but-2-en-1-yl)oxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 1)

[0052] M-2, anhydrous acetonitrile, potassium carbonate and 3-bromopropylene (first raw material) were reacted at 60-70 °C, and the reaction progress was monitored by TLC. After the reaction was complete, it was cooled until the solid was completely precipitated, filtered, and the filtrate was mixed with silica gel, and dichloromethane and methanol were used as mobile phases. The yellow intermediate was purified by Flash fast column chromatography to obtain the yellow intermediate. The intermediate obtained above was reacted with anhydrous acetonitrile, sodium hydrogen and 3-bromopropylene (second raw material) at 70-90 °C, and the reaction progress was monitored by TLC. After the reaction was complete, it was neutralized with hydrochloric acid methanol solution and mixed with silica gel. Dichloromethane and methanol were also used as mobile phases, and the yellow final product 1 was purified by Flash fast column chromatography. The NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.11 – 5.99 (m, 1H), 6.04 (s, 2H), 5.89 (tt, J = 16.4, 8.1 Hz, 1H), 5.39 (ddt, J = 16.8, 2.2, 1.0 Hz,1H), 5.31 (ddt, J = 16.8, 2.2, 1.0 Hz, 1H), 5.17 (ddt, J = 16.4, 2.1, 1.0 Hz,1H), 5.07 (ddt,J = 16.4, 2.1, 1.0 Hz, 1H), 4.67 – 4.58 (m, 4H), 3.40 (dt, J =8.1, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.96, 148.41, 148.40, 147.87, 143.00,137.82, 136.41, 132.32, 130.42, 130.40, 129.28, 122.76, 122.53, 122.03,118.82, 118.76, 116.20, 109.29, 109.20, 101.61, 69.70, 62.21, 58.66, 34.75,28.27. ESI + :402.47.

[0053] Example 2 Synthesis of 13-((E)-but-2-en-1-yl)-10-(((E)-but-2-en-1-yl)oxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 2)

[0054] The experimental steps are the same as those in Example 1, except that the first raw material is crotonyl bromide and the second raw material is crotonyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.87 –5.78 (m, 1H), 5.73 – 5.58 (m, 3H), 4.69 (dt, J = 4.4, 1.0 Hz, 2H), 4.64 (ddd, J=7.3, 4.6, 1.7 Hz, 2H), 4.01 (s, 3H), 3.43 (dt, J = 7.1, 1.1 Hz, 2H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 1.67 (ddt, J = 5.3, 1.9, 1.0 Hz, 3H),1.62 (dt, J = 5.3, 1.2 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.46, 147.54, 147.51, 142.86,136.66, 130.42, 130.25, 128.85, 128.62, 128.26, 127.61, 127.45, 122.33,122.02, 121.57, 117.85, 108.80, 108.41, 101.51, 69.24, 61.65, 58.15, 33.10,27.89, 17.90, 17.70. ESI + :430.52.

[0055] Example 3 Synthesis of 9-methoxy-13-(3-methylbut-2-en-1-yl)-10-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydro-[1,3]dioxol[4,5g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 3)

[0056] The experimental steps are the same as those in Example 1, except that the first raw material is 3,3-dimethylallyl bromide and the second raw material is 3,3-dimethylallyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.31(ddt,J = 7.3, 5.7, 1.6 Hz, 1H), 5.28 (ddt, J = 6.6, 3.2, 1.7 Hz, 1H), 4.67 –4.59 (m, 4H), 4.01 (s, 3H), 3.46 (dq, J = 7.4, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3,7.6, 4.6, 1.0 Hz, 2H), 1.75 (q, J = 1.1 Hz, 6H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.33, 147.54, 147.51, 142.84,137.69, 136.72, 130.25, 130.20, 129.75, 128.51, 123.77, 122.33, 122.02,121.52, 119.15, 117.85, 108.80, 108.41, 101.51, 66.11, 61.65, 58.15, 28.68,27.89, 24.63, 24.49, 19.90, 19.28. ESI + :458.58.

[0057] Example 4 Synthesis of 10-(3-aminopropoxy)-13-(3-aminopropyl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 4)

[0058] The experimental steps are the same as those in Example 1, except that the first raw material is 1-bromopropylamine and the second raw material is 1-bromopropylamine; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t,J = 1.0 Hz, 1H), 6.04 (s, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.09 – 4.00 (m, 5H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 2H), 2.97 – 2.89 (m, 2H), 2.87 – 2.78 (m, 6H), 2.02 (p, J = 5.6Hz, 2H), 1.87 (tt, J = 8.1, 5.3 Hz, 2H), 1.74 (t, J = 6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.33, 147.55, 147.54, 142.81,137.12, 134.45, 132.51, 132.39, 121.96, 121.92, 121.29, 118.04, 109.19,108.80, 101.51, 67.72, 61.65, 58.81, 40.83, 37.13, 31.06, 29.70, 29.09,27.89. ESI + :436.53.

[0059] Example 5 Synthesis of 13-(hept-6-en-1-yl)-10-(hept-6-en-1-yloxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 5)

[0060] The experimental steps are the same as those in Example 1, except that the first raw material is 7-bromoheptene and the second raw material is 7-bromoheptene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 0H), 7.37 (d, J = 8.8 Hz, 0H), 6.04(s, 1H), 5.77 (tt, J= 17.3, 6.9 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H),4.97 (ddt, J = 17.1, 2.2, 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.00(t, J = 6.1 Hz, 1H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 1H), 2.78 (t, J = 8.5Hz, 1H), 2.07 – 1.99 (m, 2H), 1.73 – 1.64 (m, 2H), 1.43 (qd, J = 6.7, 5.6 Hz,1H), 1.39 – 1.29 (m, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.34, 147.55, 147.54, 142.81,139.08, 138.84, 137.36, 135.30, 134.45, 132.47, 121.95, 121.89, 121.29,118.04, 114.61, 114.41, 109.19, 108.80, 101.51, 68.79, 61.65, 58.81, 33.79,33.67, 30.56, 29.09, 28.72, 28.64, 28.49, 28.44, 27.89, 25.86. ESI + :514.69.

[0061] Example 6 Synthesis of 9-methoxy-13-(pent-4-en-1-yl)-10-(pent-4-en-1-yloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 6)

[0062] The experimental steps are the same as those in Example 1, except that the first raw material is 5-bromopentene and the second raw material is 5-bromopentene; the NMR results of the final product are as follows: 1<h2 style=";text-align:left;direction:ltr">H NMR (500 MHz, DMSO-d<h2 style=";text-align:left;direction:ltr"> 6 <h2 style=";text-align:left;direction:ltr"> ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.8Hz, 1H), 7.12 (d,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.8 Hz, 1H), 6.99 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 1.0 Hz, 1H), 6.04(s, 2H), 5.73(tdt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 17.3, 10.5, 6.8 Hz, 2H), 5.12 (dddt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 17.1, 5.1, 2.1, 1.0 Hz, 2H),4.97 (dtt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 17.1, 2.2, 1.0 Hz, 2H), 4.63 (ddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.6, 4.9, 1.2 Hz, 2H), 4.06(t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 6.8 Hz, 2H), 4.02 (s, 3H), 3.16 (dddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.88 (s, 0H), 2.85 (s, 0H), 2.18 – 2.09 (m, 4H), 1.77 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.4, 6.8 Hz,2H), 1.65 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 9.3, 7.9 Hz, 2H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (125 MHz, DMSO-d<h2 style=";text-align:left;direction:ltr"> 6 <h2 style=";text-align:left;direction:ltr"> ) δ 149.57, 148.33, 147.55, 147.54, 142.81,138.25, 137.61, 137.10, 134.45, 133.11, 132.48, 121.95, 121.91, 121.29,118.04, 115.14, 114.91, 109.19, 108.80, 101.51, 69.02, 61.66, 58.81, 33.02,30.17, 30.13, 28.67, 27.89, 27.85.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ESI<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> :458.58.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0063] Example 7 Synthesis of 9-methoxy-13-(oct-7-yn-1-yl)-10-(oct-7-yn-1-yloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 7)

[0064] The experimental steps are the same as those in Example 1, except that the first raw material is 8-bromooctyne and the second raw material is 8-bromooctyne; the nuclear magnetic resonance results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 0H), 7.37 (d, J = 8.8 Hz, 0H), 6.04(s, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.00 (t, J = 6.1 Hz, 1H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 1H), 2.78 (t, J = 8.5 Hz, 1H), 2.12 (td, J =5.9, 3.0 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.77 (tt, J = 7.5, 6.1 Hz, 1H), 1.68(tt, J = 8.4, 7.2 Hz, 1H), 1.55 – 1.33 (m, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.34, 147.55, 147.54, 142.81,137.36, 135.30, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04, 109.19,108.80, 101.51, 83.82, 83.81, 69.16, 69.15, 68.79, 61.65, 58.81, 30.56,29.34, 28.81, 28.59, 28.38, 28.29, 28.06, 28.04, 27.89, 26.05, 17.92, 17.91. ESI + :538.71.

[0065] Example 8 Synthesis of 13-(hex-5-yn-1-yl)-10-(hex-5-yn-1-yloxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 8)

[0066] The experimental steps are the same as those in Example 1, except that the first raw material is 6-bromohexyne and the second raw material is 6-bromohexyne; the nuclear magnetic resonance results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.09 (t, J = 5.0 Hz, 2H), 3.16 (dddd, J = 19.3,7.6, 4.6, 1.0 Hz, 2H), 2.83 (dt, J = 15.8, 7.3 Hz, 1H), 2.74 (dt, J = 15.6, 7.3Hz, 1H), 2.47 (qd, J = 5.7, 3.0 Hz, 4H), 2.06 (td, J = 3.0, 1.6 Hz, 2H), 1.85 –1.75 (m, 4H), 1.63 – 1.54 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6) δ 149.57, 148.34, 147.55, 147.54, 142.81,137.36, 134.68, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04, 109.19,108.80, 101.51, 83.79, 83.77, 69.20, 69.16, 69.15, 61.66, 58.81, 30.57,28.67, 27.89, 27.61, 27.50, 25.28, 18.24, 18.09. ESI + :482.60.

[0067] Example 9 Synthesis of 13-(hex-5-yn-1-yl)-10-(hex-5-yn-1-yloxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 9)

[0068] The experimental steps are the same as those in Example 1, except that the first raw material is p-methylbenzyl bromide and the second raw material is p-methylbenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.30 (dt, J = 7.9, 1.1 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 7.18 – 7.11(m, 4H), 7.11 – 7.06 (m, 2H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.12 (t, J = 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.19 (t, J = 1.0 Hz, 2H),3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.33 (q, J = 0.9 Hz, 5H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.14, 147.54, 147.50, 142.79,138.34, 138.17, 137.13, 136.95, 133.99, 131.23, 130.86, 129.27, 129.09,128.45, 128.18, 128.03, 122.54, 121.99, 120.72, 118.17, 108.80, 108.18,101.51, 71.32, 61.66, 57.39, 36.00, 27.89, 21.05. ESI + :530.64.

[0069] Example 10 Synthesis of 9-methoxy-13-(4-nitrobenzyl)-10-((4-nitrobenzyl)oxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 10)

[0070] The experimental steps are the same as those in Example 1, except that the first raw material is p-nitrobenzyl bromide and the second raw material is p-nitrobenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.21 – 8.15 (m, 3H), 8.14 –8.08 (m, 3H), 7.61 (dt, J = 8.2, 1.0 Hz, 3H), 7.53 (t, J = 1.0 Hz, 1H), 7.54 –7.47 (m, 3H), 7.35 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 1.0Hz, 1H), 6.04 (s, 3H), 5.13 (t, J = 1.1 Hz, 3H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz,3H), 4.20 (t, J= 1.1 Hz, 3H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 149.54, 148.25, 148.14, 147.54,147.50, 143.96, 142.79, 141.03, 137.13, 131.23, 130.92, 128.79, 128.68,128.45, 123.81, 123.65, 122.54, 121.99, 120.72, 118.17, 108.80, 108.18,101.51, 71.41, 61.65, 57.39, 36.04, 27.89. ESI + :592.58.

[0071] Example 11 Synthesis of 13-(3,5-dimethoxybenzyl)-10-((3,5-dimethoxybenzyl)oxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 11)

[0072] The experimental steps are the same as those in Example 1, except that the first raw material is 3,5-dimethoxybenzyl bromide and the second raw material is 3,5-dimethoxybenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.01 – 6.97 (m, 1H), 6.63 (dt, J = 2.3, 1.2Hz, 2H), 6.46 (dt, J = 2.1, 1.0 Hz, 2H), 6.38 (dt, J = 12.5, 2.4 Hz, 2H), 6.04(s, 2H), 5.13 (t, J= 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.08(dt, J = 9.5, 1.0 Hz, 1H), 4.01 (s, 3H), 4.03 – 3.97 (m, 1H), 3.16 (dddd, J =19.3, 7.6, 4.6, 1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 160.51, 149.57, 148.29, 147.54,147.50, 142.79, 139.48, 138.25, 137.07, 131.24, 130.70, 128.45, 122.55,121.99, 120.72, 118.17, 108.80, 108.24, 108.18, 107.23, 101.51, 99.53, 98.82,71.52, 61.65, 57.39, 55.34, 55.33, 36.36, 27.89. ESI + :622.69.

[0073] Example 12 Synthesis of 13-allyl-10-(hept-6-yn-1-yl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 12)

[0074] The experimental steps are the same as those in Example 1, except that the first raw material is 7-bromoheptyne and the second raw material is 3-bromopropylene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.89(tt, J= 16.4, 8.1 Hz, 1H), 5.17 (ddt, J = 16.4, 2.1, 1.0 Hz, 1H), 5.07 (ddt, J =16.3, 2.1, 1.0 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.00 (t, J = 6.1Hz, 2H), 3.40 (dt, J = 8.0, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz,2H), 2.11 (td, J = 5.8, 3.0 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.74 (p, J = 6.3 Hz, 2H), 1.57 – 1.46 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.40, 147.57, 147.54, 142.88,137.27, 136.32, 130.33, 130.25, 128.69, 122.35, 122.09, 121.73, 117.97,116.29, 108.80, 108.41, 101.51, 83.79, 69.15, 68.80, 61.66, 58.15, 34.24,29.15, 27.89, 27.85, 25.70, 17.92. ESI + :456.56.

[0075] Example 13 Synthesis of 13-allyl-9-methoxy-10-((4-methylbenzyl)oxy)-5,6-dihydro-[1,3]dioxa[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 13)

[0076] The experimental steps are the same as those in Example 1, except that the first raw material is p-methylbenzyl bromide and the second raw material is 3-bromopropylene; the NMR results of the final product are as follows: 1H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 0.7Hz, 0H), 7.37 (s, 1H), 7.30 (dt, J = 7.8, 1.1 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H),7.16 (d, J = 7.7 Hz, 2H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.89 (tt, J =16.5, 8.1 Hz, 1H), 5.17 (ddt, J = 16.4, 2.1, 1.0 Hz, 1H), 5.12 (t, J = 1.0 Hz,2H), 5.07 (ddt, J = 16.3, 2.1, 1.0 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H),3.40 (dt, J = 8.0, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.34(d, J = 1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.07, 147.54, 147.47, 142.88,138.34, 137.27, 136.32, 133.99, 130.33, 130.25, 129.09, 128.69, 128.03,122.35, 121.95, 121.63, 118.20, 116.29, 108.80, 108.41, 101.51, 71.32, 61.65,58.15, 34.24, 27.89, 21.05. ESI + :466.56。

[0077] Example 14 Synthesis of (E)-10-(3-aminopropoxy)-13-(but-2-en-1-yl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 14)

[0078] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromo-1-propylamine and the second raw material is crotonyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.87 –5.78 (m, 1H), 5.72 – 5.62 (m, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.09 –4.00 (m, 5H), 3.43 (dq, J = 7.1, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0Hz, 2H), 2.93 (pd, J = 5.8, 0.7 Hz, 2H), 2.81 (t, J = 6.2 Hz, 2H), 2.02 (p, J = 5.6Hz, 2H), 1.62 (dq, J = 5.3, 1.1 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6) δ 149.57, 148.39, 147.57, 147.54, 142.86,136.66, 130.43, 130.25, 128.62, 128.26, 127.61, 122.33, 122.09, 121.71,117.97, 108.80, 108.41, 101.51, 67.72, 61.65, 58.15, 37.13, 33.10, 31.06,27.89, 17.90. ESI + :433.53.

[0079] Example 15 Synthesis of (E)-13-(but-2-en-1-yl)-9-methoxy-10-((4-nitrobenzyl)oxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 15)

[0080] The experimental steps are the same as those in Example 1, except that the first raw material is p-nitrobenzyl bromide and the second raw material is crotonyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.14 – 8.08 (m, 2H), 7.61(dt, J = 8.1, 1.0 Hz, 2H), 7.47 (s, 1H), 7.41 – 7.36 (m, 1H), 7.20 (d, J = 8.5Hz, 1H), 7.01 – 6.97 (m, 1H), 6.04 (s, 2H), 5.87 – 5.78 (m, 1H), 5.72 – 5.62(m, 1H), 5.13 (t, J = 1.1 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.01 (s,3H), 3.43 (dq, J = 7.1, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H),1.64 – 1.59 (m, 3H). 13C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.25, 148.07, 147.54, 147.47,142.86, 141.03, 136.66, 130.42, 130.25, 128.68, 128.62, 128.26, 127.61,123.65, 122.33, 121.95, 121.61, 118.20, 108.80, 108.41, 101.51, 71.41, 61.65,58.15, 33.10, 27.89, 17.90. ESI + :511.55.

[0081] Example 16 Synthesis of 10-(cyanomethoxy)-9-methoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 16)

[0082] The experimental steps are the same as those in Example 1, except that the first raw material is bromoacetonitrile and the second raw material is 3,3-dimethylallyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.5Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.31(dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 4.96 (s, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7Hz, 2H), 3.46 (dp, J = 7.4, 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz,2H), 1.68 (q, J = 1.2 Hz, 6H). 13C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 147.56, 147.54, 146.69, 142.84,136.72, 130.27, 130.25, 129.75, 128.53, 123.77, 122.33, 122.00, 121.63,118.23, 116.24, 108.80, 108.41, 101.51, 61.65, 58.15, 54.47, 28.68, 27.89,24.49, 19.28. ESI + :529.50.

[0083] Example 17 Synthesis of 9-methoxy-13-(3-methylbut-2-en-1-yl)-10-(pent-4-en-1-yloxy)-5,6-dihydro-[1,3]dioxepin[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 17)

[0084] The experimental steps are the same as those in Example 1, except that the first raw material is 5-bromopentene and the second raw material is 3,3-dimethylallyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.74(tt, J = 17.1, 6.8 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 5.11(ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.64(ddd, J= 7.3, 4.6, 1.7 Hz, 2H), 4.09 – 4.00 (m, 4H), 3.49 – 3.43 (m, 2H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.14 (tdt, J = 8.1, 6.9, 1.1 Hz, 2H),1.77 (tt, J = 8.4, 6.8 Hz, 2H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.39, 147.57, 147.54, 142.84,137.60, 136.72, 130.25, 130.20, 129.76, 128.51, 123.77, 122.33, 122.09,121.66, 117.97, 115.13, 108.80, 108.41, 101.51, 69.02, 61.66, 58.15, 30.17,28.68, 28.67, 27.89, 24.49, 19.28. ESI + :458.58.

[0085] Example 18 Synthesis of 10-(allyloxy)-13-(3-aminopropyl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 18)

[0086] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropylene and the second raw material is 3-bromopropylamine; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J= 1.0 Hz, 1H), 6.11 – 5.99 (m, 1H), 6.04 (s, 2H), 5.39 (ddt, J = 16.8, 2.1, 1.0 Hz, 1H), 5.31 (ddt, J = 16.8, 2.2,1.0 Hz, 1H), 4.67 – 4.58 (m, 4H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H),2.87 – 2.77 (m, 4H), 1.87 (tt, J = 8.1, 5.3 Hz, 2H), 1.74 (t, J = 6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 149.57, 148.20, 147.55, 147.44, 142.81,137.12, 134.45, 132.52, 132.39, 132.27, 121.92, 121.90, 121.24, 118.50,117.80, 109.19, 108.80, 101.51, 69.80, 61.65, 58.81, 40.83, 29.70, 29.09,27.89. ESI + :419.50.

[0087] Example 19 Synthesis of 13-(3-aminopropyl)-10-((3,5-dimethoxybenzyl)oxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 19)

[0088] The experimental steps are the same as those in Example 1, except that the first raw material is 3,5-dimethoxybenzyl bromide and the second raw material is 3-bromopropylamine; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.63 (dt, J = 2.3, 1.2Hz, 2H), 6.39 (t, J = 2.4 Hz, 1H), 6.04 (s, 2H), 5.13 (t, J = 1.0 Hz, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.01 (s, 3H), 3.16 (dddd, J = 19.3, 7.6, 4.6,1.0 Hz, 2H), 2.87 – 2.77 (m, 4H), 1.87 (tt, J = 8.1, 5.3 Hz, 2H), 1.74 (t, J =6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.51, 149.57, 148.15, 147.55, 147.37,142.81, 138.25, 137.12, 134.45, 132.52, 132.39, 121.92, 121.81, 121.33,118.17, 109.19, 108.80, 107.23, 101.51, 99.53, 71.52, 61.65, 58.81, 55.33,40.83, 29.70, 29.09, 27.89. ESI + :529.61.

[0089] Example 20 Synthesis of 9-methoxy-10-((3-methylbut-2-en-1-yl)oxy)-13-pentyl-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 20)

[0090] The experimental steps are the same as those in Example 1, except that the first raw material is bromoacetonitrile and the second raw material is 3,3-dimethylallyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.28(tp, J = 4.8, 1.6 Hz, 1H), 4.67 – 4.59 (m, 4H), 3.16 (dddd, J = 19.3, 7.6, 4.6,1.0 Hz, 2H), 2.86 – 2.70 (m, 2H), 1.75 (q, J = 1.1 Hz, 6H), 1.73 – 1.63 (m,2H), 1.35 (dddd, J = 8.8, 7.4, 6.2, 3.5 Hz, 4H), 0.92 – 0.86 (m, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.27, 147.55, 147.44, 142.81,137.69, 137.36, 134.69, 134.45, 132.47, 121.89, 121.21, 119.15, 117.80,109.19, 108.80, 101.51, 66.11, 61.65, 58.81, 32.42, 30.44, 28.24, 27.89,24.62, 23.18, 19.90, 14.04. ESI + :460.59.

[0091] Example 21 Synthesis of 9-methoxy-10-((3-methylbut-2-en-1-yl)oxy)-13-pentyl-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 21)

[0092] The experimental steps are the same as those in Example 1, except that the first raw material is 6-bromohexyne and the second raw material is 5-bromopentane; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d<h2 style=";text-align:left;direction:ltr"> 6 <h2 style=";text-align:left;direction:ltr"> ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.8Hz, 1H), 7.12 (d,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.8 Hz, 1H), 6.99 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 1.0 Hz, 1H), 6.04(s, 2H), 4.63(ddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.6, 4.9, 1.2 Hz, 2H), 4.09 (t,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 5.0 Hz, 2H), 3.16 (dddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 19.3,7.6, 4.6, 1.0 Hz, 2H), 2.86 – 2.70 (m, 2H), 2.47 (td,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 5.9, 3.0 Hz, 2H),2.06 (s, 1H), 2.06 (d,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 6.1 Hz, 0H), 1.81 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.5, 5.0 Hz, 2H), 1.68 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.2, 7.3 Hz, 2H), 1.58 (tt,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 7.5, 5.9 Hz, 2H), 1.35 (dddd,<h2 style=";text-align:left;direction:ltr"> J <h2 style=";text-align:left;direction:ltr"> = 8.8, 7.4,6.1, 3.5 Hz, 4H), 0.92 – 0.86 (m, 3H).<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (125 MHz, DMSO-d<h2 style=";text-align:left;direction:ltr"> 6 <h2 style=";text-align:left;direction:ltr"> ) δ 149.57, 148.34, 147.55, 147.54, 142.81,137.36, 134.69, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04, 109.19,108.80, 101.51, 83.76, 69.20, 69.15, 61.65, 58.81, 32.42, 30.44, 28.67,28.24, 27.89, 25.28, 23.18, 18.09, 14.04.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> ESI<h2 style=";text-align:left;direction:ltr"> + <h2 style=";text-align:left;direction:ltr"> :472.60.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0093] Example 22 Synthesis of 13-(hept-6-en-1-yl)-9-methoxy-10-(pentyloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 22)

[0094] The experimental steps are the same as those in Example 1, except that the first raw material is 5-bromopentane and the second raw material is 7-bromoheptene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.77(tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.1 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (d, J = 11.5Hz, 1H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J = 8.5 Hz, 2H),2.03 (tdt, J = 7.8, 6.7, 1.1 Hz, 2H), 1.78 (tt, J = 7.3, 5.6 Hz, 2H), 1.69 (tt, J =8.5, 6.8 Hz, 2H), 1.46 – 1.37 (m, 2H), 1.41 – 1.30 (m, 5H), 1.34 (s, 2H), 0.90 (t, J = 6.8 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6) δ 149.57, 148.34, 147.55, 147.54, 142.81,139.08, 137.36, 135.30, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04,114.41, 109.19, 108.80, 101.51, 69.01, 61.65, 58.81, 33.79, 30.56, 29.05,28.72, 28.49, 28.44, 28.26, 27.89, 22.50, 13.97. ESI + :488.65.

[0095] Example 23 Synthesis of 13-(hept-6-en-1-yl)-10-(hex-5-yn-1-yloxy)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 23)

[0096] The experimental steps are the same as those in Example 1, except that the first raw material is 6-bromo-n-hexyne and the second raw material is 7-bromo-n-heptene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.77(tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.1 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.09 (t, J = 5.0Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t,J = 8.5 Hz, 2H),2.47 (td, J = 5.9, 3.0 Hz, 2H), 2.09 – 1.99 (m, 3H), 1.81 (tt, J = 7.5, 5.0 Hz,2H), 1.69 (tt, J = 8.4, 6.8 Hz, 2H), 1.58 (tt, J = 7.5, 5.9 Hz, 2H), 1.39 – 1.30(m, 2H), 1.34 (s, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.34, 147.55, 147.54, 142.81,139.08, 137.36, 135.30, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04,114.41, 109.19, 108.80, 101.51, 83.76, 69.20, 69.15, 61.66, 58.81, 33.79,30.56, 28.72, 28.67, 28.49, 28.44, 27.89, 25.28, 18.09. ESI + :498.64.

[0097] Example 24 Synthesis of 9-methoxy-13-(pent-4-en-1-yl)-10-(pentyloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 24)

[0098] The experimental steps are the same as those in Example 1, except that the first raw material is 5-bromopentane and the second raw material is 5-bromopentene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J= 1.0 Hz, 1H), 6.04 (s, 2H), 5.71(tt, J = 17.2, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (d, J = 11.5Hz, 1H), 4.02 (s, 4H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.88 (s,1H), 2.85 (s, 1H), 2.14 (tdt, J = 8.0, 7.0, 1.1 Hz, 2H), 1.78 (tt, J = 7.3, 5.6Hz, 2H), 1.65 (tt, J = 9.3, 7.9 Hz, 2H), 1.46 – 1.31 (m, 5H), 0.90 (t, J = 6.8Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.34, 147.55, 147.54, 142.81,138.25, 137.10, 134.45, 133.11, 132.48, 121.95, 121.91, 121.29, 118.04,114.91, 109.19, 108.80, 101.51, 69.01, 61.65, 58.81, 33.02, 30.13, 29.05,28.26, 27.89, 27.85, 22.50, 13.97. ESI + :460.59.

[0099] Example 25 Synthesis of 9-methoxy-10-(oct-7-yn-1-yl)-13-(pent-4-en-1-yl)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 25)

[0100] The experimental steps are the same as those in Example 1, except that the first raw material is 8-bromo-n-octyne and the second raw material is 5-bromo-n-pentene; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 0H), 7.47 (s, 0H), 7.37 (d, J = 8.8Hz, 0H), 7.12 (d, J = 8.8 Hz, 0H), 6.99 (t, J = 1.0 Hz, 0H), 6.04 (s, 1H), 5.71(tt, J = 17.2, 6.8 Hz, 0H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 0H), 4.97 (ddt, J =17.1, 2.1, 1.0 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.04 – 3.97 (m,2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 1H), 2.18 – 2.04 (m, 3H), 1.77(tt, J = 7.5, 6.1 Hz, 1H), 1.65 (tt, J = 9.3, 7.9 Hz, 1H), 1.55 – 1.34 (m, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.34, 147.55, 147.54, 142.81,138.25, 137.10, 134.45, 133.11, 132.48, 121.95, 121.91, 121.29, 118.04,114.91, 109.19, 108.80, 101.51, 83.81, 69.15, 68.79, 61.66, 58.81, 33.02,30.13, 29.34, 28.28, 28.06, 27.89, 27.85, 26.05, 17.91. ESI+ :498.64.

[0101] Example 26 Synthesis of 10-(allyloxy)-9-methoxy-13-(oct-7-yn-1-yl)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 26)

[0102] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropylene and the second raw material is 8-bromooctyne; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.01 – 6.97 (m, 1H), 6.11 – 5.99 (m, 1H), 6.04 (s, 2H), 5.39 (ddt, J = 16.8, 2.2, 1.0 Hz, 1H), 5.31 (ddt, J = 16.9, 2.2,1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.61 (dt, J = 5.4, 1.0 Hz,2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J = 8.5 Hz, 2H), 2.12(td, J = 6.0, 3.1 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.68 (tt, J = 8.4, 7.2 Hz,2H), 1.52 – 1.44 (m, 2H), 1.44 – 1.33 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6) δ 149.57, 148.20, 147.55, 147.44, 142.81,137.36, 135.30, 134.45, 132.47, 132.27, 121.89, 121.21, 118.50, 117.80,109.19, 108.80, 101.51, 83.81, 69.80, 69.15, 61.65, 58.81, 30.56, 28.81,28.59, 28.38, 28.04, 27.89, 17.91. ESI + :470.59.

[0103] Example 27 Synthesis of 9-methoxy-10-((4-methylbenzyl)oxy)-13-(oct-7-yn-1-yl)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 27)

[0104] The experimental steps are the same as those in Example 1, except that the first raw material is p-methylbenzyl bromide and the second raw material is 8-bromooctyne; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.30 (dt, J = 7.8, 1.1 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.6Hz, 2H), 6.99 (t, J = 1.1 Hz, 1H), 6.04 (s, 2H), 5.12 (t, J = 1.0 Hz, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H),2.78 (t, J = 8.5 Hz, 2H), 2.34 (d, J = 1.0 Hz, 2H), 2.12 (td, J= 5.9, 3.0 Hz, 2H),2.06 (t, J = 2.9 Hz, 1H), 1.68 (tt, J = 8.4, 7.2 Hz, 2H), 1.52 – 1.41 (m, 2H), 1.44 – 1.34 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.00, 147.55, 147.37, 142.81,138.34, 137.36, 135.30, 134.45, 133.99, 132.47, 129.09, 128.03, 121.89,121.80, 121.25, 118.15, 109.19, 108.80, 101.51, 83.81, 71.32, 69.15, 61.65,58.81, 30.56, 28.81, 28.59, 28.38, 28.04, 27.89, 21.05, 17.91. ESI + :534.68.

[0105] Example 28 Synthesis of 13-(hex-5-yn-1-yl)-9-methoxy-10-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 28)

[0106] The experimental steps are the same as those in Example 1, except that the first raw material is 3,3-dimethylallyl bromide and the second raw material is 6-bromo-n-hexyne; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.31 (d, J = 8.7Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.28(ddp, J= 6.5, 3.2, 1.6 Hz, 1H), 4.67 – 4.59 (m, 4H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 2H), 2.83 (dt, J = 15.8, 7.3 Hz, 1H), 2.74 (dt, J = 15.6, 7.3 Hz,1H), 2.46 (td, J = 5.7, 3.0 Hz, 2H), 2.06 (t, J = 3.1 Hz, 1H), 1.79 (tt, J = 7.5,6.1 Hz, 2H), 1.75 (q, J = 1.1 Hz, 6H), 1.59 (p, J = 5.8 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.27, 147.55, 147.44, 142.81,137.69, 137.36, 134.70, 134.45, 132.47, 121.89, 121.21, 119.15, 117.80,109.19, 108.80, 101.51, 83.79, 69.15, 66.11, 61.65, 58.81, 30.57, 27.89,27.61, 27.50, 24.62, 19.90, 18.24. ESI + :470.59.

[0107] Example 29 Synthesis of 10-(3-aminopropoxy)-13-(hex-5-yn-1-yl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 29)

[0108] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropylamine and the second raw material is 6-bromo-n-hexyne; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 4.63(ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.09 – 4.00 (m, 5H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 2H), 2.97 – 2.89 (m, 2H), 2.88 – 2.78 (m, 3H), 2.74 (dt, J = 15.6,7.3 Hz, 1H), 2.46 (td, J = 5.7, 3.0 Hz, 2H), 2.06 (t, J = 3.1 Hz, 1H), 2.02 (p, J =5.6 Hz, 2H), 1.79 (tt, J = 7.4, 6.1 Hz, 2H), 1.59 (p, J = 5.9 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.33, 147.55, 147.54, 142.81,137.36, 134.68, 134.45, 132.47, 121.95, 121.89, 121.29, 118.04, 109.19,108.80, 101.51, 83.79, 69.15, 67.72, 61.65, 58.81, 37.13, 31.06, 30.57,27.89, 27.61, 27.50, 18.24. ESI + :459.57.

[0109] Example 30 Synthesis of 10-(allyloxy)-13-(cyanomethyl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 30)

[0110] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropylene and the second raw material is bromoacetonitrile; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.47 (s, 1H), 7.28 (d, J = 8.5Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.11 – 5.99 (m, 1H), 6.04 (s, 2H), 5.39 (ddt, J = 16.8, 2.1, 1.0 Hz, 1H), 5.31 (ddt, J = 16.9, 2.2,1.0 Hz, 1H), 4.66 – 4.58 (m, 4H), 4.20 (s, 2H), 3.16 (dddd, J = 17.3, 7.3, 4.6,1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.32, 147.62, 147.51, 142.71,136.13, 132.27, 130.26, 128.89, 127.79, 122.75, 122.04, 121.46, 118.50,117.91, 117.11, 108.80, 108.36, 101.51, 69.80, 61.65, 58.16, 27.89, 18.88. ESI + :401.44.

[0111] Example 31 Synthesis of 13-(cyanomethyl)-9-methoxy-10-((4-nitrobenzyl)oxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 31)

[0112] The experimental steps are the same as those in Example 1, except that the first raw material is p-nitrobenzyl bromide and the second raw material is bromoacetonitrile; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.14 – 8.08 (m, 2H), 7.61(dt, J = 8.1, 1.0 Hz, 2H), 7.47 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.5Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.13 (t, J = 1.1 Hz, 2H), 4.63(ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.20 (s, 2H), 3.16 (dddd, J = 17.3, 7.3, 4.6,1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.25, 148.14, 147.74, 147.51,142.71, 141.03, 136.13, 130.26, 128.89, 128.68, 127.79, 123.65, 122.75,121.97, 121.52, 118.17, 117.11, 108.80, 108.36, 101.51, 71.41, 61.65, 58.16,27.89, 18.88. ESI + :496.50.

[0113] Example 32 Synthesis of 9-methoxy-13-(4-methylbenzyl)-10-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 32)

[0114] The experimental steps are the same as those in Example 1, except that the first raw material is 3,3-dimethylallyl bromide and the second raw material is p-methylbenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d6 ) δ 9.85 (s, 1H), 7.49 (s, 1H), 7.28 (d, J = 8.7Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.14 (dq, J = 8.0, 1.2 Hz, 2H), 7.11 – 7.06(m, 2H), 6.99 (t, J = 1.0 Hz, 1H), 6.04 (s, 2H), 5.28 (ddp, J = 4.8, 3.1, 1.6 Hz,1H), 4.67 – 4.59 (m, 4H), 4.19 (t, J = 1.0 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 2H), 2.33 (d, J = 1.1 Hz, 2H), 1.75 (q, J = 1.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.39, 147.57, 147.54, 142.79,138.17, 137.69, 137.13, 136.95, 131.23, 130.86, 129.27, 128.45, 128.18,122.54, 122.05, 120.67, 119.15, 117.81, 108.80, 108.18, 101.51, 66.11, 61.65,57.39, 36.00, 27.89, 24.62, 21.04, 19.90. ESI + :494.61.

[0115] Example 33 Synthesis of 10-(hex-5-yn-1-yloxy)-9-methoxy-13-(4-methylbenzyl)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 33)

[0116] The experimental steps are the same as those in Example 1, except that the first raw material is 6-bromohexyne and the second raw material is p-methylbenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 0H), 7.49 (s, 0H), 7.34 (d, J = 8.8Hz, 0H), 7.17 – 7.06 (m, 2H), 6.04 (s, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz,1H), 4.19 (t, J = 1.0 Hz, 1H), 4.09 (t, J = 5.0 Hz, 1H), 3.16 (dddd, J = 19.3, 7.6,4.6, 1.0 Hz, 1H), 2.47 (td, J = 5.9, 3.0 Hz, 1H), 1.81 (tt, J = 7.5, 5.0 Hz, 1H),1.58 (tt, J = 7.5, 5.9 Hz, 1H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 148.46, 147.63, 147.54, 142.79,138.17, 137.13, 136.95, 131.18, 130.86, 129.27, 128.45, 128.18, 122.54,122.09, 120.60, 117.92, 108.80, 108.18, 101.51, 83.76, 69.20, 69.15, 61.65,57.39, 36.00, 28.67, 27.89, 25.28, 21.04, 18.09. ESI + :506.62.

[0117] Example 34 Synthesis of 9-methoxy-13-(4-nitrobenzyl)-10-(pentyloxy)-5,6-dihydro-[1,3]dioxepin[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 34)

[0118] The experimental steps are the same as those in Example 1, except that the first raw material is 5-bromopentane and the second raw material is p-nitrobenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.21 – 8.15 (m, 2H), 7.55 –7.47 (m, 3H), 7.34 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0Hz, 1H), 6.04 (s, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.20 (t, J = 1.1 Hz,2H), 4.02 (d, J = 11.5 Hz, 1H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 1.78(tt, J = 7.4, 5.6 Hz, 2H), 1.46 – 1.31 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 149.57, 149.54, 148.46, 147.63, 147.54,143.96, 142.79, 137.13, 131.23, 130.92, 128.79, 128.45, 123.81, 122.54,122.09, 120.60, 117.92, 108.80, 108.18, 101.51, 69.01, 61.65, 57.39, 36.04,29.05, 28.26, 27.89, 22.50, 13.97. ESI + :527.60.

[0119] Example 35 Synthesis of 9-methoxy-13-(4-nitrobenzyl)-10-(oct-7-yn-1-yloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 35)

[0120] The experimental steps are the same as those in Example 1, except that the first raw material is 8-bromooctyne and the second raw material is p-nitrobenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.21 – 8.15 (m, 2H), 7.55 –7.47 (m, 3H), 7.34 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.01 – 6.97 (m,1H), 6.04 (s, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.20 (t, J = 1.1 Hz,2H), 4.00 (t, J = 6.1 Hz, 2H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H), 2.12(td, J = 6.0, 3.0 Hz, 2H), 2.06 (t, J = 2.9 Hz, 1H), 1.77 (tt, J = 7.5, 6.1 Hz,2H), 1.55 – 1.34 (m, 6H). 13 C NMR (125 MHz, DMSO-d 6) δ 149.57, 149.54, 148.46, 147.63, 147.54,143.96, 142.79, 137.13, 131.23, 130.92, 128.79, 128.45, 123.81, 122.54,122.09, 120.60, 117.92, 108.80, 108.18, 101.51, 83.81, 69.15, 68.79, 61.65,57.39, 36.04, 29.34, 28.28, 28.06, 27.89, 26.05, 17.91. ESI + :565.65.

[0121] Example 36 Synthesis of 10-(allyloxy)-13-(3,5-dimethoxybenzyl)-9-methoxy-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 36)

[0122] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropylene and the second raw material is 3,5-dimethoxybenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 7.49 (s, 1H), 7.28 (d, J = 8.8Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.46 (dt, J = 2.2, 1.0Hz, 2H), 6.36 (t, J = 2.4 Hz, 1H), 6.11 – 5.99 (m, 1H), 6.04 (s, 2H), 5.39(ddt, J = 16.8, 2.2, 1.0 Hz, 1H), 5.31 (ddt, J = 16.8, 2.2, 1.0 Hz, 1H), 4.67 –4.58 (m, 5H), 4.08 (dt, J= 9.5, 1.0 Hz, 1H), 4.03 – 3.97 (m, 1H), 3.79 (s,6H), 3.16 (dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 149.57, 148.32, 147.57, 147.54,142.79, 139.48, 137.07, 132.27, 131.24, 130.70, 128.45, 122.55, 122.05,120.68, 118.50, 117.81, 108.80, 108.24, 108.18, 101.51, 98.82, 69.80, 61.65,57.39, 55.33, 36.36, 27.89. ESI + :512.58.

[0123] Example 37 Synthesis of 13-(3,5-dimethoxybenzyl)-9-methoxy-10-(prop-2-yn-1-yloxy)-5,6-dihydro-[1,3]dioxol[4,5-g]isoquinolin[3,2-a]isoquinolin-7-ium (Compound 37)

[0124] The experimental steps are the same as those in Example 1, except that the first raw material is 3-bromopropyne and the second raw material is 3,5-dimethoxybenzyl bromide; the NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 8.8Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 1.0 Hz, 1H), 6.46 (dt, J = 2.2, 1.0Hz, 2H), 6.36 (t, J = 2.4 Hz, 1H), 6.04 (s, 2H), 4.83 (d, J = 3.2 Hz, 2H), 4.64(ddd, J= 7.3, 4.6, 1.7 Hz, 2H), 4.08 (dt, J = 9.5, 1.0 Hz, 1H), 4.00 (s, 3H), 4.00 (dt, J = 9.3, 1.0 Hz, 1H), 3.79 (s, 6H), 3.36 (d, J = 6.1 Hz, 1H), 3.16(dddd, J = 19.3, 7.6, 4.6, 1.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 149.57, 147.54, 147.52, 146.74,142.79, 139.48, 137.07, 131.25, 130.70, 128.45, 122.55, 122.00, 120.80,118.52, 108.80, 108.24, 108.18, 101.51, 98.82, 78.41, 76.70, 61.65, 58.28,57.39, 55.33, 36.36, 27.89. ESI + :510.57.

[0125] Example 38 Activity of 10,13-Disubstituted Berberine Derivatives against Candida albicans 1) Preparation of bacterial culture The Candida albicans SC5314 was counted by hemocytometer and prepared into 2 × 10 4 -5×10 4 CFU / ml of bacterial solution.

[0126] 2) Preparation of 10,13-substituted berberine derivative solution The 10,13-substituted berberine derivatives were prepared into a 10 mg / mL stock solution using sterile DMSO as solvent, and then diluted with sterile DMSO in sequence to obtain dilutions with concentrations of 128 μg / mL, 64 μg / mL, 32 μg / mL, 16 μg / mL, 8 μg / mL, 4 μg / mL, 2 μg / mL, 1 μg / mL, 0.5 μg / mL, 0.25 μg / mL, and 0.125 μg / mL.

[0127] Positive control drugs (fluconazole, amphotericin B) were prepared in sequence as 100 μg / mL stock solutions using sterile DMSO as solvent, and then diluted in sequence with sterile DMSO to obtain dilutions with concentrations of 4 μg / mL, 2 μg / mL, 1 μg / mL, 0.5 μg / mL, 0.25 μg / mL, 0.125 μg / mL, 0.0625 μg / mL and 0.03125 μg / mL as positive control drugs for the detection of Candida albicans. 3) Determination of the minimum inhibitory concentration of 10,13-substituted berberine derivatives against Candida albicans a. Take a 96-well cell culture plate and add 100 μL RPMI1640 medium and 100 μL prepared bacterial solution to each well of the control group; b. In the positive control group, add 100 μL of prepared bacterial solution and 100 μL of positive control drug dilutions of different dilution gradients to each well; In the experimental group, 100 μL of prepared bacterial solution and 100 μL of prepared compound dilutions with different dilution gradients were added to each well; An equal amount of sterile DMSO was added to each well of the negative control group; c. After culturing at 37°C for 24 hours, observe the growth of Candida albicans in each well: if the well is turbid, it means that the compound at this concentration has no anti-Candida albicans activity; if the next well is clear, it means that the compound at this concentration has anti-Candida albicans activity, which is the minimum inhibitory concentration of the compound against Candida albicans, MIC value. The results are shown in Table 1.

[0128] Table 1

[0129] As shown in Table 1, the 10,13-position disubstituted berberine derivatives provided by the present invention have antifungal effects.

[0130] CLSM (Confocal Laser Scanning Microscopy) was used to observe the effect of berberine and its derivatives on the thickness of Candida albicans biofilm. Confocal laser scanning microscopy was used to visually examine the inhibitory effect of drugs on biofilm formation. FUNXite-1 was converted by fungal cells to produce green fluorescence by binding to the cell membrane. The biofilm formed in the control group had a dense three-dimensional structure, the bacteria grew vigorously, and a thicker biofilm was formed. Figure 1 , showing that after drug intervention, the biofilm thickness of Candida albicans was significantly reduced and the amount of bacteria decreased, indicating that berberine can inhibit the biofilm formation of Candida albicans; and berberine derivative 23 is more effective than berberine and has a stronger inhibitory effect.

[0131] Example 39 Effects of 10- and 13-position disubstituted berberine derivatives on mice with oropharyngeal candidiasis The effect of the compound of the present invention on the oropharyngeal candidiasis mouse model (the main reference is Solis NV, Filler S G. Mouse model of oropharyngeal candidiasis [J]. Nat Protoc, 2012, 7 (4): 637-42.) was evaluated. The drug dose was 50 mg / kg, 100 mg / kg, and 200 mg / kg. The final treatment effect of 100 mg / kg was the best, and subsequent experiments were carried out at this concentration.

[0132] (1) Effects on the tongue mucosa The surface of the tongue mucosa of mice with oropharyngeal candidiasis was observed. Figure 2 As shown, the tongue of the control group (untreated) was smooth and moist, and the surface of the tongue mucosa was light red; after infection with Candida albicans, the surface of the tongue mucosa was covered with white pseudomembrane, and the overall structure was severely damaged. After drug intervention (BBR or compound 23), the tongue mucosa of mice with oropharyngeal candidiasis was repaired to a certain extent, and the recovery effect of berberine derivative 23 after treatment was better than that of berberine.

[0133] (2) Oral fungal load test The fungal load in the oral cavity of mice with oropharyngeal candidiasis was measured. The Candida albicans load in the oral cavity of the mice was collected and plated. The results were as follows Figure 3 As shown, it shows that after drug treatment, the load of Candida albicans shows a gradual downward trend. With the stable intervention of the drug, the proliferation of Candida albicans can be more effectively inhibited. Compared with BBR, the berberine derivative 23 (compound 23) of the present invention has a better intervention effect.

[0134] (3) HE staining The tongue tissues of mice with oropharyngeal candidiasis were subjected to pathological sections stained with HE. Figure 4 As shown in the figure, the effect of drugs on the pathological morphology of mouse tongue tissue was observed. The filiform papillae on the surface of the tongue mucosa of mice in the uninfected control group were neatly arranged, and the surface of the tongue mucosa was intact. The overall structure was destroyed after Candida albicans infection. After treatment with drugs (BBR or compound 23), the structural damage on the surface of the tongue mucosa was gradually repaired to varying degrees, and the infiltration of inflammatory cells gradually decreased; and the berberine derivative 23 restored the degree of damage better.

[0135] In order to further observe the damage to the mouse tongue tissue and the repair after drug treatment, the effects of drugs on the tongue mucosa of mice with oropharyngeal candidiasis were observed by SEM. Figure 5As shown, the overall structure of the tongue tissue of the uninfected control group mice was intact, and the structure was destroyed after Candida albicans infection. The surface of the tongue mucosa treated with berberine was severely damaged and the degree of repair was low; after treatment with berberine derivative 23, the filiform papillae on the surface of the tongue mucosa gradually stretched, indicating that berberine derivative 23 was more effective than berberine.

[0136] (4) Effects on gene expression and protein expression In order to observe the effect of drugs on gene expression in mouse tongue tissue, qRT-PCR experiments were performed to detect gene expression in tongue tissue of mice with oropharyngeal candidiasis by qRT-PCR. Figure 6 , indicating that after drug intervention, the expression of S100a8 gene was significantly reduced, and the effect of berberine derivative 23 was better than berberine, and the difference was statistically significant.

[0137] In order to observe the effect of drugs on protein expression in mouse tongue tissue, WB was used to detect protein expression in the tongue tissue of mice with oropharyngeal candidiasis. Figure 7 As shown, it was shown that after drug intervention, the expression of EGFR protein in the tongue tissue of mice with oropharyngeal candidiasis was significantly reduced, and the protein expression level was even lower after treatment with berberine derivative 23.

[0138] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", "some implementation schemes" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0139] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, characterized in that The compound is a compound represented by the general formula (I) or a pharmaceutically acceptable salt of the compound represented by the general formula (I): R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, unsubstituted or substituted with at least one R a Substituted C1-C 10 alkyl; m=1, n=1~5, R3 is unsubstituted or substituted with at least one R b Substituted phenyl; R a is -NH2; R b is selected from -NO2, halogen, C1 alkoxy, C1 alkyl, and R1 and R2 are not both unsubstituted C1-C 10 alkyl.

2. The compound according to claim 1, characterized in that The compound is selected from one of the following structures: 。 3. A drug, characterized in that The medicament comprises the compound according to claim 1 or 2, and is used for improving or treating Candida albicans infection.

4. Use of the compound according to claim 1 or 2 in the preparation of a medicament for improving or treating Candida albicans infection.

Images