Isoquinoline medicine and application thereof in improving or treating gastrointestinal tumors

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 digestive tract tumors. The invention aims to provide a compound, a pharmaceutical composition containing the compound and application of the compound in treatment of colorectal cancer and gastric cancer, and provides a 3, 13-substituted berberine derivative which is low in toxicity, does not affect growth of human normal cells, and has a wide application prospect in development of novel anti-tumor drugs and application of the 3, 13-substituted berberine derivative in treatment of colorectal cancer and gastric cancer. Particularly, the compound has a very good application prospect in the aspect of development of anti-digestive tract tumor drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of small molecule drugs, and particularly relates to an isoquinoline drug and its application in improving or treating digestive tract tumors. Background Art

[0002] Colorectal cancer, also known as colorectal carcinoma, is one of the common malignant tumors worldwide. According to the data of the World Health Organization (WHO), the incidence and mortality of colorectal cancer have shown an upward trend in recent years, especially in developed countries. The harm of colorectal cancer is mainly reflected in its high incidence and mortality. In recent years, the prevalence and fatality rate of colorectal cancer are still on the rise globally. The high incidence and mortality of colorectal cancer have made it an important issue in global public health.

[0003] Although certain progress has been made in the diagnosis and treatment of colorectal cancer, many difficulties are still faced. Firstly, the early diagnosis rate is relatively low, and many patients are already in the middle and late stages at the time of diagnosis, missing the best treatment opportunity. Secondly, the heterogeneity of colorectal cancer is relatively high, and the tumor biological characteristics of different patients vary greatly, resulting in uneven treatment effects. In addition, the drug resistance problem of colorectal cancer is also relatively prominent, and many patients develop drug resistance during the treatment process, leading to poor treatment effects.

[0004] Currently, the drug treatment of colorectal cancer mainly includes chemotherapy, targeted therapy, and immunotherapy. Chemotherapy is the basis of colorectal cancer treatment, and commonly used chemotherapy drugs include 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, etc. Targeted therapy is an important progress in the treatment of colorectal cancer in recent years, and commonly used targeted drugs include anti-EGFR antibodies (such as cetuximab) and anti-VEGF antibodies (such as bevacizumab). Immunotherapy is an emerging field in the treatment of colorectal cancer, especially PD-1 / PD-L1 inhibitors have shown good efficacy in colorectal cancer patients with high microsatellite instability (MSI-H).

[0005] Although certain progress has been made in the drug treatment of colorectal cancer, many problems are still faced. Firstly, the drug resistance problem is prominent, and many patients develop drug resistance during the treatment process, leading to poor treatment effects. Secondly, the application scope of targeted therapy and immunotherapy is limited and only applicable to some patients. In addition, the side effects of drug treatment are relatively large, affecting the quality of life of patients. Therefore, how to improve the efficacy of drug treatment, reduce side effects, and expand the application scope are the main problems faced in the current treatment of colorectal cancer.

[0006] Current chemotherapy drugs for gastric cancer include fluorouracil (5-FU), platinum-based drugs (cisplatin, oxaliplatin), taxanes (docetaxel), etc. as the basic regimens, but there are problems such as severe drug resistance (ineffective in about 50% of patients), myelosuppression, and neurotoxicity. Moreover, the response rates of targeted therapy and immunotherapy in patients are low, and chemotherapy and targeted therapy are prone to failure due to mechanisms such as tumor heterogeneity and compensatory activation of signaling pathways. Most patients lack targetable driver gene mutations.

[0007] At the same time, the severe side effects of traditional chemotherapy (such as myelosuppression and gastrointestinal reactions) affect treatment compliance, and there is an urgent need for breakthrough therapies. The research and development of small molecule drugs for gastric cancer need to focus on overcoming drug resistance, improving precision, and reducing toxicity, the three core requirements. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems in the related art to some extent. For this reason, an object of the present invention is to provide a compound, a pharmaceutical composition containing the compound, and its use in the treatment of digestive tract tumors. The present invention provides a 3,13-disubstituted berberine derivative, which has relatively low toxicity and does not affect the growth of normal human cells, and has good application prospects in the development of new anti-tumor drugs, especially in the development of anti-drug-resistant colon cancer and gastric cancer drugs.

[0009] For this reason, in the first aspect of the present invention, there is provided a compound, which is a compound represented by the general formula (I) or a stereoisomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by the general formula (I):

[0010] Wherein, R 1 、R 2 Each independently selected from -(CH 2 ) m R 3 、-(CH 2 ) n -CN, the following groups without substitution or substituted by at least one R a : C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; m = 1 to 10, n = 1 to 10, R 3 Is an unsubstituted or at least one R b Substituted 3- to 10-membered heterocyclic group, C 6 -C 20Aryl, 5- to 20-membered heteroaryl; R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 20 alkoxy, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl.

[0011] The most serious problems faced in the current treatment of colon cancer and gastric cancer are widespread drug resistance, and the chemotherapeutic drugs applicable to colorectal cancer and gastric cancer are extremely limited. Moreover, tumor cells are prone to develop drug resistance to chemotherapeutic drugs (such as 5-fluorouracil and oxaliplatin) and targeted drugs (such as anti-EGFR and anti-VEGF), resulting in reduced or ineffective efficacy. And currently, chemotherapy and targeted therapy are often accompanied by serious side effects, such as myelosuppression and neurotoxicity, which affect the quality of life of patients and even limit the continuation of treatment. In addition, immunotherapy has obvious limitations in the treatment of colon cancer and gastric cancer. Immune checkpoint inhibitors have limited effects on microsatellite stable (MSS) colon cancer and may cause immune-related side effects. And due to the high cost of targeted drugs and immunotherapy, some patients cannot afford them, which affects the accessibility of treatment.

[0012] The compound shown by the general formula (I) of the present invention can be used to prepare anti-colon cancer and gastric cancer drugs, and this drug shows excellent inhibitory activity both in vitro and in vivo. Moreover, this drug has relatively low toxicity itself, does not affect the growth of normal human cells, is not prone to develop drug resistance, and has good application prospects in the development of new anti-tumor drugs, especially in the development of anti-drug-resistant colon cancer drugs.

[0013] According to the embodiments of the present invention, in the compound shown by the general formula (I), R 1 , R 2 are each independently selected from -(CH 2 ) m R 3 , -(CH 2 ) n -CN, the following groups which are unsubstituted or substituted by at least one R a : C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl; m = 1 to 10, n = 1 to 10, R3 is unsubstituted or substituted by at least one R b substituted C 6 -C 20 aryl, 5- to 20-membered heteroaryl; R a and R b are each independently selected from -NH 2 -, -NO 2 -, halogen, C 1 -C 15 alkoxy, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl.

[0014] According to an embodiment of the present invention, in the compound represented by the general formula (I), R 1 and R 2 are each independently selected from -(CH 2 ) m R 3 , -(CH 2 ) n -CN, an unsubstituted or at least one R a substituted group: C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl; m = 1 to 5, n = 1 to 10, R 3 is unsubstituted or substituted by at least one R b substituted C 6 -C 20 aryl; R a and R b are each independently selected from -NH 2 -, -NO 2 -, halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl.

[0015] According to an embodiment of the present invention, in the compound represented by the general formula (I), R 1 and R 2 are each independently selected from -(CH2 ) m R 3 ,-(CH 2 ) n -CN, unsubstituted or substituted by at least one R a with the following groups: C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl; m = 1 to 5, n = 1 to 10, R 3 is unsubstituted or substituted by at least one R b phenyl; R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl.

[0016] According to an embodiment of the present invention, R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl.

[0017] According to an embodiment of the present invention, R a is -NH 2 ; R b is selected from -NO 2 , halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl.

[0018] According to an embodiment of the present invention, in the compound represented by the general formula (I), R 1 , R 2 are 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 by at least one R a substituted C 1 -C 10 alkyl; m = 1 - 5, n = 1 - 10, R 3 is unsubstituted or substituted by at least one R b substituted phenyl; R a is -NH 2 ; R b is selected from -NO 2 , halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl.

[0019] According to an embodiment of the present invention, the compound is selected from one of the following structures:

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0027] The second aspect of the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises the compound described in the first aspect.

[0028] According to an embodiment of the present invention, the pharmaceutical composition further comprises pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, diluents or excipients.

[0029] Using the compound provided by the present invention to prepare drugs in various dosage forms and administering them to a subject in a therapeutically effective amount, after being absorbed by the subject, the drug can treat or improve colorectal cancer.

[0030] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more other therapeutic agents. Among them, the other therapeutic agents are similar in function to the compounds of the present invention and can all be used for treating or improving colorectal cancer.

[0031] The present invention relates to suitable pharmaceutically acceptable salts of the compounds represented by formula (I) or (I), including but not limited to hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, mesylate, benzenesulfonate or p-toluenesulfonate. According to the foregoing, any compound of the present invention mentioned herein includes its pharmaceutically acceptable salts, solvates or combinations thereof.

[0032] In addition to the pharmaceutically acceptable salts of the compounds of the present invention, the present invention also includes other salts. They can act as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.

[0033] The third aspect of the present invention provides the use of the compound described in the first aspect in the preparation of a drug for treating digestive tract tumors.

[0034] According to an embodiment of the present invention, the digestive tract tumors include colorectal cancer and gastric cancer.

[0035] The 3,13-disubstituted berberine derivatives provided by the present invention have a completely different drug mechanism from the commonly used anti-colorectal cancer and gastric cancer drugs in current clinical practice, and may play an excellent role in drug-resistant colorectal cancer and gastric cancer. The 3,13-disubstituted berberine derivatives of the present invention are expected to synergistically act with other first-line anti-colorectal cancer and gastric cancer drugs.

[0036] The additional aspects and advantages of the present invention will be partly given in the following description, partly will become obvious from the following description, or will be understood through the practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The above and / or additional aspects and advantages of the present invention will become obvious and easy to understand from the description of the embodiments in conjunction with the following drawings, wherein: Figure 1 It is the inhibitory cell proliferation activity curve and the corresponding half-maximal inhibitory concentration of the candidate compound MX51 against three colon cancer cell lines SW620, DLD-1 and SW480. Among them, A shows the half-maximal inhibitory concentration of the compound MX51 against the cell line SW620; B shows the half-maximal inhibitory concentration of the compound MX51 against the cell line DLD-1; C shows the half-maximal inhibitory concentration of the compound MX51 against the cell line SW480; Figure 2It is a diagram for evaluating the effect of MX51 on inhibiting the occurrence and development of colon cancer in subcutaneous tumor models, orthotopic cecal inoculation models, and AOM / DSS spontaneous colon cancer models; among them, DMSO was set as the control group, A is a line graph of the effect of MX51 on tumor volume, and B is a bar graph of the effect of MX51 on tumor weight; Figure 3 It is a diagram for evaluating the effect of MX51 on inhibiting tumors in the orthotopic cecum of immunodeficient mice; among them, DMSO was set as the control group, A is a cecum diagram before (upper) or after (lower) treatment with MX51; B is the count of mice corresponding to different tumor volumes; C is the count of mice corresponding to different tumor weights; D is a line graph of the survival rate of mice; Figure 4 It is a diagram for evaluating the in vivo activity of MX51 in AOM (10 mg / mL)-modeled BALb / c mice; among them, DMSO was set as the control group, A is a schematic diagram of the in vivo administration time, B is a diagram of the effect of MX51 treatment on the body weight of mice, C is a distribution map of colon tumors, D is a count diagram of colon length, E is a colon HE staining diagram (left) and a bar graph of polyp count (right), and F is a line graph of the survival rate of mice. Detailed implementation manners

[0038] The embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation to the present invention.

[0039] It should be noted that the terms "first" and "second" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly indicating the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include one or more of such features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0040] The endpoints and any values within the ranges disclosed herein are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0041] To make it easier to understand the present invention, 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 of ordinary skill in the art to which the present invention pertains.

[0042] In this text, the term "comprising" or "including" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other aspects of the content.

[0043] In this text, the terms "optionally", "optional" or "option" generally mean that the subsequent described event or condition can but does not necessarily occur, and this description includes the cases where the event or condition occurs, as well as the cases where the event or condition does not occur.

[0044] 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 combined and combined arbitrarily with each other. The group definitions and compound structures after such combination and combination should fall within the scope recorded in the specification of this application.

[0045] The term "pharmaceutically acceptable salt" refers to a non-toxic salt of a pharmaceutically acceptable 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 amines, secondary amines, 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, penicillin G, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, or polyamine resins; salts derived from inorganic acids and organic acids include, but are not limited to, organic salts formed by 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, vinylsulfonic 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, etc.

[0046] The term "stereoisomer" refers to an isomer produced by the different arrangements of atoms in space in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0047] The term "tautomer" refers to functional group isomers resulting from the rapid movement of a particular atom within a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomers of a compound may exist in two or more interconvertible forms. Prototropic tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in an equilibrium, and attempting to isolate a single tautomer usually results in a mixture that has physical and chemical properties identical to those of a mixture of the compounds. The position of the equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0048] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism, enhance the absorption of the active ingredient, and thereby exert its biological activity.

[0049] The term "solvate" refers to a stoichiometric or non-stoichiometric solvent, including water when the solvent is water, which is bound to a compound of the present invention or its salt by intermolecular non-covalent forces.

[0050] The term "prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis into a compound of the present invention having biological activity. The prodrugs of the present invention are prepared by modifying a functional group in the compound, and the modification can be removed by conventional procedures or in vivo to obtain the parent compound.

[0051] The term "C 1 -C 10 alkyl" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Examples of such alkyl groups include 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" should be understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0052] The term "C 2 -C20 "Alkynyl" should be understood to preferably denote a straight-chain or branched-chain monovalent hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0053] The term "C 2 -C 20 "Alkenyl" should be understood to preferably denote a straight-chain or branched-chain monovalent hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0054] The term "3- to 10-membered heterocyclic group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring that contains 1 to 5, preferably 1 to 3 heteroatoms selected from N, O, and S. In particular, the heterocyclic group may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5-membered ring, such as hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. A ring containing a nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. According to the present invention, the heterocyclic group is non-aromatic.

[0055] The term "C 6 -C 20 "Aryl" should be understood to preferably denote a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl.

[0056] The term "5-20 membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and containing 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S, and may be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thieno-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0057] The term "excipient" refers to pharmaceutically inert ingredients. Non-limiting examples of the types of "excipients" include binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents, etc. Excipients can enhance the handling properties of pharmaceutical formulations, i.e., make the formulations more suitable for direct compression by increasing fluidity and / or adhesiveness. Examples of typical "pharmaceutically acceptable carriers" applicable to the above formulations are: saccharides, such as lactose, sucrose, mannitol and sorbitol, or corn starch, tapioca starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal salts of stearic acid, such as magnesium stearate and calcium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and hydrolyzed cereal solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, etc., which are commonly used excipients in pharmaceutical formulations.

[0058] Colorectal cancer is one of the common malignant tumors globally, and its incidence and mortality are on the rise. Despite certain progress in diagnosis and treatment, many challenges still remain. Early diagnosis, individualized treatment, overcoming drug resistance, and reducing side effects are the main directions in current colorectal cancer treatment. Future research should focus on exploring new treatment targets, developing new drugs, and optimizing treatment regimens to improve the survival rate and quality of life of colorectal cancer patients.

[0059] Berberine (BBR) is an isoquinoline alkaloid mainly found in traditional Chinese medicine plants such as Coptis chinensis and Phellodendron amurense. Its chemical structure is in the form of a quaternary ammonium salt, with a planar aromatic ring and multiple oxygen atoms, endowing it with good biological activities such as antibacterial, anti-inflammatory, and antitumor effects.

[0060] Studies have shown that berberine can exert anti-colorectal cancer effects by inhibiting cancer cell proliferation, inducing apoptosis, anti-metastasis and anti-angiogenesis, and regulating the intestinal microbiota. In addition, berberine has advantages such as multi-target action, low toxicity and safety, synergistic enhancement, reversal of drug resistance, and improved bioavailability. Research has shown that in a clinical phase II trial, adjuvant treatment with berberine prolonged the progression-free survival of patients by 2 - 3 months. However, the anti-colonic tumor activity of berberine needs to be improved, and its mechanism is still unclear.

[0061] Aiming at the above deficiencies of the existing technology, the purpose of the present invention is to provide a class of 3,13-disubstituted berberine derivatives, their preparation methods and applications. By reasonably designing and modifying berberine (BBR), candidate drugs with improved activity, new mechanisms, less prone to drug resistance, and good safety are obtained.

[0062] According to a specific embodiment of the present invention, the present invention provides a 3,13-disubstituted berberine derivative, and its structural formula is shown as general formula (I):

[0063] Among them, R 1 、R 2 each independently selected from -(CH 2 ) m R 3 、-(CH 2 ) n -CN, the following groups without substitution or substituted by at least one R a : C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; m = 1 - 10, n = 1 - 10, R 3 is an unsubstituted or at least one R b substituted 3- to 10-membered heterocyclic group, C 6 -C 20 aryl, 5- to 20-membered heteroaryl; R a and R b are each independently selected from -NH 2 -, -NO 2 -, halogen, C 1 -C 20 alkoxy, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl.

[0064] It should be noted that m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. For example, m is 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 or 1-10, and n is 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9 or 1-10.

[0065] According to a specific embodiment of the present invention, in the compound represented by the general formula (I), R 1 and R 2 are each independently selected from -(CH 2 ) m R 3 , -(CH 2 ) n -CN, an unsubstituted or at least one R a substituted following groups: C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl; m = 1-10, n = 1-10, R 3 is an unsubstituted or at least one R b substituted C 6 -C 20 aryl, 5- to 20-membered heteroaryl; R a and R b are each independently selected from -NH 2 -, -NO 2 -, halogen, C 1 -C 15 alkoxy, C1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl.

[0066] According to a specific embodiment of the present invention, in the compound represented by the general formula (I), R 1 , R 2 are each independently selected from -(CH 2 ) m R 3 , -(CH 2 ) n -CN, the following groups which are unsubstituted or substituted by at least one R a : C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl; m = 1 to 5, n = 1 to 10, R 3 is an unsubstituted or R b -substituted C 6 -C 20 aryl; R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 10 alkoxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl.

[0067] According to a specific embodiment of the present invention, in the compound represented by the general formula (I), R 1 , R 2 are each independently selected from -(CH 2 ) m R 3 , -(CH 2 ) n -CN, the following groups which are unsubstituted or substituted by at least one R a : C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C10 Alkynyl group; m = 1 to 5, n = 1 to 10, R 3 is unsubstituted or phenyl substituted by at least one R b substituent; R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 10 alkoxy group, C 1 -C 10 alkyl group, C 2 -C 10 alkenyl group, C 2 -C 10 alkynyl group.

[0068] According to a specific embodiment of the present invention, R a , R b are each independently selected from -NH 2 , -NO 2 , halogen, C 1 -C 10 alkoxy group, C 1 -C 10 alkyl group.

[0069] According to a preferred embodiment of the present invention, R a is -NH 2 ; R b is selected from -NO 2 , halogen, C 1 -C 5 alkoxy group, C 1 -C 5 alkyl group. Among them, the halogen is fluorine, chlorine, bromine or iodine.

[0070] According to a specific embodiment of the present invention, the present invention provides a method for preparing a 3,13 - substituted berberine derivative, comprising the following steps:

[0071] React (M1), anhydrous acetonitrile, potassium carbonate and the first raw material at 60 - 70 °C, monitor the reaction progress by TLC. After the reaction is complete, cool to precipitate all the solids, filter by suction. Mix the filtrate with silica gel, and use dichloromethane and methanol as the mobile phase to purify by Flash rapid column chromatography to obtain the yellow intermediate (M2). React the above-obtained intermediate with anhydrous acetonitrile, sodium hydride and the second raw material at 70 - 90 °C, monitor the reaction progress by TLC. After the reaction is complete, neutralize with hydrochloric acid - methanol solution and mix with silica gel, and still use dichloromethane and methanol as the mobile phase to purify by Flash rapid column chromatography to obtain the yellow final product.

[0072] According to a specific embodiment of the present invention, the present invention provides the use of the above-mentioned 3,13-disubstituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation of products for preventing and / or treating colorectal cancer.

[0073] According to a specific embodiment of the present invention, the present invention provides the use of the above-mentioned 3,13-disubstituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation of drugs for preventing and / or treating anti-colon tumors.

[0074] The present invention provides a class of 3,13-disubstituted berberine derivatives represented by general formula (I), their preparation methods and applications, and specifically screened high-efficiency, low-toxicity and non-resistant compounds in the previous work. Compared with BBR, the 3,13-disubstituted berberine derivatives provided by the present invention show more promising inhibitory activities against three colon cancer cell lines. The effects of the 3,13-disubstituted berberine derivatives on tumor volume and mass were investigated in ectopic and orthotopic tumors in mice. The results showed that the 3,13-disubstituted berberine derivatives could significantly inhibit the growth of SW620 tumors and prolong the survival period of the tumor-bearing mice. At the same time, in azoxymethane AOM (10 mg / mL)-induced mice, the 3,13-disubstituted berberine derivatives significantly reduced the number of tumors, extended the length of the entire cecum, alleviated the degree of intestinal mucosal barrier damage, and extended the survival period of the mice without affecting the body weight of the mice. This has good application prospects in the development of new anti-colon cancer drugs, especially in the development of anti-resistant colon tumor treatment.

[0075] It should be noted that the use of the 3,13-disubstituted berberine derivatives represented by general formula (I) in the preparation of anti-colon cancer and anti-gastric cancer drugs, as well as in the preparation of drugs for preventing and / or treating colon cancer and gastric cancer, should all be within the protection scope of the present invention.

[0076] The solutions of the present disclosure will be explained below in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present disclosure and should not be construed as limiting the scope of the present disclosure. For those without specific technical or conditions noted in the embodiments, the techniques or conditions described in the literature in this field or according to the product specifications are followed. Those reagents or instruments without the manufacturer noted are all conventional products that can be obtained through commercial purchases.

[0077] Example 1 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX1)

[0078] React M1, anhydrous acetonitrile, potassium carbonate, and 3-nitrobenzyl bromide (the first raw material) at 65 °C. Monitor the reaction progress by TLC. After the reaction is complete, cool it until the solid completely precipitates, filter it by suction. Mix the filtrate with silica gel, and use dichloromethane and methanol as the mobile phase to purify it by Flash rapid column chromatography to obtain a yellow intermediate. React the above-obtained intermediate with anhydrous acetonitrile, sodium hydride, and 3,3-dimethylallyl bromide (the second raw material) at 85 °C. Monitor the reaction progress by TLC. After the reaction is complete, neutralize it with hydrochloric acid-methanol solution and then mix it with silica gel. Similarly, use dichloromethane and methanol as the mobile phase to purify it by Flash rapid column chromatography to obtain the yellow final product MX1. The NMR results of the final product are as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.29 (tt, J = 2.3, 1.0 Hz,1H), 8.17 (ddd, J = 8.8, 2.3, 1.2 Hz, 1H), 7.72 (ddq, J = 8.1, 2.2, 1.2 Hz, 1H),7.61 (dd, J = 8.8, 7.8 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.1 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz,1H), 5.24 (t, J= 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s,3H), 3.88 (d, J = 13.9 Hz, 5H), 3.46 (dp, J = 7.4, 1.0 Hz, 2H), 3.21 – 3.14 (m,2H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.86, 149.48, 148.45, 147.22,142.90, 137.02, 136.89, 133.35, 130.41, 130.17, 129.75, 129.26, 128.59,124.37, 123.79, 123.77, 122.76, 122.09, 121.57, 120.78, 114.29, 111.38,71.22, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.49, 19.28. ESI + : 541.62。

[0079] Synthesis of 13-Hexyl-2,9,10-trimethoxy-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX2) in Example 2

[0080] The experimental procedure was the same as in Example 1, except that the first starting material was 3-nitrobenzyl bromide and the second starting material was 1-bromopentanamine; the NMR results of the final product were as follows: 1 H NMR (500 MHz,DMSO-d 6 ) δ 9.94 (s, 1H), 8.29 (tt, J = 2.2, 1.0 Hz, 1H),8.17 (ddd, J = 8.8, 2.3, 1.2 Hz, 1H), 7.72 (dtd, J = 8.2, 2.4, 1.2 Hz, 1H), 7.61(dd, J= 8.8, 7.8 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.04(t, J = 1.0 Hz, 1H), 5.24 (t, J = 1.0 Hz, 2H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz,2H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.81 – 2.72(m, 4H), 1.87 (t, J = 6.5 Hz, 2H), 1.65 (tt, J = 8.3, 7.4 Hz, 2H), 1.56 – 1.47(m, 2H), 1.41 – 1.32 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 149.86, 149.48, 148.45, 146.81,143.03, 137.45, 137.02, 135.28, 133.35, 133.19, 130.30, 129.26, 124.37,123.79, 123.25, 122.15, 121.99, 121.50, 114.25, 111.38, 71.22, 61.81, 58.81,56.30, 55.65, 40.93, 32.65, 30.59, 28.66, 27.97, 26.74. ESI + : 558.65。

[0081] Example 3 Synthesis of 13-butyl-2,9,10-trimethoxy-3-((2-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX3)

[0082] The experimental procedure was the same as in Example 1, except that the first raw material was o-nitrobenzyl bromide and the second raw material was 1-bromobutane; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d6 ) δ 9.94 (s, 1H), 8.08 (dd, J J = 8.6, 1.4 Hz,1H), 7.63 (td, J J = 7.3, 1.2 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.51 (dq, J J = 7.2, 1.1Hz, 1H), 7.35 – 7.30 (m, 2H), 7.19 (d, J J = 8.5 Hz, 1H), 7.04 (t, J J = 1.0 Hz, 1H),5.41 (d, J J = 1.0 Hz, 2H), 4.63 (ddd, J J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (s, 3H),3.88 (d, J J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.87 – 2.70 (m, 2H), 1.65 (tt, J J = 8.9, 6.6 Hz, 2H), 1.36 (h, J J = 6.9 Hz, 2H), 0.93 (t, J J = 7.2 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 149.90, 149.51, 146.88, 146.81,143.03, 137.43, 135.15, 133.18, 131.27, 130.30, 130.16, 129.95, 127.86,125.06, 123.25, 122.15, 121.99, 121.50, 114.19, 111.38, 69.58, 61.81, 58.81,56.30, 55.65, 31.57, 30.23, 27.97, 22.36, 13.76. ESI + : 529.61。

[0083] Example 4 Synthesis of 2,9,10-trimethoxy-3-((2-nitrobenzyl)oxy)-13-(oct-7-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX4)

[0084] The experimental procedure was the same as that of Example 1, except that the first raw material was o-nitrobenzyl bromide and the second raw material was 1-bromo-1-octyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.08 (dd, J J = 8.6, 1.4 Hz, 1H), 7.63 (td, J J = 7.3, 1.2 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.51 (dq, J J = 7.2, 1.1 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.19 (d, J J = 8.5 Hz, 1H), 7.04 (t, J J = 1.0 Hz, 1H), 5.41 (d, J J = 1.0 Hz, 2H), 4.63 (ddd, J J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.78 (t, J J = 8.5 Hz, 2H), 2.12 (td, J J = 5.9, 3.0 Hz, 2H), 2.06 (t, J J = 2.9 Hz, 1H), 1.68 (tt, J 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 150.63, 149.90, 149.51, 146.88, 146.81, 143.03, 137.45, 135.26, 133.19, 131.27, 130.30, 130.16, 129.95, 127.86, 125.06, 123.25, 122.15, 121.99, 121.50, 114.19, 111.38, 83.81, 69.58, 69.15, 61.81, 58.81, 56.30, 55.65, 30.56, 28.81, 28.59, 28.38, 28.04, 27.97, 17.91. ESI + : 581.69。

[0085] Synthesis of Example 5 2,9,10-Trimethoxy-3-((2-nitrobenzyl)oxy)-13-(pent-4-yn-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX5)

[0086] The experimental procedure was the same as that of Example 1, except that the first raw material was o-nitrobenzyl bromide and the second raw material was 4-bromobutyronitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.08 (dd, J = 8.6, 1.4 Hz, 1H), 7.63 (td, J = 7.3, 1.2 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.51 (dq, J = 7.1, 1.1 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.04 (t, J = 1.0 Hz, 1H), 5.41 (d, J = 1.0 Hz, 2H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.90 (t, J= 8.5 Hz, 2H), 2.48 (t, J = 6.0 Hz, 2H), 2.11 – 1.93 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 149.90, 149.51, 146.88, 146.82, 143.03, 137.11, 132.78, 132.53, 131.27, 130.30, 130.16, 129.95, 127.86, 125.06, 123.25, 122.17, 121.99, 121.49, 119.22, 114.19, 111.38, 69.58, 61.81, 58.81, 56.30, 55.65, 29.79, 27.97, 23.88, 16.51. ESI + : 540.60。

[0087] Example 6 Synthesis of 3-(hept-6-en-1-yloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX6)

[0088] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoheptene and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 5.77 (tt, J = 17.1, 6.8 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 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), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.04 – 3.97 (m, 4H), 3.89 (d, J = 11.0 Hz, 5H), 3.46 (dp, J = 7.4, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H), 2.03 (tdt, J = 8.0, 6.9, 1.1 Hz, 2H), 1.73 – 1.64 (m, 8H), 1.43 (qd, J = 6.7, 5.5 Hz, 2H), 1.39 – 1.30 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 147.22, 142.90, 138.86, 136.89, 130.31, 130.17, 129.75, 128.59, 123.77, 122.74, 122.09, 121.57, 120.78, 114.60, 114.15, 111.29, 68.80, 61.81, 58.10, 56.30, 55.65, 33.67, 29.09, 28.68, 28.63, 27.97, 25.86, 24.49, 19.28. ESI + : 502.67。

[0089] Example 7 Synthesis of 13-(3,5-dimethoxybenzyl)-3-(hept-6-en-1-yloxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX7)

[0090] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoheptene and the second starting material was 3,5-dimethoxybromobenzene; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J= 8.8 Hz, 1H), 7.32(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 6.46 (dt, J = 2.2, 1.0Hz, 2H), 6.36 (t, J = 2.4 Hz, 1H), 5.77 (tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J =17.1, 2.2, 1.0 Hz, 1H), 4.97 (ddt, J = 17.1, 2.2, 1.1 Hz, 1H), 4.64 (ddd, J =7.3, 4.6, 1.7 Hz, 2H), 4.08 (dt, J = 9.5, 1.0 Hz, 1H), 4.02 (s, 3H), 4.03 –3.97 (m, 3H), 3.89 (d, J = 11.0 Hz, 5H), 3.79 (s, 5H), 3.21 – 3.14 (m, 2H),2.03 (tdt, J = 8.0, 6.9, 1.1 Hz, 2H), 1.69 (ddd, J = 13.0, 7.0, 6.1 Hz, 2H), 1.43(qd, J = 6.7, 5.6 Hz, 2H), 1.39 – 1.30 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 150.60, 150.29, 149.34, 147.26,143.57, 139.48, 138.86, 137.12, 131.19, 130.60, 130.33, 123.81, 122.77,121.08, 118.23, 114.60, 114.15, 111.29, 108.24, 98.82, 68.80, 61.81, 57.39,56.30, 55.65, 55.33, 36.36, 33.67, 29.09, 28.63, 27.97, 25.86. ESI+ : 584.73。

[0091] Example 8 Synthesis of 3-(hept-6-en-1-yloxy)-2,9,10-trimethoxy-13-(3-nitrobenzyl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX8)

[0092] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoheptene and the second starting material was m-nitrobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.16 (dt, J J = 8.8, 1.6 Hz,1H), 8.12 (tt, J J = 2.1, 1.0 Hz, 1H), 7.59 (dd, J J = 8.8, 7.8 Hz, 1H), 7.53 – 7.47(m, 1H), 7.37 (d, J J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J J = 8.8 Hz, 1H), 7.01(t, J J = 1.0 Hz, 1H), 5.77 (tt, J J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J J = 17.1, 2.1, 1.0Hz, 1H), 4.97 (ddt, J J = 17.1, 2.1, 1.1 Hz, 1H), 4.64 (ddd, J J = 7.3, 4.6, 1.7 Hz,2H), 4.50 (dt, J J = 9.8, 1.0 Hz, 1H), 4.08 (dt, J J = 9.8, 1.0 Hz, 1H), 4.04 – 3.97(m, 5H), 3.89 (d, J J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.03 (tdt, J J = 8.0, 6.9,1.1 Hz, 2H), 1.73 – 1.64 (m, 2H), 1.43 (qd,J = 6.7, 5.7 Hz, 2H), 1.39 – 1.30(m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 148.32, 147.26, 143.57, 138.86, 138.07, 137.12, 133.52, 131.19, 131.09, 130.33, 129.50, 124.14, 123.81, 123.36, 122.77, 121.08, 118.23, 114.60, 114.15, 111.29, 68.80, 61.81, 57.39, 56.30, 55.65, 36.55, 33.67, 29.09, 28.63, 27.97, 25.86. ESI + : 569.68。

[0093] Example 9 Synthesis of 2,9,10-trimethoxy-13-(3-methylbenzyl)-3-(pent-4-en-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX9)

[0094] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromopentene and the second starting material was 3-methylbenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32(s, 1H), 7.25 – 7.17 (m, 2H), 7.14 (ddq, J = 7.4, 2.2, 1.0 Hz, 1H), 7.09 – 7.03(m, 1H), 7.06 – 6.99 (m, 2H), 5.74 (tt, J = 17.1, 6.8 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), 4.22 (t, J = 1.0 Hz, 2H), 4.09 – 4.01 (m, 4H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.32 (s, 1H), 2.14 (tdt, J = 8.1, 6.9, 1.1Hz, 2H), 1.77 (tt, J = 8.4, 6.8 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.37, 149.34, 147.26, 143.57, 138.69, 137.60, 137.44, 137.11, 131.14, 130.73, 130.33, 129.05, 128.80, 128.67, 126.02, 123.81, 122.77, 121.08, 118.23, 115.13, 114.15, 111.29, 69.04, 61.81, 57.39, 56.30, 55.65, 36.00, 30.18, 28.68, 27.97, 21.19. ESI + : 510.65。

[0095] Synthesis of 13-(3-aminopropyl)-2,9,10-trimethoxy-3-(pent-4-en-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX10) in Example 10

[0096] The experimental procedure was the same as that in Example 1, except that the first raw material was 1-bromopentene and the second raw material was 1-bromobutylamine; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.01 (t, J= 1.1 Hz, 1H), 5.74 (tt, J = 17.1, 6.8 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),4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.09 – 4.01 (m, 4H), 3.89 (d, J = 11.0 Hz,5H), 3.21 – 3.14 (m, 2H), 2.87 – 2.77 (m, 4H), 2.14 (tdt, J = 8.1, 6.9, 1.1 Hz,2H), 1.87 (tt, J = 8.1, 5.3 Hz, 2H), 1.82 – 1.71 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.37, 149.34, 146.82, 143.03,137.60, 137.11, 132.54, 132.34, 130.22, 123.25, 122.17, 121.99, 121.49,115.13, 114.15, 111.29, 69.04, 61.81, 58.81, 56.30, 55.65, 40.83, 30.18,29.70, 29.09, 28.68, 27.97. ESI + : 463.60。

[0097] Synthesis of 3-(allyloxy)-13-(3,5-dimethoxybenzyl)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX11), Example 11

[0098] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromopropene and the second starting material was 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6) δ 9.94 (s, 1H), 7.37 (d, J J = 8.8 Hz, 1H), 7.26(s, 1H), 7.19 (d, J J = 8.8 Hz, 1H), 7.00 (t, J J = 1.0 Hz, 1H), 6.46 (dt, J J = 2.2, 1.0Hz, 2H), 6.36 (t, J J = 2.4 Hz, 1H), 6.05 (tt, J J = 16.8, 5.6 Hz, 1H), 5.39 (ddt, J J=16.8, 2.1, 1.0 Hz, 1H), 5.31 (ddt, J J = 16.8, 2.2, 1.0 Hz, 1H), 4.67 – 4.58 (m,4H), 4.08 (dt, J J = 9.5, 1.0 Hz, 1H), 4.04 – 3.97 (m, 4H), 3.88 (d, J J = 13.9 Hz,5H), 3.79 (s, 5H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 150.60, 150.02, 149.25, 147.26,143.57, 139.48, 137.12, 132.33, 131.19, 130.60, 130.36, 123.81, 122.75,121.08, 118.50, 118.23, 113.81, 111.34, 108.24, 98.82, 69.59, 61.81, 57.39,56.30, 55.65, 55.33, 36.36, 27.97. ESI + : 528.62。

[0099] Synthesis of Example 12 3-(allyloxy)-2,9,10-trimethoxy-13-(oct-7-yl-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX12)

[0100] The experimental procedure was the same as that in Example 1, except that the first raw material was 1-bromopropene and the second raw material was 1-bromooctyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.26(s, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.99 (t, J = 1.1 Hz, 1H), 6.05 (tt, J = 16.8,5.6 Hz, 1H), 5.39 (ddt, J = 16.8, 2.1, 1.0 Hz, 1H), 5.31 (ddt, J = 16.9, 2.2, 1.0Hz, 1H), 4.67 – 4.58 (m, 4H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 –3.14 (m, 2H), 2.78 (t, J = 8.5 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 – 1.33(m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.02, 149.25, 146.81, 143.03,137.45, 135.26, 133.19, 132.33, 130.25, 123.25, 122.15, 121.99, 121.50,118.50, 113.80, 111.34, 83.81, 69.59, 69.15, 61.81, 58.81, 56.30, 55.65,30.56, 28.81, 28.59, 28.38, 28.04, 27.97, 17.91. ESI +: 486.63.

[0101] Example 13 Synthesis of 13-(hept-6-en-1-yl)-2,9,10-trimethoxy-3-(vinyloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX13)

[0102] The experimental procedure was the same as in Example 1, except that the first starting material was vinyl bromide and the second starting material was 1-bromoheptene; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.53 (s, 1H), 7.32 (d, J J = 8.5Hz, 1H), 7.19 (d, J J = 8.5 Hz, 1H), 7.07 (t, J J = 1.0 Hz, 1H), 6.70 (s, 0H), 5.77(tt, J J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J J =17.1, 2.1, 1.1 Hz, 1H), 4.68 (dd, J J = 9.9, 2.8 Hz, 1H), 4.63 (ddd, J J = 7.6, 4.9,1.2 Hz, 2H), 4.27 (dd, J J = 9.9, 2.8 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J J = 17.1 Hz,5H), 3.24 (dddd, J J = 15.9, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J J = 8.5 Hz, 2H), 2.03(tdt, J J = 7.8, 6.7, 1.1 Hz, 2H), 1.69 (tt, J J = 8.4, 6.8 Hz, 2H), 1.39 – 1.30 (m,2H), 1.34 (s, 2H). 1313C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 149.09, 148.05, 147.00, 146.81,143.03, 139.08, 137.46, 135.26, 133.19, 131.35, 123.25, 122.15, 122.05,121.99, 116.01, 114.41, 110.64, 93.31, 61.81, 58.81, 56.30, 56.11, 33.79,30.56, 28.72, 28.49, 28.44, 27.55. ESI + : 460.59。

[0103] Synthesis of Example 14 13-(Cyanomethyl)-2,9,10-trimethoxy-3-(vinyloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX14)

[0104] The experimental procedure was the same as that of Example 1, except that the first raw material was vinyl bromide and the second raw material was bromoacetonitrile; the NMR results of the final product were as follows: 1 1H NMR (500 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 7.53 (s, 1H), 7.39 (d, J J = 8.5Hz, 1H), 7.19 (d, J J = 8.8 Hz, 1H), 7.07 (t, J J = 1.0 Hz, 1H), 6.70 (s, 0H), 4.68(dd, J J = 9.9, 2.8 Hz, 1H), 4.63 (ddd, J J = 7.3, 4.6, 1.1 Hz, 2H), 4.27 (dd, J J = 9.9,2.8 Hz, 1H), 4.20 (s, 2H), 4.02 (s, 3H), 3.88 (d, J J = 17.1 Hz, 5H), 3.24 (dddd, J J = 15.9, 7.6, 4.6, 1.0 Hz, 2H). 13 13C NMR (125 MHz,DMSO-d6 ) δ 150.60, 149.09, 148.05, 147.41, 147.00, 142.69, 136.10, 131.39, 128.89, 127.79, 123.47, 122.02, 121.43, 120.80, 117.11, 116.01, 110.73, 93.31, 61.81, 58.16, 56.30, 56.11, 27.55, 18.88. ESI + : 403.46。

[0105] Synthesis of Example 15 2,9,10-Trimethoxy-13-(3-nitrobenzyl)-3-(oct-7-yn-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX15)

[0106] The experimental procedure was the same as that of Example 1, except that the first raw material was 1-bromooctyne and the second raw material was m-nitrobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.16 (dt, J = 8.8, 1.6 Hz, 1H), 8.12 (tt, J = 2.0, 1.0 Hz, 1H), 7.59 (dd, J = 8.8, 7.8 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.50 (dt, J = 9.8, 1.0 Hz, 1H), 4.08 (dt, J = 9.8, 1.0 Hz, 1H), 4.04 – 3.97 (m, 4H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.12 (td,J = 6.0, 3.0 Hz, 2H), 2.06 (t, J = 2.9Hz, 1H), 1.77 (tt, J = 7.4, 6.0 Hz, 2H), 1.55 – 1.34 (m, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 148.32, 147.26, 143.57, 138.07, 137.12, 133.52, 131.19, 131.09, 130.33, 129.50, 124.14, 123.81, 123.36, 122.77, 121.08, 118.23, 114.15, 111.29, 83.81, 69.15, 68.80, 61.81, 57.39, 56.30, 55.65, 36.55, 29.35, 28.28, 28.06, 27.97, 26.05, 17.91. ESI + : 581.69。

[0107] Synthesis of 13-(3-cyanopropyl)-3-(hex-5-yn-1-yloxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX16), Example 16

[0108] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromohex-1-yne and the second starting material was 1-bromobutyronitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.32 (d, J = 8.0 Hz, 1H), 7.01(t, J = 1.1 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.08 (t, J = 5.0 Hz,1H), 4.02 (s, 1H), 3.89 (d, J= 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.90 (t, J =8.5 Hz, 1H), 2.51 – 2.44 (m, 2H), 2.11 – 1.93 (m, 2H), 1.81 (tt, J = 7.5, 5.0Hz, 1H), 1.58 (tt, J = 7.5, 5.9 Hz, 1H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.37, 149.34, 146.82, 143.03,137.11, 132.78, 132.53, 130.22, 123.25, 122.17, 121.99, 121.49, 119.22,114.15, 111.29, 83.76, 69.16, 69.15, 61.81, 58.81, 56.30, 55.65, 29.79,28.67, 27.97, 25.28, 23.88, 18.09, 16.51. ESI + : 485.60。

[0109] Synthesis of 13-(4-Bromobenzyl)-3-(4-cyanobutoxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX17), Example 17

[0110] The experimental procedure was the same as that of Example 1, except that the first starting material was 1-bromopentanenitrile and the second starting material was 4-bromobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.51 – 7.45 (m, 2H), 7.37(d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.24 – 7.16 (m, 3H), 7.01 (t, J = 1.0 Hz, 1H),4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.18 (t, J= 1.1 Hz, 2H), 4.08 (t, J = 5.0Hz, 2H), 4.02 (s, 3H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.41 (t, J = 5.8 Hz, 2H), 1.82 – 1.70 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.37, 149.34, 147.26, 143.57, 137.87, 137.11, 131.62, 131.14, 131.03, 130.33, 129.75, 123.81, 122.77, 121.08, 120.49, 119.41, 118.23, 114.15, 111.29, 69.22, 61.81, 57.39, 56.30, 55.65, 35.88, 28.57, 27.97, 22.12, 16.76. ESI + : 588.52。

[0111] Synthesis of Example 18 2,9,10-Trimethoxy-13-(4-methylbenzyl)-3-((4-methylbenzyl)oxy)-5,6-dihydroisoquinolinyl[3,2-a]isoquinolin-7-ium (MX18)

[0112] The experimental procedure was the same as that of Example 1, except that both the first raw material and the second raw material were p-methylbenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.34– 7.27 (m, 3H), 7.19 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.14 (dq, J = 7.8, 1.2Hz, 3H), 7.11 – 7.06 (m, 2H), 7.04 (t, J = 1.1 Hz, 1H), 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), 4.02 (s, 2H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.34 (q, J = 0.9 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.84, 149.48, 147.26, 143.57, 138.34, 138.17, 137.11, 136.95, 134.01, 131.14, 131.00, 130.41, 129.27, 129.09, 128.18, 128.03, 123.81, 122.77, 121.08, 118.23, 114.29, 111.38, 71.29, 61.81, 57.39, 56.30, 55.65, 36.00, 27.97, 21.05. ESI + : 546.69。

[0113] Synthesis of 13-benzyl-3-(3-cyanopropoxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX19) in Example 19

[0114] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromobutyronitrile and the second starting material was benzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.28 (dd, J = 7.9, 6.8 Hz, 2H), 7.25 – 7.20 (m, 2H), 7.23 – 7.16 (m, 2H), 7.01 (t, J = 1.0 Hz, 1H), 4.64 (ddd,J = 7.3, 4.6, 1.7 Hz, 2H), 4.16 (t, J =1.0 Hz, 2H), 4.12 (t, J = 6.2 Hz, 2H), 4.02 (s, 3H), 3.89 (d, J = 11.0 Hz, 5H),3.21 – 3.14 (m, 2H), 2.58 (t, J = 6.3 Hz, 2H), 2.13 (p, J = 6.2 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.45, 149.39, 147.26, 143.57,138.16, 137.12, 131.14, 130.99, 130.33, 127.98, 127.82, 127.18, 123.81,122.77, 121.08, 119.17, 118.23, 114.15, 111.29, 68.60, 61.81, 57.39, 56.30,55.65, 36.11, 27.97, 25.74, 14.07. ESI + : 495.6。

[0115] Example 20 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-(prop-2-yn-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX20)

[0116] The experimental procedure was the same as in Example 1, except that the first starting material was bromoacetonitrile and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.07 (t, J = 1.1 Hz, 1H), 5.31 (dddd,J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 4.82 (d, J = 2.9 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 15.9 Hz, 5H), 3.46 (dp, J = 7.4, 1.1 Hz, 2H), 3.36 (s, 0H), 3.36 (d, J = 6.1 Hz, 0H), 3.21 – 3.14 (m, 2H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.16, 149.12, 147.22, 142.90, 136.89, 130.45, 130.17, 129.75, 128.59, 123.77, 122.76, 122.09, 121.57, 120.78, 114.55, 111.30, 78.41, 76.70, 61.81, 58.28, 58.15, 56.30, 55.66, 28.68, 27.97, 24.49, 19.28. ESI + : 444.55。

[0117] Synthesis of Example 21 3-(cyanomethoxy)-13-(hex-5-yn-1-yl)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX21)

[0118] The experimental procedure was the same as in Example 1, except that the first raw material was bromoacetonitrile and the second raw material was 6-bromo-1-hexyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.35 – 7.30 (m, 2H), 7.19 (d, J = 8.5 Hz, 1H), 7.06 (t, J= 1.1 Hz, 1H), 4.98 (s, 2H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 15.9 Hz, 5H), 3.21 – 3.14 (m, 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 = 7.4, 6.1 Hz, 2H), 1.59 (p, J = 5.9 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 149.15, 148.42, 146.82, 143.03, 137.46, 134.63, 133.19, 130.35, 123.25, 122.15, 121.99, 121.49, 116.24, 114.54, 111.38, 83.79, 69.15, 61.81, 58.81, 56.30, 55.66, 54.47, 30.56, 27.97, 27.61, 27.50, 18.24. ESI + : 457.55。

[0119] Synthesis of 13-(3,5-Dimethoxybenzyl)-3-((4-fluorobenzyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX22), Example 22

[0120] The experimental procedure was the same as in Example 1, except that the first starting material was 4-fluorobenzyl bromide and the second starting material was 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.51 (ddt,J = 8.1, 5.1, 1.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.21 – 7.14 (m, 3H), 7.04 (t, J = 1.1 Hz, 1H), 6.46 (dt, J = 2.2, 1.0 Hz, 2H), 6.36 (t, J = 2.4 Hz, 1H), 5.12 (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), 4.04 – 3.97 (m, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.79 (s, 5H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 163.44, 161.42, 160.81, 150.60, 149.84, 149.48, 147.26, 143.57, 139.48, 137.12, 132.91, 132.89, 131.19, 130.60, 130.41, 129.54, 129.47, 123.81, 122.75, 121.08, 118.23, 115.26, 115.10, 114.29, 111.38, 108.24, 98.82, 71.35, 61.81, 57.39, 56.30, 55.65, 55.33, 36.36, 27.97. ESI + : 596.67。

[0121] Example 23 Synthesis of 3-((4-Fluorobenzyl)oxy)-13-(hept-6-en-1-yl)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX23)

[0122] The experimental procedure was the same as in Example 1, except that the first raw material was p-fluorobenzyl bromide and the second raw material was 7-bromo-1-heptene; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.51 (ddt, J = 8.1, 5.1, 1.0Hz, 2H), 7.35 – 7.30 (m, 2H), 7.21 – 7.14 (m, 3H), 7.04 (t, J = 1.0 Hz, 1H),5.77 (tt, J = 17.1, 6.8 Hz, 1H), 5.16 – 5.08 (m, 3H), 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 (s, 3H), 3.88 (d, J =13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.78 (t, J = 8.5 Hz, 2H), 2.03 (tdt, J = 7.8,6.7, 1.1 Hz, 2H), 1.69 (tt, J = 8.5, 6.8 Hz, 2H), 1.39 – 1.30 (m, 4H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 163.44, 161.42, 150.63, 149.84, 149.48,146.81, 143.03, 139.08, 137.45, 135.26, 133.19, 132.91, 132.89, 130.30,129.54, 129.47, 123.25, 122.15, 121.99, 121.50, 115.26, 115.10, 114.41,114.25, 111.38, 71.35, 61.81, 58.81, 56.30, 55.65, 33.79, 30.56, 28.72,28.49, 28.44, 27.97. ESI +: 542.67.

[0123] Example 24 Synthesis of 13 - allyl - 3 - ((4 - chlorobenzyl)oxy)-2,9,10 - trimethoxy - 5,6 - dihydroisoquinolino[3,2 - a]isoquinolin - 7 - ium (MX24)

[0124] The experimental procedure was the same as in Example 1, except that the first starting material was 4 - chlorobenzyl bromide and the second starting material was 3 - bromopropene; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO - d 6 ) δ 9.94 (s, 1H), 7.47 (dt, J J = 8.2, 1.0 Hz, 2H), 7.47 – 7.39 (m, 2H), 7.39 (d, J J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J J = 8.8 Hz, 1H), 7.04 (t, J J = 1.0 Hz, 1H), 5.89 (tt, J J = 16.4, 8.1 Hz, 1H), 5.21 – 5.13 (m, 1H), 5.12 (t, J J = 1.0 Hz, 2H), 5.07 (ddt, J J = 16.4, 2.1, 1.0 Hz, 1H), 4.64 (ddd, J J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J J = 13.9 Hz, 5H), 3.40 (dt, J J = 8.0, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO - d 6) δ 150.60, 149.84, 149.48, 147.22, 142.94, 137.27, 136.50, 135.07, 133.86, 130.32, 130.31, 129.30, 128.67, 128.55, 122.78, 122.09, 121.63, 120.78, 116.29, 114.25, 111.38, 71.31, 61.81, 58.10, 56.30, 55.65, 34.24, 27.97. ESI + : 503.01。

[0125] Synthesis of Example 25 3-((4-chlorobenzyl)oxy)-2,9,10-trimethoxy-13-(prop-2-yn-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX25)

[0126] The experimental procedure was the same as that of Example 1, except that the first raw material was p-chlorobenzyl bromide and the second raw material was 3-bromopropyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 7.47 (dt, J = 8.2, 1.0 Hz, 2H), 7.47 – 7.39 (m, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.0 Hz, 1H), 5.12 (t, J = 1.0 Hz, 2H), 4.74 (d, J = 2.9Hz, 2H), 4.63 (ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 13.9Hz, 5H), 3.21 – 3.14 (m, 2H), 2.69 (t, J = 2.9 Hz, 1H). 13 C NMR (125 MHz, DMSO-d6 ) δ 150.60, 149.84, 149.48, 147.29, 142.49, 136.75, 135.07, 133.86, 130.36, 130.18, 129.40, 129.30, 128.55, 122.70, 122.00, 121.29, 120.79, 114.25, 111.42, 83.55, 72.39, 71.31, 61.81, 58.16, 56.30, 55.65, 27.97, 21.95. ESI + : 501.00。

[0127] Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((3-methylbut-2-en-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX26) in Example 26

[0128] The experimental procedure was the same as that in Example 1, and both the first raw material and the second raw material were 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.26(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 1.0 Hz, 1H), 5.31 (ddt, J = 7.3,5.7, 1.6 Hz, 1H), 5.28 (ddt, J = 6.5, 3.2, 1.6 Hz, 1H), 4.67 – 4.60 (m, 3H),4.61 (dq, J = 2.1, 1.0 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.46(dp, J = 7.3, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.75 (q, J = 1.1 Hz, 6H), 1.68(q, J= 1.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.34, 149.32, 147.22, 142.90, 137.69, 136.89, 130.37, 130.17, 129.75, 128.59, 123.77, 122.76, 122.09, 121.57, 120.78, 119.22, 113.81, 111.34, 66.09, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.63, 24.49, 19.90, 19.28. ESI + : 474.62。

[0129] Synthesis of 13-heptyl-3-(hex-5-yn-1-yloxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX27), Example 27

[0130] The experimental procedure was the same as in Example 1, except that the first starting material was 6-bromo-1-hexyne and the second starting material was 1-bromononane; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.32 (d, J = 8.0 Hz, 1H), 7.01(t, J = 1.1 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.08 (t, J = 5.0 Hz,1H), 4.02 (s, 1H), 3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.78 (t, J =8.5 Hz, 1H), 2.47 (td, J = 5.9, 3.0 Hz, 1H), 1.81 (tt, J = 7.5, 5.0 Hz, 1H), 1.69(tt, J= 8.5, 7.2 Hz, 1H), 1.58 (tt, J = 7.5, 5.9 Hz, 1H), 1.39 – 1.31 (m, 1H), 1.34 – 1.22 (m, 5H), 0.92 – 0.86 (m, 1H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.37, 149.34, 146.81, 143.03, 137.45, 135.26, 133.19, 130.22, 123.25, 122.15, 121.99, 121.50, 114.15, 111.29, 83.76, 69.16, 69.15, 61.81, 58.81, 56.30, 55.65, 31.74, 30.56, 29.66, 29.34, 29.22, 29.21, 28.81, 28.67, 27.97, 25.28, 22.67, 18.09, 14.06. ESI + : 544.76。

[0131] Example 28 Synthesis of 2,9,10-trimethoxy-13-(pent-4-en-1-yl)-3-(pent-4-yn-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX28)

[0132] The experimental procedure was the same as that of Example 1, except that the first starting material was 5-bromo-1-pentyne and the second starting material was 5-bromo-1-pentyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, ) δ 7.32 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 1.1 Hz, 0H),4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.14 (t, J = 6.1 Hz, 1H), 4.02 (s, 1H),3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.89 (t, J= 8.5 Hz, 1H), 2.57(td, J = 6.1, 3.0 Hz, 2H), 2.07 (dt, J = 6.0, 3.0 Hz, 1H), 1.95 (p, J = 6.2 Hz,1H), 1.86 (tt, J = 8.4, 6.0 Hz, 1H). 13 C NMR (125 MHz, ) δ 150.63, 150.45, 149.39, 146.82, 143.03, 137.11,132.73, 132.57, 130.22, 123.25, 122.17, 121.99, 121.49, 114.15, 111.29,83.89, 83.65, 69.25, 69.15, 68.63, 61.81, 58.81, 56.30, 55.65, 29.84, 28.27,27.97, 26.69, 17.90, 15.64. ESI + : 470.59。

[0133] Example 29 Synthesis of 3-(allyloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX29)

[0134] The experimental procedure was the same as in Example 1, except that the first starting material was 3-bromopropene and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.26(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 1.1 Hz, 1H), 6.05 (tt, J = 16.8,5.6 Hz, 1H), 5.39 (ddt, J= 16.8, 2.1, 1.0 Hz, 1H), 5.35 – 5.27 (m, 2H), 4.67 –4.58 (m, 4H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.46 (dp, J = 7.3, 1.0 Hz,2H), 3.21 – 3.14 (m, 2H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.02, 149.25, 147.22, 142.90,136.89, 132.33, 130.37, 130.17, 129.75, 128.59, 123.77, 122.76, 122.09,121.57, 120.78, 118.50, 113.81, 111.34, 69.59, 61.81, 58.10, 56.30, 55.65,28.68, 27.97, 24.49, 19.28. ESI + : 446.57。

[0135] Example 30 Synthesis of (E)-3-(but-2-en-1-yloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX30)

[0136] The experimental procedure was the same as that of Example 1, except that the first starting material was crotyl bromide and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.26(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 1.1 Hz, 1H), 5.73 – 5.58 (m, 2H),5.31 (dddd, J= 9.1, 7.3, 3.3, 1.6 Hz, 1H), 4.68 – 4.61 (m, 4H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.46 (dp, J = 7.3, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.67 (ddt, J = 6.1, 1.9, 1.2 Hz, 10H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.47, 149.25, 147.22, 142.90, 136.89, 130.37, 130.17, 129.75, 128.85, 128.59, 127.26, 123.77, 122.76, 122.09, 121.57, 120.78, 113.81, 111.34, 69.18, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.49, 19.28, 17.70. ESI + : 460.59。

[0137] Example 31 Synthesis of 2,9,10-trimethoxy-13-(2-methylbenzyl)-3-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX31)

[0138] The experimental procedure was the same as that in Example 1, except that the first starting material was 3,3-dimethylallyl bromide and the second starting material was o-methylbenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.26(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.17 – 7.08 (m, 4H), 7.00 (t, J = 1.1 Hz, 1H), 5.28 (ddp, J= 6.5, 3.1, 1.6 Hz, 1H), 4.67 – 4.59 (m, 4H), 4.10 (dd, J = 11.3, 0.9 Hz, 1H), 4.07 – 4.01 (m, 1H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.32 (s, 3H), 1.75 (q, J = 1.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.34, 149.32, 147.26, 143.57, 138.68, 137.69, 137.50, 136.68, 131.17, 130.63, 130.36, 129.83, 128.61, 126.89, 126.75, 123.81, 122.77, 120.92, 119.22, 118.23, 113.81, 111.34, 66.09, 61.81, 57.39, 56.30, 55.65, 33.68, 27.97, 24.62, 19.90, 19.57. ESI + : 510.65。

[0139] Example 32 Synthesis of 2,9,10-trimethoxy-13-(2-methylbenzyl)-3-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX32)

[0140] The experimental procedure was the same as that in Example 1, except that the first raw material was 3,5-dimethylbenzyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.39 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.8 Hz, 0H), 7.06 – 6.98 (m, 2H), 6.80 (t, J= 2.2 Hz, 0H), 5.31 (dddd, J =9.1, 7.3, 3.3, 1.6 Hz, 1H), 5.08 (t, J = 1.1 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6,1.7 Hz, 1H), 4.02 (s, 1H), 3.88 (d, J = 13.9 Hz, 3H), 3.46 (dp, J = 7.3, 1.0 Hz,1H), 3.21 – 3.14 (m, 1H), 2.25 (s, 3H), 1.68 (q, J = 1.2 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.84, 149.48, 147.22, 142.90,137.61, 136.89, 136.25, 130.41, 130.17, 129.82, 129.75, 128.59, 127.53,123.77, 122.76, 122.09, 121.57, 120.78, 114.29, 111.38, 71.62, 61.81, 58.10,56.30, 55.65, 28.68, 27.97, 24.49, 21.08, 19.28. ESI + :524.68。

[0141] Example 33 Synthesis of 13-(3,5-dimethoxybenzyl)-3-((3,5-dimethylbenzyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX33)

[0142] The experimental procedure was the same as in Example 1, except that the first starting material was 3,5-dimethylbenzyl bromide and the second starting material was 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.37 (d, J = 8.8 Hz, 0H), 7.19(d, J= 8.8 Hz, 0H), 7.06 – 6.98 (m, 2H), 6.80 (t, J = 2.2 Hz, 0H), 6.46 (dt, J =2.1, 1.0 Hz, 1H), 6.36 (t, J = 2.4 Hz, 1H), 5.08 (t, J = 1.1 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 1H), 4.08 (dt, J = 9.5, 1.0 Hz, 1H), 4.04 – 3.97 (m, 2H),3.88 (d, J = 13.9 Hz, 3H), 3.79 (s, 3H), 3.21 – 3.14 (m, 1H), 2.25 (s, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 150.60, 149.84, 149.48, 147.26,143.57, 139.48, 137.61, 137.12, 136.25, 131.19, 130.60, 130.41, 129.82,127.53, 123.81, 122.75, 121.08, 118.23, 114.29, 111.38, 108.24, 98.82, 71.62,61.81, 57.39, 56.30, 55.65, 55.33, 36.36, 27.97, 21.08. ESI + :606.74。

[0143] Example 34 Synthesis of 14-(3-aminopropyl)-3-((3,5-dimethoxybenzyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX34)

[0144] The experimental procedure was the same as that in Example 1, except that the first starting material was 3,5-dimethoxybenzyl bromide and the second starting material was 4-bromobutylamine; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6) δ 9.94 (s, 0H), 7.35 – 7.30 (m, 1H), 7.19(d, J = 8.5 Hz, 0H), 7.04 (t, J = 1.0 Hz, 0H), 6.63 (dt, J = 2.3, 1.2 Hz, 1H), 6.39(t, J = 2.4 Hz, 0H), 5.12 (t, J = 1.0 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz,1H), 4.02 (s, 1H), 3.88 (d, J = 13.9 Hz, 3H), 3.79 (s, 3H), 3.21 – 3.14 (m,1H), 2.87 – 2.77 (m, 2H), 1.87 (tt, J = 8.1, 5.3 Hz, 1H), 1.74 (t, J = 6.3 Hz,1H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.51, 150.63, 149.93, 149.48, 146.82,143.03, 138.24, 137.11, 132.54, 132.34, 130.30, 123.25, 122.17, 121.99,121.49, 114.25, 111.38, 107.23, 99.53, 71.46, 61.81, 58.81, 56.30, 55.65,55.33, 40.83, 29.70, 29.09, 27.97. ESI + : 545.66。

[0145] Example 35 Synthesis of 4-(4-aminobutoxy)-13-(aminomethyl)-2,9,10-trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX35)

[0146] The experimental procedure was the same as in Example 1, except that the first starting material was 4-bromobutylamine and the second starting material was bromoethylamine; the NMR results of the final product were as follows: 11H NMR (500 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.32(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 1.1 Hz, 1H), 5.86 (q, J = 6.8 Hz,1H), 5.51 (q, J = 6.8 Hz, 1H), 4.63 (ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.01 – 3.91(m, 4H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.79 (tt, J = 6.4, 5.1Hz, 2H), 2.01 (t, J = 6.5 Hz, 2H), 1.80 – 1.71 (m, 2H), 1.64 – 1.55 (m, 2H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.37, 149.39, 146.96, 142.67,135.53, 130.71, 130.24, 126.98, 122.33, 121.73, 121.05, 120.49, 114.15,111.33, 69.09, 61.81, 58.16, 56.30, 55.65, 43.00, 40.94, 28.90, 27.97, 27.48. ESI + : 438.55。

[0147] Example 36 Synthesis of 13-Allyl-2,9,10-trimethoxy-3-(nonanoxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX36)

[0148] The experimental procedure was the same as that of Example 1, except that the first starting material was 1-bromononane and the second starting material was 3-bromopropene; the NMR results of the final product were as follows: 11H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J J = 8.8 Hz, 1H), 7.01 (t, J J = 1.1 Hz, 1H), 5.89 (tt, J J = 16.5,8.1 Hz, 1H), 5.17 (ddt, J J = 16.4, 2.1, 1.0 Hz, 1H), 5.07 (ddt, J J = 16.3, 2.1, 1.0Hz, 1H), 4.64 (ddd, J J = 7.3, 4.6, 1.7 Hz, 2H), 4.04 – 3.97 (m, 5H), 3.89 (d, J J =11.0 Hz, 5H), 3.40 (dt, J J = 8.0, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.77 (tt, J J =7.4, 6.0 Hz, 2H), 1.44 (dq, J J = 8.0, 6.9 Hz, 2H), 1.36 – 1.22 (m, 10H), 0.94 –0.85 (m, 3H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 147.22, 142.94,137.27, 136.50, 130.31, 130.21, 128.67, 122.78, 122.09, 121.63, 120.78,116.29, 114.15, 111.29, 68.80, 61.81, 58.10, 56.30, 55.65, 34.24, 31.74,29.41, 29.24, 29.11, 29.09, 27.97, 26.21, 22.67, 14.06. ESI + : 504.69。

[0149] Synthesis of 2,9,10-trimethoxy-3-(nonyloxy)-13-octyl-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX37) in Example 37

[0150] The experimental procedure was the same as that in Example 1, except that the first raw material was 1-bromooctane and the second raw material was 1-bromooctane; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.32 (d, J = 8.0 Hz, 1H), 7.01(t, J = 1.1 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.04 – 3.97 (m, 2H),3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.78 (t, J = 8.5 Hz, 1H), 1.77(tt, J = 7.4, 6.0 Hz, 1H), 1.69 (tt, J = 8.5, 7.2 Hz, 1H), 1.43 (dq, J = 7.8, 6.9Hz, 1H), 1.39 – 1.23 (m, 9H), 0.94 – 0.85 (m, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.29, 149.34, 146.81, 143.03,137.45, 135.26, 133.19, 130.22, 123.25, 122.15, 121.99, 121.50, 114.15,111.29, 68.80, 61.81, 58.81, 56.30, 55.65, 31.76, 31.69, 30.56, 29.41, 29.32,29.29, 29.25, 29.22, 29.21, 28.81, 27.97, 26.10, 22.68, 14.06. ESI + : 576.84.

[0151] Example 38 Synthesis of 3-butoxy-13-(3,5-dimethoxybenzyl)-2,9,10-trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX38)

[0152] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromobutane and the second starting material was 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.37 (d, J = 8.8 Hz, 0H), 7.19(d, J = 8.8 Hz, 0H), 7.01 (t, J = 1.0 Hz, 1H), 6.46 (dt, J = 2.2, 1.0 Hz, 1H), 6.36(t, J = 2.4 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 1H), 4.11 – 3.97 (m, 2H),4.02 (s, 2H), 3.89 (d, J = 11.0 Hz, 3H), 3.79 (s, 3H), 3.21 – 3.14 (m, 1H),1.71 (p, J = 6.6 Hz, 1H), 1.50 (h, J = 6.9 Hz, 1H), 0.97 (t, J = 7.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6) δ 160.81, 150.60, 150.29, 149.34, 147.26, 143.57, 139.48, 137.12, 131.19, 130.60, 130.33, 123.81, 122.77, 121.08, 118.23, 114.15, 111.29, 108.24, 98.82, 69.06, 61.81, 57.39, 56.30, 55.65, 55.33, 36.36, 31.06, 27.97, 19.13, 13.74. ESI + : 544.67。

[0153] Synthesis of Example 39 3-Ethoxy-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX39)

[0154] The experimental procedure was the same as that of Example 1, except that the first raw material was bromoethane and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.02 (t, J = 1.0 Hz, 1H), 5.31 (tp, J = 7.2, 1.6Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.11 (q, J = 6.3 Hz, 2H), 4.02 (s,3H), 3.89 (d, J = 11.0 Hz, 5H), 3.46 (dq, J = 7.3, 1.0 Hz, 2H), 3.21 – 3.14 (m,2H), 1.68 (q, J = 1.2 Hz, 6H), 1.41 (t, J = 6.2 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.30, 149.42, 147.22, 142.90, 136.89, 130.28, 130.17, 129.75, 128.59, 123.77, 122.75, 122.09, 121.57, 120.78, 113.77, 111.23, 65.18, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.49, 19.28, 14.60. ESI + : 434.56。

[0155] Example 40 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((4-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX40)

[0156] The experimental procedure was the same as that of Example 1, except that the first raw material was 4-nitrobenzyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.14 – 8.08 (m, 2H), 7.61 (dt, J = 8.2, 1.0 Hz, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8Hz, 1H), 7.04 (t, J = 1.1 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 5.13 (t, J = 1.1 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.46 (dp, J= 7.4, 1.1 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.68 (q, J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.84, 149.48, 148.25, 147.22, 142.90, 141.05, 136.89, 130.41, 130.17, 129.75, 128.68, 128.59, 123.77, 123.65, 122.76, 122.09, 121.57, 120.78, 114.29, 111.38, 71.39, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.49, 19.28. ESI + : 541.6。

[0157] Example 41 Synthesis of (E)-13-(but-2-en-1-yl)-3-butoxy-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX41)

[0158] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromobutane and the second starting material was crotyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (t, J = 1.1 Hz, 1H), 5.88 – 5.78 (m, 1H), 5.72 – 5.62 (m, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.07 – 4.01 (m, 5H), 3.89 (d, J = 11.0 Hz, 5H), 3.43 (dp, J= 7.1, 1.1 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.71 (p, J = 6.6 Hz, 2H), 1.62 (dq, J = 5.4, 1.1 Hz, 3H), 1.50 (h, J = 6.9 Hz, 2H), 0.97 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 147.22, 142.92, 136.81, 130.42, 130.21, 128.54, 128.26, 127.61, 122.78, 122.09, 121.61, 120.78, 114.15, 111.29, 69.06, 61.81, 58.10, 56.30, 55.65, 33.10, 31.06, 27.97, 19.13, 17.90, 13.74. ESI + : 448.25。

[0159] Example 42 Synthesis of 13-(3,5-dimethoxybenzyl)-3-((3,5-dimethoxybenzyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX42)

[0160] The experimental procedure was the same as that of Example 1, except that both the first and second starting materials were 3,5-dimethoxybenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.0 Hz, 1H), 6.63 (dt, J = 2.3, 1.2 Hz, 2H), 6.46 (dt, J= 2.1, 1.0 Hz, 2H), 6.38 (dt, J = 12.5, 2.4 Hz, 2H), 5.12(t, J = 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.08 (dt, J = 9.5, 1.0Hz, 1H), 4.04 – 3.97 (m, 4H), 3.88 (d, J = 13.9 Hz, 5H), 3.79 (s, 8H), 3.21 –3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.81, 160.51, 150.60, 149.93, 149.48,147.26, 143.57, 139.48, 138.24, 137.12, 131.19, 130.60, 130.41, 123.81,122.75, 121.08, 118.23, 114.29, 111.38, 108.24, 107.23, 99.53, 98.82, 71.46,61.81, 57.39, 56.30, 55.65, 55.34, 55.33, 36.36, 27.97. ESI + : 638.28。

[0161] Example 43 Synthesis of 3-((3,5-dimethoxybenzyl)oxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX43)

[0162] The experimental procedure was the same as in Example 1, except that the first starting material was 3,5-dimethoxybenzyl bromide and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J= 8.8 Hz, 1H), 7.04 (t, J = 1.0 Hz, 1H), 6.63 (dt, J = 2.3, 1.2Hz, 2H), 6.39 (t, J = 2.4 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H),5.12 (t, J = 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H),3.88 (d, J = 13.9 Hz, 5H), 3.79 (s, 5H), 3.46 (dp, J = 7.5, 1.1 Hz, 2H), 3.21 –3.14 (m, 2H), 1.68 (q, J = 1.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 160.51, 150.60, 149.93, 149.48, 147.22, 142.90, 138.24, 136.89, 130.41, 130.17, 129.75, 128.59, 123.77, 122.76, 122.09, 121.57, 120.78, 114.29, 111.38, 107.23, 99.53, 71.46, 61.81, 58.10, 56.30, 55.65, 55.33, 28.68, 27.97, 24.49, 19.28. ESI + : 556.27。

[0163] Example 44 Synthesis of 3-((4-Fluorobenzyl)oxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX44)

[0164] The experimental procedure was the same as in Example 1, except that the first starting material was 4-chlorobenzyl bromide and the second starting material was 4-fluorobenzyl bromide; the NMR results of the final product were as follows: 11H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.34– 7.27 (m, 3H), 7.19 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.14 (dq, J = 7.8, 1.2Hz, 3H), 7.11 – 7.06 (m, 2H), 7.04 (t, J = 1.1 Hz, 1H), 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), 4.02 (s, 2H),3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.34 (q, J = 0.9 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.84, 149.48, 147.26, 143.57,138.34, 138.17, 137.11, 136.95, 134.01, 131.14, 131.00, 130.41, 129.27,129.09, 128.18, 128.03, 123.81, 122.77, 121.08, 118.23, 114.29, 111.38,71.29, 61.81, 57.39, 56.30, 55.65, 36.00, 27.97, 21.05. ESI + :546.26。

[0165] Synthesis of 13-(4-Fluorobenzyl)-3-((4-fluorobenzyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX45), Example 45

[0166] The experimental procedure was the same as that in Example 1, except that the first raw material was p-fluorobenzyl bromide and the second raw material was p-fluorobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.51 (ddt, J = 8.1, 5.1, 1.0Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.23 (ddt, J = 7.5, 5.0, 1.0 Hz,2H), 7.23 – 7.14 (m, 3H), 7.17 – 7.07 (m, 2H), 7.04 (t, J = 1.1 Hz, 1H), 5.12(t, J = 1.0 Hz, 2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.41 (dt, J = 10.0, 1.0Hz, 1H), 4.20 (dt, J = 10.0, 1.1 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz,5H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 163.44, 163.02, 161.42, 161.00, 150.60,149.84, 149.48, 147.26, 143.57, 137.11, 135.51, 135.48, 132.91, 132.89,131.14, 131.02, 130.41, 129.71, 129.64, 129.54, 129.47, 123.81, 122.77,121.08, 118.23, 115.48, 115.32, 115.26, 115.10, 114.29, 111.38, 71.35, 61.81,57.39, 56.30, 55.65, 35.83, 27.97. ESI + : 554.21.

[0167] Synthesis of 3-(((4-Fluorobenzyl)oxy))-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX46), Example 46

[0168] The experimental procedure was the same as that in Example 1, except that the first raw material was 4-fluorobenzyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.51 (ddt, J = 8.1, 5.1, 1.0Hz, 2H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.21 – 7.14 (m, 3H), 7.04 (t, J = 1.1 Hz, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 5.12 (t, J = 1.0 Hz,2H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz,5H), 3.46 (dp, J = 7.5, 1.1 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.68 (q, J = 1.2 Hz,6H). 13 C NMR (125 MHz, DMSO-d 6) δ 163.44, 161.42, 150.60, 149.84, 149.48, 147.22, 142.90, 136.89, 132.91, 132.89, 130.41, 130.17, 129.75, 129.54, 129.47, 128.59, 123.77, 122.76, 122.09, 121.57, 120.78, 115.26, 115.10, 114.29, 111.38, 71.35, 61.81, 58.10, 56.30, 55.65, 28.68, 27.97, 24.49, 19.28. ESI + : 514.24。

[0169] Example 47 Synthesis of 3-(cyanomethoxy)-13-(cyanomethyl)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX47)

[0170] The experimental procedure was the same as that of Example 1, except that the first raw material was bromoacetonitrile and the second raw material was bromoacetonitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.06 (t, J = 1.1 Hz, 1H), 4.98 (s, 2H), 4.63 (ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.20 (s, 2H), 4.02 (s, 3H), 3.88 (d, J = 15.9 Hz, 5H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6) δ 150.60, 149.15, 148.42, 147.41, 142.69, 136.13, 130.32, 128.89, 127.79, 122.42, 122.02, 121.43, 120.80, 117.11, 116.24, 114.54, 111.57, 61.81, 58.16, 56.30, 55.66, 54.47, 27.97, 18.88. ESI + : 416.16。

[0171] Synthesis of Example 48 2,9,10 - Trimethoxy - 13 - (prop - 2 - yn - 1 - yl) - 3 - (prop - 2 - yn - 1 - yloxy) - 5,6 - dihydroisoquinolino[3,2 - a]isoquinolin - 7 - ium (MX48)

[0172] The experimental procedure was the same as that of Example 1, except that the first raw material was 3 - bromopropyne and the second raw material was 3 - bromopropyne; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO - d 6 ) δ 9.86 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.06 (t, J = 1.0 Hz, 1H), 4.82 (d, J = 2.9 Hz, 2H), 4.74 (d, J = 2.9 Hz, 2H), 4.63 (ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 15.9 Hz, 5H), 3.36 (s, 1H), 3.36 (d, J = 6.1 Hz, 1H), 3.21 – 3.14 (m, 2H), 2.69 (t, J = 2.9 Hz, 1H). 13 C NMR (125 MHz, DMSO - d 6) δ 150.60, 149.16, 149.12, 147.29, 142.49, 136.86, 130.33, 130.18, 129.40, 122.68, 122.00, 121.29, 120.79, 114.53, 111.57, 83.55, 78.41, 76.70, 72.39, 61.81, 58.28, 58.16, 56.30, 55.66, 27.97, 21.95. ESI + : 414.17。

[0173] Example 49 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-(vinyloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX49)

[0174] The experimental procedure was the same as that of Example 1, except that the first raw material was vinyl bromide and the second raw material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 1.0 Hz, 1H), 6.70 (s, 1H), 5.31 (dddd, J = 9.1, 7.3, 3.3, 1.6 Hz, 1H), 4.68 (dd, J = 9.9, 2.8 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.27 (dd, J = 9.9, 2.8 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J = 17.1 Hz, 5H), 3.46 (dp, J = 7.4, 1.1 Hz, 2H), 3.24 (dddd, J = 15.9, 7.6, 4.6, 1.0 Hz, 2H), 1.68 (q,J = 1.2 Hz, 6H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.09, 148.05, 147.22, 147.00, 142.90, 136.89, 131.64, 130.17, 129.75, 128.59, 123.77, 123.67, 122.09, 121.57, 120.78, 116.05, 110.64, 93.31, 61.81, 58.15, 56.30, 56.11, 28.68, 27.55, 24.49, 19.28. ESI + : 436.25。

[0175] Example 50 Synthesis of 2,9,10-trimethoxy-13-(3-nitrobenzyl)-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX50)

[0176] The experimental procedure was the same as that of Example 1, except that both the first raw material and the second raw material were 3-nitrobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.29 (tt, J = 2.2, 1.0 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.12 (tt, J = 2.1, 1.0 Hz, 1H), 7.72 (ddq, J = 8.0, 2.3, 1.2 Hz, 1H), 7.60 (ddd, J = 12.3, 8.8, 7.8 Hz, 2H), 7.53 – 7.47 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.04 (t, J = 1.0 Hz, 1H), 5.24 (t, J = 1.0 Hz, 2H), 4.64 (ddd,J = 7.3, 4.6, 1.7 Hz, 2H), 4.50 (dt, J = 9.8, 1.0 Hz, 1H), 4.08 (dt, J = 9.8, 1.0 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H), 3.21 – 3.14 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 149.86, 149.48, 148.45, 148.32, 147.26, 143.57, 138.07, 137.12, 137.02, 133.52, 133.35, 131.19, 131.09, 130.41, 129.50, 129.26, 124.37, 124.14, 123.81, 123.79, 123.36, 122.75, 121.08, 118.23, 114.29, 111.38, 71.22, 61.81, 57.39, 56.30, 55.65, 36.55, 27.97. ESI + : 608.20。

[0177] Synthesis of 13-(4-Fluorobenzyl)-2,9,10-trimethoxy-3-(pent-4-yn-1-yloxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX51), Example 51

[0178] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromopent-4-yne and the second starting material was 4-fluorobenzyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.23 (ddt, J = 7.5, 5.0, 1.0 Hz, 2H), 7.19 (d, J = 8.8 Hz, 1H), 7.15 – 7.07 (m, 2H), 7.01 (t,J = 1.0 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H),4.41 (dt, J = 10.0, 1.0 Hz, 1H), 4.20 (dt, J = 10.0, 1.1 Hz, 1H), 4.14 (t, J = 6.1Hz, 2H), 4.02 (s, 3H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.57(td, J = 6.3, 3.0 Hz, 2H), 2.07 (t, J = 2.9 Hz, 1H), 1.95 (p, J = 6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 163.02, 161.00, 150.60, 150.45, 149.39,147.26, 143.57, 137.11, 135.51, 135.48, 131.14, 131.02, 130.33, 129.71,129.64, 123.81, 122.77, 121.08, 118.23, 115.48, 115.32, 114.15, 111.29,83.64, 69.24, 68.63, 61.81, 57.39, 56.30, 55.65, 35.83, 28.27, 27.97, 15.64. ESI + : 512.6。

[0179] Example 52 Synthesis of 3-(4-cyanobutoxy)-13-(6-cyanohexyl)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX52)

[0180] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromohexanenitrile and the second starting material was 1-bromooctanenitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6) δ 7.32 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 1.1 Hz,0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.08 (t, J = 5.0 Hz, 1H), 4.02 (s,1H), 3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.78 (t, J = 8.5 Hz, 1H),2.40 (dt, J = 17.4, 5.8 Hz, 2H), 1.82 – 1.60 (m, 4H), 1.44 – 1.33 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.37, 149.34, 146.81, 143.03, 137.45, 135.26, 133.19, 130.22, 123.25, 122.15, 121.99, 121.50, 119.41, 114.15, 111.29, 69.22, 61.81, 58.81, 56.30, 55.65, 30.56, 28.81, 28.61, 28.57, 28.27, 27.97, 25.62, 22.12, 17.12, 16.76. ESI + : 528.29。

[0181] Synthesis of Example 53 13-(6-cyanohexyl)-3-((5-cyanopentyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX53)

[0182] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoheptanenitrile and the second starting material was 1-bromooctanenitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.32 (d, J = 8.0 Hz, 1H), 7.01 (t,J = 1.0 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.04 – 3.97 (m, 2H), 3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.78 (t, J = 8.5 Hz, 1H), 2.38 (td, J = 5.9, 3.0 Hz, 2H), 1.78 – 1.69 (m, 1H), 1.71 – 1.64 (m, 2H), 1.67 – 1.60 (m, 1H), 1.49 (p, J = 6.3 Hz, 1H), 1.44 – 1.33 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.29, 149.34, 146.81, 143.03, 137.45, 135.26, 133.19, 130.27, 123.25, 122.15, 121.99, 121.50, 119.41, 114.15, 111.29, 68.80, 61.81, 58.81, 56.30, 55.65, 30.56, 29.15, 28.81, 28.61, 28.27, 27.97, 25.62, 25.52, 24.65, 17.12, 17.06. ESI + : 542.3。

[0183] Synthesis of Example 54 13-(4-Cyanobutyl)-3-((6-cyanohexyl)oxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX54)

[0184] The experimental procedure was the same as that of Example 1, except that the first raw material was 1-bromooctanenitrile and the second raw material was 1-bromohexanenitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.32 (d, J = 8.0 Hz, 1H), 7.01 (t,J = 1.1 Hz, 0H), 4.63 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 4.04 – 3.97 (m, 2H), 3.89 (d, J = 11.0 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.87 – 2.69 (m, 1H), 2.39 (dt, J = 7.8, 5.9 Hz, 2H), 1.82 – 1.69 (m, 3H), 1.64 (p, J = 5.9 Hz, 1H), 1.50 – 1.35 (m, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.29, 149.34, 146.82, 143.03, 137.46, 134.72, 133.19, 130.22, 123.25, 122.15, 121.99, 121.50, 119.41, 114.15, 111.29, 68.80, 61.81, 58.81, 56.30, 55.65, 30.58, 29.33, 28.14, 27.97, 27.43, 26.07, 25.60, 24.40, 17.12, 16.92. ESI + : 528.29。

[0185] Synthesis of 13-(5-cyanopentyl)-2,9,10-trimethoxy-3-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX55) in Example 55

[0186] The experimental procedure was the same as in Example 1, except that the first starting material was 3,3-dimethylallyl bromide and the second starting material was 1-bromoheptanenitrile; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 0H), 7.32 (d, J = 8.5 Hz, 0H), 6.99 (t, J = 1.1 Hz, 0H), 5.28 (ddp,J = 6.5, 3.1, 1.6 Hz, 0H), 4.67 – 4.59 (m, 2H),4.02 (s, 1H), 3.88 (d, J = 13.9 Hz, 2H), 3.21 – 3.14 (m, 1H), 2.78 (t, J = 8.5Hz, 1H), 2.38 (t, J = 5.9 Hz, 1H), 1.81 – 1.72 (m, 4H), 1.67 (p, J = 5.8 Hz, 1H),1.38 (p, J = 6.1 Hz, 1H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.63, 150.34, 149.25, 146.81, 143.03,137.69, 137.45, 135.28, 133.19, 130.25, 123.25, 122.15, 121.99, 121.50,119.41, 119.22, 113.80, 111.34, 66.09, 61.81, 58.81, 56.30, 55.65, 30.60,28.64, 27.97, 27.89, 24.80, 24.62, 19.90, 17.06. ESI + : 501.28。

[0187] Example 56 Synthesis of 3-(((5-cyanopentyl)oxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX56))

[0188] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoheptanenitrile and the second starting material was 3,3-dimethylallyl bromide; the NMR results of the final product were as follows: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.32(s, 1H), 7.19 (d, J= 8.8 Hz, 1H), 7.01 (t, J = 1.0 Hz, 1H), 5.31 (dddd, J = 9.1,7.2, 3.3, 1.6 Hz, 1H), 4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.04 – 3.97 (m,5H), 3.89 (d, J = 11.0 Hz, 5H), 3.46 (dp, J = 7.5, 1.1 Hz, 2H), 3.21 – 3.14 (m,2H), 2.39 (t, J = 5.9 Hz, 2H), 1.74 (p, J = 6.2 Hz, 2H), 1.71 – 1.63 (m, 8H),1.49 (p, J = 6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.60, 150.29, 149.34, 147.22, 142.90,136.89, 130.31, 130.17, 129.75, 128.59, 123.77, 122.74, 122.09, 121.57,120.78, 119.41, 114.15, 111.29, 68.80, 61.81, 58.10, 56.30, 55.65, 29.15,28.68, 27.97, 25.52, 24.65, 24.49, 19.28, 17.06. ESI + : 501.28。

[0189] Example 57 Inhibitory Activity of the Compound against Colorectal Cancer Cells The compounds MX1 - MX56 prepared in Examples 1 - 56 were respectively co-incubated with colorectal cancer cell lines SW620, DLD-1, SW480 and gastric cancer AGS cells. The compound concentrations were 1 μM, 2 μM, 4 μM, 8 μM, 16 μM, 32 μM, 64 μM, 128 μM, and the cell concentration was 1*10^4 cells / well. The compounds were co-incubated with the cells for 24 h. The half-maximal inhibitory concentration (TC 50 value) of the compound against the cells was detected by CCK-8 in vitro, and the results are shown in Table 1.

[0190] Table 1

[0191] The above results indicate that the compounds MX1 - MX56 provided by the present invention have better activities in inhibiting the proliferation of colon cancer cells and gastric cancer cells compared to BBR.

[0192] The inhibitory activities of compound MX51 against three colon cancer cells are only shown in the following figures.

[0193] Figure 1 The effects of compound MX51 on inhibiting the proliferation of three colon cancer cell lines SW620, DLD - 1, and SW480 were detected by CCK - 8 in vitro. The IC 50 values were 11.75 μM, 8.62 μM, and 13.96 μM respectively (as shown in A - C in Figure 1 ), indicating that this compound has better activity in inhibiting the proliferation of colon cancer cells compared to BBR.

[0194] Example 58 Compound inhibits the growth of colon cancer tumors The effects of the compounds of the present invention on inhibiting the occurrence and development of colon cancer were evaluated in subcutaneous tumor models, orthotopic cecal inoculation models, and AOM / DSS spontaneous colon cancer models. Mice were adaptively fed for one week. BALb / c mice at 5 - 6 weeks old were intraperitoneally injected with azoxymethane AOM (10 mg / mL) once and then fed with regular drinking water for 1 week. Then, the drinking water was replaced with 2.5% DSS for 1 week, and then fed with regular drinking water for 2 weeks. After that, the cycle of feeding with DSS for 1 week and drinking water for 2 weeks was repeated 2 - 3 times to induce spontaneous colon cancer in mice.

[0195] Taking MX51 as an example, 1×10^6 SW620 cells were inoculated subcutaneously into immunodeficient mice. Seven days after inoculation, the tumor volume was measured and recorded. The results are as shown in Figure 2 , and it was found that from the two indicators of tumor volume and tumor weight, the tumors in the compound MX51 treatment group (10 mg / kg) were significantly improved, suggesting that it can significantly inhibit tumor growth in vivo (CTRL is the control group without compound treatment).

[0196] By inoculating 1×10^6 SW620 cells orthotopically into the cecum of immunodeficient mice, as shown in Figure 3 it was found that treatment with MX51 (10 mg / kg) could significantly inhibit the growth of SW620 tumors on the cecum, reduce the cecal tumor mass, and at the same time, MX51 treatment could significantly inhibit the occurrence of liver metastasis of tumor cells (as shown in A in Figure 3 ), and prolong the survival period of the tumor - bearing mice.

[0197] Example 59 BALb / c mice at 5 - 6 weeks of age were intraperitoneally injected with azoxymethane AOM (10 mg / mL) once, and then fed with regular drinking water for 1 week. After that, the drinking water was replaced with 2.5% DSS for 1 week, and then they were fed with regular drinking water for 2 weeks. Then the cycle of feeding with DSS for 1 week and drinking water for 2 weeks was repeated 2 - 3 times to induce spontaneous colon cancer in mice.

[0198] In this model, MX51 treatment (10 mg / kg) was given, and the results were as Figure 4 , showing that MX51 treatment had no effect on the body weight of mice, indicating that MX51 had good safety in vivo. At the same time, it was found that MX51 could significantly reduce the number of tumors, extend the length of the entire cecum, alleviate the degree of intestinal mucosal barrier damage, and prolong the survival period of mice.

[0199] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "example", "specific example", "some implementation manners" or "some examples", etc. means that the specific features, structures, materials or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0200] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions and variations to 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): in, R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted C2-C 10 Alkenyl, unsubstituted C2-C 10 Alkynyl, C1-C 10 alkyl; m=1, n=1~10, R3 is unsubstituted or substituted with at least one R b Substituted phenyl; R b is selected from -NO2, halogen, C1 alkoxy, C1 alkyl, Wherein, R1 and R2 are not C3 or C4 alkenyl at the same time.

2. The compound according to claim 1, characterized in that The compound is selected from one of the following structures:

3. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or 2.

4. Use of the compound according to claim 1 or 2 in the preparation of a medicament for treating a digestive tract tumor, wherein the alimentary tract tumor is colon cancer or gastric cancer.

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