Isoquinoline drugs and their use in improving or treating gastrointestinal tumors

Abstract

The present application relates to the technical field of small molecule drugs, in particular to a isoquinoline drug and its application in improving or treating digestive tract tumors, and aims to provide a compound, a pharmaceutical composition containing the compound and its application in treating colorectal cancer and gastric cancer, and provides a 3,13-position substituted berberine derivative, the drug itself has less toxicity and does not affect the growth of normal human cells, and has a good application prospect in the development of novel antitumor drugs, especially in the development of anti-digestive tract tumor drugs.

Description

TECHNICAL FIELD

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

[0002] Colorectal cancer, also known as colorectal cancer, is one of the most common malignant tumors worldwide. According to the data of the World Health Organization (WHO), the incidence and mortality of colorectal cancer have been increasing in recent years, especially in developed countries. The harmfulness of colorectal cancer mainly lies in its high incidence and mortality. In recent years, the prevalence and mortality of colorectal cancer are still on the rise worldwide. The high incidence and mortality of colorectal cancer make it an important problem of global public health.

[0003] Despite some progress in the diagnosis and treatment of colorectal cancer, there are still many difficulties. First, the early diagnosis rate is low, and many patients are in the middle and late stages when diagnosed, missing the best treatment opportunity. Second, the heterogeneity of colorectal cancer is high, and the biological characteristics of tumors in different patients differ greatly, leading to uneven treatment effects. In addition, the problem of drug resistance of colorectal cancer is also prominent, and many patients develop drug resistance during treatment, leading to poor treatment effect.

[0004] Currently, the drug treatment of colorectal cancer mainly includes chemotherapy, targeted therapy and immunotherapy. Chemotherapy is the basis of colorectal cancer treatment, and common 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 common targeted drugs include anti-EGFR antibodies (such as cetuximab) and anti-VEGF antibodies (such as bevacizumab). Immunotherapy is a new field of colorectal cancer treatment, especially PD-1 / PD-L1 inhibitors show good efficacy in microsatellite instability high (MSI-H) colorectal cancer patients.

[0005] Although some progress has been made in the drug treatment of colorectal cancer, there are still many problems. First, the problem of drug resistance is prominent, and many patients develop drug resistance during treatment, leading to poor treatment effect. Second, the application range of targeted therapy and immunotherapy is limited, only suitable for part of the patients. In addition, the side effects of drug treatment are large, affecting the quality of life of patients. Therefore, how to improve the efficacy of drug treatment, reduce side effects and expand the application range is the main problem faced by current colorectal cancer treatment.

[0006] The current chemotherapy drugs for gastric cancer include fluorouracil (5-FU), platinum (cisplatin, oxaliplatin), taxane (docetaxel) and the like as the basic scheme, but there are serious drug resistance (about 50% of patients are invalid), bone marrow suppression and neurotoxicity and the like. And the response rate of targeted therapy and immunotherapy patients is low, and chemotherapy and targeted therapy are easy to fail due to tumor heterogeneity, signal pathway compensation activation and the like, and most patients lack targetable driver gene mutations.

[0007] At the same time, the serious side effects (such as bone marrow suppression, gastrointestinal reaction) of traditional chemotherapy affect treatment compliance, and breakthrough therapy is urgently needed. The research and development of anti-gastric cancer small molecule drugs needs to focus on overcoming drug resistance, improving precision and reducing toxicity. SUMMARY

[0008] The present application aims to at least solve one of the technical problems in the related art. To this end, one object of the present application is to provide a compound, a pharmaceutical composition comprising the compound and the use thereof in the treatment of gastrointestinal tumors, the present application provides a 3,13-substituted berberine derivative, which has less toxicity itself and does not affect the growth of normal human cells, and has good application prospect in the development of new anti-tumor drugs, especially in the development of anti-drug resistant colon cancer and gastric cancer drugs.

[0009] To this end, the first aspect of the present application provides a compound, which is a compound represented by general formula (I) or a stereoisomer, a tautomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound represented by general formula (I):

[0010]

[0011] wherein,

[0012] R1, R2 are each independently selected from - (CH2) m R3, - (CH2) n -CN, unsubstituted or substituted with at least one R a C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl;

[0013] m = 1 ~ 10, n = 1 ~ 10,

[0014] R3 is unsubstituted or substituted with at least one R b 3-10 membered heterocyclyl, C6-C 20 aryl, 5-20 membered heteroaryl;

[0015] R a , R beach independently selected from -NH2, -NO2, halogen, C1-C 20 alkoxy, C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl.

[0016] The most serious problem currently faced in the treatment of colon cancer and gastric cancer is extensive drug resistance, and the number of chemotherapeutic drugs that can be applied to colorectal cancer and gastric cancer is extremely limited. More seriously, tumor cells are prone to drug resistance to chemotherapeutic drugs (such as 5-fluorouracil and oxaliplatin) and targeted drugs (such as anti-EGFR and anti-VEGF), resulting in decreased or failed efficacy. Moreover, current 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 effect on microsatellite stable (MSS) colon cancer and may cause immune-related side effects. Due to the high cost of targeted drugs and immunotherapy, some patients cannot afford it, which affects the accessibility of treatment.

[0017] The compound represented by the general formula (I) of the present application can be used for the preparation of an anti-colon cancer and gastric cancer drug, which exhibits excellent inhibitory activity in vivo and in vitro. Moreover, the drug itself has less toxicity, does not affect the growth of normal human cells, and is not prone to 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.

[0018] According to an embodiment of the present application, in the compound represented by the general formula (I), R1, R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, or the following group substituted by at least one R a substituted C1-C 15 alkyl, C2-C 15 alkenyl, C2-C 15 alkynyl;

[0019] m = 1-10, n = 1-10,

[0020] R3 is unsubstituted or substituted by at least one R b C6-C 20 aryl, 5-20 membered heteroaryl;

[0021] R a , R b each independently selected from -NH2, -NO2, halogen, C1-C 15 alkoxy, C1-C 15 alkyl, C2-C 15 alkenyl, C2-C15 Alkynyl.

[0022] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0023] m=1~5, n=1~10,

[0024] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 aryl;

[0025] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0026] According to an embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl;

[0027] m=1~5, n=1~10,

[0028] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0029] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0030] According to an embodiment of the present invention, R a 、R beach independently selected from -NH2, -NO2, halogen, C1-C 10 alkoxy, C1-C 10 alkyl.

[0031] According to embodiments of the present application, R a is -NH2.

[0032] R b selected from -NO2, halogen, C1-C 10 alkoxy, C1-C 10 alkyl.

[0033] According to embodiments of the present application, in the compound of general formula (I), R1, R2are each independently selected from - (CH2) m R3, - (CH2) n -CN, unsubstituted C2-C 10 alkenyl, unsubstituted C2-C 10 alkynyl, unsubstituted or substituted with at least one R a C1-C 10 alkyl;

[0034] m = 1 ~ 5, n = 1 ~ 10,

[0035] R3is unsubstituted or substituted with at least one R b phenyl;

[0036] R a is -NH2.

[0037] R b selected from -NO2, halogen, C1-C 10 alkoxy, C1-C 10 alkyl.

[0038] According to embodiments of the present application, the compound is selected from one of the following structures:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046] The second aspect of the present application provides a pharmaceutical composition. According to an embodiment of the present application, the pharmaceutical composition comprises the compound of the first aspect.

[0047] According to an embodiment of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier, diluent or excipient.

[0048] The compound provided by the present application is used to prepare various dosage forms of drugs, which are administered to a subject in a therapeutically effective amount. After the drug is absorbed by the subject, it can treat or improve colorectal cancer.

[0049] According to an embodiment of the present application, 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 application, and can be used to treat or improve colorectal cancer.

[0050] The present application relates to suitable pharmaceutically acceptable salts of the compounds of general 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, methanesulfonate, benzenesulfonate or p-toluenesulfonate. According to the foregoing, any of the compounds of the present application mentioned herein includes its pharmaceutically acceptable salt, solvate or combination thereof.

[0051] In addition to the pharmaceutically acceptable salts of the compounds of the present application, the present application also includes other salts. They can be used as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for identification, characterization or purification of the compounds of the present application.

[0052] The third aspect of the present application provides the use of the compound of the first aspect in the preparation of a medicament for treating a digestive tract tumor.

[0053] According to an embodiment of the present application, the digestive tract tumor includes colorectal cancer, gastric cancer.

[0054] The 3,13-substituted berberine derivatives provided by the present application have completely different mechanisms from the currently commonly used anti-colorectal cancer and gastric cancer drugs, and may play an excellent role in drug-resistant colorectal cancer and gastric cancer. The 3,13-substituted berberine derivatives of the present application are expected to become a synergistic effect in combination with other first-line anti-colorectal cancer and gastric cancer drugs.

[0055] Additional aspects and advantages of the present application will be in part apparent and in part pointed out hereinafter in the description of the application. BRIEF DESCRIPTION OF DRAWINGS

[0056] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0057] Figure 1 The figure shows the inhibitory activity curve of the candidate compound MX51 on three colon cancer cell lines SW620, DLD-1 and SW480 and the corresponding half-maximal inhibitory concentration (CI), wherein A shows the half-maximal inhibitory concentration of the compound MX51 on the cell line SW620; B shows the half-maximal inhibitory concentration of the compound MX51 on the cell line DLD-1; and C shows the half-maximal inhibitory concentration of the compound MX51 on the cell line SW480.

[0058] Figure 2 The following graphs evaluate the effect of MX51 on inhibiting the development of colon cancer in a subcutaneous tumor model, an orthotopic cecal inoculation model, and an AOM / DSS spontaneous colon cancer model. DMSO was used as a control group. A is a line graph showing the effect of MX51 on tumor volume, and B is a bar graph showing the effect of MX51 on tumor weight.

[0059] Figure 3 This figure shows the evaluation of the tumor inhibition effect of MX51 in situ in the cecum of immunodeficient mice. DMSO was used as a control group. A shows the cecum without (top) or after (bottom) MX51 treatment. B shows the mouse count corresponding to different tumor volumes. C shows the mouse count corresponding to different tumor weights. D shows the line graph of mouse survival rate.

[0060] Figure 4 The figure shows the in vivo activity evaluation of MX51 in BALb / c mice modeled with azomethane (AOM) (10 mg / mL). DMSO was used as a control group. A is a schematic diagram of the in vivo administration time, B is a diagram showing the effect of MX51 treatment on mouse body weight, C is a diagram showing the distribution of colon tumors, D is a diagram showing the colon length count, E is a diagram showing colon HE staining (left) and a bar graph showing polyp counts (right), and F is a line graph showing mouse survival rates. DETAILED DESCRIPTION

[0061] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0062] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0063] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0064] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present invention belongs.

[0065] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0066] As used herein, the terms "optionally," "optional," or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0067] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0068] The term "pharmaceutically acceptable salt" means a non-toxic salt of a pharmaceutically acceptable acid or base, including inorganic acids and bases, and organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts, such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc; salts derived from organic bases include, but are not limited to, salts of primary, secondary and 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, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine or polyamine resins; salts derived from inorganic and organic acids include, but are not limited to, salts of 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, ethenesulfonic 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-hydroxypropanoic acid, oxalic acid, glycolic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, or trifluoromethanesulfonic acid.

[0069] The term "stereoisomer" refers to isomers that have the same molecular formula but different spatial arrangement of atoms. Stereoisomers include enantiomers (mirror images of each other), diastereomers (isomers that are not mirror images of each other), and geometric isomers (isomers that differ in the orientation of a group in the overall structure).

[0070] The term "tautomer" refers to isomers of a molecule that differ in the position of a proton. Compounds of the present application can exhibit tautomerism. Tautomers of a compound can exist in two or more interconvertible forms. Proton-shift tautomers result from the migration of a hydrogen atom covalently bonded to two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0071] The term "pharmaceutical composition" denotes a mixture of one or more compounds of the application, or physiologically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a biological entity and to facilitate absorption

[0072] The term "solvate" means a compound of the application or a salt thereof, including where applicable a stoichiometric or non-stoichiometric number of molecules of solvent, for example water, in intermolecular non-covalent association.

[0073] The term "prodrug" means a compound of the application which can be converted under physiological conditions or by solvo lysis to a biologically active compound of the application. A prodrug of the application is prepared by modifying functional groups present in the compound in a manner known in the art, which modification can be removed in vivo to yield the parent compound.

[0074] The term "C1-C 10 The term "C1-C6alkyl" is to be understood as preferably meaning a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6 carbon atoms.

[0075] The term "C2-C 20 The term "C2-C6alkynyl" is to be understood as preferably meaning a straight or branched chain monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0076] The term "C2-C 20 The term "C2-C6alkenyl" is to be understood as preferably meaning a straight or branched chain monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0077] The term "3-10 membered heterocyclyl" means a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring which contains 1-5, preferably 1-3, heteroatoms selected from N, O and S. In particular, the heterocyclyl group can 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 heterocyclyl group can be benzo-fused. The heterocyclyl group can be bicyclic, for example, but not limited to, a 5,5 membered ring, such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or a 5,6 membered bicyclic ring, such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The ring containing a nitrogen atom can be partially unsaturated, i.e. it can contain one or more double bonds, for example, but not limited to, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to, dihydroisoquinolinyl. According to the present application, the heterocyclyl group is non-aromatic.

[0078] The term "C6-C 20 aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms. In particular a ring having 6 carbon atoms ("C6aryl"), for example phenyl; or a ring having 9 carbon atoms ("C9aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), for example fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), for example anthryl.

[0079] The term "5-20 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S, additionally in each case benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, for example benzo furanyl, benzo thienyl, benzo oxazolyl, benzo isoxazolyl, benzo imidazolyl, benzo triazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and their benzo derivatives, for example quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxazinyl and the like.

[0080] The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Non-limiting examples of the class of the term "excipient" include binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents, and the like. Excipients can enhance the handling properties of a pharmaceutical preparation, i.e. make the preparation more suitable for direct compression by increasing the flowability and / or cohesiveness. Examples of typical "pharmaceutically acceptable carriers" suitable for use in the above-mentioned preparations are: sugars, such as lactose, sucrose, mannitol and sorbitol, or corn starch, tapioca starch and potato starch; celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; calcium phosphates, such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates, such as magnesium stearate and calcium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereal hydrolyzates and other non-toxic, compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants and the like auxiliary agents commonly used in pharmaceutical preparations.

[0081] Colorectal cancer is one of the most common malignant tumors worldwide, with increasing incidence and mortality. Despite some progress in diagnosis and treatment, there are still many challenges. Early diagnosis, individualized treatment, overcoming drug resistance and reducing side effects are the main directions of current colorectal cancer treatment. Future research should focus on exploring new therapeutic targets, developing new drugs and optimizing treatment regimens to improve the survival rate and quality of life of patients with colorectal cancer.

[0082] Berberine (BBR) is an isoquinoline alkaloid mainly found in traditional Chinese medicine plants such as Coptis and Phellodendron. Its chemical structure is a quaternary ammonium salt form with a planar aromatic ring and multiple oxygen atoms, which gives it good biological activity such as antibacterial, anti-inflammatory and anti-tumor effects.

[0083] Studies have shown that berberine can inhibit cancer cell proliferation, induce apoptosis, anti-metastasis and angiogenesis, and regulate intestinal flora to achieve anti-colorectal cancer effects. In addition, berberine has the advantages of multi-target action, low toxicity and safety, synergistic effect, reversal of drug resistance, and improved bioavailability. Studies have shown that in clinical phase II trials, berberine adjuvant therapy has prolonged the progression-free survival of patients by 2-3 months. However, the anti-colorectal tumor activity of berberine needs to be improved, and its mechanism is still unclear.

[0084] In view of the above shortcomings of the prior art, the purpose of the present application is to provide a class of 3, 13-substituted berberine derivatives, their preparation methods and applications. Through rational design and modification of berberine (BBR), candidate drugs with improved activity, new mechanisms, less drug resistance and good safety are obtained.

[0085] According to one specific embodiment of the present application, the present application provides a 3, 13-substituted berberine derivative, whose structural formula is shown in general formula (I):

[0086]

[0087] Among them,

[0088] R1, R2 are each independently selected from - (CH2) m R3, - (CH2) n -CN, unsubstituted or substituted with at least one R a substituted C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl;

[0089] m = 1 ~ 10, n = 1 ~ 10,

[0090] R3 is unsubstituted or substituted with at least one R b substituted 3-10 membered heterocyclyl, C6-C20 Aryl, 5-20 membered heteroaryl;

[0091] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 20 Alkoxy, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl.

[0092] It should be noted that m can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 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.

[0093] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl;

[0094] m=1~10, n=1~10,

[0095] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 Aryl, 5-20 membered heteroaryl;

[0096] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 15 Alkoxy, C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C 15 Alkynyl.

[0097] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 15 Alkyl, C2-C 15 Alkenyl, C2-C15 Alkynyl;

[0098] m=1~5, n=1~10,

[0099] R3 is unsubstituted or substituted with at least one R b Substituted C6-C 20 aryl;

[0100] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0101] According to a specific embodiment of the present invention, in the compound represented by general formula (I), R1 and R2 are each independently selected from -(CH2) m R3, -(CH2) n -CN, unsubstituted or substituted with at least one R a Substituted with the following groups: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl;

[0102] m=1~5, n=1~10,

[0103] R3 is unsubstituted or substituted with at least one R b substituted phenyl;

[0104] R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl.

[0105] According to a specific embodiment of the present invention, R a 、R b Each independently selected from -NH2, -NO2, halogen, C1-C 10 Alkoxy, C1-C 10 alkyl.

[0106] According to a preferred embodiment of the present invention, R a is -NH2;

[0107] R bselected from -NO2, halogen, C1-C5 alkoxy, C1-C5 alkyl. Wherein, halogen is fluorine, chlorine, bromine, iodine.

[0108] According to one specific embodiment of the present application, the present application provides a preparation method of 3,13-position substituted berberine derivatives, comprising the following steps:

[0109]

[0110] The (M1), anhydrous acetonitrile, potassium carbonate and the first raw material are reacted at 60-70 ℃, the reaction progress is monitored by TLC, after the reaction is completed, it is cooled to solid completely precipitates, suction filtration, the filtrate is silica gel mixed sample, dichloromethane and methanol are used as mobile phase, and the yellow intermediate (M2) is obtained by Flash fast column chromatography purification. The above obtained intermediate is reacted with anhydrous acetonitrile, sodium hydrogen and the second raw material at 70-90 ℃, the reaction progress is monitored by TLC, after the reaction is completed, it is neutralized in hydrochloric acid methanol solution, and then silica gel mixed sample, dichloromethane and methanol are used as mobile phase, and the yellow final product is obtained by Flash fast column chromatography purification.

[0111] According to one specific embodiment of the present application, the present application provides the use of the aforementioned 3,13-position substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation of products for preventing and / or treating colorectal cancer.

[0112] According to one specific embodiment of the present application, the present application provides the use of the aforementioned 3,13-position substituted berberine derivatives or physiologically acceptable salts or pharmaceutical compositions in the preparation of products for preventing and / or treating colorectal cancer.

[0113] The present application provides a kind of 3,13-position substituted berberine derivatives shown in general formula (I) and its preparation method and application, in the early work, efficient, low toxicity, compound is screened for not easy to produce drug resistance.Compared with BBR, the 3,13-position substituted berberine derivatives provided in the present application show more promising inhibitory activity on three colon cancer cells.The effect of 3,13-position substituted berberine derivatives on tumor volume and weight was investigated on ectopic and orthotopic tumors in mice respectively.The results show that 3,13-position substituted berberine derivatives can significantly inhibit the growth of SW620 tumor and prolong the survival of tumor-bearing mice.Meanwhile, on AOM (10 mg / mL) modeling mice, 3,13-position substituted berberine derivatives significantly reduce the number of tumors, prolong the total length of the colon, reduce the degree of intestinal mucosal barrier damage, and prolong the survival of mice.This has good application prospect in the development of new anti-colon cancer drugs, especially in the development of anti-drug-resistant colon tumor treatment.

[0114] It should be noted that the application of the 3,13-substituted berberine derivative shown in the general formula (I) in the preparation of the drug for resisting colon cancer and gastric cancer, and the application of the drug in the preparation, prevention and / or treatment of colon cancer and gastric cancer, should be within the protection scope of the present application.

[0115] The scheme of the present disclosure will be explained below in combination with examples. Those skilled in the art will understand that the examples below are only for illustrating the present disclosure and should not be regarded as limiting the scope of the present disclosure. If the specific technology or condition is not specified in the examples, the technology or condition described in the literature in the art or according to the product instruction is used. If the reagent or instrument is not specified by the manufacturer, it is a conventional product that can be obtained by market purchase.

[0116] Example 1 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX1)

[0117]

[0118] M1, anhydrous acetonitrile, potassium carbonate and m-nitrobenzyl bromide (first raw material) were reacted at 65 ℃, the reaction progress was monitored by TLC, after the reaction was completed, it was cooled to solid completely precipitated, suction filtration, the filtrate was silica gel sample, with dichloromethane and methanol as mobile phase, by Flash fast column chromatography purification to obtain yellow intermediate. The above obtained intermediate was reacted with anhydrous acetonitrile, sodium hydride and 3,3-dimethylallyl bromide (second raw material) at 85 ℃, the reaction progress was monitored by TLC, after the reaction was completed, it was neutralized with hydrochloric acid methanol solution, then silica gel sample was mixed, and dichloromethane and methanol were used as mobile phase, and the yellow final product MX1 was obtained by Flash fast column chromatography purification. The nuclear magnetic resonance result of the final product is as follows:

[0119] 1 H NMR (500 MHz, DMSO-d6) 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).

[0120] 13 C NMR (125 MHz, DMSO-d6) 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.

[0121] ESI + : 541.62.

[0122] Example 2 Synthesis of 13-hexyl-2,9,10-trimethoxy-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX2)

[0123]

[0124] The experimental steps were the same as in Example 1, except that the first raw material was m-nitrobenzyl bromide and the second raw material was 1-bromopentylamine; the NMR results of the final product were as follows:

[0125] 1 H NMR (500 MHz, DMSO-d6) 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).

[0126] 13 C NMR (125 MHz, DMSO-d6) 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.

[0127] ESI + : 558.65.

[0128] Example 3 Synthesis of 13-butyl-2,9,10-trimethoxy-3-((2-nitrobenzyl)oxy)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX3)

[0129]

[0130] The experimental procedure was the same as in Example 1, except that the first starting material was o-nitrobenzyl bromide and the second starting material was 1-bromon-butane; the final product NMR results are as follows:

[0131] 1 H NMR (500 MHz, DMSO-d6) 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 = 7.2, 1.1Hz, 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), 2.87 – 2.70 (m, 2H), 1.65 (tt, J = 8.9, 6.6 Hz, 2H), 1.36 (h, J = 6.9 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H).

[0132] 13C NMR (125 MHz, DMSO-d6) 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.

[0133] ESI + : 529.61.

[0134] Synthesis of 2,9,10-trimethoxy-3-((2-nitrobenzyl)oxy)-13-(oct-7-en-1-yl-1- yl)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX4)

[0135]

[0136] The experimental procedure was the same as Example 1, except that the first starting material was o-nitrobenzyl bromide and the second starting material was 1-bromo octyne; the final product NMR results are as follows:

[0137] 1 H NMR (500 MHz, DMSO-d6) 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 = 7.2, 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= 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 – 1.34 (m, 4H). J

[0138] 13 C NMR (125 MHz, DMSO-d6) 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.

[0139] ESI + : 581.69.

[0140] Synthesis of 2,9,10-trimethoxy-3-((2-nitrobenzyl)oxy)-13-(pent-4-yn-1-yl)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX5)

[0141]

[0142] Experimental procedure as in Example 1, except that the first starting material was o-nitrobenzyl bromide and the second starting material was 4-bromobutyronitrile; the final product NMR results are as follows:

[0143] 1 H NMR (500 MHz,DMSO-d6) 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).

[0144] 13 C NMR (125 MHz, DMSO-d6) 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.

[0145] ESI + : 540.60.

[0146] Example 6 Synthesis of 3-(hept-6-en-1 -yloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1 -yl)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX6)

[0147]

[0148] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromoheptene and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results were as follows:

[0149] 1 H NMR (500 MHz, DMSO-d6) 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).

[0150] 13 C NMR (125 MHz, DMSO-d6) 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.

[0151] ESI + : 502.67.

[0152] Example 7 Synthesis of 13-(3,5-dimethoxybenzyl)-3-(hept-6-en-1-yloxy)-2,9,10- trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX7)

[0153]

[0154] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromoheptene and the second starting material was 3,5-dimethoxybenzyl bromide; the final product NMR results are as follows:

[0155] 1 H NMR (500 MHz, DMSO-d6) 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).

[0156] 13 C NMR (125 MHz, DMSO-d6) 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.

[0157] ESI + : 584.73.

[0158] Example 8 Synthesis of 3-(hept-6-en-1-yloxy)-2,9,10-trimethoxy-13-(3- nitrobenzyl)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX8)

[0159]

[0160] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromoheptene and the second starting material was m-nitrobenzyl bromide; the final product NMR results are as follows:

[0161] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.16 (dt, J = 8.8, 1.6 Hz,1H), 8.12 (tt, J = 2.1, 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), 5.77 (tt, J= 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0Hz, 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), 4.50 (dt, J = 9.8, 1.0 Hz, 1H), 4.08 (dt, J = 9.8, 1.0 Hz, 1H), 4.04 – 3.97(m, 5H), 3.89 (d, J = 11.0 Hz, 5H), 3.21 – 3.14 (m, 2H), 2.03 (tdt, 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).

[0162] 13 C NMR (125 MHz, DMSO-d6) 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.

[0163] ESI + : 569.68.

[0164] Example 9 Synthesis of 2,9,10-trimethoxy-13-(3-methylbenzyl)-3-(pent-4-en-1-yloxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX9)

[0165]

[0166] 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 m-methylbenzyl bromide; the end product had the following NMR results:

[0167] 1 H NMR (500 MHz, DMSO-d6) 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).

[0168] 13C NMR (125 MHz, DMSO-d6) 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.

[0169] ESI + : 510.65.

[0170] Synthesis of 13-(3-aminopropyl)-2,9,10-trimethoxy-3-(pent-4-en-1-yloxy)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX10)

[0171]

[0172] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromopentene and the second starting material was 1-bromobutane; the final product NMR results are as follows:

[0173] 1 H NMR (500 MHz, DMSO-d6) 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).

[0174] 13 C NMR (125 MHz, DMSO-d6) 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.

[0175] ESI + : 463.60.

[0176] Example 11 Synthesis of 3-(allyloxy)-13-(3,5-dimethoxybenzyl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX11)

[0177]

[0178] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromopropene and the second starting material was 3,5-dimethoxybenzyl bromide; the final product NMR results were as follows:

[0179] 1 H NMR (500 MHz,DMSO-d6) 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), 7.00 (t, J = 1.0 Hz, 1H), 6.46 (dt, J = 2.2, 1.0Hz, 2H), 6.36 (t, J = 2.4 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 = 16.8, 2.2, 1.0 Hz, 1H), 4.67 – 4.58 (m,4H), 4.08 (dt, J = 9.5, 1.0 Hz, 1H), 4.04 – 3.97 (m, 4H), 3.88 (d, J = 13.9 Hz,5H), 3.79 (s, 5H), 3.21 – 3.14 (m, 2H).

[0180] 13 C NMR (125 MHz, DMSO-d6) 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.

[0181] ESI + : 528.62.

[0182] Synthesis of 3-(allyloxy)-2,9,10-trimethoxy-13-(oct-7-en-1-yl-1-yl)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX12)

[0183]

[0184] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromopropene and the second starting material was 1-bromooctyne; the final product NMR results were as follows:

[0185] 1 H NMR (500 MHz,DMSO-d6) 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).

[0186] 13 C NMR (125 MHz, DMSO-d6) 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.

[0187] ESI + : 486.63.

[0188] Synthesis of 13-(hept-6-en-1-yl)-2,9,10-trimethoxy-3-(ethenyloxy)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX13)

[0189]

[0190] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoethylene and the second starting material was 1-bromoheptene; the final product NMR results were as follows:

[0191] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.53 (s, 1H), 7.32 (d, J = 8.5Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.07 (t, J = 1.0 Hz, 1H), 6.70 (s, 0H), 5.77(tt, J = 17.1, 6.8 Hz, 1H), 5.12 (ddt, J = 17.1, 2.1, 1.0 Hz, 1H), 4.97 (ddt, J =17.1, 2.1, 1.1 Hz, 1H), 4.68 (dd, J = 9.9, 2.8 Hz, 1H), 4.63 (ddd, J = 7.6, 4.9,1.2 Hz, 2H), 4.27 (dd, J = 9.9, 2.8 Hz, 1H), 4.02 (s, 3H), 3.88 (d, J = 17.1 Hz,5H), 3.24 (dddd, J = 15.9, 7.6, 4.6, 1.0 Hz, 2H), 2.78 (t, J = 8.5 Hz, 2H), 2.03(tdt, J = 7.8, 6.7, 1.1 Hz, 2H), 1.69 (tt, J = 8.4, 6.8 Hz, 2H), 1.39 – 1.30 (m,2H), 1.34 (s, 2H).

[0192] 13C NMR (125 MHz, DMSO-d6) 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.

[0193] ESI + : 460.59.

[0194] Synthesis of 13-(cyanomethyl)-2,9,10-trimethoxy-3-(ethenyloxy)-5,6-dihydroisoquinoline[3,2- a]isoquinolin-7-ium (MX14)

[0195]

[0196] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromoethene and the second starting material was bromoacetonitrile; the final product NMR results are as follows:

[0197] 1 H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.07 (t, J = 1.0 Hz, 1H), 6.70 (s, 0H), 4.68 (dd, J = 9.9, 2.8 Hz, 1H), 4.63 (ddd, J = 7.3, 4.6, 1.1 Hz, 2H), 4.27 (dd, J = 9.9, 2.8 Hz, 1H), 4.20 (s, 2H), 4.02 (s, 3H), 3.88 (d, J = 17.1 Hz, 5H), 3.24 (dddd, J = 15.9, 7.6, 4.6, 1.0 Hz, 2H).

[0198] 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.

[0199] ESI + : 403.46.

[0200] Example 15 Synthesis of 2,9,10-trimethoxy-13-(3-nitrobenzyl)-3-(oct-7-yn-1- yloxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX15)

[0201]

[0202] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromooctyne and the second starting material was m-nitrobenzyl bromide; the final product NMR results were as follows:

[0203] 1 H NMR (500 MHz, DMSO-d6) 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= 11.0Hz, 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).

[0204] 13 C NMR (125 MHz, DMSO-d6) 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.

[0205] ESI + : 581.69.

[0206] Synthesis of 13-(3-cyanopropyl)-3-(hex-5-yn-1-yloxy)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX16)

[0207]

[0208] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromohexyne and the second starting material was 1-bromobutyronitrile; the final product NMR results were as follows:

[0209] 1 H NMR (500 MHz, DMSO-d6) 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).

[0210] 13 C NMR (125 MHz, DMSO-d6) 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.

[0211] ESI + : 485.60.

[0212] Synthesis of 13-(4-bromobenzyl)-3-(4-cyanobutoxy)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX17)

[0213]

[0214] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromopentanone and the second starting material was 4- bromobenzyl bromide; the final product NMR results were as follows:

[0215] 1 H NMR (500 MHz, DMSO-d6) 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).

[0216] 13 C NMR (125 MHz, DMSO-d6) 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.

[0217] ESI + : 588.52.

[0218] Synthesis of 2,9,10-trimethoxy-13-(4-methylbenzyl)-3-((4-methylbenzyl)oxy)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX18)

[0219]

[0220] The experimental procedure was the same as Example 1, except that the first starting material and the second starting material were both p-methylbenzyl bromide; the final product NMR results were as follows:

[0221] 1 H NMR (500 MHz, DMSO-d6) 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).

[0222] 13 C NMR (125 MHz, DMSO-d6) 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.

[0223] ESI + :546.69.

[0224] Example 19 Synthesis of 13-benzyl-3-(3-cyanopropoxy)-2,9,10-trimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium (MX19)

[0225]

[0226] The experimental steps were the same as in Example 1, except that the first raw material was 1-bromobutyronitrile and the second raw material was benzyl bromide; the NMR results of the final product were as follows:

[0227] 1 H NMR (500 MHz, DMSO-d6) 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).

[0228] 13 C NMR (125 MHz, DMSO-d6) 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.

[0229] ESI + : 495.6.

[0230] Example 20 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-(prop-2-yn-1-yloxy)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX20)

[0231]

[0232] 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 final product NMR results were as follows:

[0233] 1 H NMR (500 MHz, DMSO-d6) 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).

[0234] 13 C NMR (125 MHz, DMSO-d6) 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.

[0235] ESI + : 444.55.

[0236] Synthesis of 3-(cyanomethoxy)-13-(hex-5-yn-1-yl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX21)

[0237]

[0238] The experimental procedure was the same as in Example 1, except that the first starting material was bromoacetonitrile and the second starting material was 6-bromo-1-hexyne; the final product NMR results were as follows:

[0239] 1 H NMR (500 MHz, DMSO-d6) 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).

[0240] 13 C NMR (125 MHz,DMSO-d6) 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.

[0241] ESI + : 457.55.

[0242] Example 22 Synthesis of 13-(3,5-dimethoxybenzyl)-3-((4-fluorobenzyl)oxy)-2,9,10- trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX22)

[0243]

[0244] The experimental procedure was the same as Example 1, except that the first starting material was 4-fluorobenzyl bromide and the second starting material was 3,5- dimethoxybenzyl bromide. The final product had the following NMR results:

[0245] 1 H NMR (500 MHz, DMSO-d6) 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).

[0246] 13C NMR (125 MHz, DMSO-d6) 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.

[0247] ESI + : 596.67.

[0248] Synthesis of 3-((4-fluorobenzyl)oxy)-13-(hept-6-en-1-yl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX23)

[0249]

[0250] The experimental procedure was the same as Example 1, except that the first starting material was p-fluorobenzyl bromide and the second starting material was 7-bromo-1- heptene; the final product NMR results are as follows:

[0251] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.51 (ddt, J = 8.1, 5.1, 1.0 Hz, 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= 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). J = 8.5, 6.8 Hz, 2H), 1.39 – 1.30 (m, 4H).

[0252] 13 C NMR (125 MHz, DMSO-d6) 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.

[0253] ESI + : 542.67.

[0254] Synthesis of 13-allyl-3-((4-chlorobenzyl)oxy)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX24)

[0255]

[0256] The experimental procedure was the same as Example 1, except that the first starting material was p-chlorobromobenzyl and the second starting material was 3-bromopropene; the final product NMR results were as follows:

[0257] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (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= 1.0 Hz, 1H), 5.89 (tt, J = 16.4, 8.1 Hz, 1H), 5.21 – 5.13 (m, 1H), 5.12 (t, J = 1.0 Hz, 2H), 5.07 (ddt, J = 16.4, 2.1, 1.0 Hz, 1H),4.64 (ddd, J = 7.3, 4.6, 1.7 Hz, 2H), 4.02 (s, 3H), 3.88 (d, J = 13.9 Hz, 5H),3.40 (dt, J = 8.0, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H). J

[0258] 13 C NMR (125 MHz, DMSO-d6) 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.

[0259] ESI + : 503.01.

[0260] Example 25 Synthesis of 3-((4-chlorobenzyl)oxy)-2,9,10-trimethoxy-13-(prop-2-yn-1-yl)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX25)

[0261]

[0262] The experimental procedure was the same as Example 1, except that the first starting material was p-chlorobromobenzyl and the second starting material was 3-bromopropynyl; the final product NMR results were as follows:

[0263] 1 H NMR (500 MHz, DMSO-d6) 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).

[0264] 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.

[0265] ESI + : 501.00.

[0266] Example 26 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((3-methylbut-2-en-1-yloxy)-5,6-dihydroisoquinino[3,2-a]isoquinolin-7-ium (MX26)

[0267]

[0268] The experimental procedure was the same as Example 1, and the first starting material and the second starting material were both 3,3-dimethylallyl bromide; the nuclear magnetic resonance result of the final product was as follows:

[0269] 1H NMR (500 MHz, DMSO-d6) 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).

[0270] 13 C NMR (125 MHz, DMSO-d6) 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.

[0271] ESI + : 474.62.

[0272] Synthesis of 13-Heptyl-3-(hex-5-yn-1-yloxy)-2,9,10-trimethoxy-5,6-dihydroisoquinoline[3,2- a]isoquinolin-7-ium (MX27)

[0273]

[0274] 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 end product had the following NMR results:

[0275] 1 H NMR (500 MHz, DMSO-d6) 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).

[0276] 13 C NMR (125 MHz, DMSO-d6) 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.

[0277] ESI +: 544.76.

[0278] Example 28 Synthesis of 2,9,10-trimethoxy-13-(pent-4-en-1-yl)-3-(pent-4-yn-1-yloxy)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX28)

[0279]

[0280] The experimental procedure was the same as Example 1, except that the first starting material was 5-bromo-1-pentyn-3-ol and the second starting material was 5-bromo-1- pentyn-3-ol; the final product NMR results are as follows:

[0281] 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).

[0282] 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.

[0283] ESI + : 470.59.

[0284] Synthesis of 3-(allyloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX29)

[0285]

[0286] 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 final product NMR results were as follows:

[0287] 1 H NMR (500 MHz, DMSO-d6) 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).

[0288] 13C NMR (125 MHz, DMSO-d6) 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.

[0289] ESI + : 446.57.

[0290] Example 30 Synthesis of (E)-3-(but-2-en-1-yloxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX30)

[0291]

[0292] The experimental procedure was the same as Example 1, except that the first starting material was crotyl bromide and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results are as follows:

[0293] 1 H NMR (500 MHz, DMSO-d6) 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).

[0294] 13 C NMR (125 MHz, DMSO-d6) 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.

[0295] ESI + :460.59.

[0296] Example 31 Synthesis of 2,9,10-trimethoxy-13-(2-methylbenzyl)-3-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX31)

[0297]

[0298] The experimental procedure was the same as Example 1, except that the first starting material was 3,3-dimethylallyl bromide and the second starting material was o-methylbenzyl bromide; the final product NMR results are as follows:

[0299] 1 H NMR (500 MHz, DMSO-d6) 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).

[0300] 13 C NMR (125 MHz, DMSO-d6) 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.

[0301] ESI + :510.65.

[0302] Example 32 Synthesis of 2,9,10-trimethoxy-13-(2-methylbenzyl)-3-((3-methylbut-2-en-1-yl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX32)

[0303]

[0304] The experimental procedure was the same as Example 1, except that the first starting material was 3,5-dimethylbenzyl bromide and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results are as follows:

[0305] 1 H NMR (500 MHz, DMSO-d6) 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).

[0306] 13 C NMR (125 MHz, DMSO-d6) 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.

[0307] ESI + : 524.68.

[0308] 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)

[0309]

[0310] The experimental procedure was the same as in Example 1, except that the first starting material was 3,5-dimethylbromobenzene and the second starting material was 3,5-dimethoxybromobenzene; the final product NMR results are as follows:

[0311] 1 H NMR (500 MHz, DMSO-d6) 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).

[0312] 13 C NMR (125 MHz, DMSO-d6) 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.

[0313] ESI + :606.74.

[0314] Synthesis of 14-(3-aminopropyl)-3-((3,5-dimethoxybenzyl)oxy)-2,9,10- trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX34)

[0315]

[0316] The experimental procedure was the same as Example 1, except that the first starting material was 3,5-dimethoxybenzyl bromide and the second starting material was 4-bromobutylamine; the final product NMR results were as follows:

[0317] 1 H NMR (500 MHz, DMSO-d6) 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).

[0318] 13 C NMR (125 MHz, DMSO-d6) 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.

[0319] ESI + : 545.66.

[0320] Synthesis of 4-(4-aminobutoxy)-13-(aminomethyl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX35)

[0321]

[0322] 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 final product had the following NMR results:

[0323] 1 H NMR (500 MHz, DMSO-d6) 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).

[0324] 13 C NMR (125 MHz, DMSO-d6) 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.

[0325] ESI + :438.55.

[0326] Synthesis of 13-allyl-2,9,10-trimethoxy-3-(nonyloxy)-5,6-dihydroisoquinoline[3,2- a]isoquinolin-7-ium (MX36)

[0327]

[0328] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromononane and the second starting material was 3-bromopropene; the final product NMR results were as follows:

[0329] 1 H NMR (500 MHz, DMSO-d6) 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), 5.89 (tt, J = 16.5,8.1 Hz, 1H), 5.17 (ddt, J = 16.4, 2.1, 1.0 Hz, 1H), 5.07 (ddt, J = 16.3, 2.1, 1.0Hz, 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), 3.40 (dt, J = 8.0, 1.0 Hz, 2H), 3.21 – 3.14 (m, 2H), 1.77 (tt, J =7.4, 6.0 Hz, 2H), 1.44 (dq, J = 8.0, 6.9 Hz, 2H), 1.36 – 1.22 (m, 10H), 0.94 –0.85 (m, 3H).

[0330] 13 C NMR (125 MHz, DMSO-d6) 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.

[0331] ESI + :504.69.

[0332] Synthesis of 2,9,10-trimethoxy-3-(nonyloxy)-13-octyl-5,6-dihydroisoquinoline[3,2- a]isoquinolin-7-ium (MX37)

[0333] Synthesis of 2,9,10-trimethoxy-3-(nonyloxy)-13-octyl-5,6-dihydroisoquinoline[3,2- a]isoquinolin-7-ium (MX37)

[0334] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromooctane and the second starting material was 1-bromooctane; the final product NMR results were as follows:

[0335] 1 H NMR (500 MHz, DMSO-d6) 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).

[0336] 13 C NMR (125 MHz, DMSO-d6) 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.

[0337] ESI + : 576.84.

[0338] Example 38 Synthesis of 3-butoxy-13-(3,5-dimethoxybenzyl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX38)

[0339]

[0340] 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 final product NMR results were as follows:

[0341] 1 H NMR (500 MHz, DMSO-d6) 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).

[0342] 13C NMR (125 MHz, DMSO-d6) 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.

[0343] ESI + : 544.67.

[0344] Synthesis of 3-ethoxy-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX39)

[0345]

[0346] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromoethane and the second starting material was 3,3-dimethylallyl bromide; the end product NMR results were as follows:

[0347] 1 H NMR (500 MHz, DMSO-d6) 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, 1.6 Hz, 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).

[0348] 13 C NMR (125 MHz, DMSO-d6) 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.

[0349] ESI + : 434.56.

[0350] Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-((4- nitrobenzyl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX40)

[0351]

[0352] The experimental procedure was the same as Example 1, except that the first starting material was p-nitrobenzyl bromide and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results were as follows:

[0353] 1 H NMR (500 MHz, DMSO-d6) 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).

[0354] 13 C NMR (125 MHz, DMSO-d6) 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.

[0355] ESI + : 541.6.

[0356] Example 41 Synthesis of (E)-13-(but-2-en-1-yl)-3-butoxy-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX41)

[0357]

[0358] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromobutane and the second starting material was the crotyl bromide; the final product NMR results were as follows:

[0359] 1 H NMR (500 MHz, DMSO-d6) 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).

[0360] 13 C NMR (125 MHz, DMSO-d6) 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.

[0361] ESI + : 448.25.

[0362] Synthesis of 13-(3,5-dimethoxybenzyl)-3-((3,5-dimethoxybenzyl)oxy)-2,9,10- trimethoxy-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX42)

[0363]

[0364] The experimental procedure was the same as Example 1, except that the first starting material and the second starting material were both 3,5-dimethoxybenzyl bromide; the final product NMR results were as follows:

[0365] 1 H NMR (500 MHz, DMSO-d6) 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, 1.2Hz, 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).

[0366] 13 C NMR (125 MHz, DMSO-d6) 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.

[0367] ESI + :638.28.

[0368] 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)

[0369]

[0370] The experimental steps were the same as in Example 1, except that the first raw material was 3,5-dimethoxybenzyl bromide and the second raw material was 3,3-dimethylallyl bromide. The NMR results of the final product were as follows:

[0371] 1 H NMR (500 MHz, DMSO-d6) 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).

[0372] 13 C NMR (125 MHz,DMSO-d6) 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.

[0373] ESI + : 556.27.

[0374] Example 44 Synthesis of 3-((4-fluorobenzyl)oxy)-2,9,10-trimethoxy-13-(3- methylbut-2-en-1-yl)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX44)

[0375]

[0376] The experimental procedure was the same as in Example 1, except that the first starting material was p-chlorobenzyl bromide and the second starting material was p- fluorobenzyl bromide; the final product NMR results were as follows:

[0377] 1 H NMR (500 MHz, DMSO-d6) 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).

[0378] 13C NMR (125 MHz, DMSO-d6) 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.

[0379] ESI + : 546.26.

[0380] Synthesis of 13-(4-fluorobenzyl)-3-((4-fluorobenzyl)oxy)-2,9,10-trimethoxy- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX45)

[0381]

[0382] The experimental procedure was the same as Example 1, except that the first starting material was p-fluorobenzyl bromide and the second starting material was p-fluorobenzyl bromide; the final product NMR results are as follows:

[0383] 1 H NMR (500 MHz, DMSO-d6) 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), 7.23 (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, 1.0 Hz, 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).

[0384] 13 C NMR (125 MHz, DMSO-d6) 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.

[0385] ESI + : 554.21.

[0386] Synthesis of 3-((4-fluorobenzyl)oxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX46)

[0387]

[0388] The experimental procedure was the same as Example 1, except that the first starting material was 4-fluorobenzyl bromide and the second starting material was 3,3-dimethylallyl bromide; the final product had the following NMR results:

[0389] 1 H NMR (500 MHz, DMSO-d6) 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).

[0390] 13 C NMR (125 MHz, DMSO-d6) 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.

[0391] ESI + :514.24.

[0392] Example 47 Synthesis of 3-(cyanomethoxy)-13-(cyanomethyl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX47)

[0393]

[0394] The experimental procedure was the same as Example 1, except that the first starting material was bromoacetonitrile and the second starting material was bromoacetonitrile; the final product NMR results are as follows:

[0395] 1 H NMR (500 MHz,DMSO-d6) 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 = 15.9Hz, 5H), 3.21 – 3.14 (m, 2H).

[0396] 13 C NMR (125 MHz, DMSO-d6) 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.

[0397] ESI + : 416.16.

[0398] Example 48 Synthesis of 2,9,10-trimethoxy-13-(prop-2-yn-1-yl)-3-(prop-2-yn-1-yloxy)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX48)

[0399]

[0400] The experimental procedure was the same as Example 1, except that the first starting material was 3-bromopropyne and the second starting material was 3-bromopropyne; the final product NMR results were as follows:

[0401] 1 H NMR (500 MHz, DMSO-d6) 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).

[0402] 13 C NMR (125 MHz, DMSO-d6) 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.

[0403] ESI + :414.17.

[0404] Example 49 Synthesis of 2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)-3-(ethenyloxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX49)

[0405]

[0406] The experimental procedure was the same as Example 1, except that the first starting material was bromoethene and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results were as follows:

[0407] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.5Hz, 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).

[0408] 13 C NMR (125 MHz, DMSO-d6) 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.

[0409] ESI + : 436.25.

[0410] Example 50 Synthesis of 2,9,10-trimethoxy-13-(3-nitrobenzyl)-3-((3-nitrobenzyl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX50)

[0411]

[0412] The experimental procedure was the same as Example 1, except that the first starting material and the second starting material were both m-nitrobenzyl bromide; the final product NMR results were as follows:

[0413] 1 H NMR (500 MHz, DMSO-d6) 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 = 1.0Hz, 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).

[0414] 13 C NMR (125 MHz, DMSO-d6) 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.

[0415] ESI + :608.20.

[0416] Synthesis of 13-(4-fluorobenzyl)-2,9,10-trimethoxy-3-(pent-4-yn-1-yloxy)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX51)

[0417] Synthesis of 13-(4-fluorobenzyl)-2,9,10-trimethoxy-3-(pent-4-yn-1-yloxy)-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX51)

[0418] The experimental procedure was the same as in Example 1, except that the first starting material was 1-bromopent-1-yn and the second starting material was 4- fluorobenzyl bromide; the final product had the following NMR results:

[0419] 1 H NMR (500 MHz, DMSO-d6) 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).

[0420] 13C NMR (125 MHz, DMSO-d6) 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.

[0421] ESI + : 512.6.

[0422] Synthesis of 3-(4-cyanobutyloxy)-13-(6-cyanohexyl)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX52)

[0423]

[0424] The experimental procedure was the same as Example 1, except that the first starting material was 1-bromohexane and the second starting material was 1-bromooctane; the final product NMR results were as follows:

[0425] 1 H NMR (500 MHz, DMSO-d6) 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).

[0426] 13C NMR (125 MHz, DMSO-d6) 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.

[0427] ESI + : 528.29.

[0428] Synthesis of 13-(6-cyanohexyl)-3-((5-cyanopentyl)oxy)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX53)

[0429]

[0430] The experimental procedure was same as Example 1, except that the first starting material was 1-bromoheptanenitrile and the second starting material was 1-bromooctanenitrile; the final product NMR results were as follows:

[0431] 1 H NMR (500 MHz, DMSO-d6) 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).

[0432] 13 C NMR (125 MHz, DMSO-d6) 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.

[0433] ESI + :542.3.

[0434] Synthesis of 13-(4-cyanobutyl)-3-((6-cyanohexyl)oxy)-2,9,10-trimethoxy-5,6- dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX54)

[0435]

[0436] The experimental procedure was same as Example 1, except that the first starting material was 1-bromooctanenitrile and the second starting material was 1-bromohexanenitrile; the final product NMR results were as follows:

[0437] 1 H NMR (500 MHz, DMSO-d6) 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 = 11.0Hz, 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).

[0438] 13C NMR (125 MHz, DMSO-d6) 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.

[0439] ESI + : 528.29.

[0440] Example 55 Synthesis of 13-(5-cyanopentyl)-2,9,10-trimethoxy-3-((3-methylbut-2-en-1- yl)oxy)-5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX55)

[0441]

[0442] The experimental procedure was the same as Example 1, except that the first starting material was 3,3-dimethylallyl bromide and the second starting material was 1-bromoheptane; the final product NMR results are as follows:

[0443] 1 H NMR (500 MHz, DMSO-d6) 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).

[0444] 13 C NMR (125 MHz, DMSO-d6) 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.

[0445] ESI + : 501.28.

[0446] Synthesis of 3-((5-cyanopentyl)oxy)-2,9,10-trimethoxy-13-(3-methylbut-2-en-1-yl)- 5,6-dihydroisoquinoline[3,2-a]isoquinolin-7-ium (MX56)

[0447]

[0448] The experimental procedure was same as Example 1, except that the first starting material was 1-bromoheptanenitrile and the second starting material was 3,3-dimethylallyl bromide; the final product NMR results were as follows:

[0449] 1 H NMR (500 MHz, DMSO-d6) 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= 6.2 Hz, 2H), 1.71 – 1.63 (m, 8H),1.49 (p, J = 6.3 Hz, 2H). J = 6.3 Hz, 2H).

[0450] 13 C NMR (125 MHz, DMSO-d6) 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.

[0451] ESI + :501.28.

[0452] Inhibition activity of compounds on colon cancer cells

[0453] The compounds MX1-MX56 obtained by the preparation of Examples 1-56 were respectively incubated with colon cancer cell lines SW620, DLD-1, SW480 and gastric cancer AGS cells, and the concentration of the compounds was 1 μM, 2 μM, 4 μM, 8 μM, 16 μM, 32 μM, 64 μM, 128 μM, and the concentration of the cells was 1*10^4 per well, and the compounds were incubated with the cells for 24 h. The half inhibitory concentration (TC 50 value) of the compounds on the cells was detected in vitro by CCK-8, and the results are shown in Table 1.

[0454] Table 1

[0455]

[0456] The above results show that the compounds MX1-MX56 provided by the application have better inhibitory activity on the proliferation of colon cancer cells and gastric cancer cells than BBR.

[0457] The following only shows the inhibitory activity of compound MX51 on three kinds of colon cancer cells in the form of drawings.

[0458] Figure 1The results showed that the compound MX51 could inhibit the proliferation of three colon cancer cell lines SW620, DLD-1 and SW480 by CCK-8 in vitro. 50 11.75 μM, 8.62 μM, 13.96 μM respectively (e.g. Figure 1 AC), indicating that the compound has better activity in inhibiting the proliferation of colon cancer cells than BBR.

[0459] Example 58 Compounds Inhibit Colon Cancer Tumor Growth

[0460] The inhibitory effects of the compounds of this invention on the development and progression of colon cancer were evaluated in a subcutaneous tumor model, an orthotopic cecal inoculation model, and an AOM / DSS-induced spontaneous colon cancer model. After one week of adaptive feeding, 5-6 week-old BAL b / c mice were given a single intraperitoneal injection of azomethane (AOM) (10 mg / mL). The mice were then fed with regular drinking water for one week. The drinking water was then replaced with 2.5% DSS for one week, followed by regular drinking water for two weeks. The mice were then fed with DSS for one week and drinking water for two weeks, followed by two-three more cycles of induction of spontaneous colon cancer.

[0461] Taking MX51 as an example, 1*10^6 SW620 cells were inoculated subcutaneously into immunodeficient mice, and the tumor volume was measured and recorded 7 days after inoculation. Figure 2 It was found that the tumor volume and tumor weight of the compound MX51-treated group (10 mg / kg) were significantly improved, suggesting that it can significantly inhibit tumor growth in vivo (CTRL is the control group not treated with the compound).

[0462] By inoculating 1*10^6 SW620 cells into the cecum of immunodeficient mice, Figure 3 It was found that treatment with MX51 (10 mg / kg) could significantly inhibit the growth of SW620 tumors in the cecum and reduce the volume of cecal tumors. At the same time, MX51 treatment could significantly inhibit the occurrence of tumor cell liver metastasis ( Figure 3 (A) Prolonging the survival of tumor-bearing mice.

[0463] Example 59

[0464] Spontaneous colon cancer was induced in 5-6 week old BALb / c mice after a single intraperitoneal injection of azomethane (AOM) (10 mg / mL) and regular drinking water for 1 week. Then, drinking water was replaced with 2.5% DSS for 1 week and regular drinking water for 2 weeks. Then, DSS feeding for 1 week and drinking water for 2 weeks were repeated 2-3 times to induce spontaneous colon cancer in mice.

[0465] In this model, MX51 treatment (10 mg / kg) was administered, and the results were as follows: Figure 4, showed that MX51 treatment had no effect on body weight of mice, indicating that MX51 was safe in vivo, while it was found that MX51 could significantly reduce the number of tumors, prolong the total colon length, reduce the degree of intestinal mucosal barrier damage, and prolong the survival of mice.

[0466] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", "some implementations" or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms is not necessarily directed to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, different embodiments or examples described in the present specification and the features of different embodiments or examples can be combined and combined by those skilled in the art without contradiction.

[0467] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. A compound, characterized in that The compound is a compound represented by general formula (I) or a pharmaceutically acceptable salt of the compound represented by 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; m=1, n=1~10, R3 is substituted by at least one R b substituted phenyl; R b Selected from -NO2, halogen, C1 alkyl, Wherein, R1 and R2 are not C3 or C4 alkenyl at the same time.

2. A compound, 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 digestive tract tumors, wherein the digestive tract tumors are colon cancer or gastric cancer.

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