Quaternary ammonium salt compound as well as preparation method and application thereof

Abstract

The invention discloses a quaternary ammonium salt derivative as well as a preparation method and application thereof. The structural general formula of the quaternary ammonium salt derivative is shown as a formula I or a formula II. The quaternary ammonium salt derivative disclosed by the invention plays a role in inhibiting bacteria type I signal peptidase (SPase I) and temperature-sensitive mitoprotein Z (FtsZ), and plays a key role in survival and toxicity of bacteria.

Description

TECHNICAL FIELD

[0001] The application relates to a quaternary ammonium salt compound and a preparation method and application thereof, in particular to a quaternary ammonium salt derivative based on tetrahydroacridine and quinoline and a preparation method and application thereof, and belongs to the technical field of medicines. BACKGROUND

[0002] The discovery and application of antibiotics is one of the milestones of modern medicine, which has made outstanding contributions to saving human lives and improving human health. However, with the overuse or misuse of antibiotics in the medical and agricultural fields, the problem of bacterial drug resistance has become increasingly serious. It is urgent to develop new antibacterial drugs to cope with the antibiotic resistance crisis.

[0003] The antibiotic crisis is imminent, which has prompted people to develop new strategies to combat infections. All bacteria need to export proteins through the cytoplasmic membrane, and most of the proteins are achieved through the general secretion pathway (Sec). Type I signal peptidease (SPase I) is an essential membrane-bound protease in bacteria, and is an important part of the Tat and Sec secretion system. Most secretory proteins are synthesized in the form of precursor proteins, and are released into mature secretory proteins after being transported out of the cell. Most of the pre-proteins are processed by SPase I, and inhibition of the enzyme will lead to accumulation of precursor proteins on the bacterial plasma membrane, and then cause bacterial lysis and death. Therefore, SPase I is essential for bacterial survival, and it is highly conserved in bacteria, which makes SPase I inhibitors have the potential of broad-spectrum antibacterial activity.

[0004] Temperature-sensitive mitosis protein Z (FtsZ) is a microtubulin homolog, which is the most abundant and highly conserved cell division protein in almost all bacteria. FtsZ has homology with the eukaryotic cytoskeleton protein microtubulin, and is a core participant in the cytoskeleton family, which forms a cell dynamic ring at the middle cell and recruits the division mechanism to coordinate cell division. Cells depleted or lacking functional FtsZ will not divide, and eventually grow into filaments and die due to lysis. SPase I and FtsZ are good targets for developing new antibiotics due to their important characteristics.

[0005] In summary, drug-resistant bacteria seriously threaten human life and health, although there are currently various antibacterial drugs with new mechanisms of action in clinical and preclinical stages, but traditional single-target antibacterial drugs are difficult to cope with the rapid development of drug-resistant bacteria. Dual-target drugs are expected to significantly reduce the occurrence of bacterial drug resistance by acting on multiple pathways of microorganisms, and have great prospects in the research of antibacterial drugs. Therefore, it is of great significance to design and discover new dual-target antibacterial drugs to treat drug-resistant bacterial infections and cope with the challenge of bacterial drug resistance. SUMMARY

[0006] Invention purposes: One of the purposes of the present application is to provide a quaternary ammonium salt derivative with the structure of general formula I or general formula II, which has broad-spectrum antibacterial activity, another purpose of the present application is to provide a preparation method of the quaternary ammonium salt derivative, a further purpose of the present application is to provide a pharmaceutical composition containing the quaternary ammonium salt derivative, and the last purpose of the present application is to provide the use of the quaternary ammonium salt derivative or the pharmaceutical composition containing the quaternary ammonium salt derivative in the preparation of a drug for treating microbial infection.

[0007] Technical scheme: The quaternary ammonium salt derivative provided by the present application, the structure of the quaternary ammonium salt derivative is as shown in formula I or formula II:

[0008]

[0009] Among them, R 1 is selected from hydrogen, piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetyl piperazine, 1-(3-oxetanyl) piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azetidine, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine or dimethylamine;

[0010] R 2 is selected from methyl, ethyl, propyl or butyl;

[0011] R 3 is selected from hydrogen or methyl;

[0012] n=0, 1 or 2;

[0013] R is selected from different positions of different substituents of an aromatic ring, and the aromatic ring is selected from a benzene ring, a pyridine ring, a furan ring, a thiophene ring, a different substituted benzothiophene ring or an oxazole ring;

[0014] X - is selected from halide.

[0015] Further, the aromatic ring is selected from:

[0016]

[0017] Among them, R 4 is selected from hydrogen, halogen, nitro, dimethylamine, long-chain alkyl monosubstituted or polysubstituted benzene ring.

[0018] Further, the structure of the quaternary ammonium salt derivative is as shown in formula III, formula IV or formula V:

[0019]

[0020] Among them, R5 selected from hydrogen, tetrahydropyrrole, piperidine, 4-methylpiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 6-azaspiro[2.5]octane, 3-azabicyclo[3.3.0]octane, azetidine or dimethylamine;

[0021] R 6 selected from methyl or ethyl;

[0022] R 3 selected from hydrogen or methyl;

[0023] A ring is selected from benzene ring, furan ring or thiophene ring with different substituents at different positions;

[0024] R 4 selected from hydrogen, halogen, nitro, dimethylamino, long-chain alkyl mono- or poly-substituted benzene ring. Further, R 4 selected from:

[0025]

[0026] Further, halide ion is selected from chloride ion, bromide ion or iodide ion.

[0027] Further, the quaternary ammonium salt derivative is selected from any one of the following structures:

[0028]

[0029]

[0030] The preparation method of the quaternary ammonium salt derivative described in the present application, wherein R 1 selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxetanyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azetidine, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine or dimethylamine, is synthesized according to the following route:

[0031]

[0032] Step one: the raw material Ia is hydrolyzed under alkaline conditions to obtain the intermediate Ib;

[0033] Step two: the intermediate Ib is added with Ic under the action of phosphorus oxychloride to obtain the intermediate Id;

[0034] Step three: the intermediate Id is reacted with substituted aromatic aldehyde under the catalysis of p-toluenesulfonamide to obtain the intermediate Ie;

[0035] Step four: Intermediate Ie reacts with the corresponding alkyl halide R 2 X to form the salt, to give Intermediate If;

[0036] Step five: Intermediate If reacts with various substituted cyclic aliphatic amines, substituted linear aliphatic amines, substituted branched aliphatic amines, or substituted aromatic amines under EtOH conditions;

[0037] wherein R 7 is selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxetanyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azetidine, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine.

[0038] wherein R 1 is a hydrogen atom, according to the following route:

[0039]

[0040] Step one: starting material Ila reacts with the corresponding alkyl halide R 2 X to form the salt, to give Intermediate lib;

[0041] Step two: Intermediate lib reacts with an aromatic aldehyde under piperidine and MeOH conditions.

[0042] wherein R 1 is selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxetanyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azetidine, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine, according to the following route:

[0043]

[0044] Step one: starting material Ila reacts with the corresponding alkyl halide R 2 X to form the salt, to give Intermediate lib;

[0045] Step two: Intermediate lib reacts with various substituted cyclic aliphatic amines, substituted linear aliphatic amines, substituted branched aliphatic amines, or substituted aromatic amines under EtOH conditions, to give Intermediate lie;

[0046] Step three: intermediate IIe reacts with aromatic aldehyde under the condition of piperidine and MeOH;

[0047] wherein R 8 selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxetanyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azetidine, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine.

[0048] The compounds of general formula I and general formula II of the present application can be prepared by the above-mentioned or similar methods, and the corresponding starting materials are selected according to the different substituents and the different positions of the substituents. Those skilled in the art should recognize that the above-mentioned routes are helpful for understanding the present application, but do not limit the content of the present application, and unless otherwise specified, the variables are defined as mentioned in general formula I and general formula II.

[0049] The present application also includes a pharmaceutical composition comprising the quaternary ammonium salt derivative described in the present application and a pharmaceutically acceptable carrier or excipient.

[0050] Further, the pharmaceutically acceptable excipient refers to the excipients and additives used in the production of pharmaceutical products and the dispensing of prescriptions, including solvents, propellants, solubilizers, cosolvents, emulsifiers, coloring agents, binding agents, disintegrating agents, fillers, lubricants, wetting agents, osmotic pressure adjusting agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrating agents, penetration enhancers, pH adjusting agents, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickening agents, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc. The pharmaceutically acceptable carrier refers to a system that can change the way of drug entering the human body and the distribution in the body, control the release speed of the drug and deliver the drug to the target organ, including microcapsules, microspheres, nanoparticles, liposomes, microneedles, hydrogels, etc.

[0051] Further, the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, pills, lyophilized agents, suppositories, oral liquids, suspensions or injection solutions.

[0052] The quaternary ammonium salt derivative of the present application or the pharmaceutical composition described in the present application is used for preparing a drug for treating microbial infection.

[0053] Further, quaternary ammonium salt derivatives as SPase I and FtsZ inhibitors. Microbial infections include, but are not limited to, diseases caused by infection with the following bacteria or fungi: bacteria are Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophila, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Mycobacterium aurum, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonii, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Streptococcus suis, Staphylococcus hyicus, Staphylococcus haemolyticus, and / or Staphylococcus hominis; and fungi are Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, Candida auris, Candida krusei, Candida glabrata, Trichophyton rubrum, Trichophyton mentagrophytes, and / or Trichophyton interdigitale.

[0054] The pharmaceutical compositions of the present application can be administered in a variety of known ways, e.g., orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present application can be administered alone or in combination with other drugs. Oral compositions can be in any orally acceptable dosage form including, but not limited to, tablets, capsules, pills, and suspensions, soft capsules and oral fluids. A pharmaceutically acceptable carrier is a conventional adjuvant that is pharmaceutically acceptable and that is compatible with the active compound and that does not reverse the action of the active compound or cause harm to the patient. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

[0055] Injectable solutions can be prepared using appropriate dispersing or wetting agents and suspending agents, as known in the art. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

[0056] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present application can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration, without being toxic to the patient. The selected dosage level will depend on a variety of factors including the activity of the particular compound of the present application or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0057] The present application is based on quaternary ammonium salt derivatives of tetrahydroacridine and quinoline, and a class of SPase I / FtsZ dual-target inhibitors are obtained by the strategy of drug design by splicing.

[0058] The fungal infection or bacterial infection refers to a disease or condition characterized by the invasion of the body tissues of an organism by a pathogenic agent (e.g., pathogenic bacteria), their multiplication, and the reaction of the host tissues to the infecting agent and the toxins it produces. Infectious diseases, also known as communicable diseases, are diseases caused by infections. Bacterial infections can be caused by gram-positive or gram-negative bacteria.

[0059] Beneficial effects: Compared with the prior art, the application has the following remarkable advantages: (1) The compound of general formula I or general formula II prepared by the application has excellent SPase I and FtsZ inhibiting effect. The compound blocks Sec and Tat secretion system by inhibiting SPase I, resulting in that the bacteria cannot release mature secretory proteins, and thus plays a role in inhibiting or killing bacteria. Meanwhile, the compound can inhibit FtsZ, resulting in that the cell cannot divide and eventually dies. Therefore, the quaternary ammonium salt derivative can be used for preparing a drug for preventing, treating or improving bacterial infection. For example, the drug is used for treating diseases caused by bacterial infection such as Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Escherichia coli. It is found that the compound of general formula I and general formula II has high activity of SPase I and FtsZ inhibiting effect, and thus has good antibacterial effect. (2) The synthesis route of the quaternary ammonium salt derivative is simple, easy to implement and easy to realize industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0060] Fig. 1 Figure is a morphological change diagram of Bacillus amyloliquefaciens in Example 45.

[0061] Fig. 2 Figure is a morphological change diagram of Escherichia coli in Example 45. DETAILED DESCRIPTION

[0062] The technical solutions of the application will be further described below with reference to the drawings.

[0063] In the following examples, "room temperature" refers to about 20-30℃. The proportion represented by the mixed solvent is a volume mixing proportion, and % refers to wt% unless otherwise specified. M represents molar concentration mol / L.

[0064] In the silica gel column chromatography, basic silica gel refers to silica gel combined with aminopropylsilane. The proportion of the elution solvent is a volume mixing proportion, and the elution solvent is petroleum ether, dichloromethane, ethyl acetate or methanol unless otherwise specified.

[0065] In the high performance liquid chromatography (HPLC), C18 refers to silica gel combined with octadecyl. The mobile phase A is methanol, the mobile phase B is 0.1% formic acid aqueous solution, and A:B is 20:80, isocratic elution.

[0066] In the following examples, the following abbreviations are used:

[0067] DCM: dichloromethane, EA: ethyl acetate, PE: petroleum ether, MeOH: methanol, EtOH: ethanol, THF: tetrahydrofuran, NaOH: sodium hydroxide, PTSA: p-toluenesulfonamide, HAc: acetic acid, POCl3: phosphorus oxychloride; TLC: thin layer chromatography.

[0068] MS (mass spectrum) was determined using LC / MS (liquid chromatograph mass spectrometer) with ESI (electrospray ionization) method. In the case of salts, the molecular ion peak or fragment ion peak of the free form was usually observed. 1 H-NMR (proton nuclear magnetic resonance spectrum), peak not describing active hydrogen (such as hydroxyl, amino, etc.).

[0069] MS (mass spectrum) was determined using LC / MS (liquid chromatograph mass spectrometer) with ESI (electrospray ionization) method. In the case of salts, the molecular ion peak or fragment ion peak of the free form was usually observed.

[0070] Example 1

[0071] (E)-4-(((4'-chloro-3' trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10-methyl-9-(piperidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 1) was synthesized according to the following route:

[0072]

[0073] Step one: In a 100 mL tomato flask, weigh in methyl anthranilate (5.00 g, 33.08 mmol) and lithium hydroxide monohydrate (4.16 g, 99.23 mmol), add 30 mL THF as solvent, heat to 90°C, and react for 12 h; after TLC monitoring reaction is completed, remove THF under reduced pressure, add 100 mL water, adjust pH to 3-5 with HAc, extract with 30 mL EA for 3 times, combine the organic layers, dry under reduced pressure, and purify by silica gel column chromatography (mobile phase volume ratio: petroleum ether / ethyl acetate = 100 / 20) to obtain 4.00 g of anthranilic acid as a white solid (yield 88.2%).

[0074] Step two: In a 100 mL tomato flask, weigh in anthranilic acid (2.00 g, 14.58 mmol) and cyclohexanone (1.57 g, 16.04 mmol), slowly add 15 mL POCl3, heat to 120°C and reflux for 12 h; after TLC monitoring reaction is completed, slowly add the reaction liquid to stirring crushed ice, adjust pH to 9-10 with 1M NaOH aqueous solution, add 100 mL water, extract with 30 mL EA for 3 times, combine the organic layers, dry under reduced pressure, and purify by silica gel column chromatography (mobile phase volume ratio: petroleum ether / ethyl acetate = 100 / 5) to obtain 2.50 g of tetrahydroacridine-9-chloride as a red solid (yield 78.9%).

[0075] Step three: In a 35 mL thick-walled pressure bottle, weigh in tetrahydroacridine-9- chloro (1.00 g, 4.59 mmol), 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde (1.44 g, 5.05 mmol) and PTSA (865.13 mg, 5.05 mmol), add 4 mL of toluene as solvent, and react at 140 °C for 48 h; TLC monitoring shows that the reaction is completed, and the product is directly rotary evaporated under reduced pressure and then purified by silica gel column (mobile phase volume ratio: petroleum ether / ethyl acetate = 100 / 2) to obtain 1.68 g of yellow solid (yield 75.5%).

[0076] Step four: In a 120 mL thick-walled pressure bottle, weigh in the above yellow solid (1.13 g, 2.33 mmol) and 3 mL of methyl iodide, add 4 mL of sulfolane as solvent, and react at 60 °C for 72 h; TLC monitoring shows that the reaction is completed, 15 mL of EA is added, and a large amount of orange-red solid is precipitated, which is placed in the refrigerator for 5 h, and then filtered under suction to obtain 1.28 g of orange-red solid (yield 87.7%).

[0077] Step five: In a test tube, weigh in the above orange-red solid (0.10 mg, 0.16 mmol) and piperidine (40.79 mg, 0.48 mmol), add 2 mL of anhydrous EtOH as solvent, and react at 50 °C for 4 h; TLC monitoring shows that the reaction is completed, and the product is directly rotary evaporated under reduced pressure and then purified by silica gel column (mobile phase volume ratio: dichloromethane / methanol = 100 / 4) to obtain 0.09 g of yellow solid compound 1 (yield 85.4%).

[0078] Compound 1 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.33 (s, 1H), 8.12-8.06 (m, 2H), 8.04 (dd, J = 8.4, 2.3 Hz, 1H), 7.90 (s, 1H), 7.88-7.79 (m, 3H), 7.67-7.60 (m, 2H), 7.11 (s, 1H), 4.42 (s, 3H), 3.66 (s, 4H), 3.09 (s, 2H), 2.76 (s, 2H), 1.78 (s, 8H). LC-MS m / z: 547.21 [M+H] + From the above analysis, the structure of compound 1 is shown in Table 1.

[0079] Example 2

[0080] The preparation method of (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10-methyl-9-(4-methylpiperidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 2) refers to Example 1, except that piperidine is replaced by 4-methylpiperidine, and the target Compound 2 is prepared as a yellow solid, 0.08 g, with a yield of 73.2%.

[0081] Compound 2 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 6.8 Hz, 2H), 8.14-8.01 (m, 3H), 7.91-7.80 (m, 4H), 7.64 (d, J = 4.6 Hz, 2H), 7.12 (s, 1H), 4.43 (s, 3H), 3.81-3.56 (m, 4H), 3.16 (s, 2H), 2.76 (s, 2H), 1.82 (d, J = 12.8 Hz, 5H), 1.48 (s, 2H), 1.05 (d, J = 5.6 Hz, 3H). LC-MS m / z: 561.23 [M+H] + From the above analysis, the structure of Compound 2 is shown in Table 1.

[0082] Example 3

[0083] The preparation method of (E)-4-((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-ylmethylene)-10-methyl-9-morpholino-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 3) refers to Example 1, except that piperidine is replaced by morpholine, and the target Compound 3 is prepared as a yellow solid, 0.08 g, with a yield of 69.9%.

[0084] Compound 3 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.48-8.37 (m, 2H), 8.19-8.03 (m, 3H), 7.98-7.81 (m, 4H), 7.73-7.61 (m, 2H), 7.17 (s, 1H), 4.50 (s, 3H), 3.92 (d, J = 4.8 Hz, 4H), 3.76 (s, 4H), 3.14 (s, 2H), 2.82 (s, 2H), 1.95 (s, 2H). LC-MS m / z: 549.19 [M+H] + From the above analysis, the structure of Compound 3 is shown in Table 1.

[0085] Example 4

[0086] The preparation method of (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10-methyl-9-(piperidin-1-yl)-1,2,3,4-tetrahydroacridine-10-ium iodide (Compound 4) refers to Example 1, except that piperidine is replaced by thiomorpholine, and the target compound is prepared as a yellow solid, 0.08 g, with a yield of 68.7%.

[0087] Compound 4 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.7 Hz, 2H), 8.17-8.03 (m, 3H), 7.95-7.82 (m, 4H), 7.66 (d, J = 4.9 Hz, 2H), 7.17 (s, 1H), 4.51 (s, 3H), 3.86 (t, J = 4.9 Hz, 4H), 3.12 (s, 2H), 2.94 (d, J = 6.0 Hz, 4H), 2.80 (s, 2H), 1.87 (s, 2H). LC-MS m / z: 565.17 [M+H] + From the above analysis, the structure of Compound 4 is shown in Table 1.

[0088] Example 5

[0089] The preparation method of (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10-methyl-9-(piperidin-1-yl)-1,2,3,4-tetrahydroacridine-10-ium iodide (Compound 4) refers to Example 1, except that piperidine is replaced by thiomorpholine, and the target compound is prepared as a yellow solid, 0.08 g, with a yield of 68.7%.

[0090] Compound 5 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.7 Hz, 2H), 8.17-8.03 (m, 3H), 7.95-7.82 (m, 4H), 7.66 (d, J = 4.9 Hz, 2H), 7.17 (s, 1H), 4.51 (s, 3H), 3.86 (t, J = 4.9 Hz, 4H), 3.12 (s, 2H), 2.94 (d, J = 6.0 Hz, 4H), 2.80 (s, 2H), 1.87 (s, 2H). LC-MS m / z: 565.17 [M+H] + From the above analysis, the structure of Compound 5 is shown in Table 1.

[0091] Example 6

[0092] (E)-4-((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-ylmethyl)-10-methyl-9-(4- methylpiperazin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 6) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by N-methylpiperazine to give the target compound as a yellow solid, 0.09 g, in 82.4% yield.

[0093] Compound 6 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 1H NMR (300 MHz, DMSO-d6) δ 8.39 (d, J = 8.8 Hz, 2H), 8.17 - 8.03 (m, 3H), 7.95 - 7.79 (m, 4H), 7.70 - 7.60 (m, 2H), 7.15 (s, 1H), 4.47 (s, 3H), 3.69 (d, J = 25.2 Hz, 4H), 3.11 (s, 2H), 2.87 - 2.55 (m, 6H), 2.35 (s, 3H), 1.86 (s, 2H). LC-MS m / z: 562.22 [M+H] + From the above analysis, the structure of Compound 6 was as shown in Table 1.

[0094] Example 7

[0095] (E)-9-(4-acetylpiperazin-1-yl)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3- yl)methyl)-10-methyl-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 7) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by 1-acetylpiperazine to give the target compound as a yellow solid, 0.09 g, in 80.4% yield.

[0096] Compound 7 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1H NMR (500 MHz, DMSO-d6) δ 8.44 - 8.38 (m, 2H), 8.17 - 8.12 (m, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.4, 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.92 - 7.81 (m, 3H), 7.69 - 7.63 (m, 2H), 7.19 - 7.17 (m, 1H), 4.51 (s, 3H), 3.81 - 3.62 (m, 8H), 3.13 (s, 2H), 2.80 (s, 2H), 2.12 (s, 3H), 1.87 (s, 2H). LC-MS m / z: 590.22 [M+H] + From the above analysis, the structure of compound 7 is shown in Table 1.

[0097] Example 8

[0098] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10-methyl-9-(4-(3- oxetanyl)piperazin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (compound 8) was prepared according to the method described in Reference Example 1, except that piperidine was replaced by 1-(3-oxetanyl)piperazine, and the target compound was obtained as a yellow solid, 0.08 g, with a yield of 78.4%.

[0099] Compound 8 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J = 8.7 Hz, 2H), 8.18 - 8.04 (m, 3H), 7.96 - 7.82 (m, 4H), 7.67 (d, J = 3.3 Hz, 2H), 7.16 (s, 1H), 4.63 (t, J = 6.6 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.49 (s, 3H), 3.77 (s, 4H), 3.64 (t, J = 6.3 Hz, 1H), 3.13 (s, 2H), 2.80 (s, 2H), 2.61 (s, 4H), 1.94 (s, 2H). LC-MS m / z: 604.23 [M+H] + From the above analysis, the structure of compound 8 is shown in Table 1.

[0100] Example 9

[0101] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10- methyl-9-(6-azaspiro[2.5]octan-6-yl)-1,2,3,4-tetrahydroacridine-10- iodonium ammonium (Compound 9) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by 6- azaspiro[2.5]octane, to give the target compound as a yellow solid, 0.08 g, in 78.4% yield.

[0102] Compound 9 was analyzed by NMR and mass spectrometry, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.35 (m, 2H), 8.14 - 8.04 (m, 3H), 7.92 (s, 1H), 7.90 - 7.82 (m, 3H), 7.69 - 7.61 (m, 2H), 7.14 (d, J = 2.4 Hz, 1H), 4.46 (s, 3H), 3.73 (t, J = 5.2 Hz, 4H), 3.14 (d, J = 21.1 Hz, 2H), 2.80 (s, 2H), 1.86 (s, 2H), 1.66 (s, 4H), 0.48 (s, 4H). LC-MS m / z: 573.23 [M+H] + From the above analysis, the structure of Compound 9 was as shown in Table 1.

[0103] Example 10

[0104] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-9-( hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-10-methyl-1,2,3,4-tetrahydroacridine-10- iodonium ammonium (Compound 10) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by 3- azabicyclo[3.3.0]octane, to give the target compound as a yellow solid, 0.07 g, in 70.8% yield.

[0105] Compound 10 was analyzed by NMR and mass spectrometry, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.92 - 7.85 (m, 2H), 7.84 - 7.78 (m, 2H), 7.69 - 7.58 (m, 3H), 7.13 (s, 1H), 4.29 (s, 3H), 3.83 (d, J = 8.4 Hz, 1H), 3.02 (t, J = 7.0 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.01 - 1.94 (m, 2H), 1.89 - 1.58 (m, 8H), 1.36 - 1.27 (m, 2H). LC-MS m / z: 561.23 [M+H] + From the above analysis, the structure of compound 10 is shown in Table 1.

[0106] Example 11

[0107] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-9-(cyclohexylamino)-10-methyl-1,2,3,4-tetrahydroacridin-10-ium iodide (compound 11) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by cyclohexylamine, to give the target compound as a yellow solid, 0.06 g, in 66.4% yield.

[0108] Compound 11 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.92 - 7.85 (m, 2H), 7.84 - 7.78 (m, 2H), 7.69 - 7.58 (m, 3H), 7.13 (s, 1H), 4.29 (s, 3H), 3.83 (d, J = 8.4 Hz, 1H), 3.02 (t, J = 7.0 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.01 - 1.94 (m, 2H), 1.89 - 1.58 (m, 8H), 1.36 - 1.27 (m, 2H). LC-MS m / z: 561.23 [M+H] + From the above analysis, the structure of compound 11 is shown in Table 1.

[0109] Example 12

[0110] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10- methyl-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 12) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by tetrahydropyrrole to give the target compound as a yellow solid, 0.08 g, in 80.7% yield.

[0111] Compound 12 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (dd, J = 8.6, 1.4 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.09 - 8.04 (m, 2H), 7.95 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.83 - 7.79 (m, 1H), 7.65 - 7.59 (m, 3H), 7.14 (s, 1H), 4.14 (s, 3H), 3.99 (s, 4H), 2.96 (t, J = 6.7 Hz, 2H), 2.70 (t, J = 5.8 Hz, 2H), 1.97 - 1.78 (m, 6H). LC-MS m / z: 533.20 [M+H] + From the above analysis, the structure of Compound 12 is shown in Table 1.

[0112] Example 13

[0113] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-10- methyl-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 12) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by tetrahydropyrrole to give the target compound as a yellow solid, 0.08 g, in 80.7% yield.

[0114] Compound 13 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.17 - 8.09 (m, 2H), 8.08 - 8.03 (m, 1H), 7.91 (s, 1H), 7.89 - 7.80 (m, 3H), 7.65 (d, J = 6.8 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.20 - 7.11 (m, 3H), 4.45 (s, 3H), 3.03 (q, J = 4.8 Hz, 2H), 2.19 (t, J = 5.9 Hz, 2H), 1.71 (d, J = 6.0 Hz, 2H). LC-MS m / z: 555.18 [M+H] + From the above analysis, the structure of compound 13 is shown in Table 1.

[0115] Example 14

[0116] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-9-((2- methoxyethyl)amino)-10-methyl-1,2,3,4-tetrahydroacridin-10-ium iodide (compound 14) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by 2-methoxyethylamine, to give the target compound as a yellow solid, 0.07 g, in 73.6% yield.

[0117] Compound 14 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.08 - 8.02 (m, 2H), 7.95 (t, J = 5.8 Hz, 1H), 7.90 - 7.84 (m, 2H), 7.83 - 7.75 (m, 2H), 7.66 - 7.59 (m, 2H), 7.14 (d, J = 2.4 Hz, 1H), 4.28 (s, 3H), 3.94 (q, J = 5.4 Hz, 2H), 3.67 (t, J = 5.3 Hz, 2H), 3.25 (s, 3H), 3.05 - 2.96 (m, 2H), 2.76 (t, J = 6.2 Hz, 2H), 1.89 - 1.78 (m, 2H). LC-MS m / z: 537.19 [M+H] + From the above analysis, the structure of compound 14 is shown in Table 1.

[0118] Example 15

[0119] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-9-(dimethylamino)-10-methyl-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 15) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by ethylenediamine to give the target compound as a yellow solid, 0.08 g, in 77.4% yield.

[0120] Compound 15 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.45 - 8.30 (m, 2H), 8.14 - 8.04 (m, 3H), 7.93 (d, J = 1.9 Hz, 1H), 7.90 - 7.80 (m, 3H), 7.66 (d, J = 6.5 Hz, 2H), 7.14 (d, J = 2.4 Hz, 1H), 4.43 (s, 3H), 3.43 (s, 6H), 3.12 (s, 2H), 2.78 (s, 2H), 1.84 (s, 2H). LC-MS m / z: 507.18 [M+H] + From the above analysis, the structure of Compound 15 was as shown in Table 1.

[0121] Example 16

[0122] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-9-(dimethylamino)-10-methyl-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 15) was prepared according to the procedure described in Reference Example 1, except that piperidine was replaced by ethylenediamine to give the target compound as a yellow solid, 0.08 g, in 77.4% yield.

[0123] Compound 16 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.35 (d, J = 8.4 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.98 - 7.77 (m, 3H), 7.74 - 7.47 (m, 4H), 7.13 (d, J = 8.2 Hz, 1H), 4.07 (d, J = 90.2 Hz, 7H), 3.21 - 2.96 (m, 2H), 2.47 - 2.17 (m, 2H), 1.93 (s, 5H), 1.18 - 0.95 (m, 3H). LC-MS m / z: 547.21 [M+H] + From the above analysis, the structure of Compound 4 was as shown in Table 1.

[0124] Example 17

[0125] (E)-4-(((4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-ylidene)methyl)-2,10- dimethyl-9-(4-methylpiperidin-1-yl)-1,2,3,4-tetrahydroacridine-10-ium iodide (Compound 17) was prepared according to the procedure described in Reference Example 1, except that cyclohexanone was replaced with 4-methylcyclohexanone and piperidine was replaced with 4-methylpiperidine. The target compound was obtained as a yellow solid, 0.06 g, in 64.6% yield.

[0126] Compound 17 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.34 (t, J = 8.5 Hz, 2H), 8.05 (d, J = 14.9 Hz, 3H), 7.91 - 7.79 (m, 4H), 7.65 (d, J = 6.4 Hz, 2H), 7.11 (s, 1H), 4.44 (s, 3H), 3.79 (d, J = 12.8 Hz, 2H), 3.69 - 3.49 (m, 2H), 2.37 (d, J = 13.7 Hz, 1H), 1.98 (s, 2H), 1.82 (s, 3H), 1.17 - 1.12 (m, 3H), 1.06 (d, J = 5.6 Hz, 3H). LC-MS m / z: 575.24 [M+H] + From the above analysis, the structure of Compound 17 was as shown in Table 1.

[0127] Example 18

[0128] (E)-4-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)methyl)-10-methyl-9-(pyrrolidin-1-yl)- 1,2,3,4-tetrahydroacridine-10-ium iodide (Compound 18) was prepared according to the procedure described in Reference Example 1, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced with 3',4'-dichloro-[1,1'-biphenyl]-3-carbaldehyde and piperidine was replaced with pyrrolidine. The target compound was obtained as a yellow solid, 0.08 g, in 78.5% yield.

[0129] Compound 18 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.02 - 7.67 (m, 6H), 7.66 - 7.53 (m, 3H), 7.13 (s, 1H), 4.14 (s, 3H), 4.05 - 3.93 (m, 4H), 3.04 - 2.59 (m, 4H), 1.97 - 1.80 (m, 6H). LC-MS m / z: 499.17 [M+H] + From the above analysis, the structure of compound 18 is shown in Table 1.

[0130] Example 19

[0131] (E)-4-(((5-(4-chloro-3-trifluoromethyl)phenyl)furan-2-yl)methylene)-10- methyl-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (compound 19) was prepared according to the method described in Reference Example 1, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde was replaced by 5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2- carboxaldehyde, and piperidine was replaced by tetrahydropyrrole. The target compound was obtained as an orange red solid, 0.07 g, with a yield of 70.2%.

[0132] Compound 19 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.02 - 7.67 (m, 6H), 7.66 - 7.53 (m, 3H), 7.13 (s, 1H), 4.14 (s, 3H), 4.05 - 3.93 (m, 4H), 3.04 - 2.59 (m, 4H), 1.97 - 1.80 (m, 6H). LC-MS m / z: 499.17 [M+H] + From the above analysis, the structure of compound 19 is shown in Table 1.

[0133] Example 20

[0134] (E)-4-(((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-10-methyl-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 20) was prepared according to Reference Example 1, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 5-(3,4-dichlorophenyl)furan-2-carbaldehyde, and piperidine was replaced by tetrahydropyrrole. The target compound was obtained as an orange solid, 0.07 g, in a yield of 77.0%.

[0135] Compound 20 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 9.3 Hz, 2H), 7.93 (t, J = 7.8 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 3.6 Hz, 1H), 7.00 (d, J = 3.7 Hz, 1H), 6.95 (s, 1H), 4.08 (s, 3H), 4.02 - 3.88 (m, 4H), 3.10 (t, J = 7.2 Hz, 2H), 2.74 (t, J = 5.6 Hz, 2H), 1.97 - 1.88 (m, 6H). LC-MS m / z: 489.15 [M+H] + From the above analysis, the structure of Compound 20 was as shown in Table 1.

[0136] Example 21

[0137] (E)-4-(((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-10-methyl-9-(pyrrolidin-1-yl)-1,2,3,4-tetrahydroacridin-10-ium iodide (Compound 20) was prepared according to Reference Example 1, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 5-(3,4-dichlorophenyl)furan-2-carbaldehyde, and piperidine was replaced by tetrahydropyrrole. The target compound was obtained as an orange solid, 0.07 g, in a yield of 77.0%.

[0138] Compound 21 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.30 (t, J = 7.4 Hz, 2H), 8.12 - 8.00 (m, 2H), 7.88 - 7.69 (m, 3H), 7.44 (d, J = 3.7 Hz, 1H), 7.11 - 6.97 (m, 2H), 4.38 (s, 3H), 3.65 (s, 4H), 3.13 (t, J = 6.2 Hz, 2H), 2.84 (s, 2H), 1.98 - 1.69 (m, 8H). LC-MS m / z: 503.17 [M+H] + From the above analysis, the structure of compound 21 is shown in Table 1.

[0139] Example 22

[0140] The preparation method of (E)-4-(4-(dimethylamino)benzylidene)-10-methyl-9-(4- methylpiperidin-l-yl)-l,2,3,4-tetrahydroacridin-10-ium iodide (compound 22) refers to Example 1, except that 4'-chloro-3'-(trifluoromethyl)-[l,l'-biphenyl]-3-carbaldehyde is replaced by 4-N,N-dimethylaminobenzaldehyde, and piperidine is replaced by 4-methylpiperidine, and the target compound is prepared as an orange red solid, 0.08 g, with a yield of 80.6%.

[0141] The compound 22 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.25 (m, 2H), 8.09 - 8.02 (m, 1H), 7.86 - 7.79 (m, 1H), 7.53 - 7.45 (m, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.84 - 6.77 (m, 2H), 4.37 (s, 3H), 3.64 (s, 4H), 3.00 (s, 8H), 2.83 (s, 2H), 1.80 (d, J = 12.7 Hz, 7H), 1.46 (s, 3H), 1.05 (d, J = 6.0 Hz, 3H). LC-MS m / z: 426.29 [M+H] + From the above analysis, the structure of compound 22 is shown in Table 1.

[0142] Example 23

[0143] (E)-2-((2-(4'-chloro-3'-trifluoromethyl)-[l,l'-biphenyl]-3-yl)vinyl)-l-methyl-4-(4- methylpiperidin-l-yl)quinolin-l-ium iodide (compound 23) was synthesized according to the following route:

[0144] (E)-2-((2-(4'-chloro-3'-trifluoromethyl)-[l,l'-biphenyl]-3-yl)vinyl)-l-methyl-4-(4- methylpiperidin-l-yl)quinolin-l-ium iodide (compound 23) was synthesized according to the following route:

[0145] Step one: In a 120 mL thick-walled pressure bottle, 4-chloroquinaldine (2.00 g, 11.26 mmol) and 4 mL of methyl iodide were weighed in, 15 mL of acetonitrile was added as solvent, and the reaction was carried out at 80 °C overnight; TLC monitoring showed that the reaction was completed, 45 mL of EA was added, and a large amount of dark green solid was precipitated, which was placed in the refrigerator for 5 h, and then filtered under reduced pressure to obtain dark green solid 3.33 g (yield 92.6%).

[0146] Step two: In a 100 mL tomato-shaped bottle, the above dark green solid (0.50 g, 1.56 mmol) and 4-methylpiperidine (0.47 g, 4.68 mmol) were weighed in, 5 mL of anhydrous EtOH was added as solvent, and the reaction was carried out at 50 °C for 4 h; TLC monitoring showed that the reaction was completed, and the purple solid was directly dried under reduced pressure to obtain the product for the next step.

[0147] Step three: In a 100 mL tomato-shaped bottle, the above purple solid (0.60 g, 1.56 mmol), 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde (0.47 g, 1.72 mmol) and piperidine (0.17 g, 2.03 mmol) were weighed in, 8 mL of MeOH was added as solvent, and the reaction was carried out at 85 °C under nitrogen protection for 12 h; TLC monitoring showed that the reaction was completed, 25 mL of EA was added, and a large amount of yellow solid was precipitated, which was placed in the refrigerator for 5 h, and then filtered under reduced pressure to obtain the target compound 0.62 g as a green solid (0.62 g, yield 60.8%).

[0148] Compound 23 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 9.0 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 8.17-8.10 (m, 3H), 8.07-8.02 (m, 1H), 7.98-7.94 (m, 1H), 7.92-7.83 (m, 4H), 7.75 (t, J = 7.7 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 4.24 (s, 4H), 4.19 (s, 1H), 3.43 (t, J = 12.6 Hz, 2H), 1.92-1.78 (m, 3H), 1.54-1.41 (m, 2H), 1.03 (d, J = 6.1 Hz, 3H). LC-MS m / z: 521.20 [M+H] + From the above analysis, the structure of compound 23 is shown in Table 1.

[0149] Example 24

[0150] (E)-2-(2-(4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-4-yl)vinyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 24) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde to give the title compound as a green solid, 0.64 g, in 62.8% yield.

[0151] Compound 24 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 8.9 Hz, 1H), 8.17 - 8.10 (m, 3H), 8.05 - 7.99 (m, 3H), 7.95 (d, J = 8.5 Hz, 2H), 7.89 - 7.78 (m, 3H), 7.74 (t, J = 7.7 Hz, 1H), 7.48 (s, 1H), 4.23 (s, 5H), 3.43 (t, J = 12.5 Hz, 2H), 1.93 - 1.79 (m, 3H), 1.48 (q, J = 11.0 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H). LC-MS m / z: 521.20 [M+H] + From the above analysis, the structure of Compound 24 is shown in Table 1.

[0152] Example 25

[0153] (E)-2-(2-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)vinyl)-1-methyl-4-(4- methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 25) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 3',4'-dichloro-[1,1'-biphenyl]-4-carbaldehyde to give the title compound as a yellow solid, 0.57 g, in 63.9% yield.

[0154] Compound 25 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.08 - 8.01 (m, 2H), 8.00 - 7.96 (m, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.81 - 7.71 (m, 4H), 7.47 (s, 1H), 4.24 - 4.15 (m, 5H), 3.42 (t, J = 12.6 Hz, 2H), 1.92 - 1.80 (m, 3H), 1.48 (q, J = 12.8 Hz, 2H), 1.03 (d, J = 6.0 Hz, 3H). LC-MS m / z: 487.17 [M+H] + From the above analysis, the structure of compound 25 is shown in Table 1.

[0155] Example 26

[0156] The preparation method of (E)-2-(2-(3',4'-dichloro-[1,1'-biphenyl]-3-yl)alkenyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (compound 26) refers to Example 23, except that 3',4'-dichloro-[1,1'-biphenyl]-3-carbaldehyde is replaced by 4'-chloro-3'- (trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde, and the target compound is prepared as a yellow solid, 0.58 g, with a yield of 64.5%.

[0157] Compound 26 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.08 - 8.01 (m, 2H), 8.00 - 7.96 (m, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H), 7.81 - 7.71 (m, 4H), 7.47 (s, 1H), 4.24 - 4.15 (m, 5H), 3.42 (t, J = 12.6 Hz, 2H), 1.92 - 1.80 (m, 3H), 1.48 (q, J = 12.8 Hz, 2H), 1.03 (d, J = 6.0 Hz, 3H). LC-MS m / z: 487.17 [M+H] + From the above analysis, the structure of compound 26 is shown in Table 1.

[0158] Example 27

[0159] (E)-2-(2-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)vinyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 27) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde to give the title compound as a red solid, 0.55 g, in 64.4% yield.

[0160] Compound 27 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.24 (m, 3H), 8.11 (dd, J = 8.3, 1.5 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.89 - 7.82 (m, 2H), 7.76 - 7.70 (m, 1H), 7.58 (d, J = 14.7 Hz, 1H), 7.52 (d, J = 3.7 Hz, 1H), 7.46 (s, 1H), 7.21 (d, J = 3.7 Hz, 1H), 4.23 (s, 3H), 4.18 (d, J = 12.9 Hz, 2H), 3.41 (t, J = 12.4 Hz, 2H), 1.92 - 1.77 (m, 3H), 1.55 - 1.41 (m, 2H), 1.03 (d, J = 6.1 Hz, 3H). LC-MS m / z: 511.18 [M+H] + From the above analysis, the structure of Compound 27 is shown in Table 1.

[0161] Example 28

[0162] (E)-2-(2-(5-(3,4-dichlorophenyl)furan-2-yl)vinyl)-1-methyl-4-(4- methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 28) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde was replaced by 5-(3,4-dichlorophenyl)furan-2-carbaldehyde to give the title compound as a tan solid, 0.58 g, in 58.1% yield.

[0163] Compound 28 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.93 (dd, J = 8.5, 2.1 Hz, 1H), 7.82 (d, J = 14.6 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.57 (d, J = 14.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 3.6 Hz, 1H), 4.23 (s, 3H), 4.16 (d, J = 12.8 Hz, 2H), 3.40 (t, J = 11.9 Hz, 2H), 1.91 - 1.78 (m, 3H), 1.52 - 1.40 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H). LC-MS m / z: 477.15 [M+H] + From the above analysis, the structure of compound 28 is shown in Table 1.

[0164] Example 29

[0165] The preparation method of (E)-2-(2-(5-(2,3-dichlorophenyl)furan-2-yl)vinyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (compound 29) refers to Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carbaldehyde is replaced by 5-(2,3-dichlorophenyl)furan-2-carbaldehyde, and the target compound is prepared as an orange-red solid, 0.60 g, with a yield of 64.0%.

[0166] Compound 29 was subjected to nuclear magnetic hydrogen spectrum and mass spectrum analysis, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.93 (dd, J = 8.5, 2.1 Hz, 1H), 7.82 (d, J = 14.6 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.57 (d, J = 14.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 3.6 Hz, 1H), 4.23 (s, 3H), 4.16 (d, J = 12.8 Hz, 2H), 3.40 (t, J = 11.9 Hz, 2H), 1.91 - 1.78 (m, 3H), 1.52 - 1.40 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H). LC-MS m / z: 477.15 [M+H] + From the above analysis, the structure of compound 29 is shown in Table 1.

[0167] Example 30

[0168] (E)-1 -Methyl-4-(4-methylpiperidin-1 -yl)-2-(2-(5-(4-nitrophenyl)furan-2- yl)vinyl)quinolin-1 -ium iodide (Compound 30) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1 '-biphenyl]-3- carboxaldehyde was replaced by 5-(4-nitrophenyl)furan-2-carboxaldehyde to give the title compound as a brownish red solid, 0.59 g, in 63.5% yield.

[0169] Compound 30 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.31 (m, 2H), 8.28 (d, J = 8.9 Hz, 1H), 8.23 - 8.16 (m, 2H), 8.12 (dd, J = 8.4, 1.5 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.85 (d, J = 14.6 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.61 (d, J = 14.8 Hz, 1H), 7.56 (d, J = 3.7 Hz, 1H), 7.47 (s, 1H), 7.23 (d, J = 3.7 Hz, 1H), 4.24 (s, 3H), 4.18 (d, J = 13.0 Hz, 2H), 3.42 (t, J = 12.4 Hz, 2H), 1.91 - 1.81 (m, 3H), 1.47 (q, J = 11.6 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H). LC-MS m / z: 454.21 [M+H] + From the above analysis, the structure of Compound 30 was as shown in Table 1.

[0170] Example 31

[0171] (E)-2-(2-(5-(4-chloro-3-(trifluoromethyl)phenyl)thiophene-2-yl)vinyl)-1 - methyl-4-(4-methylpiperidin-1 -yl)quinolin-1 -ium iodide (Compound 31) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1 '-biphenyl]-3-carboxaldehyde was replaced by 5-(4-chloro-3-(trifluoromethyl)phenyl)thiophene-2-carboxaldehyde to give the title compound as a yellow solid, 0.60 g, in 62.0% yield.

[0172] Compound 31 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.8 Hz, 1H), 8.13 - 7.98 (m, 5H), 7.88 (d, J = 3.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.50 - 7.43 (m, 2H), 4.18 (s, 5H), 3.41 (t, J = 12.1 Hz, 2H), 1.92 - 1.76 (m, 3H), 1.47 (q, J = 11.9 Hz, 2H), 1.03 (d, J = 6.1 Hz, 3H). LC-MS m / z: 527.15 [M+H] + From the above analysis, the structure of compound 31 is shown in Table 1.

[0173] Example 32

[0174] (E)-2-(2-(6-(4-chloro-3-(trifluoromethyl)phenyl)azinophen-3-yl)vinyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (compound 32) was prepared according to the procedure of Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde was replaced by 6-(4-chloro-3-(trifluoromethyl)phenyl)nicotinaldehyde, to give the target compound as a yellow solid, 0.58 g, in 60.9% yield.

[0175] Compound 32 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.52 - 8.47 (m, 2H), 8.30 (dd, J = 14.5, 8.7 Hz, 2H), 8.12 (d, J = 7.0 Hz, 1H), 8.04 (t, J = 8.7 Hz, 1H), 7.92 - 7.85 (m, 3H), 7.73 (t, J = 8.0 Hz, 1H), 7.48 (s, 1H), 4.22 (s, 4H), 4.19 (s, 1H), 3.44 (t, J = 12.5 Hz, 2H), 1.92 - 1.80 (m, 3H), 1.49 (t, J = 12.1 Hz, 2H), 1.03 (d, J = 6.0 Hz, 3H). LC-MS m / z: 522.19 [M+H] + From the above analysis, the structure of compound 32 is shown in Table 1.

[0176] Example 33

[0177] (E)-2-(2-(2-(4-chloro-3-trifluoromethyl)phenyl)oxazol-5-yl)vinyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 33) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde was replaced by 2-(4-chloro-3-(trifluoromethyl)phenyl)oxazole-5-carboxaldehyde to give the title compound as a ginger solid, 0.72 g, in 78.4% yield.

[0178] Compound 33 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 7.2 Hz, 2H), 8.28 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.07 - 7.98 (m, 2H), 7.89 (t, J = 7.9 Hz, 2H), 7.77 - 7.66 (m, 2H), 7.45 (s, 1H), 4.26 - 4.15 (m, 5H), 3.44 (t, J = 12.6 Hz, 2H), 1.92 - 1.78 (m, 3H), 1.48 (dd, J = 18.0, 7.9 Hz, 2H), 1.02 (d, J = 5.9 Hz, 3H). LC-MS m / z: 512.17 [M+H] + From the above analysis, the structure of Compound 23 is shown in Table 1.

[0179] Example 34

[0180] (E)-2-(2-(6-(4-hexylphenyl)pyridin-3-yl)vinyl)-1-methyl-4-(4-methylpiperidin-1- yl)quinolin-1-ium iodide (Compound 34) was prepared according to the procedure described in Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'- biphenyl]-3-carboxaldehyde was replaced by 6-(4-hexylphenyl)nicotinaldehyde to give the title compound as a yellow solid, 0.60 g, in 66.4% yield.

[0181] Compound 34 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.8 Hz, 1H), 8.45 - 8.41 (m, 1H), 8.30 - 8.25 (m, 1H), 8.08 - 8.03 (m, 1H), 7.88 - 7.79 (m, 2H), 7.72 - 7.60 (m, 4H), 7.25 - 7.14 (m, 3H), 4.22 (s, 3H), 3.53 - 3.30 (m, 4H), 2.67 - 2.61 (m, 2H), 1.98 - 1.25 (m, 14H), 1.07 - 0.99 (m, 3H), 0.92 - 0.87 (m, 3H). LC-MS m / z: 503.34 [M+H] + From the above analysis, the structure of compound 34 is shown in Table 1.

[0182] Example 35

[0183] The preparation method of (E)-2-(2-(6-bromobenzo[b]thiophene-2-yl)alkenyl)-1- methyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (compound 35) refers to Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde is replaced by 6-bromobenzo[b]thiophene-2-carboxaldehyde, and the target compound is prepared as a ginger yellow solid, 0.48 g, with a yield of 50.7%.

[0184] Compound 35 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.17 - 8.08 (m, 2H), 8.03 (t, J = 8.0 Hz, 1H), 7.89 (d, J = 10.1 Hz, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.52 - 7.41 (m, 2H), 4.27 - 4.12 (m, 5H), 3.44 (t, J = 12.6 Hz, 2H), 1.92 - 1.78 (m, 3H), 1.54 - 1.40 (m, 2H), 1.02 (d, J = 6.0 Hz, 3H). LC-MS m / z: 477.10 [M+H] + From the above analysis, the structure of compound 35 is shown in Table 1.

[0185] Example 36

[0186] (E)-2-(2-(4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)vinyl)-1- ethyl-4-(4-methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 36) was prepared according to the procedure described in Reference Example 23, except that methyl iodide was replaced with ethyl iodide, to give the target compound as a yellow solid, 0.62 g, in 62.0% yield.

[0187] Compound 36 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 9.0 Hz, 1H), 8.22 (t, J = 1.8 Hz, 1H), 8.17 - 8.13 (m, 2H), 8.10 (dd, J = 8.4, 2.3 Hz, 1H), 8.07 - 8.03 (m, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.94 - 7.85 (m, 3H), 7.80 (d, J = 14.8 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.46 (s, 1H), 4.84 (q, J = 7.1 Hz, 2H), 4.19 (d, J = 12.9 Hz, 2H), 3.43 (t, J = 2.5 Hz, 2H), 1.91 - 1.80 (m, 3H), 1.52 - 1.44 (m, 5H), 1.03 (d, J = 6.4 Hz, 3H). LC-MS m / z: 535.21 [M+H] + From the above analysis, the structure of Compound 36 is shown in Table 1.

[0188] Example 37

[0189] (E)-2-(2-(5-(3,4-dichlorophenyl)furan-2-yl)vinyl)-1-ethyl-4-(4- methylpiperidin-1-yl)quinolin-1-ium iodide (Compound 37) was prepared according to the procedure described in Reference Example 23, except that methyl iodide was replaced with ethyl iodide, 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde was replaced with 5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2- carboxaldehyde, to give the target compound as an orange solid, 0.50 g, in 53.1% yield.

[0190] Compound 37 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.27 (m, 2H), 8.23 (dd, J = 8.5, 2.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (t, J = 7.9 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.45 (s, 1H), 7.23 (d, J = 3.7 Hz, 1H), 4.85 - 4.77 (m, 2H), 4.16 (d, J = 12.9 Hz, 2H), 3.39 (t, J = 12.6 Hz, 2H), 1.91 - 1.78 (m, 3H), 1.51 - 1.41 (m, 5H), 1.02 (d, J = 6.1 Hz, 3H). LC-MS m / z: 525.19 [M+H] + From the above analysis, the structure of compound 37 is shown in Table 1.

[0191] Example 38

[0192] (E)-2-(2-(4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)vinyl)-1-methyl-4- (pyrrolidin-1-yl)quinolin-1-ium iodide (compound 38) was prepared according to the method described in reference example 23, except that piperidine was replaced by tetrahydropyrrole, to give the target compound as a yellow solid, 0.79 g, in a yield of 80.2%.

[0193] Compound 38 was analyzed by1H NMR and mass spectrometry, and the results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.4 Hz, 1H), 8.23 - 8.14 (m, 3H), 8.10 (dd, J = 8.4, 2.3 Hz, 1H), 8.04 - 7.99 (m, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.86 - 7.78 (m, 3H), 7.72 - 7.61 (m, 2H), 7.02 (s, 1H), 4.12 (s, 3H), 4.04 (s, 4H), 2.14 - 2.01 (m, 4H). LC-MS m / z: 493.17 [M+H] + From the above analysis, the structure of compound 38 is shown in Table 1.

[0194] Example 39

[0195] (E)-2-(2-(3',4'-Dichloro-[1,1'-biphenyl]-3-yl)vinyl)-1-methyl-4- (pyrrolidin-1-yl)quinolin-1-ium iodide (Compound 39) was prepared according to the procedure of Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde was replaced by 3',4'-dichloro-[1,1'-biphenyl]-3-carboxaldehyde, and piperidine was replaced by tetrahydropyrrole, to give the title compound as a yellow solid, 0.75 g, in 77.8% yield.

[0196] Compound 39 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.54 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 7.5 Hz, 2H), 8.07 - 7.98 (m, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 5.4 Hz, 5H), 7.69 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.02 (s, 1H), 4.13 (s, 3H), 4.03 (s, 4H), 2.11 - 2.02 (m, 4H). LC-MS m / z: 459.14 [M+H] + From the above analysis, the structure of Compound 38 was as shown in Table 1.

[0197] Example 40

[0198] (E)-2-(2-(5-(4-Chloro-3-trifluoromethyl)phenyl)furan-2-yl)vinyl)-1-methyl-4- (pyrrolidin-1-yl)quinolin-1-ium iodide (Compound 40) was prepared according to the procedure of Reference Example 23, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde was replaced by 5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2- carboxaldehyde, and piperidine was replaced by tetrahydropyrrole, to give the title compound as a yellow solid, 0.62 g, in 65.8% yield.

[0199] Compound 40 was analyzed by1H NMR and mass spectrometry, and the results were as follows: 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 8.5 Hz, 1H), 8.28 - 8.14 (m, 3H), 8.00 (t, J = 7.9 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.57 - 7.46 (m, 2H), 7.13 (d, J = 3.6 Hz, 1H), 7.00 (s, 1H), 4.12 (s, 3H), 4.00 (d, J = 6.5 Hz, 4H), 2.07 (d, J = 6.1 Hz, 4H). LC-MS m / z: 483.14 [M+H] + The structure of compound 40 is shown in Table 1 according to the above analysis.

[0200] Example 41

[0201] (E)-2-(2-(4'-chloro-3'-trifluoromethyl)-[1,1'-biphenyl]-3-yl)vinyl)-1- methylquinolinium-1-iodide (compound 41) was synthesized according to the following route:

[0202]

[0203] Step one: In a 120 mL thick-walled pressure bottle, 2-methylquinoline (2.00 g, 13.97 mmol) and 4 mL of methyl iodide were weighed in, 15 mL of acetonitrile was added as the solvent, and the reaction was carried out at 80°C overnight; after TLC monitoring, 45 mL of EA was added, and a large amount of yellow solid was precipitated, which was placed in the refrigerator for 5 h, and then filtered to obtain a yellow solid 3.12 g (yield 78.3%).

[0204] Step two: In a 100 mL tomato-shaped bottle, the above yellow solid (0.50 g, 1.75 mmol), 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-formaldehyde (0.55 g, 1.93 mmol) and piperidine (0.19 g, 2.28 mmol) were weighed in, 8 mL of MeOH was added as the solvent, and the reaction was carried out at room temperature for 4 h under nitrogen protection; after TLC monitoring, 25 mL of EA was added, and a large amount of yellow-green solid was precipitated, which was placed in the refrigerator for 5 h, and then filtered to obtain the target compound 0.71 g as a green solid (0.71 g, yield 72.8%).

[0205] Compound 41 was subjected to nuclear magnetic hydrogen spectrum and mass spectrum analysis, and the results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 8.9 Hz, 1H), 8.61 (dd, J = 8.9, 2.5 Hz, 2H), 8.42 - 8.36 (m, 2H), 8.29 (d, J = 14.0 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.15 - 8.08 (m, 2H), 8.05 (d, J = 7.9 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.95 - 7.89 (m, 2H), 7.69 (t, J = 7.8 Hz, 1H), 4.63 (s, 3H). LC-MS m / z: 424.11 [M+H] + From the above analysis, the structure of compound 41 is shown in Table 1.

[0206] Example 42

[0207] The preparation method of (E)-2-(4-(dimethylamino)styryl)-1-methylquinolin-1- iodonium ammonium (compound 42) refers to Example 41, except that 4'-chloro-3'- (trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde is replaced by 4-N,N- dimethylaminobenzaldehyde, and the target compound is obtained as a yellow solid, 0.64 g, with a yield of 73.0%.

[0208] The compound 42 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results are as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.81 (d, J = 9.1 Hz, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.32 - 8.19 (m, 2H), 8.15 - 8.04 (m, 1H), 7.94 - 7.78 (m, 3H), 7.55 (d, J = 15.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 4.45 (s, 3H), 3.08 (s, 6H). LC-MS m / z: 289.17 [M+H] + From the above analysis, the structure of compound 42 is shown in Table 1.

[0209] Example 43

[0210] The preparation method of (E)-2-(2-(5-(4-chlorophenyl)furan-2-yl)vinyl)-1- methylquinolin-1-iodonium ammonium (compound 43) refers to Example 41, except that 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde is replaced by 5-(4- chlorophenyl)furan-2-carboxaldehyde, and the target compound is obtained as a yellow solid, 0.55 g, with a yield of 68.7%.

[0211] Compound 43 was analyzed by nuclear magnetic hydrogen spectrum and mass spectrum, and the results were as follows: 1 H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 9.0 Hz, 1H), 7.66 (t, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 14.5 Hz, 1H), 6.68 (d, J = 8.2 Hz, 2H), 6.49 - 6.43 (m, 2H), 3.69 (s, 3H). LC-MS m / z: 346.10 [M+H] + From the above analysis, the structure of compound 43 is shown in Table 1.

[0212] Table 1 Structural formula of compounds 1-43

[0213]

[0214]

[0215]

[0216] Biological activity of Example 44 (minimum inhibitory concentration test)

[0217] By using microdilution method, the minimum inhibitory concentration of compounds 1-43 on different strains was detected to evaluate the bacteriostatic activity of the compounds.

[0218] The broth dilution method is one of the earliest used methods for determining bacterial drug sensitivity, which can be divided into constant broth dilution method and micro-broth dilution method. The basic principles of the two methods are the same. A certain concentration of antibacterial drugs is diluted with culture solution containing test bacteria, and after incubation at a suitable temperature, the minimum drug concentration contained in the well plate without bacterial growth is observed by naked eye as the minimum inhibitory concentration (MIC).

[0219] Experimental steps:

[0220] 1. Preparation of bacterial suspension:

[0221] (1) Bacterial liquid culture: Take 10 μL of the bacterial liquid to be tested and add it to 1 mL of MH broth (which can be adjusted according to actual needs), and incubate it at 37°C in an incubator for 12 hours or so.

[0222] (2) OD 600 value determination: The OD value is determined by using a UV spectrophotometer. The bacterial liquid concentration is adjusted to make the OD 600 value = 0.1, at which the bacterial liquid concentration is about 108 CFU / mL (about 7-10 times dilution of the culture liquid is required);

[0223] (3) Dilution of the sample liquid: the sample liquid is diluted by 1000 times based on the dilution factor obtained in step (2), and the concentration of the sample liquid is about 10 5 CFU / mL at this time, and the sample liquid at this time is the sample bacterial suspension;

[0224] Note: The sample liquid for measuring the OD value should be sampled aseptically in a clean bench, and the remaining sample liquid should be reserved for experiments.

[0225] 2. Preparation of the antibacterial drug:

[0226] Preparation of the antibiotic mother liquor: the antibacterial drug to be tested (the mother liquor concentration is much higher than the R value, at least 160 times) is prepared by using compounds 1-43 according to the R (drug resistance) value of the corresponding antibacterial drug in the CLSI standard, and is divided into sterile small tubes and stored at -20°C for standby.

[0227] Note: Aseptic operation, and the dilution liquid of the antibacterial drug should be sterilized, and should be filtered (the pore size of the filter membrane is 0.22 μm) after being dissolved.

[0228] 3. Operation of the drug sensitivity test:

[0229] (1) The antibacterial drug to be tested is diluted by 10 times;

[0230] (2) 100 μL of sterilized MH broth is added to columns 1-11 of the sterile 96-well plate;

[0231] (3) 100 μL of the 10-fold diluted drug liquid is added to column 1 of the sterile 96-well plate, and is sequentially diluted by 10 times to column 11 (the final volume of the liquid in each well is 100 μL);

[0232] (4) 100 μL of the sample bacterial liquid is added to each well of the sterile 96-well plate, and the final volume of the liquid in each well is 200 μL (since the whole plate is of one drug, each row of the 96-well plate can perform the drug sensitivity test of one bacterium, in order to ensure the reliability of the experiment, each strain is repeated 1-2 times, that is, 2-3 rows are performed for one strain, and 2-4 strains of drug sensitivity test can be performed on one plate);

[0233] (5) 200 μL of sterilized MH broth is added to the upper 4 wells of column 12 of the sterile 96-well plate as the negative control, and 200 μL of the bacterial liquid is added to the lower 4 wells of column 12 as the positive control;

[0234] (6) After the drug and the bacterial liquid are added, the plate cover is covered, and the plate is placed in a 37°C incubator for 18-22 h for observation (the result is interpreted according to the CLSI antibacterial drug sensitivity test interpretation standard). The existing ampicillin is used as a control, and the results are shown in Table 2.

[0235] Table 2 Results of bioactivity experiments (MIC, pg / mL)

[0236]

[0237]

[0238] As shown by the results in Table 2, the above-mentioned compounds 1-43 have good antibacterial effects on bacteria, wherein the compounds of Examples 1, 2, 10, 12, 16-21, 23, 26-29, 33, 35-40 and 42 all exhibit good antibacterial activity (MIC < 2 pg / mL) against Gram-positive bacteria, and the compounds of Examples 1, 2, 12, 16, 17, 18, 20, 21, 29, 36, 37 and 39 all exhibit good antibacterial activity (MIC < 8 pg / mL) against Gram-negative bacteria, and some of the compounds even have better antibacterial activity against specific bacterial strains than the positive control ampicillin.

[0239] Example 45 Study of bacterial morphology

[0240] Changes in the morphology of bacterial cells, such as elongation of bacilli or swelling of cocci, are an important phenotype for the action of FtsZ inhibitors.

[0241] In this example, the growth morphology of Bacillus amyloliquefaciens and Escherichia coli under the action of tetrahydroazepine and quinoline-based quaternary ammonium salt derivatives was observed using an Olympus IX71 inverted fluorescence microscope; the tested compound was compound 2 in Table 1; since the growth of bacteria was effectively inhibited when the concentration of compound 2 was at the MIC value, the experimental concentration was 0.5xMIC, and a certain concentration of bacterial suspension was observed.

[0242] Experimental steps:

[0243] 1. Dilute the bacterial solution after the expansion culture to a concentration of about 5x10 5 CFU / mL with sterilized MH broth medium.

[0244] 2. Add the diluted bacterial solution and compound 2 stock solution to a sterilized 5 mL centrifuge tube, with a total volume of 1 mL, and the final concentration of compound 2 is 0.5xMIC value of compound 2 inhibiting Escherichia coli, so as to determine the amount of compound 2 to be added. That is, the MIC value of compound 2 against Escherichia coli is 8 pg / mL, so the concentration of compound 2 acting on the bacteria is 4 pg / mL, that is, 1.25 pL of compound 2 is added to 1 mL of bacterial solution. However, the small volume is prone to error, so in this experiment, the concentration of compound 2 is diluted 10 times with MH broth medium in advance, and then 12.5 pL is added to the bacterial solution.

[0245] 3. Put the centrifuge tube in step 2 into a constant temperature shaker, cultivate at 200 rpm, 37℃ for 4-5h until the turbidity of bacterial growth is visible, observe the bacterial morphology under 20x lens. The results are shown in Table 2. Figs. 1-2

[0246] Figs. 1-2 The results show that compared with the untreated group of bacteria, compound 2 can make the two kinds of bacillus morphological filamentous, and produce elongated state, so as to preliminarily judge that the compound can act on the target FtsZ protein, so that the bacteria are elongated due to the failure to divide normally, and then die.

[0247] Therefore, the compound prepared by the present application has excellent SPase I and FtsZ inhibiting effect. The compound can block the Sec and Tat secretion system by inhibiting SPase I, so as to cause the bacteria to fail to release mature secreted proteins, and thus play an inhibiting effect. At the same time, the compound can cause the cell to fail to divide and eventually die by inhibiting FtsZ. Therefore, the above-mentioned compound can be used for preparing a drug for preventing, treating or improving bacterial infection. For example, the compound can be used for preparing a drug for treating diseases caused by staphylococcus aureus, enterococcus faecalis, streptococcus pyogenes, escherichia coli and other bacterial infections.

[0248] As described above, although the present application has been shown and described with reference to specific preferred embodiments, it is to be understood that such is by way of illustration and not of limitation. Various changes and modifications can be made therein without departing from the spirit and scope of the present application as defined in the appended claims.​

Claims

1. A quaternary ammonium salt derivative, characterized in that, The structures of the quaternary ammonium salt derivatives are shown in Formula I or Formula II: Among them, R 1 Selected from hydrogen, piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxacyclobutyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azacyclobutane, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine or dimethylamine; R 2 Selected from methyl, ethyl, propyl, or butyl; R 3 Selected from hydrogen or methyl; n = 0, 1, or 2; R is selected from aromatic rings with different substitutions at different positions, and the aromatic rings are selected from benzene rings, pyridine rings, furan rings, thiophene rings, benzothiophene rings with different substitutions, or oxazole rings; X - Selected from halide ions.

2. The quaternary ammonium salt derivative according to claim 1, characterized in that, Aromatic rings are selected from: Among them, R 4 It is selected from benzene rings that are mono- or poly-substituted, including those with hydrogen, halogen, nitro, dimethylamino, or long-chain alkyl groups.

3. The quaternary ammonium salt derivative according to claim 2, characterized in that, The structures of quaternary ammonium salt derivatives are shown in Formula I, II, or IV: Among them, R 5 Selected from hydrogen, tetrahydropyrrole, piperidine, 4-methylpiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 6-azaspiro[2.5]octane, 3-azabicyclo[3.3.0]octane, azacyclobutane, or dimethylamine; R 6 Selected from methyl or ethyl; R 3 Selected from hydrogen or methyl; Ring A is selected from benzene rings, furan rings, or thiophene rings with different substitutions at different positions; R 4 It is selected from benzene rings that are mono- or poly-substituted, including those with hydrogen, halogen, nitro, dimethylamino, or long-chain alkyl groups.

4. The quaternary ammonium salt derivative according to claim 3, characterized in that, R 4 Selected from:

5. The quaternary ammonium salt derivative according to claim 4, characterized in that, R 4 Selected from:

6. The quaternary ammonium salt derivative according to any one of claims 1-5, characterized in that, Halogen ions are selected from chloride ions, bromide ions, or iodide ions.

7. The quaternary ammonium salt derivative according to any one of claims 1-5, characterized in that, Quaternary ammonium salt derivatives are selected from any of the following structures:

8. The method for preparing the quaternary ammonium salt derivative according to claim 1, characterized in that, In compounds of general formula I, R 1 Synthesized from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxacyclobutyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azacyclobutane, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine, according to the following route: Step 1: Raw material Ia undergoes a hydrolysis reaction under alkaline conditions to obtain intermediate Ib; Step 2: Intermediate Ib and Ic undergo addition reaction under the action of phosphorus oxychloride to obtain intermediate Id; Step 3: Intermediate Id reacts with a substituted aromatic aldehyde under the catalysis of p-toluenesulfonamide to give intermediate Ie; Step 4: Intermediate Ie reacts with the corresponding haloalkane R 2 X reacts to form a salt, yielding intermediate IF; Step 5: Intermediate IF undergoes nucleophilic substitution reactions with various substituted cyclic aliphatic amines, substituted linear aliphatic amines, substituted branched aliphatic amines, or substituted aromatic amines under EtOH conditions; Among them, R 7 Selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxacyclobutyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azacyclobutane, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine or dimethylamine; In compounds of general formula II, R 1 To synthesize hydrogen atoms, follow this route: Step 1: Raw material IIa reacts with the corresponding haloalkane R 2 X reacts to form a salt, yielding intermediate IIb; Step 2: Intermediate IIb reacts with aromatic aldehydes under piperidine and MeOH conditions; In compounds of general formula II, R 1 The following route was used to synthesize the following compounds: piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxacyclobutyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azacyclobutane, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine: Step 1: Raw material IIc reacts with the corresponding haloalkane R 2 X reacts to form a salt, yielding intermediate IId; Step 2: Intermediate IId undergoes a nucleophilic substitution reaction with various substituted cyclic aliphatic amines, substituted straight-chain aliphatic amines, substituted branched aliphatic amines, or substituted aromatic amines under EtOH conditions to obtain intermediate IIe; Step 3: Intermediate IIe reacts with aromatic aldehydes under piperidine and MeOH conditions; Among them, R 8 Selected from piperidine, 4-methylpiperidine, 4-fluoropiperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, 1-acetylpiperazine, 1-(3-oxacyclobutyl)piperazine, 6-azaspiro[2.5]octane, cyclohexylamine, trans-4-methylcyclohexylamine, cis-4-methylcyclohexylamine, tetrahydropyrrole, azacyclobutane, 3-azabicyclo[3.3.0]octane, aniline, 2-methoxyethylamine, N,N-diethylethylenediamine, or dimethylamine.

9. A pharmaceutical composition, characterized in that, This includes, but is not limited to, the quaternary ammonium salt derivatives as described in any one of claims 1-7, as well as pharmaceutically acceptable carriers or excipients.

10. The use of the quaternary ammonium salt derivative of any one of claims 1-7 or the pharmaceutical composition of claim 9 or 10 in the preparation of a medicament for treating microbial infections.

Images