A tetrahydroacridine-9-carboxylic acid derivative, a preparation method and use thereof

Abstract

The present application belongs to tetrahydroacridine-9 carboxylic acid, and particularly relates to a tetrahydroacridine-9 carboxylic acid derivative, a preparation method and application thereof. The compound has broad-spectrum biological activity. In various embodiments, the compound exerts an effect by inhibiting bacterial type I signal peptidease (SPase I), which plays a key role in the survival and virulence of bacteria. The present application also provides a preparation method of a pharmaceutical composition containing the compound, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier or excipient.

Description

TECHNICAL FIELD

[0001] The present application belongs to tetrahydroacridine-9 carboxylic acid, and particularly relates to a tetrahydroacridine-9 carboxylic acid derivative, a preparation method and use thereof. 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. Therefore, the demand for new antibiotics is imminent.

[0003] The imminent antibiotic crisis has prompted people to develop new strategies to combat infections. All bacteria need to export proteins through the cytoplasmic membrane. Most proteins are achieved through the general secretory pathway (Sec), and the last step is to release mature proteins through the action of type I signal peptidase. Therefore, type I signal peptidase is essential for bacterial survival, and it is highly conserved in bacteria, which makes type I signal peptidase inhibitors have the potential for broad-spectrum antibacterial activity. Due to the very important characteristics of type I signal peptidase, it has become a target for the development of new antibiotics. SUMMARY

[0004] One of the purposes of the present application is to provide a tetrahydroacridine-9 carboxylic acid derivative or a pharmaceutically acceptable salt thereof having the structure of general formula V, which has broad-spectrum antibacterial activity.

[0005] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0006] A tetrahydroacridine-9 carboxylic acid derivative or a pharmaceutically acceptable salt thereof, characterized in that the structure of the tetrahydroacridine-9 carboxylic acid derivative is shown in general formula (V):

[0007]

[0008] wherein,

[0009] R1 is selected from a hydrogen atom, a hydroxyl group, a methoxy group or a 2-methylethoxy group;

[0010] R2 is selected from a hydrogen atom, a thiomorpholine, a morpholine or an N-methylpiperazine;

[0011] R3 is selected from different sizes of aliphatic rings, including cyclopentane, cyclohexane, methylcyclohexane, dimethylcyclohexane or cycloheptane; Ar is selected from aromatic rings with different substitutions at different positions, including benzene ring, pyridine ring, furan ring, thiophene ring, thiazole ring, benzothiazole ring with different substitutions, oxazole ring or imidazole ring;

[0012] R4 is selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, an amino group, a cyano group, a mono-substituted or poly-substituted benzene ring, wherein the mono-substituted or poly-substituted benzene ring includes:

[0013]

[0014]

[0015] The tetrahydroacridine-9 carboxylic acid derivative or pharmaceutically acceptable salt thereof, characterized in that the tetrahydroacridine-9 carboxylic acid derivative is any one of the following compounds:

[0016] (E)-4-(furan-2-ylmethylidene)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0017] (E)-4-(furan-2-ylmethylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0018] (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylidene)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0019] (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0020] (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0021] (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylidene)-2,2-dimethyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0022] (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylidene)-2,2-dimethyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0023] (E)-4-((5-(4-methoxyphenyl)furan-2-yl)methylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0024] (E)-4-((5-(2-chloro-4-methylphenyl)furan-2-yl)methylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0025] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,2-dimethyl- 1,2,3,4-tetrahyd roquinoline-9-carboxylic acid

[0026] (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0027] (E)-2-methyl-4-((1-methyl-5-nitro-1H-imidazol-2-yl)methylene)-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0028] (E)-2-methyl-4-((5-nitrofuran-2-yl)methylene)-1,2,3,4-tetrahydroquinoline-9- carboxylic acid

[0029] (E)-2-methyl-4-((5-(4-nitrophenyl)furan-2-yl)methylene)-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0030] (E)-3-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,3- dihydro-1H-cyclopenta[b]quinoline-9-carboxylic acid

[0031] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-9-carboxylic acid

[0032] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-9-carboxylic acid

[0033] (E)-4-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0034] (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2- methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0035] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methylene)-7- hydroxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0036] (E)-4-((4'-hexyl-[1,1'-biphenyl]-4-yl)methylene)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0037] (E)-7-methoxy-2-methyl-4-(4'-octyl-[1,1'-biphenyl]-4-ylmethylene)- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-2-methyl-4-(3-nitrobenzylidene)-1,2,3,4-tetrahydroacridine-9- carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7-(2- methoxyethoxy)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0038] (E)-4-((2',3'-dichloro-[1,1'-biphenyl]-4-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0039] (E)-4-((3',4'-dichloro-[1,1'-biphenyl]-4-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0040] (E)-4-((3',4'-dichloro-[1,1'-biphenyl]-3-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0041] (E)-4-(4-cyanobenzylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9- carboxylic acid

[0042] (E)-2-methyl-4-((2',4',6'-trichloro-[1,1'-biphenyl]-4-yl)methylene)-1,2,3,4- tetrahydroacridine-9-carboxylic acid (E)-4-((2',6'-dichloro-4'-(trifluoromethyl)- [1,1'-biphenyl]-4-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- morpholino-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0043] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- morpholino-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0044] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- morpholino-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0045] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0046] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7-methoxy- 2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0047] (E)-4-((6-(4-hexylphenyl)pyridin-3-yl)methylene)-7-methoxy-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0048] (E)-4-((6-bromobenzo[b]thiophen-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine- 9-carboxylic acid

[0049] (E)-4-((4-(3-chloro-4-(trifluoromethyl)phenyl)thiazol-2-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)oxazol-2-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid or a pharmaceutically acceptable salt of the aforementioned compounds.

[0050] The tetrahydroacridine-9-carboxylic acid derivative or its pharmaceutically acceptable salt, characterized in that the salt is a salt formed with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid.

[0051] The preparation method of the tetrahydroacridine-9-carboxylic acid derivative or its pharmaceutically acceptable salt, characterized in that the compound of the general formula V is prepared by the following steps:

[0052] (1) When R2 is a hydrogen atom, the synthesis route is as shown below

[0053]

[0054] Step one: different substituted isatin compounds I undergo Pfitzinger reaction with cyclopentanone, cyclohexanone, 4-methylcyclohexanone, cycloheptanone under alkaline conditions to obtain intermediate III;

[0055] Step two: compound III reacts with aldehyde IV under the catalysis of p-toluenesulfonamide to obtain part of the compound of the general formula V;

[0056] When R2 is thiomorpholine, morpholine or N-methylpiperazine, the synthesis route is as shown below

[0057]

[0058] Wherein X = O, S or N-CH3

[0059] Step one: different substituted isatin compounds I undergo Pfitzinger reaction with cyclopentanone, cyclohexanone, 4-methylcyclohexanone, cycloheptanone under alkaline conditions to obtain intermediate III;

[0060] Step two: compound III reacts with aldehyde IV under the catalysis of p-toluenesulfonamide to obtain intermediate VI;

[0061] Step three: the carboxyl group of compound VI is protected by benzyl bromide to obtain intermediate VII;

[0062] Step four: compound VIII is prepared by Buchwald-Hartwig cross-coupling reaction;

[0063] Step five: the benzyl group is removed under the condition of sodium hydroxide water and EtOH, and the carboxyl group is free to obtain part of the compound of the general formula V.

[0064] A pharmaceutical composition, characterized in that it comprises the tetrahydroacridine-9-carboxylic acid derivative or its pharmaceutically acceptable salt according to any one of claims 1-3, and a pharmaceutically acceptable excipient.

[0065] The present application discloses a pharmaceutical composition comprising the N-benzyl-3-phenylamide derivative and a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable excipient refers to excipients and additives used in the production of pharmaceutical products and the dispensing of prescriptions, including solvents, propellants, solubilizers, co-solvents, emulsifiers, coloring agents, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integration agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc. The pharmaceutically acceptable carrier refers to a system capable of changing the way of drug entering the human body and the distribution in the body, controlling the release speed of the drug and delivering the drug to the target organ, including microcapsules and microspheres, nanoparticles, liposomes, etc.

[0066] The pharmaceutical composition of the present application can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via implanted reservoir. The pharmaceutical composition 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. The pharmaceutically acceptable drug carrier refers to the conventional drug carrier in the pharmaceutical field, which can be one or several inert, non-toxic solid or liquid fillers, diluents, adjuvants, etc., which do not adversely affect the active compound or the patient. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, coloring agents, fillers, emulsifiers, etc.

[0067] The injection solution can be prepared according to the known techniques in the art using suitable dispersants or wetting agents and suspending agents. The pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, etc.

[0068] The actual dose level of the active ingredients in the pharmaceutical composition 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, composition, and mode of administration, without being toxic to the patient. The selected dose level depends on a variety of factors including the activity of the specific compound of the present application or its salt used, the route of administration, the time of administration, the rate of excretion of the specific composition used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific composition used, the age, sex, weight, general health status and prior medical history of the patient to be treated, and similar factors well known in the medical arts.

[0069] The tetrahydroacridine-9 carboxylic acid derivative has antibacterial activity, and the application further discloses an application of the tetrahydroacridine-9 carboxylic acid derivative.

[0070] The pharmaceutical composition is characterized in that the dosage form of the pharmaceutical composition is a tablet, a capsule, a pill, a suppository, an oral liquid, a suspension or an injection.

[0071] The application of the tetrahydroacridine-9 carboxylic acid derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 5 or 6 in the preparation of a drug for treating bacterial infection.

[0072] The infection or bacterial infection refers to a disease or condition characterized by the invasion of the body tissues of an organism by pathogenic agents (e.g., pathogenic bacteria), their multiplication, and the reaction of the host tissues to the infecting agents and their produced toxins. Infectious diseases, also known as infectious diseases, are diseases caused by infections. The bacterial infection includes diseases caused by infection of the following bacteria: Elizabethkingia meningitidis, 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, Chlamydia, 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 subsp. hyicus, Staphylococcus hominis, or Staphylococcus lugdunensis.

[0073] The compounds of the present application of general formula V can be prepared by the above or similar methods described above, using the corresponding starting materials according to the different substituents and their positions. Those skilled in the art will recognize that the above routes are useful in understanding the present application but do not limit the scope of the present application, unless otherwise specified, the variables are defined as mentioned in general formula V.

[0074] Advantages

[0075] (1) The compound of general formula V and pharmaceutically acceptable salts thereof prepared by the present application have excellent type I signal peptide enzyme inhibition effect on bacteria. The compound can inhibit the Sec and Tat secretion system by inhibiting type I signal peptide enzyme of bacteria, so as to block the release of mature secretory protein of bacteria, and thus play an antibacterial role. 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 bacterial infection such as Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Escherichia coli. It is found that the compound of general formula V has high activity of type I signal peptide enzyme inhibition on bacteria, and has good antibacterial effect.

[0076] (2) The compound of the present application has a simple synthesis route, strong implementation, and is easy to realize industrial production. DETAILED DESCRIPTION

[0077] The technical solutions of the present application will be described in detail below through specific examples, but the protection scope of the present application is not limited to the examples.

[0078] In the following examples, "room temperature" refers to about 10°C to about 35°C. The ratio indicated by the mixed solvent is the mixed ratio by volume, and % refers to wt% unless otherwise specified.

[0079] In the silica gel column chromatography, the basic silica gel refers to the silica gel combined with aminopropylsilane. In high performance liquid chromatography (HPLC), C18 refers to the use of octadecyl combined silica gel. The ratio of elution solvent is the mixed ratio by volume unless otherwise specified.

[0080] In the following examples and experimental examples, the following abbreviations are used.

[0081] DCM: dichloromethane

[0082] EA: ethyl acetate

[0083] NaOH: sodium hydroxide

[0084] KOH: potassium hydroxide

[0085] K2CO3: potassium carbonate

[0086] BnBr: benzyl bromide

[0087] MeOH: methanol

[0088] EtOH: EtOH

[0089] THF: tetrahydrofuran

[0090] PTSA: p-toluenesulfonamide

[0091] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

[0092] BINAP: 1,1'-BINAPHATYL-2,2'-BISDIPHENYLPHOSPHINE

[0093] DIPEA: N,N-DIISOPROPYLETHYLAMINE

[0094] HATU: 2-(7-AZABENZOTRIAZOL)-N,N,N',N'-TETRAMETHYLURONIUM HEXAFLUOROPHOSPHATE

[0095] M: molar concentration.

[0096] 1H-NMR (proton nuclear magnetic resonance spectrum) was determined using Fourier transform type NMR. For analysis, ACD / SpecMaNager was used. Peaks of active hydrogens (e.g., hydroxyl group, amino group, etc.) were not described.

[0097] MS (mass spectrum) was determined using LC / MS (liquid chromatograph mass spectrometer). As an ionization method, ESI (electrospray ionization) method or the like was used. Data indicates those actually measured values. Usually, molecular ion peak was observed. In the case of a salt, usually, molecular ion peak or fragment ion peak in free form was observed.

[0098] The following is a method for producing some of the compounds of the present application:

[0099] Example 1

[0100] (E)-4-(Furan-2-ylmethylidene)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0101]

[0102] Preparation method:

[0103] Step 1: In a 100 ml three-necked flask, indol-2,3-dione (5 g, 34 mmol) and 33% KOH aqueous solution (118 mmol) (33% KOH aqueous solution preparation: 6.6 g of KOH was dissolved in 20 ml of pure water by ultrasonic) were weighed and added, and under the condition of N2 protection, heated to 100°C and refluxed for 1 hour, then a constant pressure dropping funnel was slowly added dropwise with cyclohexanone EtOH solution (cyclohexanone 6.67 g (68 mmol) was added with 20 ml of anhydrous EtOH), after the dropwise addition was completed, the reflux reaction was continued for 12 h, after the reaction was completed, the heating was stopped, and after the room temperature was restored, the EtOH was removed by rotary evaporation under reduced pressure, then 100 ml of water was added, and the filter cake was discarded after filtration, the organic layer was discarded after the filtrate was extracted with 30 ml of EA for 3 times, the filter cake was dried under reduced pressure for 24 h after the filtrate was filtered with 3M dilute hydrochloric acid, and the PH was adjusted to 5-6, a large amount of white solid was precipitated, and the ice water bath was cooled for 2 h, and the filter cake was dried under reduced pressure for 24 h, and the dried solid was added with 20 ml of acetonitrile and stirred for 2 h to purify, and tetrahydroacridine-9 carboxylic acid 6.22 g (yield 80.6%) was obtained.

[0104] Step two: In a thick-walled pressure bottle of 25 ml, tetrahydroacridine-9 carboxylic acid (500 mg, 2.2 mmol), p-toluenesulfonamide (414 mg, 2.4 mmol) and furan-2-carboxaldehyde (423 mg, 4.4 mmol) were weighed in, 3 ml of toluene was added as solvent, and the reaction was carried out at 140 °C for 24 h. After the reaction was completed, it was directly rotary evaporated under reduced pressure and then purified by silica gel column to obtain 525 mg of red solid (yield 78.2%). 1 HNMR (300 MHz, DMSO-d6) δ 8.07 - 7.95 (m, 2H), 7.85 (d, J = 1.3 Hz, 1H), 7.79 - 7.70 (m, 2H), 7.65 - 7.53 (m, 1H), 6.82 (d, J = 3.4 Hz, 1H), 6.67 (dd, J = 3.1, 1.8 Hz, 1H), 3.04 (s, 2H), 2.94 (t, J = 5.8 Hz, 2H), 1.91 (s, 2H).

[0105] Example 2

[0106] (E)-4-(Furan-2-ylmethylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0107]

[0108] The preparation method is referred to Example 1, and 4-methylcyclohexanone is replaced by cyclohexanone to prepare the target compound, which is a red solid with a yield of 63.2%. 1 HNMR (300 MHz, DMSO-d6) δ 8.02 (d, J = 9.6 Hz, 2H), 7.87 (s, 1H), 7.80 - 7.69 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 3.2 Hz, 1H), 6.68 (s, 1H), 2.97 (d, J = 14.6 Hz, 1H), 2.77 - 2.53 (m, 3H), 2.01 (td, J = 11.7, 11.3, 6.2 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H).

[0109] Example 3

[0110] (E)-4-((5-(4-Chlorophenyl)furan-2-yl)methylene)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0111]

[0112] The title compound was prepared according to the procedure described in Reference Example 1 by replacing 5-(4-chlorophenyl)-2-furaldehyde with 5-(3- chlorophenyl)-2-furaldehyde. The target compound was obtained as a red solid in 79.2% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.78 (d, J = 16.4 Hz, 4H), 7.66 - 7.42 (m, 3H), 7.22 (s, 1H), 6.96 (s, 1H), 3.17 (d, J = 9.9 Hz, 2H), 2.98 (s, 2H), 1.93 (s, 2H).

[0113] Example 4

[0114] (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0115]

[0116] The title compound was prepared according to the procedure described in Reference Example 1 by replacing 5-(4-chlorophenyl)-2-furaldehyde with 5-(3- chlorophenyl)-2-furaldehyde. The target compound was obtained as a red solid in 79.2% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.78 (d, J = 16.4 Hz, 4H), 7.66 - 7.42 (m, 3H), 7.22 (s, 1H), 6.96 (s, 1H), 3.17 (d, J = 9.9 Hz, 2H), 2.98 (s, 2H), 1.93 (s, 2H).

[0117] Example 5

[0118] (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0119]

[0120] The title compound was prepared according to the procedure described in Reference Example 1 by replacing 5-(4-chlorophenyl)-2-furaldehyde with 5-(3- chlorophenyl)-2-furaldehyde. The target compound was obtained as a red solid in 79.2% yield. 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 7.86 - 7.71 (m, 4H), 7.57 (dd, J = 22.6, 8.0 Hz, 3H), 7.22 (d, J = 3.4 Hz, 1H), 6.94 (d, J = 3.2 Hz, 1H), 3.39 (s, 1H), 3.01 (d, J = 15.3 Hz, 1H), 2.78 - 2.56 (m, 2H), 2.07 (s, 1H), 1.17 (d, J = 6.1 Hz, 3H).

[0121] Example 6

[0122] (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0123]

[0124] The target compound was prepared according to the preparation method of Reference Example 1, by replacing 4,4-dimethylcyclohexanone with cyclohexanone and replacing furan-2-carboxaldehyde with 5-(3-chlorophenyl)-2-furan carboxaldehyde. The target compound was obtained as a red solid in a yield of 63.0%. 1 H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 7.86 - 7.71 (m, 4H), 7.57 (dd, J = 22.6, 8.0 Hz, 3H), 7.22 (d, J = 3.4 Hz, 1H), 6.94 (d, J = 3.2 Hz, 1H), 3.39 (s, 1H), 3.01 (d, J = 15.3 Hz, 1H), 2.78 - 2.56 (m, 2H), 2.07 (s, 1H), 1.17 (d, J = 6.1 Hz, 3H).

[0125] Example 7

[0126] (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0127]

[0128] The target compound was prepared according to the preparation method of Reference Example 1, by replacing 4,4-dimethylcyclohexanone with cyclohexanone and replacing furan-2-carboxaldehyde with 5-(3-chlorophenyl)-2-furan carboxaldehyde. The target compound was obtained as a red solid in a yield of 63.0%. 1H NMR (300 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 21.0, 8.3 Hz, 4H), 7.23 (dd, J = 17.1, 8.0 Hz, 3H), 6.88 (d, J = 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 2.63 (s, 2H), 2.48 (s, 2H), 0.70 (s, 6H).

[0129] Example 8

[0130] (E)-4-((5-(4-methoxyphenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0131]

[0132] The target compound was prepared according to the method described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and 5-(4-methoxyphenyl)-2-furaldehyde with furan-2-carboxaldehyde. The target compound was obtained as a red solid in a yield of 48.5%. 1 H NMR (300 MHz, DMSO-d6) δ 8.07 - 8.00 (m, 2H), 7.80 - 7.70 (m, 4H), 7.58 (dd, J = 8.6, 6.5 Hz, 1H), 7.10 - 6.99 (m, 3H), 6.90 (d, J = 3.6 Hz, 1H), 3.81 (s, 3H), 3.41 (d, J = 3.9 Hz, 1H), 3.06 - 2.94 (m, 1H), 2.66 (td, J = 17.8, 17.1, 10.7 Hz, 2H), 2.07 (d, J = 9.6 Hz, 1H), 1.17 (d, J = 6.5 Hz, 3H).

[0133] Example 9

[0134] (E)-4-((5-(2-chloro-4-methylphenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0135]

[0136] The target compound was prepared according to the method described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and 5-(4-methoxyphenyl)-2-furaldehyde with furan-2-carboxaldehyde. The target compound was obtained as a red solid in a yield of 48.5%. 1H NMR (300 MHz, DMSO-d6) δ 8.04 (dd, J = 7.2, 2.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.64 - 7.55 (m, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.3, 1.8 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.98 (d, J = 3.7 Hz, 1H), 3.08 - 2.91 (m, 1H), 2.76 - 2.53 (m, 3H), 2.35 (s, 3H), 2.03 (d, J = 15.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H).

[0137] Example 10

[0138] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0139]

[0140] The target compound was prepared according to the method described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde with 5-(2,3-dichlorophenyl)furan-2- carboxaldehyde. The target compound was obtained as a red solid in a yield of 75.0%. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (dd, J = 7.2, 2.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.64 - 7.55 (m, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.3, 1.8 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 6.98 (d, J = 3.7 Hz, 1H), 3.08 - 2.91 (m, 1H), 2.76 - 2.53 (m, 3H), 2.35 (s, 3H), 2.03 (d, J = 15.7 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H).

[0141] Example 11

[0142] (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,4- tetrahydroacridine-9-carboxylic acid

[0143]

[0144] The target compound was prepared according to the method described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde with 5-(2,3-dichlorophenyl)furan-2- carboxaldehyde. The target compound was obtained as a red solid in a yield of 75.0%.1 H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.61 (q, J = 7.6 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.99 (d, J = 3.7 Hz, 1H), 2.99 (d, J = 15.7 Hz, 1H), 2.68 (dd, J = 16.9, 11.0 Hz, 3H), 2.13 - 1.96 (m, 1H), 1.15 (d, J = 6.5 Hz, 3H).

[0145] Example 12

[0146] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,2-dimethyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0147]

[0148] The target compound was prepared according to the method described in Reference Example 1, by replacing 4,4-dimethylcyclohexanone with cyclohexanone and 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde with 5-(2,3-dichlorophenyl)furan-2- carboxaldehyde. The target compound was obtained as a red solid in a yield of 59.0%. 1 H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.61 (q, J = 7.6 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.99 (d, J = 3.7 Hz, 1H), 2.99 (d, J = 15.7 Hz, 1H), 2.68 (dd, J = 16.9, 11.0 Hz, 3H), 2.13 - 1.96 (m, 1H), 1.15 (d, J = 6.5 Hz, 3H).

[0149] Example 13

[0150] (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0151]

[0152] The target compound was prepared according to the method described in Reference Example 1, by replacing 4,4-dimethylcyclohexanone with cyclohexanone and 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde with 5-(2,3-dichlorophenyl)furan-2- carboxaldehyde. The target compound was obtained as a red solid in a yield of 59.0%. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 21.5 Hz, 2H), 7.94 - 7.24 (m, 7H), 6.96 (s, 1H), 2.95 (s, 2H), 2.81 (s, 2H), 1.02 (s, 6H).

[0153] Example 14

[0154] (E)-2-methyl-4-((5-nitrofuran-2-yl)methylene)-1,2,3,4-tetrahydroacridine-9- carboxylic acid

[0155]

[0156] The target compound was prepared according to the procedure described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and furan-2-carboxaldehyde with N-methyl-lH-imidazole-2-carboxaldehyde. The target compound was obtained as a yellow solid in 83.0% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 21.5 Hz, 2H), 7.94 - 7.24 (m, 7H), 6.96 (s, 1H), 2.95 (s, 2H), 2.81 (s, 2H), 1.02 (s, 6H).

[0157] Example 15

[0158] (E)-2-methyl-4-((5-nitrofuran-2-yl)methylene)-1,2,3,4-tetrahydroacridine-9- carboxylic acid

[0159]

[0160] The target compound was prepared according to the procedure described in Reference Example 1, by replacing 4-methylcyclohexanone with cyclohexanone and furan-2-carboxaldehyde with 5-nitrofurfural. The target compound was obtained as a yellow solid in 77.5% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 21.5 Hz, 2H), 7.94 - 7.24 (m, 7H), 6.96 (s, 1H), 2.95 (s, 2H), 2.81 (s, 2H), 1.02 (s, 6H).

[0161] Example 16

[0162] (E)-2-methyl-4-((5-(4-nitrophenyl)furan-2-yl)methylene)-1,2,3,4-tetrahydroacridine-9- carboxylic acid

[0163]

[0164] The title compound was prepared according to the procedure described in Reference Example 1 by replacing cyclohexanone with 4-methylcyclohexanone and furan-2-carboxaldehyde with 5-(4-methylphenyl)-2-furfuraldehyde. The target compound was obtained as a yellow solid in 76.3% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J = 8.4 Hz, 2H), 7.99 (t, J = 13.4 Hz, 4H), 7.69 (t, J = 7.8 Hz, 2H), 7.59 - 7.41 (m, 2H), 6.98 (d, J = 3.8 Hz, 1H), 3.33 (d, J = 16.8 Hz, 1H), 2.99 (d, J = 15.8 Hz, 1H), 2.59 (s, 2H), 2.02 (s, 1H), 1.15 (d, J = 6.3 Hz, 3H).

[0165] Example 17

[0166] (E)-3-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,3-dihydro-1H- cyclopenta[b]quinoline-9-carboxylic acid

[0167]

[0168] The title compound was prepared according to the procedure described in Reference Example 1 by replacing cyclohexanone with cyclopentanone and furan-2-carboxaldehyde with 5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carboxaldehyde. The target compound was obtained as a yellow solid in 43.3% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 - 8.16 (m, 2H), 8.06 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.53 (s, 1H), 7.45 (d, J = 4.5 Hz, 2H), 6.91 (d, J = 3.6 Hz, 1H), 3.22 (s, 4H).

[0169] Example 18

[0170] (E)-6-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7,8,9,10-tetrahydro-6H- cyclohepta[b] quinoline-11 -carboxylic acid

[0171]

[0172] The title compound was prepared according to the procedure described in Reference Example 1 by replacing cycloheptanone with 4-methylcyclohexanone and furan-2-carboxaldehyde with 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde. The target compound was obtained as a yellow solid in 45% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.86 - 7.73 (m, 3H), 7.65 (q, J = 8.3, 7.5 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 3.7 Hz, 1H), 2.92 (d, J = 27.2 Hz, 4H), 1.82 (d, J = 33.7 Hz, 4H).

[0173] Example 19

[0174] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0175]

[0176] The title compound was prepared according to the procedure described in Reference Example 1 by replacing cycloheptanone with 4-methylcyclohexanone and furan-2-carboxaldehyde with 5-(4-chloro-3- (trifluoromethyl)phenyl)furan-2-carboxaldehyde. The target compound was obtained as a yellow solid in 45% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.86 - 7.73 (m, 3H), 7.65 (q, J = 8.3, 7.5 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 3.7 Hz, 1H), 2.92 (d, J = 27.2 Hz, 4H), 1.82 (d, J = 33.7 Hz, 4H).

[0177] Example 20

[0178] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0179]

[0180] The compound obtained in Example 21 was used as the raw material for preparation. The specific operation was as follows: (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7-methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (170 mg, 0.32 mmol) was weighed in a 100 ml single-mouthed flask, 10 ml of dichloromethane was added as the solvent, the cold trap was cooled to -30 °C, and then 0.3 ml of boron tribromide (806 mg, 3.2 mmol) was added dropwise. After the dropwise addition was completed, the reaction was maintained for 1 hour, and then the reaction was continued at room temperature for 12 h.

[0181] Post-treatment: saturated aqueous sodium bicarbonate solution was added to quench the reaction, and then glacial acetic acid was added to adjust the pH to 5-6. An appropriate amount of water was added, and then 30 ml of EA was used for extraction three times. The organic phases were combined, and then rotary evaporation was performed under reduced pressure. After drying, the product was purified by silica gel column chromatography to obtain 103 mg of a yellow solid (yield 62.42%). 1 H NMR (300 MHz, DMSO-d6) δ 13.99 (s, 1H), 10.22 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.96-7.86 (m, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 3.6 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.03-6.89 (m, 2H), 2.95 (d, J = 15.0 Hz, 1H), 2.69-2.58 (m, 2H), 2.02 (s, 1H), 1.17 (d, J = 6.4 Hz, 3H).

[0182] Example 21

[0183] (E)-4-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0184]

[0185] The preparation method was as in Example 1, and isatin and 4-methylcyclohexanone were used as the starting materials. Furan-2-carboxaldehyde was replaced with 5-(3,4-dichloro)furan-2-carboxaldehyde to prepare the target compound, which was a yellow solid with a yield of 66.7%. 1H NMR (500 MHz, DMSO-d6) δ 8.07 - 7.94 (m, 3H), 7.76 - 7.66 (m, 4H), 7.52 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.92 (d, J = 3.7 Hz, 1H), 3.33 (dd, J = 17.0, 4.2 Hz, 1H), 3.05 - 2.92 (m, 1H), 2.59 (dt, J = 16.2, 11.3 Hz, 2H), 2.08 - 1.97 (m, 1H), 1.15 (d, J = 6.5 Hz, 3H).

[0186] Example 22

[0187] (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-7-methoxy-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0188]

[0189] Preparation method refers to example 1, using 5-methoxyisatin, 4-methylcyclohexanone as starting material, replacing furan-2-carboxaldehyde with 5-(2,3-dichlorophenyl)furan-2- carboxaldehyde, the target compound is prepared as a yellow solid with a yield of 38%. 1 H NMR (300 MHz, DMSO-d6) δ 8.07 - 7.72 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 8.1 Hz, 2H), 7.02 (s, 1H), 6.98 - 6.83 (m, 1H), 3.88 (s, 3H), 3.35 (d, J = 16.8 Hz, 1H), 2.97 (d, J = 15.9 Hz, 1H), 2.72 - 2.54 (m, 2H), 2.02 (s, 1H), 1.14 (d, J = 6.4 Hz, 3H).

[0190] Example 23

[0191] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0192]

[0193] Preparation method refers to example 1, replacing furan-2-carboxaldehyde with 4'-chloro-3'- (trifluoromethyl)-[1,1'-biphenyl]-3-carboxaldehyde, the target compound is prepared as a yellow solid with a yield of 40.5%. 1H NMR (300 MHz, Methanol-d4) δ 8.09 - 7.97 (m, 2H), 7.93 - 7.84 (m, 2H), 7.77 - 7.68 (m, 2H), 7.64 (s, 1H), 7.60 - 7.46 (m, 5H), 3.07 (ddd, J = 15.6, 8.4, 3.4 Hz, 2H), 2.59 (dd, J = 16.5, 10.9 Hz, 1H), 2.41 (ddd, J = 14.9, 11.3, 2.4 Hz, 1H), 1.97 - 1.78 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H).

[0194] Example 24

[0195] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0196]

[0197] The target compound was prepared according to the procedure described in Reference Example 19, by replacing furan-2-carboxaldehyde with 4'-chloro-3'-(trifluoromethyl)-[1,1'- biphenyl]-3-carboxaldehyde. The target compound was obtained as a yellow solid in 49.5% yield. 1 H NMR (300 MHz, Methanol-d4) δ 8.09 - 7.97 (m, 2H), 7.93 - 7.84 (m, 2H), 7.77 - 7.68 (m, 2H), 7.64 (s, 1H), 7.60 - 7.46 (m, 5H), 3.07 (ddd, J = 15.6, 8.4, 3.4 Hz, 2H), 2.59 (dd, J = 16.5, 10.9 Hz, 1H), 2.41 (ddd, J = 14.9, 11.3, 2.4 Hz, 1H), 1.97 - 1.78 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H).

[0198] Example 25

[0199] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0200]

[0201] The target compound was prepared according to the procedure described in Reference Example 20, by replacing the starting material with the compound obtained in Example 24. The target compound was obtained as a yellow solid in 60.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 13.99 (s, 1H), 10.26 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.88 - 7.75 (m, 2H), 7.67 (s, 1H), 7.56 (s, 2H), 7.33 (d, J = 9.4 Hz, 1H), 7.04 (s, 1H), 3.05 (dd, J = 39.8, 15.7 Hz, 2H), 2.79 - 2.55 (m, 2H), 1.93 (s, 1H), 1.07 (d, J = 6.3 Hz, 3H).

[0202] Example 26

[0203] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methylene)-7-methoxy-2- methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0204]

[0205] The title compound was prepared according to the procedure described in Reference Example 19, by replacing furan-2-carboxaldehyde with 4'-chloro-3'-(trifluoromethyl)-[1,1'- biphenyl]-4-carboxaldehyde. The yield was 57.2% as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.12 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.4, 2.3 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.84 (dd, J = 8.4, 6.9 Hz, 3H), 7.64 (d, J = 8.2 Hz, 2H), 7.43 (dd, J = 9.2, 2.7 Hz, 1H), 7.02 (d, J = 2.7 Hz, 1H), 3.89 (s, 3H), 3.20 - 3.09 (m, 1H), 3.00 (ddd, J = 16.3, 4.1, 1.9 Hz, 1H), 2.77 - 2.54 (m, 2H), 1.96 (ddd, J = 14.4, 10.7, 6.2 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H).

[0206] Example 27

[0207] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methylene)-7-methoxy-2- methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0208]

[0209] The title compound was prepared according to the procedure described in Reference Example 19, by replacing furan-2-carboxaldehyde with 4'-hexyl-[l,l'-biphenyl]-4-carboxaldehyde. The target compound was obtained as a yellow solid in 50.2% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.60 (dd, J = 18.9, 7.9 Hz, 4H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 2.8 Hz, 1H), 3.89 (s, 3H), 3.15 (d, J = 15.4 Hz, 1H), 3.09 - 2.94 (m, 1H), 2.79 - 2.56 (m, 4H), 1.95 (dq, J = 11.5, 6.2 Hz, 1H), 1.59 (p, J = 6.9 Hz, 2H), 1.36 - 1.18 (m, 10H), 1.09 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 6.5 Hz, 3H).

[0210] Example 28

[0211] (E)-7-methoxy-2-methyl-4-((4'-octyl-[l,l'-biphenyl]-4-yl)methylene)-l,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0212]

[0213] The title compound was prepared according to the procedure described in Reference Example 19, by replacing furan-2-carboxaldehyde with 4'-hexyl-[l,l'-biphenyl]-4-carboxaldehyde. The target compound was obtained as a yellow solid in 50.2% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.60 (dd, J = 18.9, 7.9 Hz, 4H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 2.8 Hz, 1H), 3.89 (s, 3H), 3.15 (d, J = 15.4 Hz, 1H), 3.09 - 2.94 (m, 1H), 2.79 - 2.56 (m, 4H), 1.95 (dq, J = 11.5, 6.2 Hz, 1H), 1.59 (p, J = 6.9 Hz, 2H), 1.36 - 1.18 (m, 10H), 1.09 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 6.5 Hz, 3H).

[0214] Example 29

[0215] (E)-2-methyl-4-(3-nitrobenzylidene)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0216]

[0217] The title compound was prepared according to the procedure described in Reference Example 1 by replacing furan-2-carboxaldehyde with 3-nitrobenzaldehyde. The yield was 84.84% as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J = 10.1 Hz, 2H), 8.18 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 10.0 Hz, 3H), 7.65 (d, J = 7.4 Hz, 1H), 3.05 (t, J = 14.7 Hz, 2H), 2.70 (dd, J = 31.3, 14.3 Hz, 2H), 1.98 (s, 1H), 1.07 (d, J = 6.4 Hz, 3H).

[0218] Example 30

[0219] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7-(2- methoxyethoxy)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0220]

[0221] Prepared from the target compound of Example 25, in detail: in a 100 ml single-mouth reaction bottle, (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- hydroxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (200 mg, 0.381 mmol), K2CO3(158 mg, 1.15 mmol), 2-bromoethyl methyl ether (117 mg, 0.84 mmol) and KI (13 mg, 0.076 mmol) were weighed in, then 5 ml of DMF was added, protected by N2, heated to 110 °C for 12 hours. After the reaction was completed, 100 ml of water was added, extracted with 30 ml of EA for 3 times, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column. 100 mg of the obtained solid was weighed into a 50 ml single-mouth reaction bottle, 2M NaOH aqueous solution 3 ml, EtOH 3 ml and THF 3 ml were added, heated to 50 °C, reacted for 12 hours, the EtOH and THF were removed by rotary evaporation, 50 ml of water was added, 3M dilute hydrochloric acid was added to adjust the pH to neutral, 15 ml of EA was added for extraction for 3 times, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column to obtain a light yellow solid, which was vacuum dried for 2 hours, slurried with 3 ml of acetonitrile, suction filtered, and vacuum dried to obtain 35 mg of a light yellow solid, with a yield of 15.8%. 1 H NMR (300 MHz, DMSO-d6) δ 8.18 - 7.96 (m, 3H), 7.93 - 7.79 (m, 3H), 7.61 (dd, J = 8.3, 3.5 Hz, 2H), 7.55 - 7.20 (m, 2H), 7.16 (d, J = 3.1 Hz, 1H), 4.14 (dt, J = 9.0, 4.6 Hz, 2H), 3.68 (dt, J = 9.5, 4.1 Hz, 2H), 3.32 (s, 3H), 3.18 - 2.97 (m, 2H), 2.80 - 2.53 (m, 2H), 1.91 (s, 1H), 1.08 (dd, J = 17.7, 6.4 Hz, 3H).

[0222] Example 31

[0223] (E)-4-((2',3'-dichloro-[1,1'-biphenyl]-4-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0224]

[0225] Preparation method according to Example 1, furan-2-carboxaldehyde is replaced by 2',3'-dichloro-[1,1'-biphenyl]-4-carboxaldehyde, and the target compound is prepared as a yellow solid with a yield of 92.3%. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J = 19.6 Hz, 1H), 8.00 (s, 1H), 7.55 (dd, J = 54.6, 25.1 Hz, 10H), 3.06 (dd, J = 36.4, 15.6 Hz, 2H), 2.64 (d, J = 16.6 Hz, 2H), 1.92 (s, 1H), 1.05 (s, 3H).

[0226] Example 32

[0227] (E)-4-((3',4'-Dichloro-[1,1'-biphenyl]-4-yl)methylene)-2-methyl-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0228]

[0229] The title compound was prepared according to the procedure described in Reference Example 1 by replacing furan-2-carboxaldehyde with 3',4'-dichloro-[1,1'-biphenyl]-4- carboxaldehyde. The target compound was obtained as a yellow solid in 82.5% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.00 (s, 2H), 7.80 (s, 1H), 7.68 (d, J = 25.8 Hz, 5H), 7.54 (s, 3H), 3.05 (dd, J = 34.1, 15.8 Hz, 2H), 2.61 (dd, J = 25.8, 12.7 Hz, 2H), 1.92 (s, 1H), 1.08 (d, J = 30.4 Hz, 3H).

[0230] Example 33

[0231] (E)-4-((3',4'-Dichloro-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-1,2,3,4- tetrahydroquinoline-9-carboxylic acid

[0232]

[0233] The title compound was prepared according to the procedure described in Reference Example 1 by replacing furan-2-carboxaldehyde with 3',4'-dichloro-[1,1'-biphenyl]-3- carboxaldehyde. The target compound was obtained as a yellow solid in 77.5% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.00 (s, 2H), 7.80 (s, 1H), 7.68 (d, J = 25.8 Hz, 5H), 7.54 (s, 3H), 3.05 (dd, J = 34.1, 15.8 Hz, 2H), 2.61 (dd, J = 25.8, 12.7 Hz, 2H), 1.92 (s, 1H), 1.08 (d, J = 30.4 Hz, 3H).

[0234] Example 34

[0235] (E)-4-(4-cyanobenzylidene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0236]

[0237] The target compound was prepared according to the procedure described in Reference Example 1, replacing furan-2-carboxaldehyde with 4-cyanobenzaldehyde. The target compound was obtained as a yellow solid in 89.2% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.72 (t, J = 9.1 Hz, 4H), 7.59 (t, J = 7.7 Hz, 1H), 3.03 (t, J = 13.7 Hz, 2H), 2.65 (dd, J = 28.5, 12.9 Hz, 2H), 1.98 (d, J = 14.9 Hz, 1H), 1.07 (d, J = 6.4 Hz, 3H).

[0238] Example 35

[0239] (E)-2-methyl-4-((2',4',6'-trichloro-[1,1'-biphenyl]-4-yl)methylene)-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0240]

[0241] The target compound was prepared according to the procedure described in Reference Example 1, replacing furan-2-carboxaldehyde with 2',4',6'-trichloro-[1,1'-biphenyl]-4-carboxaldehyde. The target compound was obtained as a yellow solid in 76.0% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.81 (s, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 7.7 Hz, 2H), 3.12 (s, 1H), 3.01 (d, J = 17.0 Hz, 1H), 2.62 (dt, J = 20.1, 14.3 Hz, 2H), 1.93 (d, J = 13.7 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H).

[0242] Example 36

[0243] (E)-4-((2',6'-dichloro-4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methylene)-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0244]

[0245] The title compound was prepared according to the procedure described in Reference Example 1, using 2',4',6'-trichloro-[1,1'-biphenyl]-4-carbaldehyde instead of furan-2- carboxaldehyde. The yield was 73.1% as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.07 (s, 2H), 8.04 - 7.96 (m, 1H), 7.69 (dd, J = 13.3, 8.8 Hz, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 3.08 (dd, J = 38.3, 15.8 Hz, 2H), 2.63 (dd, J = 16.3, 11.3 Hz, 2H), 1.93 (d, J = 12.3 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H).

[0246] Example 37

[0247] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- morpholino-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0248]

[0249] Preparation method:

[0250] Step 1: Refer to Step 1 of Reference Example 1, use 6-bromoindoine-2,3-dione instead of indole-2,3-dione to prepare 6-bromo-2-methyl-1,2,3,4-tetrahydroacridine-9- carboxylic acid;

[0251] Step 2: Refer to Step 2 of Reference Example 1, use 6-bromo-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid and 4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3- carboxaldehyde as raw materials to prepare (E)-6-bromo-4-((4'-chloro-3'-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid;

[0252] Step three: In a 50 ml single necked flask, the compound from step two (1.6 g, 2.73 mmol), BnBr (1.4 g, 8.18 mmol), K2CO3(1.5 g, 10.91 mmol) were weighed in, 10 ml of acetone was added as solvent, the reaction was stirred at room temperature for 12 hours, directly spin dried and purified by silica gel column to get 1.8 g of light yellow solid;

[0253] Step four: In a 50 ml three necked flask, the compound from step three (200 mg, 0.295 mmol), morpholine (26 mg, 0.295 mmol), sodium tert-butoxide (43 mg, 0.443 mmol), Pd2(dba)3(4 mg) and BINAP (8 mg) were weighed in, 10 ml of 1,4-dioxane dried by molecular sieves was added as solvent, the reaction was heated to 100 °C for 12 hours under N2protection, 60 ml of water was added, extracted with 20 ml of EA for 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column to get 102 mg of light yellow solid;

[0254] Step five: In a 50 ml single necked flask, the compound from step four (70 mg, 0.103 mmol), 3 ml of EtOH and 1 ml of water were weighed in, then NaOH (415 mg, 10.4 mmol) was weighed in, N2protected, heated to 105 °C and refluxed for 12 hours, after the reaction was completed, 50 ml of water was added, extracted with 15 ml of EA for 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, dried under reduced pressure, and purified by silica gel column to get 30 mg of red solid, with a yield of 50.0%. 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.11 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.89 - 7.78 (m, 2H), 7.72 - 7.65 (m, 1H), 7.62 - 7.53 (m, 3H), 7.45 (d, J = 9.6 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 3.78 (t, J = 4.8 Hz, 4H), 3.29 (d, J = 9.3 Hz, 4H), 3.10 (d, J = 15.4 Hz, 1H), 3.00 - 2.88 (m, 1H), 2.61 (dd, J = 15.8, 11.1 Hz, 2H), 1.91 (s, 1H), 1.05 (d, J = 6.4 Hz, 3H).

[0255] Example 38

[0256] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- (piperazin-1-yl)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0257]

[0258] Preparation Method Reference Example 37, replace morpholine in step three with N- methylpiperazine as starting material, yield 63.2% of red solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.4, 2.3 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.70 - 7.64 (m, 2H), 7.56 (d, J = 4.8 Hz, 2H), 7.29 (dd, J = 9.3, 2.5 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 3.30 (t, J = 4.6 Hz, 4H), 3.05 (ddd, J = 22.1, 15.2, 2.9 Hz, 2H), 2.56 (dt, J = 10.0, 5.9 Hz, 6H), 2.29 (s, 3H), 1.85 (td, J = 12.3, 9.8, 4.9 Hz, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[0259] Example 39

[0260] (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-6- (piperazin-1-yl)-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0261]

[0262] Preparation Method Reference Example 37, replace morpholine in step three with N- methylpiperazine as starting material, yield 63.2% of red solid. 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.13 - 7.99 (m, 2H), 7.87 - 7.78 (m, 2H), 7.66 (d, J = 4.6 Hz, 1H), 7.56 (t, J = 4.5 Hz, 3H), 7.27 (d, J = 10.0 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 3.69 (t, J = 5.0 Hz, 4H), 3.41 (s, 1H), 3.17 (s, 1H), 3.11 - 2.96 (m, 2H), 2.75 - 2.66 (m, 4H), 1.85 (s, 1H), 1.02 (d, J = 6.4 Hz, 3H).

[0263] Example 40

[0264] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-2- methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0265]

[0266] The preparation method refers to example 1, and 5-(4-chloro-3- (trifluoromethyl) phenyl) thiophene-2-carboxaldehyde is used instead of furan-2- carboxaldehyde to prepare the target compound, which is a yellow solid with a yield of 82.1%. 1 H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.99 (dd, J = 19.3, 11.2 Hz, 3H), 7.73 (dd, J = 21.7, 11.8 Hz, 4H), 7.49 (d, J = 9.5 Hz, 2H), 3.18 (d, J = 16.2 Hz, 1H), 2.95 (d, J = 16.1 Hz, 1H), 2.60 (d, J = 12.5 Hz, 2H), 2.01 (s, 1H), 1.22 - 1.00 (m, 3H).

[0267] Example 41

[0268] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0269]

[0270] The preparation method refers to example 1, and 5-(4-chloro-3- (trifluoromethyl) phenyl) thiophene-2-carboxaldehyde is used instead of furan-2- carboxaldehyde to prepare the target compound, which is a yellow solid with a yield of 82.1%. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, J = 2.2 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.5, 2.3 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 3.9 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 7.41 (dd, J = 9.3, 2.8 Hz, 1H), 7.01 (d, J = 2.7 Hz, 1H), 3.88 (s, 3H), 3.26 - 3.16 (m, 1H), 2.97 (ddd, J = 15.9, 3.9, 1.7 Hz, 1H), 2.67 (dd, J = 16.0, 10.7 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.05 (ddq, J = 14.5, 9.8, 5.3, 3.8 Hz, 1H), 1.17 (d, J = 6.5 Hz, 3H).

[0271] Example 42

[0272] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0273]

[0274] The title compound was prepared according to the procedures described in Reference Example 1 by replacing 4-methylcyclohexanone with cyclohexanone and 6-(4-chloro-3- (trifluoromethyl)phenyl)nicotinaldehyde with 6-(4-hexylphenyl)picolinic aldehyde. The target compound was obtained as a red solid in 67.9% yield. 1 H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.58 (d, J = 12.8 Hz, 1H), 8.39 (s, 1H), 8.28 - 7.95 (m, 4H), 7.76 (d, J = 25.6 Hz, 3H), 7.55 (s, 1H), 3.27 - 2.87 (m, 2H), 2.62 (s, 2H), 1.93 (s, 1H), 1.07 (s, 3H).

[0275] Example 43

[0276] (E)-4-((6-(4-hexylphenyl)pyridin-3-yl)methylene)-7-methoxy-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0277]

[0278] The preparation method refers to example 1, taking 5-methoxyindigo and 4-methylcyclohexanone as the starting materials, replacing furan-2-carboxaldehyde with 6-(4- hexylphenyl)nicotinaldehyde to prepare the target compound, which is a yellow solid with a yield of 79.8%. 1 H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 7.8 Hz, 3H), 7.50-7.39 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.11-6.98 (m, 1H), 3.90 (s, 3H), 3.20-2.91 (m, 2H), 2.67 (dt, J = 28.2, 9.1 Hz, 4H), 1.97 (s, 1H), 1.59 (q, J = 7.4 Hz, 2H), 1.29 (s, 6H), 1.10 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H).

[0279] Example 44

[0280] (E)-4-((6-bromobenzo[b]thiophene-2-yl)methylene)-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid

[0281]

[0282] The preparation method refers to example 1, taking 5-methoxyindigo and 4-methylcyclohexanone as the starting materials, replacing furan-2-carboxaldehyde with 6-(4- hexylphenyl)nicotinaldehyde to prepare the target compound, which is a yellow solid with a yield of 79.8%. 1 H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 7.8 Hz, 3H), 7.50-7.39 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.11-6.98 (m, 1H), 3.90 (s, 3H), 3.20-2.91 (m, 2H), 2.67 (dt, J = 28.2, 9.1 Hz, 4H), 1.97 (s, 1H), 1.59 (q, J = 7.4 Hz, 2H), 1.29 (s, 6H), 1.10 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H).

[0283] Example 44

[0284] (E)-4-((4-(3-chloro-4-(trifluoromethyl)phenyl)thiazol-2-yl)methylene)-2- methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0285]

[0286] The preparation method refers to example 1, and 4-methylcyclohexanone is used as the starting material. 5-(4-chloro-3-(trifluoromethyl)phenyl)oxazole-2-carboxaldehyde is used instead of furan-2-carboxaldehyde to give the target compound as a yellow solid in a yield of 76.3%.

[0287] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.50 (s, 1H), 8.35 (dd, J = 20.4, 12.3 Hz, 2H), 8.12 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 7.5 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 3.69 (d, J = 17.0 Hz, 1H), 3.02 (d, J = 16.0 Hz, 1H), 2.73 (dd, J = 17.0, 9.5 Hz, 2H), 2.10 (s, 1H), 1.19 (d, J = 6.5 Hz, 3H).

[0288] Example 46

[0289] (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)oxazol-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid

[0290]

[0291] The preparation method refers to example 1, and 4-methylcyclohexanone is used as the starting material. 5-(4-chloro-3-(trifluoromethyl)phenyl)oxazole-2-carboxaldehyde is used instead of furan-2-carboxaldehyde to give the target compound as a yellow solid in a yield of 76.3%. 1 H NMR (300 MHz, DMSO-d6) δ 8.39 - 8.18 (m, 2H), 8.12 - 7.86 (m, 3H), 7.71 (s, 3H), 7.51 (t, J = 7.3 Hz, 1H), 3.23 (d, J = 15.0 Hz, 2H), 2.95 (d, J = 15.2 Hz, 2H), 1.95 (d, J = 19.4 Hz, 1H), 1.17 - 0.97 (m, 3H).

[0292] Example 47: Biological activity (minimum inhibitory concentration test)

[0293] The minimum inhibitory concentration of the compound on different strains is detected by using the microdilution method to evaluate the antibacterial activity of the compound.

[0294] Broth dilution method is one of the earliest used methods for bacterial drug sensitivity determination, 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 the bacteria to be tested, and after incubation at a suitable temperature, the lowest drug concentration in the test tube without bacterial growth is observed by naked eye as the minimum inhibitory concentration (MIC). Experimental steps:

[0295] 1. Preparation of bacterial suspension:

[0296] (1) Bacterial liquid culture: Take 10 μL of the bacteria to be tested from the storage solution and add 1 mL of MH broth (which can be adjusted according to actual needs), and place it in a 37°C incubator for overnight static culture for about 12 hours;

[0297] (2) OD600 value determination: Use a UV spectrophotometer to measure the OD value, adjust the concentration of the bacterial liquid to make its OD600 value = 0.1, at this time the concentration of the bacterial liquid is about 10 8 cfu / mL (about 7-10 times dilution of the cultured bacterial liquid is required);

[0298] (3) Sample bacterial liquid dilution: Dilute the bacterial liquid obtained in step ② by 1000 times based on the dilution factor, at this time the concentration of the bacterial liquid is about 10 5 cfu / mL, at this time the bacterial liquid is the sample bacterial suspension;

[0299] Note: The bacterial liquid required for OD value determination should be sampled aseptically in a clean bench, and the remaining bacterial liquid should be tested.

[0300] 2. Preparation of antibacterial drugs:

[0301] Antibiotic mother liquor preparation: Refer to the corresponding R (drug resistance) value of the antibacterial drug in the CLSI standard to prepare the antibacterial drug to be tested (the mother liquor concentration is much higher than the R value, at least 160 times), and store it in sterile small tubes at -20°C for standby.

[0302] Note: Aseptic operation, the dilution of antibacterial drugs should be sterilized, and should be filtered after dissolution (filter membrane pore size is 0.22 μm).

[0303] 3. Operation of drug sensitivity test:

[0304] (1) Dilute the antibacterial drug to be tested by 10 times;

[0305] (2) Add 100 μL of sterilized MH broth to the first to eleventh columns of the sterile 96-well plate (one drug per plate);

[0306] (3) Add 100 μL of 10-fold diluted drug solution to the first column of the sterile 96-well plate, and sequentially dilute by 10 times to the eleventh column (the final volume of each well is 100 μL);

[0307] (4) Add 100 μL of the bacteria solution to be tested to each well of the sterile 96-well plate, and the final volume of liquid in each well is 200 μL (as the whole plate is of one drug, each row of the 96-well plate can perform drug sensitivity test of one bacterium, in order to ensure the reliability of the experiment, each strain is repeated 1-2 times, i.e. one strain is made into 2-3 rows, and one plate can perform drug sensitivity test of 2-4 strains of bacteria);

[0308] (5) Add 200 μL / well of sterilized MH broth to the 4 wells in the 12th column of the sterile 96-well plate as negative control, and add 200 μL / well of bacteria solution to the 4 wells below the 12th column as positive control;

[0309] (6) After the drug and bacteria solution are loaded, cover the plate cover, and place it in a 37°C incubator for 18-22 hours to observe the results (the interpretation of the results refers to the CLSI Antimicrobial Susceptibility Test Interpretive Criteria).

[0310] Table 1: Results of biological activity experiment

[0311]

[0312]

[0313] The results show that the above compounds have good bacteriostatic effect on bacteria, wherein the compounds of Examples 5, 9, 10, 11, 13, 24, 26, 30, 32, 40, 41, 43, and 45 all exhibit good antibacterial activity on gram-positive bacteria, and the activity of some of the compounds is even superior to that of the positive control ampicillin on specific strains.

[0314] Therefore, the compound of general formula V and its pharmaceutically acceptable salt prepared by the present application have excellent Type I signal peptide enzyme inhibition effect on bacteria. By inhibiting Type I signal peptide enzyme of bacteria, the Sec and Tat secretion system is blocked, which leads to the failure of bacteria to release mature secretory proteins, thereby exerting a bacteriostatic effect. Therefore, the above-mentioned compounds can be used for preparing drugs for preventing, treating, or improving bacterial infection. For example, the compounds can be used for preparing drugs for treating diseases caused by bacterial infection such as Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, Escherichia coli, and the like.

[0315] As described above, although the present application has been indicated and expressed with reference to specific preferred embodiments, it should not be construed as a limitation on the present application itself. Various changes can be made in form and details without departing from the spirit and scope of the present application defined in the appended claims.

Claims

1. A tetrahydroacrylidine-9 carboxylic acid derivative or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the tetrahydroacrylidine-9 carboxylic acid derivative is shown in general formula (V): Specifically, it is any one of the following compounds: (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylene)-1,2,3,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(4-chlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(3-chlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(4-methoxyphenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(2-chloro-4-methylphenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,4-tetrahydroacryl-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-2,2-dimethyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-2-methyl-4-((5-nitrofuran-2-yl)methylene)-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-3-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-2,3-dihydro-1H-cyclopentano[b]quinoline-9-carboxylic acid (E)-6-((5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)methylene)-7,8,9,10-tetrahydro-6H-cycloheptano[b]quinoline-11-carboxylic acid (E)-4-((5-(3,4-dichlorophenyl)furan-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((5-(2,3-dichlorophenyl)furan-2-yl)methylene)-7-methoxy-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacrylidine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- methoxy-2-methyl-1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((4'-chloro-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methylene)-7- (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)thiophen-2-yl)methylene)-7-methoxy-2-methyl- 1,2,3,4-tetrahydroacridine-9-carboxylic acid (E)-4-((6-(4-hexylphenyl)pyridin-3-yl)methylene)-7-methoxy-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid (E)-4-((6-bromobenzo[b]thiophen-2-yl)methylene)-2-methyl-1,2,3,4-tetrahydroacridine-9- carboxylic acid (E)-4-((4-(3-chloro-4-(trifluoromethyl)phenyl)thiazol-2-yl)methylene)-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid (E)-4-((5-(4-chloro-3-(trifluoromethyl)phenyl)oxazol-2-yl)methylene)-2-methyl-1,2,3,4- tetrahydroacridine-9-carboxylic acid or a pharmaceutically acceptable salt of the above-mentioned compounds.

2. The tetrahydroacridine-9-carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized by The salt is a salt with hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid.

3. A process for preparing a tetrahydroacridine-9 carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized by, The compound of general formula V is prepared by the following steps: (1) When R2 is hydrogen atom, the synthetic route is as follows Step one: Pfitzinger reaction of different substituted isatin compounds I with cyclopentanone, cyclohexanone, 4-methylcyclohexanone, cycloheptanone under alkaline conditions to obtain intermediate III; Step two: compound III reacts with aldehyde IV under the catalysis of p-toluenesulfonamide to obtain part of the compound of general formula V; (2) When R2 is thiomorpholine, morpholine or N-methylpiperazine, the synthetic route is as follows wherein X = O, S or N-CH3 Step one: Pfitzinger reaction of different substituted isatin compounds I with cyclopentanone, cyclohexanone, 4-methylcyclohexanone, cycloheptanone under alkaline conditions to obtain intermediate III; Step two: compound III reacts with aldehyde IV under the catalysis of p-toluenesulfonamide to obtain intermediate VI; Step three: the carboxyl group of compound VI is protected by benzyl bromide to obtain intermediate VII; Step four: compound VIII is prepared by Buchwald-Hartwig cross-coupling reaction; Step five: debenzyl protection under the condition of sodium hydroxide water and EtOH to free the carboxyl group to obtain part of the compound of general formula V.

4. A pharmaceutical composition, characterized by, The tetrahydroacridine-9-carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, wherein The dosage form of the pharmaceutical composition is tablet, capsule, pill, suppository, oral liquid, suspension or injection.

6. Use of the tetrahydroacridine-9-carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, or the pharmaceutical composition according to claim 4 or 5 in the preparation of a medicament for treating bacterial infection.

7. Use according to claim 6, characterized in that, The bacterial infection is caused by a disease of a bacterial infection of Elizabethkingia meningitidis, 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, Chlamydia, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, 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 subspecies hyicus, Staphylococcus haemolyticus, or Staphylococcus hominis.

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