A 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, its preparation method and application

Abstract

This invention discloses a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, its preparation method, and its applications, selected from at least one of compounds having the following structure or a pharmaceutically acceptable salt thereof, a solvent compound of a pharmaceutically acceptable salt, an enantiomer, a non-corresponding isomer, and a tautomer: wherein R 1 It is a phenyl or substituted phenyl; R 2 It is a 5- to 7-membered nitrogen heterocycle or a secondary amine.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, its preparation method, and its application, particularly its application as an AcrB efflux pump inhibitor. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] The overuse of antibiotics exerts intense selective pressure on bacteria, contributing to the emergence of drug-resistant strains. Racing against the rate of bacterial evolution is a recognized challenge and problem in the medical field.

[0004] On May 17, 2024, the World Health Organization released an updated version of the "2024 Priority List of Bacterial Pathogens," continuing to identify Escherichia coli pathogens as a key priority for developing new treatments. The mechanisms by which Gram-negative bacteria resist antibiotics are diverse, but they primarily prevent antibiotic accumulation within the bacteria through the intrinsic efflux pump transporter system (AcrAB-TolC), belonging to the RND superfamily. AcrB, the inner membrane transporter of this system, plays a crucial role in substrate recognition and energy transfer; inhibiting its related functions is an effective way to enhance the efficacy of existing antimicrobial drugs. Efflux pump inhibitors are a promising and effective strategy for combating antibiotic resistance, capable of restoring or enhancing the efficacy of conventional antibiotics and reducing the spread of bacterial resistance. Studies have shown that efflux pump inhibitors can reduce bacterial efflux, increase the accumulation of antibiotics within bacterial cells, thereby reversing resistance levels. Furthermore, efflux pump inhibitors are involved in key bacterial physiological processes such as intercellular communication (quorum sensing), virulence factors, and biofilm formation. Therefore, novel and effective AcrB efflux pump inhibitors are needed to overcome infections caused by multidrug-resistant Gram-negative bacteria. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, its preparation method, and its applications. When used in conjunction with antibiotics, the compounds of the present invention can reduce the minimum inhibitory concentration (MIC) against AcrB-expressing Escherichia coli by 32-fold.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] In a first aspect, the present invention provides a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, selected from at least one of compounds having the structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a solvent compound of a pharmaceutically acceptable salt, an enantiomer, a non-corresponding isomer, and a tautomer:

[0008]

[0009] Among them, R 1 It is a phenyl or substituted phenyl; R 2 It is a 5- to 7-membered nitrogen heterocycle or a secondary amine.

[0010] In some embodiments, the R 1 It is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, naphthyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, phenyl, or 4-methoxyphenyl; R 2 It can be pyrrolidine, piperidine, morpholine, cycloheximine, 4-methylpiperidine, dimethylamine, diethylamine, or dipropylamine.

[0011] Preferably, the compound of formula I is specifically selected from one of the following compounds:

[0012]

[0013] Preferably, the compound of formula II is specifically selected from one of the following compounds:

[0014]

[0015]

[0016]

[0017]

[0018] Secondly, the present invention provides a method for preparing the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, comprising the following steps:

[0019] In an inert atmosphere and at low temperature, an aqueous solution of sodium nitrite was added to a concentrated hydrochloric acid solution of 3-benzyloxyaniline, and the mixture was stirred. Then, stannous chloride was added, and the mixture was stirred at room temperature to obtain intermediate 2.

[0020] Add 4,4-dimethylcyclohexanone and concentrated sulfuric acid to the solution of the intermediate, and heat to react, to obtain intermediate 3;

[0021] Potassium tert-butoxide and 4-fluorobenzyl bromide were added to the solution of intermediate 3, and the reaction was carried out at room temperature to obtain intermediate 4a;

[0022] Boron trichloride solution was added to the solution of intermediate 4a at a temperature of -80 to -70°C and reacted at this temperature for 0.5 to 3 hours to obtain intermediate 4a-1.

[0023] Cesium carbonate and benzyl bromosubstituted with different groups were added to a solution of intermediate 4a-1, and the reaction was carried out at room temperature to give the compound of formula I.

[0024] or,

[0025] Potassium tert-butoxide and 1-(chloroacetyl)pyrrolidine or 2-chloro-1-piperidin-1-yl acetone or 4-(2-chloroacetyl)morpholine or 2-chloro-N,N-dimethylacetamide or N,N-diethylchloroacetamide or 2-chloro-N,N-dipropylacetamide or 1-azacyclohepten-1-yl-2-chloro-acetone or 2-chloro-1-(4-methylpiperidin-1-yl)acetone were added to a solution of intermediate 3, and the mixture was reacted at room temperature to generate intermediate 5'.

[0026] Add boron trichloride solution to the solution of intermediate 5' at a temperature of -80 to -70°C and react at this temperature for 0.5 to 3 hours to generate intermediate 6'.

[0027] Cesium carbonate and benzyl bromosubstituted with different groups were added to the solution of intermediate 6', and the reaction was carried out at room temperature to give the compound of general formula II.

[0028]

[0029] In some embodiments, the sodium nitrite aqueous solution is added to the concentrated hydrochloric acid solution of 3-benzyloxyaniline at a temperature below 0°C, and the reaction is stirred at this temperature for 0.5-2 hours.

[0030] Preferably, after adding stannous chloride, the reaction is stirred at room temperature for 1-3 hours.

[0031] In some embodiments, 4,4-dimethylcyclohexanone and concentrated sulfuric acid are added to the intermediate 2 solution, and the mixture is reacted at 70-90°C for 1-3 hours to generate intermediate 3.

[0032] Thirdly, the present invention provides a pharmaceutical composition comprising the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative and at least one pharmaceutically acceptable excipient.

[0033] Preferably, the pharmaceutically acceptable excipient is selected from solvents, disintegrants, flavoring agents, preservatives, colorants, or binders.

[0034] In some embodiments, the dosage form of the pharmaceutical composition is selected from injections, tablets, pills, capsules, suspensions, or emulsions.

[0035] Fourthly, the present invention provides the use of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative or the pharmaceutical composition thereof in the preparation of a medicament for treating bacterial infections, wherein the bacteria are bacteria carrying the AcrB protein.

[0036] In some embodiments, the drug is a drug with antibacterial and sensitizing activity.

[0037] Preferably, the bacteria are Gram-negative bacteria that overexpress AcrB protein.

[0038] More preferably, the bacteria is Escherichia coli that overexpresses the AcrB protein.

[0039] In some embodiments, the medicament further includes an antibacterial agent selected from linezolid, oxacillin, azithromycin, erythromycin, tetracycline, fusidic acid, minocycline, ampicillin, or piperacillin.

[0040] Fifthly, the present invention provides the use of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative or the pharmaceutical composition thereof in the treatment of bacterial infections, wherein the bacteria are bacteria carrying the AcrB protein.

[0041] Preferably, the bacteria are Gram-negative bacteria that overexpress AcrB protein.

[0042] More preferably, the bacteria is Escherichia coli that overexpresses the AcrB protein.

[0043] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0044] The AcrB efflux pump inhibitors of the present invention, specifically the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives, exhibit good antibacterial sensitization activity against Escherichia coli expressing the AcrB protein when used in combination with antibacterial drugs. In particular, compounds I4, I5, I7, I8, I9, I10, and I11 of the present invention, having the general formula I structure, can reduce the minimum inhibitory concentration (MIC) of linezolid, oxacillin, and azithromycin by 4-8 times when used in combination. Compounds II1 to II10, having the general formula II structure, can reduce the MIC of erythromycin, linezolid, oxacillin, tetracycline, fusidic acid, and azithromycin by 4-16 times when used in combination. In particular, compound II10 can enhance the antibacterial efficacy of linezolid by 16 times. Compounds II11–II21, when used in combination with erythromycin, linezolid, oxacillin, tetracycline, fusidic acid, and azithromycin, can reduce their minimum inhibitory concentration (MIC) by 4–32 times. In particular, compound II17 can increase the potency of azithromycin by 32 times, and compound II19 can increase the potency of linezolid by 32 times. Compounds II22–II47, having the general formula II, can increase the antibacterial efficacy of antibiotics by 4–8 times when used in combination with erythromycin, linezolid, oxacillin, tetracycline, fusidic acid, azithromycin, minocycline, ampicillin, and piperacillin. In particular, II19, II31, II33, and II35 all exhibit antibacterial sensitization effects on the combined antibiotics, demonstrating a broad-spectrum synergistic antibacterial sensitization effect.

[0045] In embodiments of the present invention, the compounds exhibit good efflux inhibition activity. In particular, compounds I4, I7, II10, II11, II17, II22, and II31 demonstrate strong Nile red efflux inhibition activity, completely inhibiting Nile red efflux at a concentration of 50 μM. Compounds II2 and II19 also completely inhibit Nile red efflux at a concentration of 100 μM. Compound II12 exhibits general Nile red efflux inhibition activity.

[0046] This invention evaluates the outer membrane permeation stability of AcrB efflux pump inhibitors, specifically 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives. Experimental results showed that compounds I4, I7, II2, II10, II11, II12, II17, II19, II22, and II31 had no effect on bacterial outer membrane permeability at a concentration of 128 μg / mL, demonstrating that the antibacterial sensitization efficacy produced when these compounds are used in combination with antibiotics is not a mechanism of action involving outer membrane permeation.

[0047] This invention verifies the effect of AcrB efflux pump inhibitors, such as 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives, on the proton gradient of the bacterial inner membrane. This experiment was characterized using the DiSC3(5) fluorescence assay. The potential gradient of the proton kinetic potential of the fluorescent dye DiSC3(5) was measured using a fluorescence spectrophotometer to verify whether the compounds affect the cell inner membrane. Compounds I4, I7, II2, II10, II11, II12, II17, II19, II22, and II31 did not affect the proton gradient of the inner membrane at a measured concentration of 128 μg / mL, demonstrating that their antibacterial sensitizing activity is unrelated to the mechanism of disrupting the proton gradient of the inner membrane. Attached Figure Description

[0048] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0049] Figure 1 The results show the Nile infrared emission inhibition activity of compound II19 in general formula II of this invention. Detailed Implementation

[0050] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0051] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0052] Example 1

[0053] Preparation of 3-benzyloxyphenylhydrazine hydrochloride (2):

[0054]

[0055] 3-Benzyloxyaniline (starting material 1, 5.74 g, 28.8 mmol) was dissolved in 100 mL of concentrated hydrochloric acid. Under nitrogen protection, an aqueous solution of sodium nitrite (2.18 g, 31.7 mmol) (10 mL) was slowly added dropwise to the system below 0 °C, and the reaction mixture was stirred at this temperature for 1 hour. A solution of stannous chloride (14.3 g, 63.4 mmol) in concentrated hydrochloric acid (20 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. A large amount of precipitate precipitated. The precipitate was filtered, washed with anhydrous diethyl ether, and dried under vacuum to give 4.52 g of a pinkish-purple solid, i.e., intermediate 2, with a yield of 73%.

[0056] Preparation of 7-(benzyloxy)-3,3-dimethyl-2,3,4-9-tetrahydro-1H-carbazole (3):

[0057]

[0058] Intermediate 2 (5 g, 0.02 mol) was dissolved in 100 mL of anhydrous ethanol, and 4,4-dimethylcyclohexanone (3.03 g, 0.024 mol) and concentrated sulfuric acid (2 mL) were added. The reaction mixture was reacted at 80 °C for 2 hours. The solvent was evaporated to dryness under reduced pressure, and then ethyl acetate was added to the reaction mixture for extraction. The organic phases were combined and washed three times with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give 3.21 g of white solid, i.e., intermediate 3, with a yield of 45%.

[0059] Preparation of 7-(benzyloxy)-9-(4-fluorobenzyl)-3,3-dimethyl-2,3,4-9-tetrahydro-1H-carbazole (4a)

[0060]

[0061] Using N,N-dimethylformamide as a solvent, intermediate 3 (2.74 g, 8.98 mmol) prepared in Example 2 was dissolved therein, and potassium tert-butoxide (3.02 g, 26.93 mmol) and 4-fluorobenzyl bromide (1.43 g, 9.88 mol) were added. The mixture was reacted at room temperature for 6 hours, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed three times with saturated NaHCO3 solution, three times with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography yielded 2.51 g of a white solid, intermediate 4a, with a yield of 68%.

[0062] Preparation of 9-(4-fluorobenzyl)-3,3-dimethyl-2,3,4-9-tetrahydro-1H-carbazole-7-ol (4a-1):

[0063]

[0064] Intermediate 4a (1 g, 2.42 mmol) prepared in Example 3 was dissolved in dichloromethane, and a dichloromethane solution of boron trichloride was slowly added dropwise at -78°C. The reaction was carried out at -78°C for 1 hour. The reaction was quenched with anhydrous methanol, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography yielded 0.42 g of a white solid, i.e., intermediate 4a-1, with a yield of 54%.

[0065] Preparation of 9-(4-fluorobenzyl)-3,3-dimethyl-7-((2-methylbenzyl)oxy)-2,3,4-9-tetrahydro-1H-carbazole (I1):

[0066]

[0067] Using N,N-dimethylformamide as a solvent, intermediate 4a-1 (163 mg, 0.50 mmol) prepared in Example 4 was dissolved therein, and cesium carbonate (493.27 mg, 1.51 mmol) and 2-methylbenzyl bromide (106.44 mg, 0.77 mmol) were added. The reaction was carried out overnight at room temperature, water was added, and the mixture was extracted three times with an appropriate amount of ethyl acetate. The aqueous phase was discarded, and the combined organic phases were washed three times with saturated sodium chloride solution. After drying with anhydrous sodium sulfate and filtering, the mixture was evaporated to dryness under reduced pressure. The crude product was eluted by silica gel column chromatography to obtain the corresponding target product of general formula I, i.e., I1, in 81% yield.

[0068] Compounds I2-I11 were prepared according to the method described above.

[0069] The relevant characterization information of the target products of general formula I, namely I1-I11, is shown in Table 1.

[0070] Table 1

[0071]

[0072]

[0073]

[0074] Example 2

[0075] Preparation of 2-(7-(benzyloxy)-3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-1-(pyrrolidone-1-yl)acet-1-one (5a):

[0076]

[0077] Using N,N-dimethylformamide as a solvent, intermediate 3 (5 g, 16.38 mmol) prepared in Example 1 was dissolved therein, and potassium tert-butoxide (5.52 g, 49.15 mmol) and 1-(chloroacetyl)pyrrolidine (3.63 g, 24.58 mmol) were added. The reaction was carried out at room temperature for 6 hours, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed three times with saturated NaHCO3 solution, three times with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography yielded 4.23 g of a white solid, i.e., intermediate 5a, with a yield of 62%.

[0078] Intermediates 6a, 7a, 8a, 9a, 10a, 11a and 12a were prepared according to the method described above.

[0079] Preparation of 2-(7-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole-9-yl)-1-(pyrrolidone-1-yl)ethyl-1-one (5a-1):

[0080]

[0081] Intermediate 5a (1 g, 2.40 mmol) was dissolved in dichloromethane, and a dichloromethane solution of boron trichloride was slowly added dropwise at -78 °C. The reaction was carried out at -78 °C for 1 hour. The reaction was quenched with anhydrous methanol, and the solvent was evaporated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography yielded 0.36 g of a white solid, intermediate 5a-1, with a yield of 46%.

[0082] Intermediates 6a-1, 7a-1, 8a-1, 9a-1, 10a-1, 11a-1 and 12a-1 were prepared according to the method described above.

[0083] Preparation of 2-(3,3-dimethyl-7-((2-methylbenzyl)oxy)-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-1-(pyrrolidone-1-yl)acet-1-one (II1):

[0084]

[0085] The intermediate 5a-1 (1644 mg, 0.50 mmol) was dissolved in N,N-dimethylformamide as a solvent. Cesium carbonate (491.73 mg, 1.51 mmol) and 2-methylbenzyl bromide (139.65 mg, 0.75 mmol) were added, and the mixture was reacted overnight at room temperature. Water was added, and the mixture was extracted three times with an appropriate amount of ethyl acetate. The aqueous phase was discarded, and the combined organic phases were washed three times with saturated sodium chloride solution. After drying with anhydrous sodium sulfate and filtering, the mixture was evaporated to dryness under reduced pressure. The crude product was eluted by silica gel column chromatography to obtain the target product of general formula II, i.e., II1, in 78% yield.

[0086] Compound II2-II47 was prepared according to the method described above.

[0087] The relevant characterization information of the target product of general formula II, namely II2-II47, is shown in Table 2.

[0088] Table 2

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] Example 3

[0100] Assay of the antibacterial sensitizing activity of AcrB efflux pump inhibitors, specifically 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives:

[0101] This embodiment determines the minimum inhibitory concentration (MIC) of the target compounds (i.e., compounds I1-I11 and II1-II47 of the present invention) against E. coli BW25113 (wild-type, expressing AcrB protein) to eliminate the influence of the target compounds themselves on the engineered strain during combined drug administration, and to determine the concentration range of the target compounds during combined drug administration.

[0102] The MI of each of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives (i.e., compounds I1-I11 and II1-II47 of this invention) and linezolid (LIN), oxacillin (OXA), azithromycin (AZM), erythromycin (ERY), tetracycline (TET), fusidic acid (FUS), minocycline (MIN), ampicillin (AMP), and piperacillin (PIP) in this application was determined using the serial micropore two-fold dilution method. C. Based on the MIC results, the drug concentration ranges of linezolid, oxacillin, azithromycin, erythromycin, tetracycline, fusidic acid, minocycline, ampicillin, and piperacillin when used in combination with compounds I1-I11 and II1-II47 were determined. The antibacterial sensitizing effects of compounds I1-I11 and II1-II47 at concentrations of 8 μg / mL, 16 μg / mL, 32 μg / mL, 64 μg / mL, and 128 μg / mL were also determined.

[0103] Using the checkerboard micropore two-fold dilution method, compounds with strong antibacterial synergistic effects were screened based on the results of the above combined applications.

[0104] Tables 3 to 8 show the results of in vitro antibacterial activity studies of the compounds of the present invention in combination with antibacterial agents.

[0105] Table 3

[0106]

[0107]

[0108] Table 4

[0109]

[0110]

[0111] Table 5

[0112]

[0113]

[0114] Table 6

[0115]

[0116]

[0117] Table 7

[0118]

[0119]

[0120] Table 8

[0121]

[0122]

[0123] Experimental results show that the AcrB efflux pump inhibitor 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative of this invention exhibits good antibacterial sensitization activity against AcrB-expressing Escherichia coli. This is the first time such a compound has been discovered, possessing a novel structure and demonstrating good antibacterial sensitization activity against multiple classes of antibiotics.

[0124] Example 4

[0125] Assay of the efflux inhibition activity of AcrB efflux pump inhibitors, specifically 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives:

[0126] This embodiment verifies that the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives of the present invention (compounds I4, I7, II2, II10, II11, II12, II17, II19, II22, and II32 of the present invention) inhibit the efflux level of Nile Red, an efflux substrate of AcrB protein. The inhibitory effect on the efflux substrate Nile Red was characterized by fluorescence experiments. Nile Red usually shows very weak fluorescence in water-soluble media, which can be ignored. However, in non-polar environments such as cell membranes, its fluorescence level will rapidly increase. Based on this characteristic, compounds I4, I7, II2, II10, II11, II12, II17, II19, II22, and II32 were selected. Nile Red was mixed with the ion carrier CCCP and pre-loaded into bacterial cells, causing the cells to lose their energy source. Glucose was added to restore the cells' energy. The efflux of Nile Red will reduce its concentration in the cells, resulting in a decrease in fluorescence intensity. The fluorescence intensity at different times was observed using a fluorescence spectrophotometer to determine the degree of inhibition of efflux of Nile Red by the target compound, thereby determining its efflux inhibition effect.

[0127] Let's take compound II19 as an example for illustration, such as... Figure 1 As shown. Figure 1 The change in fluorescence intensity showed that compound II19 (i.e. Figure 1 Compound B9 significantly inhibited the efflux of Nile Red in a concentration-dependent manner, exhibiting excellent inhibitory activity. At a concentration of 100 μM, it showed superior effects compared to the positive control (PAβN), with an inhibition rate of 100% against Nile Red. In contrast, the wild-type E. coli BW25113 strain showed almost no inhibitory effect on Nile Red in the negative control.

[0128] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A 3,3-dimethyl-1,2,3,4-tetrahydro-9 H -Carbazole derivatives, characterized in that: Selected from at least one compound having the structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof: The compound of formula I is specifically selected from one of the following compounds: ； Alternatively, the compound of formula II may be specifically selected from one of the following compounds: 。 2. The 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-1,3 ... H A method for preparing carbazole derivatives, characterized in that: Includes the following steps: In an inert atmosphere and at low temperature, an aqueous solution of sodium nitrite was added to a concentrated hydrochloric acid solution of 3-benzyloxyaniline, and the mixture was stirred. Then, stannous chloride was added, and the reaction was carried out with stirring at room temperature to obtain intermediate 2. The structural formula of intermediate 2 is as follows: ; Add 4,4-dimethylcyclohexanone and concentrated sulfuric acid to a solution of intermediate 2, and heat to react, yielding intermediate 3. The structural formula of intermediate 3 is as follows: ; Potassium tert-butoxide and 4-fluorobenzyl bromide were added to a solution of intermediate 3, and the reaction was carried out at room temperature to obtain intermediate 4a. The structural formula of intermediate 4a is as follows: ; Boron trichloride solution was added to the solution of intermediate 4a at a temperature of -80 to -70°C, and the reaction was carried out at this temperature for 0.5 to 3 hours to obtain intermediate 4a-1. The structural formula of intermediate 4a-1 is as follows: ; Cesium carbonate and R were added to the solution of intermediate 4a-1. 1 -CH2Br, reacted at room temperature, yields compound of formula I; or, Add potassium tert-butoxide and 1-(chloroacetyl)pyrrolidine or 2-chloro-1-piperidin-1-yl ethyl ketone or 4-(2-chloroacetyl)morpholine or 2-chloro- N , N -Dimethylacetamide or N , N -Diethylchloroacetamide or 2-chloro- N , N -Dipropylacetamide or 1-azacyclohepta-1-yl-2-chloro-ethyl ketone or 2-chloro-1-(4-methylpiperidin-1-yl)ethyl ketone, reacted at room temperature, to generate intermediate 5', the structural formula of intermediate 5' is as follows. ; Boron trichloride solution was added to the solution of intermediate 5' at a temperature of -80 to -70°C, and the reaction was carried out at this temperature for 0.5 to 3 hours to generate intermediate 6'. The structural formula of intermediate 6' is as follows: ; Add cesium carbonate and R to the solution of intermediate 6' 1 -CH2Br, reacted at room temperature, yields a compound of general formula II; Among them, R 1 and R 2 As defined in claim 1.

3. The 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro ... H A method for preparing carbazole derivatives, characterized in that: Sodium nitrite aqueous solution is added to a concentrated hydrochloric acid solution of 3-benzyloxyaniline at a temperature below 0°C, and the mixture is stirred at this temperature for 0.5-2 hours.

4. The 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-1,3 ... H A method for preparing carbazole derivatives, characterized in that: After adding stannous chloride, the reaction is stirred at room temperature for 1-3 hours.

5. The 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro ...tetrahydro-1,2,3,4-tetrahydro-1,2,3,3-tetrahydro-1,2,3,3-te H A method for preparing carbazole derivatives, characterized in that: After adding 4,4-dimethylcyclohexanone and concentrated sulfuric acid to the intermediate 2 solution, the reaction is carried out at 70-90℃ for 1-3 hours to generate intermediate 3.

6. A pharmaceutical composition, characterized in that: This includes the 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-1,3 ... H - Carbazole derivatives and at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, characterized in that: The pharmaceutically acceptable excipients are selected from solvents, disintegrants, flavoring agents, preservatives, colorants, or binders; Alternatively, the dosage form of the pharmaceutical composition may be selected from injections, tablets, pills, capsules, suspensions, or emulsions.

8. The 3,3-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-9-dimethyl-1,2,3,4-tetrahydro-9-dimethyl-1,3 ... H - Use of carbazole derivatives or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating bacterial infections; The bacteria in question are those carrying the AcrB protein.

9. The application according to claim 8, characterized in that: The bacteria are Gram-negative bacteria that overexpress AcrB protein.

10. The application according to claim 9, characterized in that: The bacteria in question are Escherichia coli that overexpress the AcrB protein.

11. The application according to claim 8, characterized in that: The drug also includes an antibacterial drug selected from linezolid, oxacillin, azithromycin, erythromycin, tetracycline, fusidic acid, minocycline, ampicillin, or piperacillin.

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