3, 3-dimethyl-1, 2, 3, 4-tetrahydro-9H-carbazole derivative as well as preparation method and application thereof

Abstract

The invention discloses a 3, 3-dimethyl-1, 2, 3, 4-tetrahydro-9H-carbazole derivative as well as a preparation method and application thereof, the 3, 3-dimethyl-1, 2, 3, 4-tetrahydro-9H-carbazole derivative is selected from at least one of a compound with a structure shown in the following formula or pharmaceutically acceptable salt thereof, a solvent compound of the pharmaceutically acceptable salt, an enantiomer, a non-enantiomer and a tautomer: # imgabs0 #, in the formula, R1 is phenyl or substituted phenyl; and R2 is a 5-7-membered nitrogen heterocyclic ring or secondary amine.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative and a preparation method and application thereof, and in particular to an application thereof as an AcrB efflux pump inhibitor. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] The overuse of antibiotics has exerted strong selection pressure on bacteria, contributing to the emergence of drug-resistant strains. How to race against the speed of bacterial evolution is a challenge and problem recognized by the medical community.

[0004] On May 17, 2024, the World Health Organization released an updated version of the "2024 List of Priority Bacterial Pathogens", which still identified Escherichia coli pathogens as a key priority for the development of new treatment options. The mechanisms by which Gram-negative bacteria resist antibiotics are diverse, but they mainly prevent antibiotics from accumulating in bacteria through efflux pump transporters (AcrAB-TolC triple system) belonging to the RND superfamily. AcrB is an inner membrane transporter of the triple system, responsible for substrate recognition and energy transfer, and plays a decisive role in the system. 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 to combat antibiotic resistance, which can restore or improve the antimicrobial efficacy of traditional antibiotics and reduce the spread of bacterial resistance. Studies have shown that efflux pump inhibitors can reduce bacterial efflux, increase the accumulation of antibiotics in bacterial cells, and thus reverse the level of resistance. Moreover, efflux pump inhibitors are also 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 multidrug-resistant Gram-negative bacterial infections. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide a 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative and its preparation method and application. The compound of the present invention can reduce the minimum inhibitory concentration of Escherichia coli expressing AcrB by 32 times when used in conjunction with antibiotics.

[0006] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[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 a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a solvent compound of a pharmaceutically acceptable salt, an enantiomer, a diastereomer, and a tautomer:

[0008]

[0009] Among them, R 1 is 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 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 is pyrrolidine, piperidine, morpholine, cycloheximide, 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] In a second aspect, the present invention provides a method for preparing the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives, comprising the following steps:

[0019] In an inert atmosphere, at low temperature, an aqueous sodium nitrite solution is added to a concentrated hydrochloric acid solution of 3-benzyloxyaniline, the mixture is stirred and mixed, and then stannous chloride is added thereto, and the mixture is stirred and reacted at room temperature to obtain an 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 reacted at room temperature to obtain intermediate 4a;

[0022] Add boron trichloride solution to the solution of intermediate 4a at a temperature of -80 to -70°C and react at this temperature for 0.5 to 3 hours to obtain intermediate 4a-1;

[0023] Add cesium carbonate and benzyl bromide substituted with different groups to the solution of intermediate 4a-1, and react at room temperature to obtain a compound of formula I;

[0024] or,

[0025] Potassium tert-butoxide and 1-(chloroacetyl)pyrrolidine or 2-chloro-1-piperidin-1-yl ethanone or 4-(2-chloroacetyl)morpholine or 2-chloro-N,N-dimethylacetamide or N,N-diethylchloroacetamide or 2-chloro-N,N-dipropylacetamide or 1-azacycloheptan-1-yl-2-chloro-ethanone or 2-chloro-1-(4-methylpiperidin-1-yl)ethanone are added to the solution of intermediate 3 and reacted at room temperature to generate intermediate 5';

[0026] Adding boron trichloride solution to the solution of intermediate 5' at a temperature of -80 to -70°C and reacting at the temperature for 0.5 to 3 hours to generate intermediate 6';

[0027] Cesium carbonate and benzyl bromide substituted with different groups are added to the solution of intermediate 6' and reacted at room temperature to obtain a compound of formula II.

[0028]

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

[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 solution of intermediate 2, and the mixture is reacted at 70-90° C. for 1-3 hours to generate intermediate 3.

[0032] In a third aspect, 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 a solvent, a disintegrant, a flavoring agent, a preservative, a colorant or a binder.

[0034] In some embodiments, the pharmaceutical composition is in the form of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.

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

[0036] In some embodiments, the drug is a drug having antibacterial sensitization activity.

[0037] Preferably, the bacterium is a Gram-negative bacterium that overexpresses AcrB protein.

[0038] Further preferably, the bacterium is Escherichia coli overexpressing AcrB protein.

[0039] In some embodiments, the drug further comprises an antibacterial drug, and the antibacterial drug is selected from linezolid, oxacillin, azithromycin, erythromycin, tetracycline, fusidic acid, minocycline, ampicillin or piperacillin.

[0040] In a fifth aspect, the present invention provides the use of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives or the pharmaceutical composition in treating bacterial infections, wherein the bacteria are bacteria carrying AcrB proteins.

[0041] Preferably, the bacterium is a Gram-negative bacterium that overexpresses AcrB protein.

[0042] Further preferably, the bacterium is Escherichia coli overexpressing AcrB protein.

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

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

[0045] In an embodiment of the present invention, the compounds of the present invention have good efflux inhibition activity, especially compounds I4, I7, II10, II11, II17, II22 and II31 show strong Nile red efflux inhibition activity, and can completely inhibit the efflux of Nile red at a concentration of 50 μM. Compounds II2 and II19 can also completely inhibit the efflux of Nile red at a concentration of 100 μM. Compound II12 shows general efflux inhibition activity against Nile red.

[0046] The present invention evaluates the outer membrane permeability stability of AcrB efflux pump inhibitor 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives. The experimental results show that I4, I7, II2, II10, II11, II12, II17, II19, II22 and II31 have no effect on the bacterial outer membrane permeability at a concentration of 128 μg / mL, proving that the antibacterial sensitization effect produced when the compound is used in combination with antibiotics is not a mechanism of action for permeating the outer membrane.

[0047] The present invention verifies the effect of 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives, an AcrB efflux pump inhibitor, on the proton gradient of the bacterial inner membrane. The experiment is characterized by DiSC3(5) fluorescence determination method. The fluorescence spectrophotometer measures the potential gradient of the proton motive force of the fluorescent dye DiSC3(5) to verify whether the reaction compound has an effect on the cell inner membrane. Compounds I4, I7, II2, II10, II11, II12, II17, II19, II22 and II31 do not affect the inner membrane proton gradient at a determination concentration of 128 μg / mL, proving that the antibacterial sensitization activity produced by them is unrelated to the mechanism of destroying the inner membrane proton gradient. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0049] Figure 1 These are the results of the investigation of the Nile IR-rejection inhibitory activity of compound II19 in the general formula II of the present invention. DETAILED DESCRIPTION

[0050] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0051] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0052] Example 1

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

[0054]

[0055] 3-Benzyloxyaniline (raw material 1, 5.74 g, 28.8 mmol) was dissolved in 100 mL of concentrated hydrochloric acid. Under the protection of nitrogen, an aqueous solution (10 mL) of sodium nitrite (2.18 g, 31.7 mmol) was slowly added dropwise to the above system at below 0°C, and the reaction mixture was stirred at this temperature for 1 hour. A solution (20 mL) of stannous chloride (14.3 g, 63.4 mmol) in concentrated hydrochloric acid was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. A large amount of precipitate was precipitated, filtered, and the filter cake was washed with anhydrous ether. The filter cake was vacuum dried to obtain 4.52 g of a pink-purple solid, namely 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, and the mixture was reacted at 80 ° C for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and then ethyl acetate was added to the reaction solution for extraction. The organic phases were combined and washed three times with a saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 3.21 g of a white solid, namely 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 solvent, the intermediate 3 (2.74 g, 8.98 mmol) prepared in Example 2 was dissolved therein, potassium tert-butoxide (3.02 g, 26.93 mmol) and 4-fluorobenzyl bromide (1.43 g, 9.88 mol) were added, and the mixture was reacted at room temperature for 6 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic phase was washed three times with a saturated NaHCO3 solution, three times with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. Purification by silica gel column chromatography gave 2.51 g of a white solid, namely, 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] The 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, and the mixture was reacted at -78°C for 1 hour. Anhydrous methanol was added to quench the mixture, and the solvent was evaporated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography gave 0.42 g of a white solid, namely, 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 solvent, the intermediate 4a-1 (163 mg, 0.50 mmol) prepared in Example 4 was dissolved therein, cesium carbonate (493.27 mg, 1.51 mmol) and 2-methylbenzyl bromide (106.44 mg, 0.77 mmol) were added, and the mixture was reacted overnight at room temperature, and water was added, and an appropriate amount of ethyl acetate was extracted three times, and the aqueous phase was discarded, and the organic phase was combined and washed three times with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was eluted by silica gel column chromatography to obtain the corresponding target product of formula I, i.e., I1, with a yield of 81%.

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

[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-carbazole-9-yl)-1-(pyrrolidin-1-yl)ethan-1-one (5a):

[0076]

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

[0078] Intermediates 6a, 7a, 8a, 9a, 10a, 11a and 12a were prepared as described above.

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

[0080]

[0081] The prepared 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, and the mixture was reacted at -78°C for 1 hour. Anhydrous methanol was added to quench the mixture, and the solvent was evaporated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography gave 0.36 g of a white solid, namely 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 as described above.

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

[0084]

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

[0086] Compounds II2-II47 were prepared according to the above method.

[0087] The relevant characterization information of the target products 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] Determination of antibacterial sensitization activity of AcrB efflux pump inhibitor 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives:

[0101] In this example, the minimum inhibitory concentration (MIC) of the target compound (i.e., compounds I1-I11 and II1-II47 of the present invention) on E. coli BW25113 (wild type, expressing AcrB protein) was determined to exclude the effect of the target compound itself on the engineered strain when used in combination, and to determine the concentration range of the target compound when used in combination.

[0102] The MI of each 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative (i.e., compounds I1-I11 and II1-II47 of the present invention) and linezolid (LIN), oxacillin (OXA), azithromycin (AZM), erythromycin (ERY), tetracycline (TET), fusidic acid (FUS), minocycline (MIN), ampicillin (AMP), piperacillin (PIP) was determined by a continuous microwell 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, and the antibacterial sensitization effects of compounds I1-I11 and II1-II47 at concentrations of 8μg / mL, 16μg / mL, 32μg / mL, 64μg / mL and 128μg / mL were measured.

[0103] The checkerboard microwell two-fold dilution method was used to screen out compounds with stronger antibacterial synergistic effects 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] The experimental results show that the AcrB efflux pump inhibitor 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives of the present invention have good antibacterial sensitization activity against Escherichia coli expressing AcrB. This is the first time that such compounds have been discovered, with novel structures and good antibacterial sensitization activity against multiple types of antibiotics.

[0124] Example 4

[0125] Determination of the efflux inhibitory activity of AcrB efflux pump inhibitor 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives:

[0126] This example 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, and the inhibitory effect on the efflux substrate Nile red is characterized by a fluorescence experiment. Nile red usually shows very weak fluorescence in a water-soluble medium, which can be ignored, but in a non-polar environment such as a cell membrane, its fluorescence level will increase rapidly. According to this feature, compounds I4, I7, II2, II10, II11, II12, II17, II19, II22 and II32 are selected, and Nile red is mixed with the ion carrier CCCP and pre-loaded in bacterial cells, so that the cells lose their energy source, and glucose is added to restore energy to the cells. The efflux of Nile red will reduce its concentration in the cell, resulting in a weakening of the fluorescence intensity. The fluorescence intensity corresponding to different time periods is observed by a fluorescence spectrophotometer to judge the degree of inhibition of the efflux of Nile red by the target compound, thereby determining its efflux inhibition effect.

[0127] Take compound II19 as an example to illustrate. Figure 1 shown. Figure 1 The change in fluorescence intensity showed that compound II19 (i.e. Figure 1 Compound B9) in the assay significantly inhibited the efflux of Nile red in a concentration-dependent manner, showing excellent inhibitory activity. At a concentration of 100 μM, it showed an effect superior to that of the positive control (PAβN), with an inhibition rate of 100% against Nile red. In contrast, the wild-type E. coli BW25113 strain had almost no inhibitory effect on Nile red under the negative control.

[0128] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative, characterized in that: At least one selected from a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a solvent compound of a pharmaceutically acceptable salt, an enantiomer, a diastereomer, and a tautomer: Among them, R 1 is phenyl or substituted phenyl; R 2 It is a 5- to 7-membered nitrogen heterocycle or a secondary amine.

2. The 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative according to claim 1, characterized in that: The R 1 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 is pyrrolidine, piperidine, morpholine, cycloheximide, 4-methylpiperidine, dimethylamine, diethylamine or dipropylamine.

3. The 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative according to claim 1, characterized in that: The compound of formula I is specifically selected from one of the following compounds: Or, the compound of formula II is specifically selected from one of the following compounds:

4. The method for preparing the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives according to any one of claims 1 to 3, characterized in that: The steps include: In an inert atmosphere, at low temperature, an aqueous sodium nitrite solution is added to a concentrated hydrochloric acid solution of 3-benzyloxyaniline, the mixture is stirred and mixed, and then stannous chloride is added thereto, and the mixture is stirred and reacted at room temperature to obtain an intermediate 2; Add 4,4-dimethylcyclohexanone and concentrated sulfuric acid to the solution of the intermediate, and heat to react to obtain intermediate 3; Potassium tert-butoxide and 4-fluorobenzyl bromide were added to the solution of intermediate 3 and reacted at room temperature to obtain intermediate 4a; Add boron trichloride solution to the solution of intermediate 4a at a temperature of -80 to -70°C and react at this temperature for 0.5 to 3 hours to obtain intermediate 4a-1; Add cesium carbonate and benzyl bromide substituted with different groups to the solution of intermediate 4a-1, and react at room temperature to obtain a compound of formula I; or, Potassium tert-butoxide and 1-(chloroacetyl)pyrrolidine or 2-chloro-1-piperidin-1-yl ethanone or 4-(2-chloroacetyl)morpholine or 2-chloro-N,N-dimethylacetamide or N,N-diethylchloroacetamide or 2-chloro-N,N-dipropylacetamide or 1-azacycloheptan-1-yl-2-chloro-ethanone or 2-chloro-1-(4-methylpiperidin-1-yl)ethanone are added to the solution of intermediate 3 and reacted at room temperature to generate intermediate 5'; Adding boron trichloride solution to the solution of intermediate 5' at a temperature of -80 to -70°C and reacting at the temperature for 0.5 to 3 hours to generate intermediate 6'; Cesium carbonate and benzyl bromide substituted with different groups are added to the solution of intermediate 6' and reacted at room temperature to obtain a compound of formula II.

5. The method for preparing 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives according to claim 4, characterized in that: The temperature of adding the sodium nitrite aqueous solution to the concentrated hydrochloric acid solution of 3-benzyloxyaniline is below 0°C, and the reaction is stirred at this temperature for 0.5-2h; Preferably, after adding stannous chloride, the stirring reaction time at room temperature is 1-3 hours; Preferably, after adding 4,4-dimethylcyclohexanone and concentrated sulfuric acid to the solution of intermediate 2, the mixture is reacted at 70-90°C for 1-3h to generate intermediate 3.

6. A pharmaceutical composition, characterized in that: The invention comprises the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative according to any one of claims 1 to 3 and at least one pharmaceutically acceptable excipient.

7. The pharmaceutically acceptable excipient is selected from solvents, disintegrants, flavoring agents, preservatives, colorants or adhesives; Alternatively, the pharmaceutical composition is in the form of an injection, tablet, pill, capsule, suspension or emulsion.

8. Use of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivatives according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 6 in the preparation of drugs for treating bacterial infections; Or, use of the 3,3-dimethyl-1,2,3,4-tetrahydro-9H-carbazole derivative or the pharmaceutical composition in treating bacterial infection; The bacteria are bacteria carrying AcrB protein.

9. The use according to claim 8, characterized in that: The bacteria are Gram-negative bacteria that overexpress AcrB protein; Preferably, the bacterium is Escherichia coli overexpressing AcrB protein.

10. The use according to claim 8, characterized in that: The medicine also includes antibacterial drugs, which are selected from linezolid, oxacillin, azithromycin, erythromycin, tetracycline, fusidic acid, minocycline, ampicillin or piperacillin.

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