WO2023151359A1

WO2023151359A1 - Tetrahydrocarbazole derivative as well as preparation method therefor and use thereof

Info

Publication number: WO2023151359A1
Application number: PCT/CN2022/136302
Authority: WO
Inventors: 陈杰安; 陈学明; 蒋晨然; 刘运; 尹登
Original assignee: 深圳湾实验室; 深圳湾实验室坪山生物医药研发转化中心
Priority date: 2022-02-11
Filing date: 2022-12-02
Publication date: 2023-08-17
Also published as: CN114560804A

Abstract

Provided are a tetrahydrocarbazole derivative represented by general formula (I) as well as a preparation method therefor and the use thereof. By means of design of the molecular structure, the tetrahydrocarbazole derivative has an excellent anti-mycobacterium tuberculosis effect which is even better than that of isoniazid, and does not generate drug resistance to most mycobacterium tuberculosis. The preparation method has a high target product yield, few side reactions and controllable process conditions, and the tetrahydrocarbazole derivative prepared by the method has stable yield and performances.

Description

Tetrahydrocarbazole derivative and its preparation method and application

This application claims the priority of the Chinese patent application with the application number 202210131202.4 and the title of the invention "tetrahydrocarbazole derivatives and their preparation methods and applications" filed at the China Patent Office on February 11, 2022, the entire content of which Incorporated in this application by reference.

technical field

The application belongs to the technical field of medicinal chemistry, and specifically relates to tetrahydrocarbazole derivatives and their preparation methods and applications.

Background technique

Tuberculosis (TB) is an infectious disease caused by airborne transmission of its pathogen, Mycobacterium tuberculosis. At present, drug-resistant tuberculosis, especially multidrug-resistant and extensively drug-resistant tuberculosis, poses a serious threat to human health and even life, and has become a major challenge facing the world. According to the World Health Organization (WHO), tuberculosis has become the number one deadly infectious disease. my country is one of the countries with a high burden of tuberculosis in the world and one of the countries with the most serious problem of tuberculosis drug resistance.

Folic acid is involved in the synthesis of nucleic acid and protein, and is an important target of anti-tuberculosis drugs. DHFR (dihydrofolate reductase) is an important enzyme in organisms, which can catalyze the reduction of dihydrofolate to tetrahydrofolate. Different sources of DHFR have different primary protein structures. DHFR inhibitors can specifically combine with DHFR to inhibit its activity, so that dihydrofolate cannot be converted into tetrahydrofolate, hinder the metabolism of folic acid, and produce anti-tuberculosis and anti-cancer effects.

Since the advent of anti-tuberculosis drugs one after another, the treatment of tuberculosis has played an epoch-making change. However, due to the irregular treatment and management of tuberculosis patients, irregular chemotherapy and abuse of anti-tuberculosis drugs, the drug resistance of tuberculosis is becoming more and more serious, and the change of drug resistance tends to be multi-drug resistance at the same time. work caused great difficulty. Therefore, finding new anti-tuberculosis drugs, especially anti-multidrug resistance anti-tuberculosis drugs, is of great significance to protect people's health.

Although there are also public reports of anti-tuberculosis drugs, such as isoniazid. However, in clinical application, it is found that existing anti-tuberculosis drugs such as isoniazid have unsatisfactory anti-tuberculosis effects or lead to drug resistance and other deficiencies.

technical problem

The purpose of this application is to overcome the above-mentioned deficiencies in the prior art, provide a tetrahydrocarbazole derivative and its preparation method, to solve the existing anti-tuberculosis drugs have unsatisfactory anti-tuberculosis Mycobacterium effect or lead to the existence of drug resistance, etc. Inadequate technical issues.

technical solution

In order to achieve the purpose of the above application, the first aspect of the present application provides a tetrahydrocarbazole derivative. The molecular structural formula of the tetrahydrocarbazole derivatives of the present application is shown in the following general formula I:

Wherein, the same or different R1 and R2 in the general formula I are any one of aryl and heteroaryl.

The second aspect of the present application provides the preparation method of the tetrahydrocarbazole derivatives of the present application. The preparation method of tetrahydrocarbazole derivative of the present application comprises the steps:

The reactant A shown in the following structural formula I A and the reactant B shown in the following structural formula I B and the base catalyst are carried out in the first reaction solvent for the first substitution reaction, generating the first intermediate product shown in the following structural formula I Z1;

The first intermediate product, reducing agent and acidic additive are reversely carried out redox reaction in the second reaction solvent to generate the second intermediate product shown in the following structural formula I Z2;

The second intermediate product is carried out with the reactant C shown in the following structural formula I C and the composite catalyst in the third reaction solvent to carry out the second substitution reaction to generate the third intermediate product shown in the following structural formula I Z3;

In a protective atmosphere, the third intermediate product is condensed with aminoguanidine bicarbonate in a fourth reaction solvent to generate a tetrahydrocarbazole derivative shown in the following structural formula I;

Wherein, the same or different M1 in the formula I B and the M2 in the formula I c are halogen atoms, and the same or different R1 in the formula I B and the R2 in the formula I C are aryl, hetero Any of the aryl groups.

The third aspect of the present application provides the application of the tetrahydrocarbazole derivatives of the present application. The application of tetrahydrocarbazole derivatives as Mycobacterium tuberculosis inhibitors or in the preparation of anti-tuberculosis drugs.

Compared with the prior art, the tetrahydrocarbazole derivative provided by the first aspect of the present application has excellent anti-tuberculosis effect through the design of its molecular structure, and its anti-tuberculosis effect is even excellent for isoniazid, and it is effective for most Mycobacterium tuberculosis does not develop drug resistance.

The method for preparing tetrahydrocarbazole derivatives provided in the second aspect of the present application can synthesize the target product by designing the synthesis route of the reactant, so that the synthesized target product has excellent anti-tuberculosis effect. In addition, the yield of the target product is high, the side reactions are few, the process conditions are easy to control, and the yield and performance of the tetrahydrocarbazole derivatives prepared by the preparation are stable.

The tetrahydrocarbazole derivatives of the present application provided by the third aspect of the present application can effectively inhibit and kill Mycobacterium tuberculosis when used as Mycobacterium tuberculosis inhibitors or in the preparation of anti-tuberculosis drugs, the anti-tuberculosis effect is remarkable, and the anti-tuberculosis The MIC value of Mycobacterium tuberculosis is low; And most of Mycobacterium tuberculosis will not produce drug resistance.

Embodiments of the present invention

In order to make the technical problems, technical solutions and beneficial effects to be solved in the present application clearer, the present application will be further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described here are only used to explain the present application, and are not intended to limit the present application.

In this application, the term "and/or" describes the association relationship of associated objects, indicating that there may be three relationships, for example, A and/or B may mean: A exists alone, A and B exist simultaneously, and B exists alone Condition. Among them, A and B can be singular or plural. The character "/" generally indicates that the contextual objects are an "or" relationship.

In this application, "at least one" means one or more, and "multiple" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or plural items. For example, "at least one item (unit) of a, b, or c", or "at least one item (unit) of a, b, and c" can mean: a, b, c, a-b( That is, a and b), a-c, b-c, or a-b-c, where a, b, and c can be single or multiple.

It should be understood that in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not mean the order of execution, and some or all steps may be executed in parallel or sequentially, and the execution order of each process shall be based on its functions and The internal logic is determined and should not constitute any limitation to the implementation process of the embodiment of the present application.

Terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a" and "the" used in the embodiments of this application and the appended claims are also intended to include plural forms unless the context clearly indicates otherwise.

The weight of the relevant components mentioned in the description of the embodiments of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the various components. The scaling up or down of the content of the fraction is within the scope disclosed in the description of the embodiments of the present application. Specifically, the mass in the description of the embodiments of the present application may be μg, mg, g, kg and other well-known mass units in the chemical industry.

In the first aspect, the embodiment of the present application provides a tetrahydrocarbazole derivative. The molecular structural formula of the tetrahydrocarbazole derivative of the embodiment of the present application is shown in the following general formula I:

Wherein, the same or different R1 and R2 in the general formula I are any one of aryl and heteroaryl. In this way, the tetrahydrocarbazole derivatives in the examples of the present application have excellent anti-tuberculosis effects through the design of their molecular structures. It is known from the test that the tetrahydrocarbazole derivatives of the present application have low anti-tuberculosis MIC values, and their anti-tuberculosis effects are even superior to isoniazid, and they will not produce drug resistance to most tuberculosis bacteria.

Among them, the inventor found in the research that the types of R1 and R2 contained in the tetrahydrocarbazole derivatives of the embodiments of the present application have an impact on their anti-tuberculosis effect, such as R1 and R2 are the same or different for aryl, hetero On the basis of any one of the aryl groups, by further optimizing the groups represented by R1 and R2, the anti-tuberculosis effect of the tetrahydrocarbazole derivatives in the examples of the present application can be further optimized and improved.

As in the embodiment, when the same or different R1 and R2 are aryl groups, the aryl groups may include any of phenyl, monosubstituted phenyl, and polysubstituted phenyl. In a specific embodiment, the substituent group in the monosubstituted phenyl group may include any one of a halogen atom, -CF3, -C≡CH, -C≡N, -NO2, -OCH3. In other specific embodiments, the substituent groups in the polysubstituted phenyl group may include at least one of halogen atoms and -OCH3. Select these phenyls, monosubstituted phenyls, polysubstituted phenyls, or further control and optimize the substituting groups of the monosubstituted phenyls, polysubstituted phenyls, and further improve the tetrahydrocarbazole derivatives of the present application examples. The anti-tuberculosis activity further reduces the MIC value of its anti-tuberculosis.

As in other embodiments, when R1 and R2 are identical or not identical to heteroaryl, the heteroaryl may include any of pyrrole, substituted pyrrole, thiophene, substituted thiophene, pyridine, substituted pyridine, pyrimidine, and substituted pyrimidine kind. In a specific embodiment, the substituent group in the substituted pyrrole may include -OCH3. Substituent groups in substituted thiophenes may include -C≡N. Heteroaryl, or further control and optimize the substituent groups of these substituted pyrroles, substituted thiophenes, substituted pyridines, and substituted pyrimidines to further improve the anti-tuberculosis activity of tetrahydrocarbazole derivatives in the examples of the present application, and further reduce their MIC value against tuberculosis is low.

Based on the groups represented by R1 and R2 in the above-mentioned embodiments, in specific embodiments, the tetrahydrocarbazole derivatives in the embodiments of the present application can at least be at least one of the following molecular structural formulas I 1 to structural formula I 10:

Each tetrahydrocarbazole derivative mentioned above has high anti-tuberculosis activity, and its anti-tuberculosis MIC value is low. As shown in the in vitro anti-mycobacterium tuberculosis activity test of the tetrahydrocarbazole derivatives shown in I 1 to I 10 above, the activities of I 3 to I 5 and I 8 are equivalent to isoniazid, and the activities of I 6 and I 7 are equivalent to those of isoniazid. Activity is better than isoniazid.

On the other hand, the examples of the present application provide the preparation method of tetrahydrocarbazole derivatives in the above examples of the application. The preparation method of the tetrahydrocarbazole derivative of the embodiment of the present application comprises the following steps:

S01: The reactant A shown in the following structural formula I A, the reactant B shown in the following structural formula I B and the base catalyst are subjected to the first substitution reaction in the first reaction solvent to generate the first intermediate shown in the following structural formula I Z1 product;

S02: the first intermediate product, reducing agent, and acidic additive are reversely carried out in a second reaction solvent for oxidation-reduction reaction to generate the second intermediate product shown in the following structural formula I Z2;

S03: the second intermediate product is carried out with the reactant C shown in the following structural formula I C and the composite catalyst in the third reaction solvent for the second substitution reaction, generating the third intermediate product shown in the following structural formula I Z3;

S04: In a protective atmosphere, the third intermediate product is condensed with aminoguanidine bicarbonate in a fourth reaction solvent to generate a tetrahydrocarbazole derivative shown in the following structural formula I.

Wherein, reactant A and reaction B in step S01 can be obtained according to existing methods. As in the examples, the reactant A (Chinese name: 2(6-nitro-7-fluoro-2,3,4,9-tetrahydrocarbazol-1-one)) shown in structural formula I A can but not only Synthesize only as follows:

S011: 4-nitro-5-fluorophenylhydrazine (reaction product A1) shown in the following structural formula I A1, 2-cyclohexanedione (reaction product A2) shown in structural formula I A2 in the first acid reaction solution Carry out substitution reaction in, generate the reaction product A3 shown in structural formula Ⅰ A3;

S012: Refluxing the reaction product A3 with the second acid reaction solution to generate reactant A.

According to the synthesis route of reactant A in the above-mentioned embodiment, the total synthetic chemical reaction formula of reactant A is shown in the following reaction formula (1):

Wherein, the mixing ratio of 4-nitro-5-fluorophenylhydrazine and 2-cyclohexanedione in step S011 can be mixed according to the molar ratio shown in chemical reaction formula (1), in order to improve the yield of reaction product A3 , wherein one of the reactants 4-nitro-5-fluorophenylhydrazine or 2-cyclohexanedione can be in excess. In an embodiment, the first acid reaction solution includes one or more of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc., and hydrochloric acid is further selected. The concentration of the first acid reaction solution should be conducive to the yield of the reaction product A3 and the forward reaction rate. As in a specific embodiment, when the first acid reaction solution is hydrochloric acid, its concentration can be but not only 1moL/L. The addition amount of reactant 4-nitro-5-fluorophenylhydrazine can also be mixed according to the hydrochloric acid solution mixing ratio of 30g 4-nitro-5-fluorophenylhydrazine and 700mL (1moL/L). In addition, the substitution reaction in step S011 may be under reflux conditions and the temperature may be 30°C to 150°C, further 105°C. Fully react, such as stirring at reflux for 20 hours.

In a specific embodiment, S011 can be carried out as follows:

According to the ratio of 30g of 4-nitro-5-fluorophenylhydrazine, 21g of 1,2-cyclohexanedione and 700mL of 1moL/L hydrochloric acid solution, the components were mixed, and then refluxed and stirred for 12 hours to form a reaction Product A3.

The second acid reaction solution in step S012 may include one or more of hydrochloric acid, sulfuric acid, nitric acid, acetic acid, etc., and further be a mixed solvent of hydrochloric acid and acetic acid. In a specific embodiment, in the mixed solvent of hydrochloric acid and acetic acid, concentrated hydrochloric acid and glacial acetic acid can be but not only according to 400mL: 100mL. The concentration of the reaction product A3 in the mixture reaction solution of concentrated hydrochloric acid and glacial acetic acid can be, but not only mixed according to the mixing ratio of 30 g of 4-nitro-5-fluorophenylhydrazine reactant in step S011 and 400 mL of concentrated hydrochloric acid. The temperature of the reflux reaction in step S012 is controlled at 20°C to 200°C, further to 90°C.

In a specific embodiment, S012 can be carried out as follows:

The reaction product A3 in step S011 was mixed with concentrated hydrochloric acid and glacial acetic acid at a volume ratio of 400:100, and stirred under reflux for 20 hours to generate reactant A.

The R1 contained in the reactant B in step S01 is the R1 contained in the general formula I of the tetrahydrocarbazole derivative molecular structure in the above application example. Therefore, R1 is any of aryl and heteroaryl. The M1 contained in the reactant B is a halogen atom, specifically but not only a bromine atom (Br). Therefore, reactant B may be a benzyl bromide compound. Then, during the first substitution reaction between the reactant A and the reactant B in step S01, the R1 contained in the reactant B replaces the hydrogen atom of the secondary amine contained in the reactant A.

In an embodiment, the first reaction solvent in step S01 may include N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diethylene glycol dimethyl At least one of ether, toluene and methylene chloride. The base catalyst includes at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide, and is further cesium carbonate. The concentration of the base catalyst in the first reaction solvent can be but not only 0.025moL/L. In the first substitution reaction system, the reactant B can be slightly excessive relative to the reactant, as in the example, the reactant A and the reactant B can be mixed according to the molar ratio of 5:5.1, but not only. The concentration of reactant A in the first reaction solvent can be but not only 0.025 moL/L. The temperature of the first substitution reaction may range from 0°C to 100°C. By controlling and selecting the reactants, solvents and types of the first substitution reaction system, the yield of the first intermediate product can be increased, and the rate of the forward reaction can be increased.

Therefore, the chemical reaction formula of the first substitution reaction between reactant A and reactant B in step S01 is shown in the following reaction formula (2):

In a specific embodiment, the first substitution reaction in step S01 can be carried out as follows:

According to the mixing ratio of 5mmol compound A, 200mL DMF, 5mmol cesium carbonate and 5.1mmol reactant B, the components were mixed and reacted at room temperature to generate the first intermediate product.

After the first substitution reaction is completed, the first intermediate product can be separated and purified. In an embodiment, the method for separating and purifying the first intermediate product includes the following steps:

Carry out solid-liquid separation to the mixed solution after the first substitution reaction, filter out the solid, add saturated ammonium chloride solution, adjust the pH of the solution to 6-7, extract three times with ethyl acetate, combine the organic phases, and wash with saturated sodium chloride The solution was washed, and the organic phase was rotary evaporated to obtain the first intermediate product as a solid.

In step S02, according to the second intermediate product shown in the structural formula I Z2 generated, the chemical reaction formula of the redox reaction is shown in the following reaction formula (3):

In the first intermediate product in step S02, in the presence of a reducing agent and an acidic additive, the nitro group contained in the first intermediate product reacts to generate -NH2, that is, to generate aniline. In an embodiment, the acidic additive in step S02 adjusts the pH value of the second reaction solvent, if it is acidic, it ensures that the nitro group finally generates -NH2. Thus, in embodiments, the acidic additive may include ammonium chloride. In an embodiment, the concentration of the acidic additive in the second reaction solvent may be 1moL/L. The second reaction solvent can be a solution that can effectively dissolve the reactants and acidic compounds, such as dichloromethane, acetone, 1,4-dioxane, acetonitrile, ethanol, isopropanol, isopropanol and water One or more of the mixed solutions. Wherein, in the mixed solution of isopropanol and water, the volume ratio of isopropanol to water may be but not only 4:1.

In an embodiment, the reducing agent may include at least one of iron powder and zinc powder. In the oxidation-reduction reaction system, the reducing agent can be mixed with the reducing agent in a molar ratio of 25:5 according to the molar ratio of the first intermediate product. The concentration of the reducing agent in the second reaction solvent may be 0.5 moL/L. In addition, the temperature of the redox reaction may be 20°C to 200°C. By controlling and selecting the reactants, concentrations and types of the redox reaction, the yield of the second intermediate product can be increased, and the rate of the forward reaction of the redox reaction can be increased.

In a specific embodiment, the redox reaction in step S02 can be carried out as follows:

According to the ratio of 5mmoL of the first intermediate product, 25mmol of iron powder, 50mmoL of ammonium chloride, and 50ml of isopropanol-water (4:1), the components were mixed and reacted at 90°C for 15 hours under reflux and stirring.

After the redox reaction is finished, the second intermediate product can be separated and purified. In an embodiment, the method for separating and purifying the second intermediate product includes the following steps:

After the mixed solution after redox reaction was cooled, the solvent was evaporated under reduced pressure, water was added to dissolve the residue, the pH value was adjusted to 8-9 with sodium bicarbonate, extracted with ethyl acetate, and the organic layer was washed twice with water. Wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure; the residue is purified by silica gel column chromatography with ethyl acetate as the eluent to obtain the second intermediate product.

The R2 contained in the reactant C in step S03 is the R2 contained in the general formula I of the tetrahydrocarbazole derivative molecular structure in the above application example. Therefore, R2 is any of aryl and heteroaryl. The M2 contained in the reactant C is a halogen atom, specifically but not only a bromine atom (Br). Thus, reactant C may be an aryl bromide. Then in step S03, during the second substitution reaction between the second intermediate product and the reactant C, the R2 contained in the reactant C replaces the hydrogen atom of -NH2 contained in the second intermediate product. According to the reaction type, in the embodiment, in the second substitution reaction system, in the embodiment, the composite catalyst includes at least one or a mixture of palladium catalyst, ligand and base. Wherein, the palladium catalyst may include at least one of palladium acetate, tetrakistriphenylphosphine palladium and palladium dichloride, and its concentration in the third reaction solvent may be 0.0002 mol/L. The ligand may include at least one of binaphthol and bipyridine. The base may include at least one of sodium tert-butoxide, sodium hydride and potassium tert-butoxide, and its concentration in the third reaction solvent may be 0.02moL/L.

The third reaction solvent should be a solvent that can effectively dissolve each reactant, such as including N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diethyl At least one of glycol dimethyl ether, toluene and methylene chloride.

In the second substitution reaction system, the reactant C may be in a slight excess relative to the reactant. As in the embodiment, the second intermediate product and the reactant C may be mixed in a molar ratio of 1:1. The concentration of the second intermediate product in the third reaction solvent may be 0.02 moL/L. In addition, the temperature of the second substitution reaction is 20°C to 200°C. By controlling and selecting the reactant, solvent concentration and type of the second substitution reaction system, the yield of the third intermediate product can be increased, and the rate of the forward reaction can be increased. Therefore, the second substitution reaction chemical reaction formula between the second intermediate product and reactant C in step S03 is shown in the following reaction formula (4):

In a specific embodiment, the second substitution reaction in step S03 can be carried out as follows:

Under argon protection, according to the mixing ratio of the second intermediate product (2mmoL), reactant C (2mmol), palladium acetate (0.02mmoL), binaphthol (0.04mmoL), sodium tert-butoxide (2mmol) and toluene 100ml The reactants were mixed with the solvent and reacted at 100°C for 10 hours.

After the second substitution reaction is completed, the third intermediate product can be separated and purified. In an embodiment, the method for separating and purifying the third intermediate product includes the following steps:

Filter the mixed solution after the second substitution reaction with diatomaceous earth, add saturated ammonium chloride solution to adjust the pH value to 6-7, extract with ethyl acetate and wash with saturated brine; the organic phase is evaporated under reduced pressure. Solvent, the residue was subjected to silica gel column chromatography, and the eluent was a mixed solvent of dichloromethane and methanol; the pure product fractions were collected, and the solvent was rotary evaporated under reduced pressure to obtain the pure product third intermediate product.

In step S04, the chemical reaction formula of the condensation reaction between the third intermediate product and aminoguanidine bicarbonate in the fourth reaction solvent is shown in the following reaction formula (5):

In an embodiment, the concentration of the aminoguanidine bicarbonate in the fourth reaction solvent may be 0.05moL/L. The fourth reaction solvent may be a solution capable of effectively dissolving various reactants, for example, may include one or more of methanol, ethanol, acetone, 1,4-dioxane, acetonitrile, toluene and methylene chloride. In the condensation reaction system, the aminoguanidine bicarbonate can be slightly excessive relative to the third intermediate product. As in the embodiment, the aminoguanidine bicarbonate and the third intermediate product can be mixed in a molar ratio of 2:1.5. In addition, the temperature of the condensation reaction may be 20°C to 200°C. By controlling and selecting the reactants and their concentrations in the condensation reaction system, the yield of the final product tetrahydrocarbazole derivatives can be increased, and the rate of the forward reaction can be increased.

In a specific embodiment, the condensation reaction in step S04 can be carried out as follows:

According to the mixing ratio of 2mmol aminoguanidine bicarbonate, 1.5mmoL of the third intermediate product, and 40ml of ethanol solution, the components were mixed and treated, protected by argon, and refluxed for 10 hours.

After the condensation reaction is finished, the final product tetrahydrocarbazole derivatives can be separated and purified. In the embodiment, the method for separating and purifying the final product tetrahydrocarbazole derivative includes the following steps:

After cooling the mixed solution after the condensation reaction, the solvent was distilled off under reduced pressure to obtain a brown residue; after separation by silica gel column chromatography (dichloromethane:methanol=10:1), the pure product represented by structural formula I was obtained. Tetrahydrocarbazole derivatives.

From the above-mentioned preparation method of tetrahydrocarbazole derivatives in the examples of the present application, it can be seen that the target product can be synthesized by designing the synthesis route of the reactant, so that the synthesized target product has excellent anti-tuberculosis effect. In addition, the yield of the target product is high, the side reactions are few, the process conditions are easy to control, and the yield and performance of the tetrahydrocarbazole derivatives prepared by the preparation are stable.

In the research, the inventor found that the tetrahydrocarbazole derivatives in the above application examples have the effect of inhibiting and killing Mycobacterium tuberculosis, and the effect is excellent. Therefore, based on the tetrahydrocarbazole derivative and its preparation method in the above application example, the application method of the tetrahydrocarbazole derivative in the above application example is also provided in the example of the present application. Based on the examples of the present application, tetrahydrocarbazole derivatives have the effect of inhibiting and killing Mycobacterium tuberculosis, and can be used as Mycobacterium tuberculosis inhibitors or in the preparation of anti-tuberculosis drugs. In this way, tuberculosis can be effectively inhibited and killed, and the effect of anti-tuberculosis is remarkable, and it is known through experiments that the MIC value of anti-tuberculosis is low, and drug resistance to most tuberculosis will not be produced.

In order to make the above-mentioned implementation details and operations of the present application clearly understood by those skilled in the art, as well as the remarkable performance of the tetrahydrocarbazole derivatives and their preparation methods and applications in the embodiments of the present application, the following are described through multiple examples Give an example to illustrate the above-mentioned technical solution.

1. Tetrahydrocarbazole derivatives and their preparation methods and their preparation methods

Example 1

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I1.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in above formula I 1 comprises the steps:

S1: Synthesis of reactant A3 and reactant A above:

Synthesis of reactant A3: According to the synthetic route shown in the above reaction formula (1), in a 1000mL round bottom flask, add 30g of 4-nitro-5-fluorophenylhydrazine, 21g of 1,2-cyclohexanedi Ketone and 1M hydrochloric acid solution 700mL, then refluxed and stirred for 12 hours; cooled and filtered to obtain crude product 1, which was directly carried out to the next step without purification.

Synthesis of reactant A: According to the synthetic route shown in the above reaction formula (1), add 400 mL of concentrated hydrochloric acid and 100 mL of glacial acetic acid to the crude product of synthetic reactant A3, and stir at reflux for 20 hours; The solvent was removed and recrystallized from ethanol to obtain 15 g of solid reactant A (2(6-nitro-7-fluoro-2,3,4,9-tetrahydrocarbazol-1-one)).

S2: Synthesis of the first intermediate product shown in the above structural formula Ⅰ Z1:

Take 5mmol of reactant A, add DMF 200mL, cesium carbonate 5mmol and corresponding p-fluorobenzyl bromide 5.1mmol, and react at room temperature. After the reaction was complete, filter out the solid, add 200 mL of saturated ammonium chloride solution, adjust the pH of the solution to 6-7, extract three times with ethyl acetate, combine the organic phases, and wash once with saturated sodium chloride solution. The organic phase was rotary evaporated to obtain a solid residue, that is, the first intermediate product shown in the above structural formula I Z1, without purification, directly proceed to the next step.

S3: Synthesis of the second intermediate product shown in the above structural formula I Z2:

Add the first intermediate product (5mmoL), iron powder (25mmol) and ammonium chloride (50mmoL) into 50ml of isopropanol-water (4:1), and react under reflux at 90°C for 15 hours; Solvent, add water to the residue to dissolve, adjust the pH value to 8-9 with sodium bicarbonate, extract with ethyl acetate, wash the organic layer twice with water, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, evaporate under reduced pressure The solvent was removed; the residue was purified by silica gel column chromatography, the eluent was ethyl acetate, and the pure product was the second intermediate product.

S4: Synthesis of the third intermediate product shown in the above structural formula I Z3:

Under argon protection, in a 250mL round bottom flask, add the second intermediate product (2mmoL) synthesized in step S3, bromobenzene (2mmol), palladium acetate (0.02mmoL), binaphthol (0.04mmoL), tert-butyl Sodium alkoxide (2mmol) and 100ml of toluene were reacted at 100°C for 10 hours; after the reaction, the solution was filtered with diatomaceous earth, and then saturated ammonium chloride solution was added to adjust the pH value to 6-7; extracted three times with ethyl acetate, saturated salt Wash once with water; the organic phase was evaporated under reduced pressure to remove the solvent, and the residue was subjected to silica gel column chromatography, and the eluent was a mixed solvent of dichloromethane and methanol; Three intermediate products (R2 contained in the structural formula I Z3 is phenyl).

S5: Synthesis of 2,3,4,9-tetrahydrocarbazole derivatives shown in the above structural formula I 1:

Put 2mmol of aminoguanidine bicarbonate and 1.5mmol of the third intermediate product synthesized in step S4 into a 50mL round-bottomed flask, protect with argon, then add 40ml of ethanol solution, and reflux for 10 hours; TLC detection, after the disappearance of raw materials, cool , the solvent was distilled off under reduced pressure to obtain a brown residue. After separation by silica gel column chromatography (dichloromethane:methanol=10:1), 0.62 g of the target compound represented by the above structural formula I1 was obtained with a yield of 90%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I1 are as follows:

1H NMR (400MHz, DMSO-d6) 11.01(s, 1H), 8.02(d, J=9.4Hz, 1H), 7.25-7.45(m, 5H), 7.22-7.34(m, 4H), 7.18(s, 1H ),6.92(s,1H),5.20(s,2H),4.20(m,1H),1.70-2.84(m,6H).HRMS theoretical value C27H26F2N6[M+H]+: theoretical value: 472.2234, measured value : 472.2237.

Example 2

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 2.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in above formula I 2 comprises the steps:

S1: Synthesis of reactant A3 and reactant A respectively with reference to step S1 in Example 1:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by p-nitrobenzyl bromide.

S3: Synthesize the second intermediate product shown in the above structural formula I Z3 with reference to step S3 in Example 1.

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by p-fluorobromobenzene.

S5: Referring to step S5 in Example 1, 0.64 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized with a yield of 85%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I2 are as follows:

1H NMR (400MHz, DMSO-d6) 11.01 (s, 1H), 8.16 (d, J = 15Hz, 2H), 8.03 (d, J = 9.4Hz, 1H), 7.42 (d, J = 15Hz, 2H), 7.39 (d,J=9.6Hz,2H),7.28(d,J=9.6Hz,2H),7.18(s,1H),6.92(s,1H),5.18(s,2H),4.21(m,1H) ,1.70-2.84(m,6H). HRMS theoretical value C27H25F2N7O2[M+H]+: 517.2014, measured value: 517.2016.

Example 3

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 3.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in formula I 3 above comprises the steps:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by p-methoxybenzyl bromide.

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by p-trifluoromethyl bromobenzene.

S5: Referring to step S5 in Example 1, 0.77 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized; the yield was 95%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I are as follows:

1H NMR (400MHz, DMSO-d6) 11.03 (s, 1H), 8.03 (d, J = 9.4Hz, 1H), 7.52 (d, J = 13Hz, 2H), 7.39 (d, J = 13Hz, 2H), 7.29 (d,J=9.2Hz,2H),7.18(s,1H),6.92(s,1H),6.78(d,J=9.2Hz,2H),5.18(s,2H),4.21(m,1H) ,3.80(s,3H),1.70-2.84(m,6H).HRMS theoretical value C29H28F4N6O[M+H]+: 552.2304, found value: 552.2305.

Example 4

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 4.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in above formula I 4 comprises the steps:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by p-ethynylbenzyl bromide.

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by 3,4-difluorobromobenzene.

S5: Referring to step S5 in Example 1, 0.70 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized; the yield was 93%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I are as follows:

1HNMR (400MHz, DMSO-d6) 11.03(s, 1H), 8.03(d, J=9.4Hz, 1H), 7.20-7.44(m, 7H), 7.18(s, 1H), 6.92(s, 1H), 5.18(s,2H), 4.21(m,1H), 3.04(s,1H), 1.72-2.83(m,6H). HRMS theoretical value C29H25F3N6[M+H]+: 514.2104, measured value: 514.2105.

Example 5

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I5.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in formula I 5 above comprises the steps:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by 1,4-dibenzyl bromide.

S5: Referring to step S5 in Example 1, 0.62 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized, with a yield of 89%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I are as follows:

1H NMR (400MHz, DMSO-d6) 11.01 (s, 1H), 8.17 (d, J = 15Hz, 2H), 8.01 (d, J = 10.4Hz, 2H), 7.21-7.42 (m,, 3H), 7.18 ( s,1H),7.05(d,J=10.4Hz,2H),6.92(s,1H),5.11(s,2H),4.21(m,1H),1.70-2.84(m,6H).HRMS theoretical value C27H24BrF3N6.[M+H]+: 568.1210, found: 568.1211.

Example 6

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 6.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in formula I 6 above comprises the steps:

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by p-ethynyl bromobenzene.

S5: Referring to step S5 in Example 1, 0.75 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized with a yield of 92%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I6 are as follows:

1H NMR (400MHz, DMSO-d6) 11.01 (s, 1H), 7.89 (d, J = 14Hz, 2H), 8.03 (d, J = 9.4Hz, 1H), 7.42 (d, J = 10Hz, 2H), 7.25 (d,J=10Hz,2H),7.15(s,1H),7.05(d,J=14Hz,2H),6.93(s,1H),5.19(s,2H),4.21(m,1H),3.01 (s, 1H), 1.70-2.84 (m, 6H). HRMS theoretical value C29H26BrFN6[M+H]+: 556.1421, found value: 556.1420.

Example 7

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 7.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in formula I 7 above comprises the steps:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by 1-bromo-3,4,5-trimethoxybenzyl.

S5: Referring to step S5 in Example 1, 0.72 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized; the yield was 87%. The obtained product confirms the structure through high resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I are as follows:

1H NMR (400MHz, DMSO-d6) 11.01(s, 1H), 8.03(d, J=9.4Hz, 1H), 7.44(d, J=10Hz, 2H), 7.23(d, J=10Hz, 2H), 7.15 (s,1H),6.93(s,1H),6.54(s,2H),4.21(m,1H),3.78(s,9H),3.03(s,1H),1.70-2.84(m,6H). HRMS theoretical value C32H33FN6O3[M+H]+: 568.2610, found value: 568.2613.

Example 8

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in the above formula I 8.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in above formula I 8 comprises the steps:

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by p-cyanobromobenzene.

S5: Referring to step S5 in Example 1, 0.71 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized with a yield of 85%. The obtained product confirms the structure through high-resolution mass spectrometry and nuclear magnetic resonance, and the mass spectrometry and nuclear magnetic resonance results of the 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I8 are as follows:

1H NMR (400MHz, DMSO-d6) 10.98(s, 1H), 8.04(d, J=9.4Hz, 1H), 7.48(d, J=10Hz, 2H), 7.23(d, J=10Hz, 2H), 7.15 (s,1H),6.93(s,1H),6.55(s,2H),4.21(m,1H),3.78(s,9H),1.70-2.84(m,6H).HRMS theoretical value C31H32FN7O3[M+ H]+: theoretical value: 569.2620, measured value: 568.2618.

Example 9

This example provides a 2,3,4,9-tetrahydrocarbazole derivative and a preparation method thereof. The structural formula of the 2,3,4,9-tetrahydrocarbazole derivative is shown in Formula I 9 above.

The preparation method of 2,3,4,9-tetrahydrocarbazole derivatives shown in formula I 9 above comprises the steps:

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by 2-bromo-6-methoxypyridine.

S4: Synthesize the third intermediate product shown in the above structural formula IZ3 with reference to step S4 in Example 1. The difference is that the reactant bromobenzene is replaced by 3-bromopyridine.

S5: Referring to step S5 in Example 1, 0.58 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized; the yield was 92%. The resulting product is confirmed by high-resolution mass spectrometry and nuclear magnetic resonance. The mass spectrometry and nuclear magnetic resonance results of 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I9 are as follows:

1HNMR (400MHz, DMSO-d6) 11.03(s, 1H), 8.05(s, 1H), 8.03(d, J=9.4Hz, 1H), 7.30-7.92(m, 8H), 5.01(s, 2H), 4.21 (m, 1H), 3.80 (s, 3H), 1.70-2.84 (m, 6H). HRMS theoretical value C26H27FN8O[M+H]+: theoretical value: 486.2304, measured value: 486.2303.

Example 10

S2: Synthesize the first intermediate product shown in the above structural formula IZ1 with reference to step S2 in Example 1. The difference is that the reactant p-fluorobenzyl bromide is replaced by 2-bromomethyl-6-cyanothiophene.

S5: Referring to step S5 in Example 1, 0.59 g of the 2,3,4,9-tetrahydrocarbazole derivative shown in the above structural formula I2 was synthesized; the yield was 84%. The resulting product is confirmed by high-resolution mass spectrometry and nuclear magnetic resonance. The mass spectrometry and nuclear magnetic resonance results of 2,3,4,9-tetrahydrocarbazole derivatives shown in structural formula I9 are as follows:

1HNMR (400MHz, DMSO-d6) 11.03(s, 1H), 8.05(s, 1H), 8.03(d, J=9.4Hz, 1H), 7.30-7.92(m, 7H), 5.14(s, 2H), 4.21(m,1H),1.70-2.84(m,6H).HRMSC25H23FN8S[M+H]+: theoretical value: 486.1814, measured value: 486.1815.

other embodiments

Based on the method of the above-mentioned embodiment 1 to embodiment 10, the types of the group R1 contained in the reactant B and the group R2 contained in the reactant C can be selected, such as the group R1 contained in the reactant B in the above-mentioned embodiment 1 The same or different group R2 contained in reactant C is replaced by substituted or unsubstituted pyrrole, pyrimidine and other groups to synthesize the corresponding tetrahydrocarbazole derivatives.

2. Determination of the activity of tetrahydrocarbazole derivatives against Mycobacterium tuberculosis

(Reference material: "Tuberculosis Diagnostic Laboratory Inspection Regulations", edited by the Basic Professional Committee of the Chinese Anti-tuberculosis Association, China Education and Culture Press, January 2006)

Transfer the tested strain H37Rv into a liquid medium, culture it at 37°C for 2 weeks, absorb a little culture liquid, put it in 4mL liquid medium, add 10-20 sterile glass beads with a diameter of 2-3mm, shake for 20-30S , static precipitation for 10-20min, absorb the supernatant of the bacterial suspension, and adjust the turbidity to 1 McFarland unit with liquid medium, which is equivalent to 1*107CFU/mL for later use. Each drug was dissolved to 1 mg/mL with an appropriate amount of DMSO, and filtered through a 0.22 μm filter. Then dilute to the required experimental concentration with liquid culture medium. The final concentrations of each test drug (Example 1 to Example 10 and isoniazid in the control group) were set as follows: 0.0039 μg/mL, 0.0078 μg/mL, 0.0156 μg/mL, 0.03125 μg/mL, 0.0625 μg/mL, 0.125 μg/mL μg/mL, 0.25μg/mL, 0.5μg/mL, 1.0μg/mL, 2.0μg/mL, 4.0μg/mL, 11 concentration gradients in total. Take 100 μL of each test drug solution above, add it to a 96-well microwell plate, and then add 100 μL of bacterial solution with a concentration of 1 mg/mL to make the drug concentration reach the set final concentration, and incubate at 37°C. Three groups of parallel controls were set up at the same drug dilution. The control group received no drug, and the inoculation amount was set to 100%, 10% and 1%, respectively. After culturing at 37°C for 14 days, observe the colony growth of each group, and take the lowest concentration of the drug group without colony growth as the MIC value of the test compound for the strain. Observe the minimum inhibitory concentration (MIC) of each compound against Mycobacterium tuberculosis, and compare it with the MIC result of the control drug isoniazid.

The measured MIC results are shown in Table 1 below:

Table 1

It can be seen from Table 1 that the tetrahydrocarbazole derivatives shown in I 1 to I 10 provided in the examples of the present application all have excellent anti-tuberculosis effects, and the activities of I 3 to I 5 and I 8 are equivalent to that of isoniazid , Ⅰ 6, Ⅰ 7 are more active than isoniazid. Further drug resistance experiments showed that the tetrahydrocarbazole derivative anti-tuberculosis bacteria provided in the examples of the present application did not produce drug resistance to most tubercle bacilli.

The above-mentioned embodiments only express several implementation modes of the present application, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the scope of protection of the patent application should be based on the appended claims.

Claims

A tetrahydrocarbazole derivative, characterized in that the molecular structural formula of the tetrahydrocarbazole derivative is as shown in the following general formula I:

Wherein, the same or different R1 and R2 in the general formula I are any one of aryl and heteroaryl.
The tetrahydrocarbazole derivative according to claim 1, wherein the aryl group includes any one of phenyl, monosubstituted phenyl, and polysubstituted phenyl;

The heteroaryl group includes any one of pyrrole, substituted pyrrole, thiophene, substituted thiophene, pyridine, substituted pyridine, pyrimidine, and substituted pyrimidine.
Tetrahydrocarbazole derivatives according to claim 2, characterized in that: the substituting groups in the monosubstituted phenyl include halogen atoms, -CF3, -C≡CH, -C≡N, -NO2, - Any of OCH3;

The substituent groups in the multi-substituted phenyl group include at least one of halogen atoms and -OCH3.
The tetrahydrocarbazole derivative according to claim 2, characterized in that: the substituting group in the substituted pyrrole comprises -OCH3;

The substituent group in the substituted thiophene includes -C≡N.
The tetrahydrocarbazole derivative according to any one of claims 1-4, characterized in that it comprises at least one of the following molecular structural formula I1 to structural formula I10:
A preparation method of tetrahydrocarbazole derivatives, comprising the steps of:

The reactant A shown in the following structural formula IA, the reactant B shown in the following structural formula IB and the base catalyst are subjected to the first substitution reaction in the first reaction solvent to generate the first intermediate product shown in the following structural formula IZ1;

Reverse redox reaction of the first intermediate product, reducing agent and acidic additive in the second reaction solvent to generate the second intermediate product shown in the following structural formula IZ2;

The second intermediate product is subjected to a second substitution reaction with reactant C shown in the following structural formula IC and a composite catalyst in a third reaction solvent to generate a third intermediate product shown in the following structural formula IZ3;

In a protective atmosphere, the third intermediate product is condensed with aminoguanidine bicarbonate in a fourth reaction solvent to generate a tetrahydrocarbazole derivative shown in the following structural formula I;

Wherein, the same or different M1 in the formula IB and the M2 in the formula Ic are halogen atoms, and the same or different R1 in the formula IB and the R2 in the formula IC are aryl and heteroaryl any kind.
The preparation method according to claim 6, characterized in that: the first reaction solvent comprises N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, At least one of acetonitrile, diglyme, toluene, and methylene chloride; and/or

The base catalyst includes at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide; and/or

The temperature of the first substitution reaction is 0°C to 100°C.
The preparation method according to claim 6, characterized in that:

The second reaction solvent includes at least one of dichloromethane, acetone, 1,4-dioxane, acetonitrile, ethanol, isopropanol, and water; and/or

The reducing agent includes at least one of iron powder and zinc powder; and/or

The acidic additive comprises ammonium chloride; and/or

The temperature of the redox reaction is 20°C to 200°C.
The preparation method according to claim 6, characterized in that: the third reaction solvent comprises N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, At least one of acetonitrile, diglyme, toluene, and methylene chloride; and/or

The composite catalyst includes a palladium catalyst, a ligand and a base; and/or

The temperature of the second substitution reaction is 20°C to 200°C; and/or

The fourth reaction solvent includes at least one of methanol, ethanol, acetone, 1,4-dioxane, acetonitrile, toluene and methylene chloride; and/or

The temperature of the condensation reaction is 20°C to 200°C.
Use of the tetrahydrocarbazole derivative according to any one of claims 1-5 in the preparation of Mycobacterium tuberculosis inhibitors or in the preparation of anti-tuberculosis drugs.