A kind of anti-tuberculosis compound containing sulfuric acid and its preparation method and application

Abstract

The present application provides an anti-tuberculosis drug and a preparation method and application thereof. Specifically, the present application provides a compound shown in formula I or an enantiomer, diastereoisomer, solvate thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a preparation method and application thereof. The compound of the present application has excellent bacteriostatic activity and can effectively treat diseases related to bacterial infection, especially diseases related to infection of Mycobacterium tuberculosis.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more particularly to an anti-tuberculosis compound, its preparation method, and its application. Background Technology

[0002] Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis and remains a major threat to global public health. Statistics from the World Health Organization show that the annual incidence of TB remains high. It is estimated that more than 1.2 million people died from TB in 2022. In recent years, co-infection with HIV / TB and the emergence of new drug-resistant strains have further exacerbated the harm caused by the disease. my country has one of the largest TB patients in the world, accounting for approximately 9% of the global total, and the proportion of multidrug-resistant TB patients in my country is as high as 11%. The severe domestic and international situation regarding TB infection calls for the urgent research and development of better diagnostic methods, vaccines, and drugs.

[0003] Currently, the main treatment for tuberculosis patients is a long-term combination therapy regimen using antibiotics such as rifampin, isoniazid, streptomycin, pyrazinamide, and ethambutol. Patients with multidrug-resistant tuberculosis require at least 18 to 24 months of treatment, involving thousands of expensive pills and daily injections. This not only places a heavy economic and psychological burden on ordinary families, but also greatly increases the risk of drug resistance in Mycobacterium tuberculosis due to prolonged antibiotic combination therapy. 。 At the same time, the combined use of multiple drugs can also lead to decreased patient tolerance and an increased incidence of various adverse reactions (such as hepatotoxicity and neurotoxicity).

[0004] Therefore, there is a need in the field for a novel anti-tuberculosis drug with excellent activity that can be used alone. Summary of the Invention

[0005] The purpose of this invention is to provide an anti-tuberculosis drug with excellent activity.

[0006] In a first aspect of the invention, a compound of Formula I or an enantiomer, diastereomer, solvate, prodrug, or pharmaceutically acceptable salt thereof is provided: Among them, Z is independently selected from: ; R1 is selected from: hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, benzyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 Cycloalkyl, benzyl, phenyl, pyrimidinyl, pyridyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; X1 is selected from: CR a Or N, where R a Selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; X2 is selected from: CR2 or N, where R2 is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R3 is -L-R3'-, where L is a chemical bond, -O-, -NH-, or -NR'-, and R3' is selected from: C 1-6 Alkylene, C 2-6 alkenyl, 4-10 membered heterocyclic sub-heterocyclic group, C 3-6 Cycloalkylene, 6-10 aryl, and 4-7 heterocyclic alkylene, wherein the above groups are optionally surrounded by 1-4 atoms selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 cycloalkyl, oxo, amino, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups, R' is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; the R3' is written with the left chemical bond connected to L and the right chemical bond connected to the quinolone ring; R4 is selected from: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0007] In another preferred embodiment, the compound represented by Formula I is shown as either Formula Ia or Formula Ib: Z is selected from: ; Among them, X1, X2, R1, R3, R 4、 The definitions of R5 and R6 are the same as described above.

[0008] In another preferred embodiment, the compound represented by Formula I is shown in Formula II as follows: R1 is selected from: hydrogen, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, pyridinyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R a Selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; R2 is selected from: hydrogen, deuterium, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, nitro, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R3 is -L-R3'-, where L is a chemical bond, -O-, -NH-, or -NR'-, and R3' is selected from: C 3-6 Cycloalkylene The above-mentioned groups are optionally surrounded by 1-4 atoms selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, oxo, amino, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups, R' is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; the R3' is written with the left chemical bond connected to L and the right chemical bond connected to the quinolone ring; R4 is selected from: hydrogen, C 1-4 alkyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-4 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from halogenated alkoxy, halogen atom, amino, cyano, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 3-6Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, carboxyl, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups.

[0009] In another preferred embodiment, the compound represented by formula II is shown as either formula II-a or II-b: In another preferred embodiment, the compound represented by Formula II is shown in Formula III as follows: in, m1 is selected from 0, 1, 2, 3 or 4; R1 is selected from: hydrogen, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, pyridinyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, C 1-4 Alkyl substituents; R a Selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituent is one or more of the following: haloalkoxy, halogen atom, amino, or cyano group; R2 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, nitro, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; R4 is selected from: hydrogen, methyl, ethyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, hydroxyl, nitro, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from halogenated alkoxy, halogen atom, amino, cyano, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups.

[0010] In another preferred embodiment, the compound represented by Formula III is shown in Formula III-a or III-b as follows: in, m1, R1, R2, R4, R5, R6, R a R b The definition is the same as described above.

[0011] In another preferred embodiment, R1 is independently selected from: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, benzyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, and pyridinyl groups are optionally surrounded by 1-3 groups selected from halogen, amino, and C. 1-6 Alkyl, nitro, C 1-6 Substitution of alkoxy groups.

[0012] In another preferred embodiment, R1 is independently selected from: hydrogen, deuterium, and C. 1-4 Alkyl, C 3-6Cycloalkyl, benzyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-6 Alkyl, C 3-6 The cycloalkyl, phenyl, pyrimidinyl, and pyridinyl groups are optionally substituted with 1 to 3 substituents selected from fluorine, amino, methyl, ethyl, nitro, and methoxy groups.

[0013] In another preferred embodiment, R1 is independently selected from: hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, benzyl, phenyl, pyrimidinyl, or pyridyl, wherein the methyl, ethyl, propyl, cyclopropyl, benzyl, phenyl, pyrimidinyl, or pyridyl group is optionally substituted by 1 to 3 substituents selected from fluorine, amino, methyl, ethyl, nitro, or methoxy groups.

[0014] In another preferred embodiment, R1 is independently selected from: methyl, ethyl, cyclopropyl, pyridyl, and the methyl, ethyl, propyl, cyclopropyl, benzyl, phenyl, pyrimidinyl, or pyridyl group is optionally substituted by 1 to 3 substituents selected from fluorine, amino, methyl, ethyl, nitro, and methoxy groups.

[0015] In another preferred embodiment, R1 is independently selected from: methyl, ethyl, cyclopropyl, ... , .

[0016] In another preferred embodiment, X is independently N.

[0017] In another preferred embodiment, X is independently CR. a .

[0018] In another preferred embodiment, the R a Independently selected from: hydrogen, halogen atom, mercapto group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0019] In another preferred embodiment, the R a Independently selected from: hydrogen, halogen atom, mercapto group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, hydroxyl, oxo, nitro, carboxyl, amino, cyano, mercapto, C 1-6Alkoxy, C 1-6 Halogenated alkoxy groups.

[0020] In another preferred embodiment, the R a Independently selected from: fluorine atom, chlorine atom, mercapto, methyl, ethyl, trifluoromethyl, vinyl, cyclopropane, phenyl, hydroxyl, oxo, nitro, carboxyl, amino, cyano, methoxy, mercapto, C 1-6 Halogenated alkoxy groups.

[0021] In another preferred embodiment, the R a Independently selected from: fluorine atom, chlorine atom, hydroxyl group, cyano group, methoxy group, mercapto group, .

[0022] In another preferred embodiment, R a R1 and its attached N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from methyl, ethyl, methoxy, -CH2-OH, halogen atom, amino, cyano, nitro, hydroxyl.

[0023] In another preferred embodiment, R a R1 and the N attached thereto form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from methyl, methoxy, -CH2-OH, fluorine atom, cyano, hydroxyl.

[0024] In another preferred embodiment, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally substituted by one or more substituents selected from methyl fluorine atoms, cyano groups, and hydroxyl groups.

[0025] In another preferred embodiment, R2 is independently selected from: hydrogen, deuterium, halogen atom, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, nitro, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

[0026] In another preferred embodiment, R2 is independently selected from: hydrogen, deuterium, halogen atom, methyl, ethyl, trifluoromethyl, vinyl, ethynyl, hydroxyl, nitro, carboxyl, amino, cyano, ethoxy.

[0027] In another preferred embodiment, R2 is independently selected from: hydrogen, deuterium, fluorine atom, chlorine atom, methyl, trifluoromethyl, vinyl, hydroxyl, nitro, carboxyl, amino.

[0028] In another preferred embodiment, R2 is independently selected from: hydrogen and fluorine atoms.

[0029] In another preferred embodiment, R3 is -L-R3'-, where L is a chemical bond, -O-, -NH-, or -NR'-.

[0030] In another preferred embodiment, L is a chemical bond, -O-, or -NH-.

[0031] In another preferred embodiment, L is -NR'-, wherein R' is selected from: hydrogen, F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, cyclopentyl, phenyl, benzofuranyl, hydroxyl, oxo, nitro, amide, amino, cyano, mercapto, methoxy.

[0032] In another preferred embodiment, R3' is selected from: C 1-6 Alkylene, C 2-6 alkenyl, 4-10 membered heterocyclic sub-heterocyclic group, C 3-6 Cycloalkylene, 6-10 aryl, and 4-7 heterocyclic alkylene, wherein the above groups are optionally surrounded by 1-4 atoms selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, oxo, amino, C 1-6 Alkoxy, C 1-6 The substituent of the haloalkoxy group is used, and the R3' is written with the left chemical bond connected to L and the right chemical bond connected to the quinolone ring.

[0033] In another preferred embodiment, R3' is independently selected from: cyclopropane, cyclohexane, pyrrolidine, piperidine, The above-mentioned groups are optionally replaced by 1-4 substituents selected from fluorine atoms, methyl, ethyl, methylene, and carboxyl groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N.

[0034] In another preferred embodiment, R3' is independently selected from: cyclopropane, cyclohexane, pyrrolidine, piperidine, .

[0035] In another preferred embodiment, R4 is independently selected from: hydrogen, methyl, ethyl, propyl, cyclopropane.

[0036] In another preferred embodiment, R4 is independently selected from: hydrogen, methyl, ethyl.

[0037] In another preferred embodiment, R5 is independently selected from: hydrogen, halogen atom, mercapto group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 The haloalkoxy group, wherein the heterocyclic or heteroaryl group contains 1-3 N heteroatoms.

[0038] In another preferred embodiment, R5 is independently selected from: hydrogen, halogen atom, mercapto group, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 alkenyl, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, carboxyl, amino, cyano, C 1-4 Alkoxy, C 1-6 The haloalkoxy group, wherein the heterocyclic or heteroaryl group contains 1-3 N heteroatoms.

[0039] In another preferred embodiment, R5 is independently selected from: hydrogen, fluorine atom, mercapto, methyl, ethyl, trifluoromethyl, vinyl, cyclopropyl, hydroxy, carboxyl, amino, cyano, methoxy.

[0040] In another preferred embodiment, R5 is independently selected from: hydrogen, fluorine atom, and mercapto group.

[0041] In another preferred embodiment, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 It is replaced by one or more substituents selected from hydroxyalkyl, halogen atom, amino, cyano, nitro, and hydroxyl.

[0042] In another preferred embodiment, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally replaced by one or more substituents selected from methyl, ethyl, methoxy, -CH2-OH, fluorine atom, amino, cyano, nitro, hydroxyl.

[0043] In another preferred embodiment, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally replaced by one or more substituents selected from methyl, fluorine, and hydroxyl groups.

[0044] In another preferred embodiment, the compound is selected from: .

[0045] A second aspect of the present invention provides a method for preparing a compound or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts as described in the first aspect of the present invention, comprising the following steps: ; Compound A undergoes a condensation reaction with raw material ZH to prepare compound I; The definition of Z is the same as that described in the first aspect of this invention.

[0046] In another preferred embodiment, step one includes: in an inert solvent, under the action of an alkaline reagent, a condensation reaction is carried out between the compound shown in formula A and the compound shown in formula B to obtain the compound shown in formula III.

[0047] In another preferred embodiment, the inert solvent is selected from ketone solvents, ester solvents, or ether solvents, preferably from one or a combination of acetone, 2-butanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethers, DMF, DMAc, DMSO, NMP, toluene, acetonitrile, dichloromethane, and water, with acetonitrile and dichloromethane being preferred.

[0048] In another preferred embodiment, the alkaline reagent is selected from: pyridine, triethylamine, DMAP, potassium carbonate, and sodium carbonate.

[0049] In another preferred embodiment, the compound shown in Formula A and the compound shown in Formula B undergo a condensation reaction in the presence of a condensing agent selected from: DCC, EDCI, DIC, HATU, HBTU, CDI, and HOBt.

[0050] In a third aspect, the present invention provides a pharmaceutical composition comprising a first active ingredient, the first active ingredient comprising one or more selected from the compounds described in the first aspect of the present invention or their enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, and optionally, one or more pharmaceutically acceptable excipients, diluents, carriers, excipients, or adjuvants.

[0051] In another preferred embodiment, the carrier is selected from the group consisting of emulsifiers, excipients, fillers, diluents, adhesives, wetting agents, lubricants, flow aids, anti-adhesion agents, antioxidants, anti-caking agents, buffers, chelating agents, preservatives, solubilizers, stabilizers, viscosity modifiers, transdermal penetration enhancers, or combinations thereof.

[0052] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, oral liquids, syrups, pills, powders, tinctures, and injections.

[0053] In a fourth aspect, the present invention provides the use of a compound as described in the first aspect of the invention or an enantiomer, diastereomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect of the invention, for the preparation of a medicament for the pretreatment of diseases related to bacterial infections, particularly diseases related to Mycobacterium tuberculosis.

[0054] In another preferred embodiment, the disease associated with Mycobacterium tuberculosis infection is selected from the group consisting of: pulmonary tuberculosis, lymph node tuberculosis, tuberculous pleurisy, bone and joint tuberculosis, tuberculous meningitis, genitourinary tuberculosis, and miliary tuberculosis.

[0055] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0056] Figure 1 The effects of compounds P9 and 9-P10 on Mycobacterium smegmatis were demonstrated.

[0057] Figure 2 The effects of compounds 3-P11 and 5-12 on Mycobacterium smegmatis were demonstrated.

[0058] Figure 3 The effects of compounds L8 and L10 on Mycobacterium smegmatis were demonstrated. Detailed Implementation

[0059] Through extensive and in-depth research, the inventors have discovered for the first time a class of highly effective antibacterial inhibitors (the compounds of this invention). This invention utilizes a simple chemical linkage of two antibacterial fragments, unexpectedly revealing excellent antibacterial effects. The chemically linked compounds of this invention are more effective than the individual combinations of the two antibacterial fragments, exhibiting superior synergistic effects. Therefore, the compounds of this invention can effectively prevent and / or treat diseases related to bacterial infections. This invention was completed based on this.

[0060] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0061] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0062] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, either alone or as part of other substituents, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number definiteness (e.g., C...), it is used to indicate a carbon atom number. 1-10 When ), it refers to the alkyl group containing 1-10 carbon atoms. For example, C 1-8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups. Unless otherwise specified, the alkyl group refers to an alkyl group containing 1 to 10 carbon atoms.

[0063] As used herein, the term "alkenyl," whether alone or as part of other substituents, refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number definiteness (e.g., C...), it signifies a carbon chain group. 2-6 When ), it refers to the alkenyl group containing 2-6 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups. Unless otherwise specified, the alkenyl group refers to an alkenyl group containing 2-10 carbon atoms.

[0064] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of other substituents. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number limit (e.g., C...), it is considered a alkynyl group. 2-6 When alkynyl is used, it means that the alkynyl group contains 2-6 carbon atoms. For example, the term "C 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups. Unless otherwise specified, the alkynyl group refers to an alkynyl group containing 2-6 carbon atoms.

[0065] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated or partially saturated monocyclic ring, bicyclic or polycyclic (fused, bridged or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number determination (e.g., C...), it is used to indicate the presence of a carbon number limit (e.g., C...). 3-10 When ), it refers to the cycloalkyl group containing 3-10 carbon atoms. In some preferred embodiments, the term "C" is used. 3-6 "Cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom). These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to a fully carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. All atoms in the cycloalkyl group are carbon atoms. Unless otherwise specified, the cycloalkyl group refers to a cycloalkyl group containing 3-6 carbon atoms. The following are some examples of cycloalkyl groups; the present invention is not limited to the cycloalkyl groups described below. Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0066] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system. The aryl group can be substituted or unsubstituted; unless otherwise specified, the aryl group refers to an aryl group containing 6-10 carbon atoms. Some examples of aryl groups are given below; this invention is not limited to the aryl groups described below. "Heteroaryl" refers to a heteroaryl group containing one or more heteroatoms, possessing a fully conjugated π-electron system. The heteroatoms referred to here include oxygen, sulfur, and nitrogen, such as furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. When the heteroaryl group is a fused structure, the heteroaryl ring can be fused to an aryl or heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted. Some examples of heteroaryl groups are given below; the present invention is not limited to the heteroaryl groups described below. Preferably, the heteroatom in the heteroaryl group can be N, O, or S. Unless otherwise specified, the heteroaryl group is a 5-10 member heteroaryl group. "Heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups. "Spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but at least one ring does not have a fully conjugated π-electron system, and one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. These groups may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Furthermore, one or more ring atoms are selected from nitrogen, oxygen, or sulfur, while the remaining ring atoms are carbon. Preferably, the heteroatom of the heterocyclic group can be N, O, or S. Unless otherwise specified, the heterocyclic group is a 3-9 member heterocyclic group. The following are some examples of heterocyclic groups; however, this invention is not limited to the heterocyclic groups described below. As used herein, the term "halogen" refers to F, Cl, Br, and I, either alone or as part of other substituents.

[0067] As used herein, the term "substitution" (with or without the "arbitrarily" modified) refers to the substitution of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, i.e., two rings sharing a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents include, for example (but are not limited to): C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Acyl group, C 2-10 Ester group, amino group.

[0068] "Tautomerism" refers to structural isomers with different energies that can overcome a low energy barrier and thus interconvert. For example, proton tautomerism (i.e., proton transmutation) includes interconversion via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, etc. and Valence tautomers include those that undergo tautomerism through some recombination of bonding electrons.

[0069] "Stereoisomers" refer to molecules that have atoms with the same connectivity but different spatial arrangements. For example, two compounds containing a chiral center and having the same two-dimensional connectivity, such as R-glyceraldehyde and S-glyceraldehyde, or R-serine and S-serine.

[0070] "Enantiomers" refer to stereoisomers that are mirror images of each other and cannot be superimposed. For example, R-serine and S-serine.

[0071] "Diarrhetinic isomers" refer to stereoisomers of molecules that have two or more chiral centers and are not mirror images of each other. Tartaric acid is an example.

[0072] Unless otherwise specified, all compounds mentioned in this invention are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0073] The pharmaceutically acceptable salts described in this invention can be salts formed by anion and a positively charged group on a compound of formula (I). Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Similarly, salts can be formed by cations and negatively charged groups on a compound of formula (I). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium ions.

[0074] In addition, "pharmaceutically acceptable salts" refer to salts formed by compounds of formula (I) with acids selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pyric acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, and hydroxyethanesulfonic acid; or sodium, potassium, calcium, aluminum, or ammonium salts formed by compounds of formula (I) with inorganic bases; or methylamine, ethylamine, or ethanolamine salts formed by compounds of general formula I with organic bases.

[0075] The term "prodrug" refers to a compound that is biologically inactive or has low activity, but can release an active pharmaceutical ingredient after metabolic transformation in vivo (such as enzymatic catalysis, hydrolysis, reduction, etc.), thereby exerting a therapeutic effect. When the compounds of the present invention have one of the following defects: (a) oral bioavailability less than 20%; (b) blood-brain barrier penetration < 5%; (c) plasma half-life < 1 hour; (d) degradation rate > 30% in the gastric acid environment, the prodrug includes, but is not limited to, pharmaceutically acceptable amide forms, ester derivatives (including alkyl esters, aryl esters, amino acid esters), phosphate esters, carbonates, or acetal / ketal derivatives of the compound, designed to overcome the aforementioned defects and maintain or enhance the original activity through metabolic activation.

[0076] Pharmaceutical Composition The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of the compound of the present invention or its stereoisomers, enantiomers, diastereomers, transisomers, optical isomers, racemates, tautomers or their pharmaceutically acceptable salts, prodrugs, hydrates or solvates, or isotopically labeled compounds.

[0077] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 50-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0078] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0079] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0080] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0081] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0082] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0083] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0084] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0085] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0086] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0087] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0088] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-inflammatory drugs).

[0089] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0090] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0091] The main advantages of this invention include: (1) The compounds of the present invention can effectively treat bacterial infection-related diseases, especially tuberculosis-related diseases.

[0092] (2) The compound prepared by combining thioctic acid with other antibacterial fragments in this invention has a better effect than the two antibacterial fragments used alone, and has an excellent synergistic effect.

[0093] 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. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0094] Example 1: Preparation of compound 9-P10 Procedure: Starter A (30 mg, 1.0 eq) was dissolved in 3 mL of dichloromethane. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl, 29.13 mg, 1.05 eq), 4-dimethylaminopyridine (DMAP, 22.11 mg, 1.05 eq), and starter C (40.20 mg, 1.0 eq) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, a suitable amount of deionized water was added to quench the reaction mixture. The mixture was extracted multiple times with ethyl acetate (EA), and the organic phases were combined. The organic phase was washed with saturated brine until neutral, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15:1, v / v) to give 45.61 mg of the target product as a pale yellow solid, with a yield of 79.90%. [M+H + ]=393.6 Example 2: Preparation of compound 3-P11 Starting material A (30 mg, 1.0 eq) was dissolved in 3 mL of dichloromethane. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl, 29.13 mg, 1.05 eq), 4-dimethylaminopyridine (DMAP, 22.11 mg, 1.05 eq), and starting material D (40.20 mg, 1.0 eq) were added sequentially, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, a suitable amount of deionized water was added to quench the reaction mixture. The mixture was extracted multiple times with ethyl acetate (EA), and the organic phases were combined. The organic phase was washed with saturated brine until neutral, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 18:1, v / v) to give 57.64 mg of the target product as a white solid, with a yield of 51.22%. [M+H + ]=774.9 Example 3: Preparation of compound 5-12 Starting material A (30 mg, 1.0 eq) was dissolved in 3 mL of acetonitrile, and N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (TCFH, 30.56 mg, 1.2 eq) and N-methylimidazole (35.81 mg, 3.0 eq) were added sequentially. The mixture was stirred and activated at room temperature for 15 minutes. Then, starting material D (48.17 mg, 1.0 eq) was added, and the reaction was continued at room temperature with stirring for 3 hours. After the reaction was complete, an appropriate amount of deionized water was added to quench the reaction mixture, and the mixture was extracted multiple times with ethyl acetate (EA). The organic phases were combined, washed with saturated brine until neutral, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1, v / v) to give 51.25 mg of the target product as a white solid, with a yield of 67.83%. [M+H + ]=520.6 Example 4: Preparation of compound P9 Procedure: Raw material A (30 mg, 1.0 eq) was dissolved in 3 mL of acetonitrile. N,N,N',N'-tetramethylchloromethanemidane hexafluorophosphate (30.56 mg, 1.2 eq) and N-methylimidazole (35.81 mg, 3.0 eq) were added sequentially, and the mixture was stirred and activated at room temperature for 15 minutes. Then, raw material B (69.92 mg, 1.0 eq) was added, and the reaction was continued at room temperature with stirring for 3 hours. After the reaction was complete, an appropriate amount of water was added to quench the reaction mixture. The mixture was extracted multiple times with ethyl acetate (EA), and the organic phases were combined. The organic phase was washed with saturated brine until neutral, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20:1, v / v) to give 62.2 mg of a white solid product, yield 67.68%. [M+H + ]=633.7 Example 5: Inhibitory effect of the compound on bacteria Experimental methods: This invention uses the Resazurin microplate method to determine the minimum inhibitory concentration (MIC) of the test compound against Mycobacterium smegmatis.

[0095] Experimental steps: Under aseptic conditions, 5 mg of resazurin powder was accurately weighed and dissolved in 1 mL of sterile ultrapure water to prepare a stock solution with a concentration of 5 mg / mL. 20 μL of this stock solution was diluted with 980 μL of sterile ultrapure water to obtain a working solution of resazurin with a concentration of 0.1 mg / mL, which was then set aside. The analyte compound was dissolved in dimethyl sulfoxide (DMSO) to prepare an initial stock solution with a concentration of 12.8 mg / mL. Subsequently, a series of compound dilutions with varying concentrations were prepared under aseptic conditions using a two-fold serial dilution method, resulting in a total of eight different concentrations.

[0096] Mycobacterium smegmatis was cultured overnight in suitable liquid medium with shaking. The bacterial concentration was determined by turbidimetry, and the concentration of each culture was adjusted to approximately 2 × 10^5 CFU / mL using corresponding blank medium. Mycobacterium smegmatis was diluted and cultured using 7H9 medium.

[0097] Method 1 The initial well was set to a 400 μl system, and the remaining wells to a 200 μl system. The concentration in the first well was 128 μg / ml (178 μL diluted bacterial suspension, 20 μl × 2 respazine, and 2 μl × 2 compound), which was thoroughly mixed by pipetting, and 200 μl was transferred to the next well. The concentration in the second well was 64 μg / ml (180 μL diluted bacterial suspension and 20 μl respazine), which was thoroughly mixed by pipetting, and 200 μl was transferred to the next well. The concentration in the third well was 32 μg / ml (180 μL diluted bacterial suspension and 20 μl respazine), which was thoroughly mixed by pipetting, and 200 μl was transferred to the next well. The concentration in the fourth well was 16 μg / ml (180 μL diluted bacterial suspension and 20 μl respazine), which was thoroughly mixed by pipetting, and 200 μl was transferred to the next well. For the fifth well, mix 180 μL of diluted bacterial solution and 20 μL of resazurin, then pipette 200 μL to the next well. For the sixth well, mix 4 μg / ml of diluted bacterial solution and 20 μL of resazurin, then pipette 200 μL to the next well. For the seventh well, mix 2 μg / ml of diluted bacterial solution and 20 μL of resazurin, then pipette 200 μL to the next well. For the eighth well, mix 1 μg / ml of diluted bacterial solution and 20 μL of resazurin, then pipette 200 μL and discard.

[0098] Method 2 Each well contained 178 μL of diluted bacterial culture, 20 μL of resveratrol, and 2 μL of the compound. Then, the compound, which had been diluted to the required final concentration for each well, was added directly.

[0099] Experimental results: As shown in Table 1, combining lipoic acid with compound L-10 formed a novel compound 9-P10. Experimental data confirmed that the antibacterial activity of compound 9-P10 against Mycobacterium smegma was significantly and unexpectedly higher than that of lipoic acid and compound L-10, exhibiting excellent synergistic effects. Combining lipoic acid with compound L-13 formed a novel compound 5-12. Experimental data confirmed that the antibacterial activity of compound 5-12 was also significantly higher than that of lipoic acid and compound L-13, demonstrating excellent synergistic effects. Furthermore, we tested the antibacterial activity of the newly synthesized compound 3-P11, which also showed superior activity.

[0100] Table 1. Minimum inhibitory concentrations of compounds against Mycobacterium smegma discuss This invention is the first to covalently bind lipoic acid with compound L-10 to form a novel compound 9-P10. Experimental data confirm that compound 9-P10 exhibits significantly and unexpectedly higher antibacterial activity than both lipoic acid and compound L-10, demonstrating excellent synergistic effects. Combining lipoic acid with compound L-13 forms a novel compound 5-12. Experimental data show that compound 5-12 also exhibits significantly higher antibacterial activity than both lipoic acid and compound L-13, similarly demonstrating excellent synergistic effects.

[0101] Based on this discovery, the inventors conducted extensive screening and structurally integrated the lipoic acid fragment with other antibacterial fragments (including but not limited to various known pharmacophores, such as quinolone antibacterial compounds). The resulting series of new compounds consistently exhibited excellent synergistic antibacterial effects.

[0102] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of Formula I or an enantiomer, diastereomer, solvate, prodrug, or pharmaceutically acceptable salt thereof: in, Z is selected independently from: ； R1 is selected from: hydrogen, deuterium, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, benzyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, benzyl, phenyl, pyrimidinyl, pyridyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; X1 is selected from: CR a Or N, where R a Selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; X2 is selected from: CR2 or N, where R2 is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R3 is -L-R3'-, where L is a chemical bond, -O-, -NH-, or -NR'-, and R3' is selected from: C 1-6 Alkylene, C 2-6 alkenyl, 4-10 membered heterocyclic sub-heterocyclic group, C 3-6 Cycloalkylene, 6-10 aryl, and 4-7 heterocyclic alkylene, wherein the above groups are optionally surrounded by 1-4 atoms selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, oxo, amino, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups, R' is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; the R3' is written with the left chemical bond connected to L and the right chemical bond connected to the quinolone ring; R4 is selected from: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-9 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amide, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups.

2. The compound of claim 1 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, The compound represented by Formula I is shown in Formula Ia or Formula Ib: in, Z is selected from: ； Among them, X1, X2, R1, R3, R 4、 The definitions of R5 and R6 are the same as those in claim 1.

3. The compound of claim 1 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, The compound represented by Formula I is shown in Formula II below: in, R1 is selected from: hydrogen, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, pyridinyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, nitro, C 1-6 Alkyl, C 1-6 Substitution of alkoxy groups; R a Selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 It is substituted by one or more substituents selected from haloalkoxy, halogen atom, amino, cyano, nitro, and hydroxyl groups; R2 is selected from: hydrogen, deuterium, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, hydroxyl, oxo, nitro, carboxyl, amino, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; R3 is -L-R3'-, where L is a chemical bond, -O-, -NH-, or -NR'-, and R3' is selected from: C 3-6 cycloalkylene The above-mentioned groups are optionally surrounded by 1-4 atoms selected from hydrogen, halogen, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, oxo, amino, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups, R' is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy group; the R3' is written with the left chemical bond connected to L and the right chemical bond connected to the quinolone ring; R4 is selected from: hydrogen, C 1-4 alkyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-4 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, oxo, nitro, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from halogenated alkoxy, halogen atom, amino, cyano, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 6-10 aryl, 3-7 heterocyclic, 5-10 heteroaryl, hydroxyl, carboxyl, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups.

4. The compound of claim 3 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, The compound represented by formula II is shown in formula II-a or II-b as follows: Among them, R1, R2, R3, R4, R5, R6, R a The definition is the same as that described in claim 3.

5. The compound of claim 3 or its enantiomers, diastereomers, mixtures thereof, solvates, prodrugs thereof, or pharmaceutically acceptable salts thereof, characterized in that, The compound represented by Formula II is shown in Formula III below: in, m1 is selected from 0, 1, 2, 3 or 4; R1 is selected from: hydrogen, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, or pyridinyl, wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, pyrimidinyl, pyridinyl are optionally surrounded by 1-3 groups selected from halogen, amino, hydroxyl, C 1-4 Alkyl substituents; R a Selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, hydroxyl, nitro, carboxyl, amino, cyano, mercapto, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Or, R a R1 and its associated N form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituent is one or more of the following: haloalkoxy, halogen atom, amino, or cyano group; R2 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, 6-10 aryl, nitro, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups; R4 is selected from: hydrogen, methyl, ethyl; R5 is selected from: hydrogen, halogen atom, mercapto group, C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, hydroxyl, nitro, amino, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, wherein the heterocyclic or heteroaryl group contains 1-3 heteroatoms that are N; Alternatively, R5 and R1 together with the N they are attached to form a 4-8 member nitrogen-containing heterocyclic group, wherein the 4-8 member nitrogen-containing heterocyclic group is optionally selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substance is substituted by one or more substituents selected from halogenated alkoxy, halogen atom, amino, cyano, and hydroxyl groups; R6 is selected from: hydrogen, halogen atom, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, hydroxyl, carboxyl, amino, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups.

6. The compound of claim 5 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, The compound represented by Formula III is shown in either Formula III-a or III-b: in, m1, R1, R2, R4, R5, R6, R a R b The definition is the same as that described in claim 5.

7. The compound of any one of claims 1-6, or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, The compound is selected from: 。 8. A method for preparing the compound as described in claim 1 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, characterized in that, Includes the following steps: ； Compound A undergoes a condensation reaction with raw material ZH to prepare compound I; The definition of Z is the same as in claim 1.

9. A pharmaceutical composition, characterized in that, It comprises a first active ingredient, which comprises one or more of the compound as described in any one of claims 1-7 or its enantiomers, diastereomers, solvates, prodrugs, or pharmaceutically acceptable salts, and optionally, one or more pharmaceutically acceptable excipients, diluents, carriers, excipients, or adjuvants.

10. Use of a compound as described in any one of claims 1-7, or an enantiomer, diastereomer, solvate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, characterized in that, This is used to prepare drugs for the pretreatment of bacterial infection-related diseases, preferably diseases related to Mycobacterium tuberculosis.

Images