FabI enzyme inhibitors and their use

Abstract

This application discloses a FabI enzyme inhibitor and its use. The FabI enzyme inhibitor is a compound represented by formula I and provides a novel option for the clinical screening and / or preparation of drugs for diseases related to FabI enzyme activity. [Formula 1] JPEG2026534277000039.jpg75156

Description

[Technical Field]

[0001] This application relates to the pharmaceutical technology, and more particularly to FabI enzyme inhibitors and their use. [Background technology]

[0002] Fatty acid synthases (FAS) are involved in the entire saturated fatty acid biosynthesis pathway in all organisms. Each cycle of fatty acid biosynthesis in bacteria consists of the following four steps: In the first step, malonyl-ACP is condensed with acetyl-CoA catalyzed by β-ketoacyl-ACP synthase. In the second step, the keto acid ester is reduced by NADPH-dependent β-ketoacyl-ACP reductase. In the third step, dehydration occurs by β-hydroxyacyl-ACP dehydrase to obtain trans-2-enoyl-ACP. In the fourth step, trans-2-enoyl-ACP is converted to acyl-ACP with two additional carbon atoms by NADH-dependent enoyl-ACP reductase (FabI). This cycle is repeated until palmitoyl-ACP (C16) is finally obtained. The FabI enzyme has been found to be an important regulatory enzyme in the fatty acid biosynthesis process. Inhibiting the activity of the FabI enzyme blocks fatty acid biosynthesis in bacteria, suppressing bacterial growth and reproduction, and thus providing a therapeutic effect against bacterial infections.

[0003] Currently, several compounds possess FabI enzyme inhibitory activity, but with the increasing number of patients suffering from infections caused by multiple bacteria and drug resistance, further development of new drugs to treat bacterial infections is needed. [Overview of the project] [Problems that the invention aims to solve]

[0004] This application aims to solve at least one of the above-mentioned technical problems present in the prior art. Therefore, the object of this application is to provide a FabI enzyme inhibitor and its use. Means for Solving the Problems

[0005] In order to achieve the above objectives, the technical solution adopted by the present application is as follows.

[0006] In a first aspect of the present application, a compound represented by Formula I, a stereoisomer thereof, a deuterated compound thereof, an isotopically labeled derivative thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof is proposed. ##STR## Formula I (wherein X is selected from O, CR X1 R X2 , NR X1 , and S, Y is selected from O, -CH2-, NR Y , -O-CH2-, -CH2-O-, -NR Y -CH2-, -CH2-NR Y -, R X1 , R X2 are each independently selected from hydrogen, -C 1~6 alkyl group, halogen-substituted -C 1~6 alkyl group, R Y is hydrogen, -C 1~6 alkyl group, halogen-substituted -C 1~6 alkyl group, -C 0~2 alkylene-C(O)R Y1 , -C 0~2 alkylene-C(O)NR Y1 R Y2 , -C 0~2 alkylene-NR Y1 R Y2 , -C 0~2 alkylene-NR Y1 C(O)R Y2 , -C 0~2 alkylene-(3 to 10-membered cycloalkyl group), -C 0~2 alkylene-(3 to 10-membered heterocycloalkyl group), -C 0~2 alkylene-(6 to 10-membered aromatic ring), -C 0~2Selected from alkylenes (5-10 member aromatic heterocycles), R Y1 , R Y2 These are, independently, hydrogen and -C. 1~6 Alkyl, halogen-substituted -C 1~6 Selected from alkyl groups, R 1 These are hydrogen, halogen, cyano group, nitro group, and -C 1~6 Alkyl, halogen-substituted -C 1~6 Alkyl alkyl group, -C 0~2 Alkilen-OR 11 , -C 0~2 Alkylene-C(O)R 11 , -C 0~2 Alkylene-C(O)NR 11 R 12 , -C 0~2 Alkilen-NR 11 R 12 , -C 0~2 Alkilen-NR 11 C(O)R 12 , -C 0~2 Alkylene-(3-10 membered cycloalkyl group), -C 0~2 Alkylene-(3-10 member heterocycloalkyl group), -C 0~2 Alkylene-(6-10 member aromatic ring), -C 0~2 Selected from alkylenes (5-10 member aromatic heterocycles), R 11 , R 12 These are, independently, hydrogen, halogen, and -C. 1~6 Alkyl, halogen-substituted -C 1~6 Alkyl alkyl group, -C 0~2 Alkylene-(3-10 membered cycloalkyl group), -C 0~2 Alkylene-(3-10 member heterocycloalkyl group), -C 0~2 Alkylene-(6-10 member aromatic ring), -C 0~2 Selected from alkylenes (5-10 member aromatic heterocycles), R 2 These are hydrogen, halogen, cyano group, nitro group, and -C 1~6 Alkyl, halogen-substituted -C 1~6 Alkyl alkyl group, -C 0~2 Alkilen-OR21 , -C 0~2 alkylene-C(O)R 21 , -C 0~2 alkylene-C(O)NR 21 R 22 , -C 0~2 alkylene-NR 21 R 22 , -C 0~2 alkylene-NR 21 C(O)R 22 , -C 0~2 alkylene-(3- to 10-membered cycloalkyl group), -C 0~2 alkylene-(3- to 10-membered heterocycloalkyl group), -C 0~2 alkylene-(6- to 10-membered aromatic ring), -C 0~2 alkylene-(5- to 10-membered aromatic heterocycle), selected from R 21 , R 22 each independently is selected from hydrogen, halogen, -C 1~6 alkyl group, halogen-substituted -C 1~6 alkyl group, -C 0~2 alkylene-(3- to 10-membered cycloalkyl group), -C 0~2 alkylene-(3- to 10-membered heterocycloalkyl group), selected from R 3 is hydrogen, halogen, cyano group, nitro group, hydroxy group, -C 1~6 alkyl group, halogen-substituted -C 1~6 alkyl group, -C 0~2 alkylene-OR 31 , -C 0~2 alkylene-C(O)R 31 , -C 0~2 alkylene-C(O)NR 31 R 32 , -C 0~2 alkylene-NR 31 R 32 , -C 0~2 alkylene-NR 31 C(O)R 32 , -C 0~2 alkylene-(3- to 10-membered cycloalkyl group), -C 0~2 alkylene-(3- to 10-membered heterocycloalkyl group), -C 0~2Alkylene-(6-10 member aromatic ring), -C 0~2 Selected from alkylenes (5-10 membered aromatic heterocycles), R 31 , R 32 These are, independently, hydrogen, halogen, and -C. 1~6 Alkyl, halogen-substituted -C 1~6 Alkyl alkyl group, -C 0~2 Alkilen-NR 33 R 34 , -C 0~2 Alkylene-(3-10 membered cycloalkyl group), -C 0~2 Alkylene-(3-10 member heterocycloalkyl group), -C 0~2 Alkylene-(6-10 member aromatic ring), -C 0~2 Selected from alkylenes (5-10 membered aromatic heterocycles), R 33 , R 34 These are, independently, hydrogen, halogen, and -C. 1~6 Alkyl, halogen-substituted -C 1~6 Selected from alkyl groups, R 4 is hydrogen, -C 1~6 Alkyl, halogen-substituted -C 1~6 Selected from alkyl groups, m is selected from 0, 1, or 2, and n is selected from 1 or 2. Here, a C value of 0 indicates that the group in question does not exist.

[0007] In some embodiments of this application, R 1 is hydrogen, -C 1~3 Alkyl alkyl group, -C 0~2 Alkilen-NR 11 R 12 Selected from ,-(3-6 member cycloalkyl group).

[0008] In some embodiments of this application, R 1 The group is selected from hydrogen, a methyl group, a cyclopropyl group, and -NH2.

[0009] In some embodiments of this application, R 2is halogen, -C 1~3 Alkyl alkyl group, -C 0~2 Selected from alkylene-(3-10 membered cycloalkyl groups).

[0010] In some embodiments of this application, R 2 The group is selected from hydrogen, a methyl group, a halogen, and a cyclopropyl group.

[0011] In some embodiments of this application, R 3 is -C 0~2 Alkilen-OR 31 , -C 0~2 Alkilen-NR 31 R 32 , -C 0~2 Alkilen-NR 31 C(O)R 32 Selected from ,-(3-6 member heterocycloalkyl groups), R 31 , R 32 These are, independently, hydrogen and -C. 1~3 Alkyl alkyl group, -C 0~2 Alkilen-NR 33 R 34 Selected from, R 33 , R 34 These are, independently, hydrogen and -C. 1~3 Selected from alkyl groups.

[0012] In some embodiments of this application, R 3 is -NH2, formula [ka] Selected from the bases shown.

[0013] In some embodiments of this application, R 4 The group is selected from hydrogen and methyl groups.

[0014] In some embodiments of this application, R X1 , R X2 Each of these is independently selected from hydrogen and a methyl group.

[0015] In some embodiments of this application, the R Y It consists of hydrogen, a methyl group, and -C(O)R Y1 Selected from.

[0016] In some embodiments of this application, the R Y1 is hydrogen, -C 1~3 Selected from alkyl groups.

[0017] In some embodiments of this application, the compound represented by formula I is represented by formula II. [ka] Formula II (Here, the R 1 , R 2 , R 3 , R 4 X and n are as defined above.

[0018] In some embodiments of this application, the compound represented by formula I is represented by formula III. [ka] Formula III (Here, the R 1 , R 2 , R 3 , R 4 X, m, and n are as defined above.

[0019] In some embodiments of this application, the compound represented by formula I is represented by formula IV. [ka] Formula IV (Here, the R 1 , R 2 , R 3 , R 4 X and n are as defined above.

[0020] In some embodiments of this application, the compound represented by formula I is represented by formula V. [ka] Formula V (Here, the R 1 , R 2 , R 3 , R 4 , R Y X and n are as defined above.

[0021] In some embodiments of this application, the compound represented by formula I is selected from the following compounds. [ka] JPEG2026534277000009.jpg169170

[0022] A second aspect of this application provides a pharmaceutical composition comprising a compound represented by formula I, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate.

[0023] In some embodiments of this application, the above-described pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or auxiliary material and / or vehicle.

[0024] The pharmaceutical composition of this application is suitable for multiple routes of administration and can therefore be formulated into any pharmaceutically acceptable dosage form. For example, the pharmaceutical composition can be administered orally, parenterally, rectally, or pulmonaryly to patients or subjects requiring such treatment. For oral administration, the pharmaceutical composition can be formulated into oral formulations, such as conventional oral solid formulations like tablets, capsules, pills, or granules, or oral liquid formulations like oral solutions, oral suspensions, or syrups. When formulating into oral formulations, appropriate fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, the pharmaceutical composition can also be formulated into injectable formulations, including injectable solutions, sterile powders for injection, and concentrated solutions for injection. When formulating into injectable formulations, they can be produced using conventional methods in the existing pharmaceutical field. When preparing injectable formulations, no additives may be added, or appropriate additives may be added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories, etc. For intrapulmonary administration, the above-mentioned pharmaceutical composition can be formulated into inhalants, aerosols, powder inhalants, sprays, etc.

[0025] Pharmaceutically acceptable adjuvants are substances that are non-toxic, compatible with the active ingredient, and possess other biological properties suitable for use in living organisms. The selection of specific adjuvants depends on the method of administration in the treatment of a particular patient or on the type and condition of the disease. Examples of pharmaceutically acceptable adjuvants include, but are not limited to, those commonly used in the pharmaceutical field, such as solvents, diluents, dispersants, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, wettable powders, emulsifiers, buffers, absorbents, colorants, ion exchangers, release agents, coatings, flavoring agents, and antioxidants. Flavoring agents, preservatives, sweeteners, etc., may also be added to pharmaceutical compositions as needed.

[0026] A third aspect of this application provides the use of a compound represented by formula I, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing FabI enzyme-mediated diseases.

[0027] In some embodiments of this application, FabI enzyme inhibitors are provided that are effective in treating diseases caused by organisms that require FabI as a major reductase. Such organisms include, but are not limited to, one or more of the following: Francisella tularensis, Staphylococcus aureus, Bacillus anthrax, Plasmodium falciparum, Plasmodium yersinum, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus saprophyticus, Bordetella pertussis, Clostridium jejuense, Brucella, Legionnaires' disease, Neisseria gonorrhoeae, Neisseria meningitidis, Rickettsia, Salmonella enterica, Salmonella, Vibriocholerae, Chlamydia trachomatis, Chlamydia trachomatis pneumoniae, Chlamydial pneumoniae, Chlamydia psittaci, Mycoplasma tuberculosis, Mycoplasma pneumoniae, and Listeria monocytogenes.

[0028] A fourth aspect of this application provides a method for treating and / or preventing FabI enzyme-mediated diseases, comprising administering an effective amount of a compound represented by formula I as described in any of the preceding aspects, its stereoisomer, its deuterated compound, its isotopically labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate, or the above-mentioned pharmaceutical composition. The diseases herein are as described above.

[0029] The methods described in this application may be combination therapies in combination with other therapies known in the art for treating specific diseases or indications. Such other therapies include the administration of other active drugs, which may be administered simultaneously, separately, or sequentially with, the compound of this application or a pharmaceutical composition containing it.

[0030] Other treatments may include physical or indirect treatments such as surgery, laser therapy, and endocrine therapy (also known as hormone therapy). Specifically, the above other treatments may be used simultaneously with the administration of the compound of this application or a pharmaceutical composition containing it, or the two treatments may be used with an interval between them.

[0031] The compounds and derivatives described herein may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, Ohio) naming system.

[0032] With regard to the definitions of terms used in this application, unless otherwise specified, the first definition of a base or term in this specification shall apply to that base or term throughout the entire specification. Terms not specifically defined herein should be understood to have the meaning given by a person skilled in the art, based on the disclosure and context.

[0033] "Substitution" refers to replacing a hydrogen atom in a molecule with another different atom or group, or replacing a lone pair of electrons of an atom in a molecule with another atom or group. For example, replacing the lone pair of electrons of an S atom with an O atom results in the formula [ka] The base or formula shown by [ka] It can form the group shown by .

[0034] "Further substitution may occur" means that substitution is possible but not necessarily required, and this statement includes both cases where substitution occurs and cases where it does not.

[0035] "Multiple" refers to two or more groups. Therefore, substitution by multiple groups as described in this application means substitution by two or more groups. The specific number of substituents is influenced by the number of substitutable sites of the group being substituted and steric hindrance. Typically, this means substitution by two, three, four, five, or six groups, and more preferably by two or three groups.

[0036] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix. For example, "C a~b The prefix "alkyl group" represents an alkyl group containing a to b carbon atoms. Therefore, for example, C 1~6 An alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0037] An alkyl group refers to a saturated hydrocarbon chain having a specific number of constituent atoms. Alkyl groups can be linear or branched. Typical branched alkyl groups have one, two, or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl groups. Alkyl groups include, for example, -O(C 1~6 It may also be part of another group, such as an alkyl group.

[0038] An "alkylene group" refers to a divalent saturated aliphatic hydrocarbon group that has a specific number of constituent atoms. a~b An alkylene group refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched hydrocarbon groups and straight-chain hydrocarbon groups. For example, the term "propylene group" is defined by the following formula. [ka] This can be illustrated by the structure shown. Similarly, the term "dimethylbutylene group" can be used, for example, by formula [ka] The structure or formula shown [ka] This can be illustrated by any of the structures shown.

[0039] -C in this application 0~4 The alkylene group may be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-), a C3 alkylene group, or a C4 alkylene group. A C0 alkylene group refers to a group where no other group is present and is linked by a chemical bond, and A-C0 alkylene-B refers to A and B, meaning that group A and group B are directly linked by a chemical bond.

[0040] An "alkenyl group" refers to a linear or branched hydrocarbon group having at least one vinyl unsaturated moiety (>C=C<). For example, C a~b An alkenyl group refers to an alkenyl group having a to b carbon atoms, and includes, for example, vinyl, propenyl, isopropenyl, and 1,3-butadienyl groups.

[0041] An "alkynyl group" refers to a straight-chain monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl group" also includes hydrocarbon groups having one triple bond and one double bond. For example, C 2~6 Alkynyl groups include ethynyl groups and propynyl groups.

[0042] In this application, the term "cycloalkyl group" refers to a saturated or partially saturated cyclic group having multiple carbon atoms, not containing heterocyclic atoms, and having a monocyclic or polycyclic (including fused) structure. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and polycyclic alkyl rings such as dicyclopropyl, dicyclohexyl, dicyclopentyl, and dicyclooctyl. Here, each ring in a polycyclic alkyl ring is, for example, a compound of the formula... [ka] As shown in the structure, they may be linked to the same carbon atom, and formula [ka] As shown in the structure, they may be linked to adjacent and / or separated different carbon atoms.

[0043] In this application, the term "heterocycloalkyl group" or "heterocycle" refers to a saturated ring or a non-aromatic partially saturated ring having a monocyclic or polycyclic (condensed, bridged, or spirocondensed) structure, comprising at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. This typically represents a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system having multiple ring atoms, containing one, two, or three heterocyclic atoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyl groups in monoheterocycloalkyl systems include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidine-3-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, and oxazepanyl groups. Examples of heterocycloalkyl groups in condensed heterocycloalkyl systems include 8-azabicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-azabicyclo[3.2.1]octyl, and 9-azabicyclo[3.3.1]nonyl groups. Examples of crosslinked heterocycloalkyl systems include the formula [ka] This includes groups such as those shown by the formula. An example of a heterocycloalkyl group in the spiroheterocycloalkyl system is the formula [ka] This includes groups such as those shown in formula. Examples of partially saturated heterocycloalkyl groups include dihydrofuranyl, imidazolinyl, tetrahydropyridyl, and dihydropyranyl groups. The term "heterocycloalkyl group" also includes partially saturated cyclic groups formed by the condensation of an aromatic ring containing at least one heteroatom and a non-aromatic ring, the linkage site of which may be located on a non-aromatic carbon atom, an aromatic carbon atom, or a heteroatom, for example, formula [ka] It contains the group indicated by .

[0044] In this specification, “aromatic ring” refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aryl groups having multiple carbon atoms. Furthermore, as used herein, the term “aryl group” refers to an aromatic substituent that is a single aromatic ring or a fused group of aromatic rings. Examples, though not limited to these, include phenyl, naphthyl, or tetrahydronaphthyl groups.

[0045] In this application, the term "aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom, where a heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Typically, it refers to an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, of which one or more ring atoms are selected from O, N, and S heteroatoms. Preferably, it has 1 to 3 heteroatoms. Examples of heterocycloaryl groups include pyridyl group, indolyl group, quinoxalinyl group, quinolinyl group, isoquinolinyl group, benzothienyl group, benzofuranyl group, benzothienyl group, benzopyranyl group, benzothiapyranyl group, furanyl group, pyrrolyl group, thiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, pyrazolyl group, imidazolyl group, thienyl group, oxadiazolyl group, benzimidazolyl group, benzothiazolyl group, and benzoxazolyl group.

[0046] In this application, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0047] In this application, the term "halogen-substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms are substituted with halogens. For example, halogen-substituted C 1~4 Alkyl groups refer to alkyl groups containing 1 to 4 carbon atoms, in which one or more hydrogen atoms are substituted with halogen atoms. Other examples include monofluoromethyl, difluoromethyl, and trifluoromethyl groups.

[0048] In this application, "-OR", "-NR", "-NRR", etc., mean that the R group is linked to an oxygen atom or a nitrogen atom by a single bond.

[0049] In this application, "-C(O)R", "-S(O)2R", etc., mean that an oxygen atom is double-bonded to a carbon atom or a sulfur atom.

[0050] In this application, "-C(O)R", "-S(O)2R", etc., mean that an oxygen atom is double-bonded to a carbon atom or sulfur atom, and the R group is single-bonded to an oxygen atom or sulfur atom. Also, for example, "-S(O)(NH)R" means that an oxygen atom and a nitrogen atom are double-bonded to a sulfur atom, and the R group is single-bonded to a sulfur atom.

[0051] In this application, "oxo" refers to =O, meaning that an oxygen atom substitutes two hydrogen atoms or a lone pair of electrons via a double bond.

[0052] JPEG2026534277000020.jpg17170 [ka] JPEG2026534277000022.jpg16170

[0053] In this application, "deuterated compound" refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, and the proportion of deuterium atoms is greater than the amount of deuterium present in nature.

[0054] "Stereoisomers" include not only enantiomers and diastereomers, but also cis-trans isomers and tautomers.

[0055] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, auxiliary material, and / or salt formed is typically chemically or physically compatible with the other components that make up the drug dosage form and physiologically compatible with the receptor.

[0056] The terms “salt” and “pharmaceutical salt” refer to acidic and / or basic salts formed from the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including amphoteric salts (intramolecular salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final separation and purification process of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds or their stereoisomers with an appropriate amount (e.g., isostocal) of acid or base. These salts can be obtained by precipitation in solution and recovery by filtration, recovery by evaporation of the solvent, or by reaction in an aqueous medium followed by freeze-drying.

[0057] The term "prodrug" as used in this application refers to a compound that is rapidly converted into the parent compound of the above formula in a living organism, and can be converted into the compound of this application by chemical or biochemical methods in a living or extra-living environment, such as hydrolysis in the blood.

[0058] The compounds of this application can exist in both non-solvated and solvated forms, with the solvated form including the hydrated form. Generally, the solvated form is equivalent to the non-solvated form and is also included within the scope of this application.

[0059] In some embodiments, one or more of the compounds of this application may be used in combination with each other. Alternatively, the compounds of this application may be used in combination with any other active reagents to prepare drugs or pharmaceutical compositions for regulating cellular function or treating diseases. When using the group of compounds, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0060] In this application, if any variable appears multiple times in the composition or structure of a compound, its definition is independent in each case, and the substituents may be the same or different. For example, multiple R 11 If replaced by each R 11 They are independent of each other.

[0061] Of course, various modifications, substitutions, or changes can be made based on the above-mentioned content of this application and in accordance with ordinary technical knowledge and customary means in the relevant art, without departing from the basic technical concept of this application. [Effects of the Invention]

[0062] The beneficial effects of this application are as follows: Compared to existing FabI inhibitors in clinical studies, the FabI enzyme inhibitor of this application has superior drug potential, can be administered directly in the form of an active pharmaceutical ingredient, and has better in vivo drug exposure. In terms of antimicrobial spectrum, compared to existing FabI inhibitors in clinical studies, the compound of this application has a broader antimicrobial spectrum against common community-acquired pathogens such as Moraxella catarrhalis. In terms of in vivo efficacy, the compound of this application shows superior in vivo efficacy compared to FabI inhibitors in clinical studies. As described above, this application provides a new option for clinical screening and / or preparation of drugs for diseases related to FabI enzyme activity. [Brief explanation of the drawing]

[0063] [Figure 1] These are the results of pharmacokinetic studies of compound 1a of this application in rats. [Figure 2] These are the results of a pharmacokinetic study of Debio-1450 in rats. [Figure 3] This shows the results of in vivo efficacy tests of the compound of this application in mice. [Modes for carrying out the invention]

[0064] The contents of this application will be described in more detail below with reference to specific examples. Unless otherwise specified, all raw materials, reagents, or apparatus used in the examples and comparative examples are conventionally available commercially or can be obtained by existing technical methods. Unless otherwise specified, the tests or test methods are conventional methods in the art.

[0065] The structure of the compound is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is 10 -6 The values ​​are expressed in ppm. NMR measurements are performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers. Deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) are used as solvents, and tetramethylsilane (TMS) is used as the internal standard.

[0066] LC-MS measurements are performed using a Shimadzu LC-MS 2020 (ESI) liquid chromatography / mass spectrometer. HPLC measurements are performed using a Shimadzu LC-20A high-performance liquid chromatography system. MPLC (medium-pressure preparative chromatography) is performed using a Gilson GX-281 reverse-phase preparative chromatography system. For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used, with a size of 0.4-0.5 mm used for products separated and purified by thin-layer chromatography. For column chromatography, Yantai Huanghai 200-300 mesh silica gel is commonly used as the support.

[0067] The known starting materials used in this application can be synthesized using methods known in the art, or purchased from companies such as Energy Chemical, Chengdu Kelong Chemical, Accela ChemBio Co. Ltd, and J&K Scientific.

[0068] Unless otherwise specified in the examples, the reactions are carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Unless otherwise specified in the examples, M is the number of moles per liter.

[0069] Example 1 This example prepares compound 1a / 1b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)-N-((3,7-dimethylbenzofuran-2-yl)methyl)-N-methylacrylamide), and the specific process is as follows. [ka] Step 1 Compound 1-1 (6.0 g, 29.5 mmol) was dissolved in dichloromethane (200.0 mL), and then activated manganese dioxide (25.7 g, 295.0 mmol) was added at room temperature. The reaction mixture was stirred at 40°C for 3 hours. After monitoring by TLC, the reaction was completed, and the resulting filtrate was filtered. The solvent was removed by vacuum distillation, and the resulting crude product 1-2 (5.0 g, 24.9 mmol, yield: 84.3%) was used directly in the next step. MS-ESI calculated value [M+H] + 202.0, measured value 202.0. Step 2 Compounds 1-2 (5.0 g, 24.9 mmol), diethyl malonate (39.8 g, 249.0 mmol), and piperidine (4.2 g, 49.7 mmol) were mixed. The mixture was reacted at 120°C for 2 hours. The reaction was monitored by LC-MS. Once the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (20 x 3 mL). The resulting crude product 1-3 (5.8 g, 19.5 mmol, yield: 78.4%) was used directly in the next step. MS-ESI calculated value [M+H] + 298.0, actual measured value 298.0. Step 3 Trimethylsulfoxonium iodide (8.0 g, 40.0 mmol) was dissolved in dimethyl sulfoxide (150.0 mL), sodium hydride (2.4 g, 60.0 mmol) was added, and the mixture was reacted with stirring at 25°C under nitrogen protection for 1 hour. Then, compound 1-3 (5.8 g, 19.5 mmol) was added and the mixture was reacted for 3 hours. After the starting materials were completely used up in the reaction, the reaction solution was injected into saturated ammonium chloride aqueous solution (500.0 mL) to quench the reaction, and the mixture was extracted with ethyl acetate (200.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was removed by vacuum distillation to remove the solvent. The resulting crude product 1-4 (4.5 g, 14.5 mmol, yield: 74.2%) was used directly in the next step. MS-ESI calculated value [M+H] + 312.0, measured value 312.0. Step 4 Compound 1-4 (4.5 g, 14.5 mmol) was dissolved in tetrahydrofuran (60.0 mL) and water (60.0 mL), and lithium hydroxide (693.5 mg, 28.9 mmol) was added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to less than 6, and ethyl acetate (100.0 mL x 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was removed by vacuum distillation to remove the solvent. The resulting crude product 1-5 (2.9 g, 10.2 mmol, yield: 70.4%) was used directly in the next step. MS-ESI calculated value [M+H] + 284.0, measured value 284.0. Step 5 Compound 1-5 (2.9 g, 10.2 mmol) was added to toluene (45.0 mL), followed by the sequential addition of diphenyl phosphate azide (4.2 g, 15.4 mmol), triethylamine (3.1 g, 30.7 mmol), and tert-butanol (1.1 g, 15.4 mmol). The reaction mixture was stirred at 100 °C for 4 hours. After the reaction was complete, toluene was removed by vacuum distillation, and the resulting crude product was purified by liquid chromatography to obtain compound 1-6 (1.5 g, 4.2 mmol, yield: 41.5%). MS-ESI calculated value [M+H] + 355.0, actual measured value 355.0. Step 6 Compound 1-6 (1.5 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (40.0 mL). Tert-butyl acrylate (1.1 g, 8.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (388.0 mg, 0.4 mmol), tri(o-tolyl)phosphine (257.7 mg, 0.85 mmol), and N,N-diisopropylethylamine (1.1 g, 8.5 mmol) were added at room temperature. The reaction was carried out at 100 °C for 3 hours. Once the reaction was complete, water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was removed by vacuum distillation to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain compounds 1-7 (1.0 g, 2.5 mmol, yield: 58.8%). MS-ESI calculated value [M+H] + 402.2, measured value 402.2. Step 7 Compound 1-7 (1.0 g, 2.5 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the resulting solution was filtered, and the solvent was removed by vacuum distillation to obtain crude product 1-8 (2.0 g). MS-ESI calculated value [M+H] + 246.1, measured value 246.1. Step 8 Crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL), and then compound 1-9 (70.0 mg, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were added sequentially at room temperature. The reaction mixture was allowed to react at 25°C for 1 hour with stirring. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was removed by vacuum distillation to remove the solvent. The resulting crude product was purified by liquid chromatography, and then separated by SFC to obtain compound 1a (30.0 mg, 0.07 mmol, purity: 100.0%) and compound 1b (26.5 mg, 0.06 mmol, purity: 100.0%). SFC division conditions: Column specification: 3μm, 150mm*3mm. Mobile Phase:A:CO2B:EtOH / 0.1%DEA, Flow Rate:1mL / min Column Temperature:40℃.[P1, 2.834min;P2, 3.718min]. 1a: MS-ESI calculated value [M+H] + 417.2, measured value 417.2. 1b: MS-ESI calculated value [M+H] + 417.2, measured value 417.2. 1a:1H NMR(400MHz,DMSO)δ8.34(d,J=12.9Hz,1H),8.26(s,1H),7.49(dd,J=14.6,12. 0Hz,1H),7.38(d,J=7.4Hz,1H),7.22(dd,J=25.2,9.8Hz,1H),7.17-7.05(m,2H ),4.84(t,J=42.4Hz,2H),3.27-2.96(m,3H),2.59(dt,J=16.2,8.1Hz,1H),2.4 7-2.33(m,3H),2.24(t,J=7.3Hz,3H),1.68-1.58(m,1H),0.75(d,J=4.6Hz,1H). 1b:1HNMR(400MHz,DMSO)δ8.37(d,J=12.2Hz,1H),8.29(s,1H),7.62-7.44(m, 1H),7.38(d,J=7.4Hz,1H),7.23(d,J=15.4Hz,1H),7.18-7.02(m,2H),4.89(d ,J=73.8Hz,2H),3.28-2.94(m,3H),2.71(dd,J=9.4,5.7Hz,1H),2.38(d,J=36 .2Hz,3H),2.24(t,J=7.4Hz,3H),1.71(d,J=5.1Hz,1H),0.87(d,J=4.1Hz,1H).

[0070] Example 2 This example prepares compound 2a / 2b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)-N-((7-cyclopropyl-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide), and the specific process is as follows. [ka] Crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL), and then compound 2-1 (80.0 mg, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were added sequentially at room temperature. The reaction mixture was allowed to react at 25°C for 1 hour with stirring. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was removed by vacuum distillation to remove the solvent. The resulting crude product was purified by liquid chromatography, and then separated by SFC to obtain compound 2a (35.0 mg, 0.08 mmol, purity: 96.0%) and compound 2b (30.5 mg, 0.07 mmol, purity: 96.0%). SFC segmentation conditions: Column specification: 3μm, 150mm*3mm. Mobile Phase: A: CO2B: EtOH / 0.1%DEA, Flow Rate: 1mL / min Column Temperature: 40℃. [P1, 3.897min; P2, 4.780min]. 2a: MS-ESI calculation value [M+H] + 443.2, measured value 443.2. 2b: MS-ESI calculation value [M+H] + 443.2, measured value 443.2. 2a:1H NMR(400MHz,DMSO)δ8.34(d,J=11.0Hz,1H),8.27(d,J=8.1Hz,1H),7.52(dt,J=15.3,11.5Hz,1H),7.3 3(d,J=6.9Hz,1H),7.22(d,J=15.4Hz,1H),7.15(td,J=7.5,3.9Hz,1H),6.90(dd,J=16.6,7.4Hz,1H), 4.92(dd,J=52.0,33.8Hz,2H),3.12(d,J=102.5Hz,3H),2.66(s,1H),2.25(d,J=7.3Hz,3H),2.11(d,J =73.1Hz,1H),1.68(d,J=4.6Hz,1H),1.03(d,J=6.4Hz,1H),0.89(s,2H),0.79(dd,J=14.0,8.7Hz,2H). 2b:1H NMR(400MHz,DMSO)δ8.43(d,J=12.3Hz,1H),8.36(d,J=9.8Hz,1H),7.55(dt,J=15.1,9.9Hz,1H), 7.33(d,J=7.6Hz,1H),7.27(t,J=12.5Hz,1H),7.15(td,J=7.6,3.1Hz,1H),6.91(dd,J=19.2,7.4H z,1H),4.88(d,J=69.2Hz,2H),3.29-2.98(m,3H),2.94(s,1H),2.25(d,J=6.2Hz,3H),2.22-1.98( m,1H),1.97-1.86(m,1H),1.03(d,J=6.3Hz,1H),0.87(dd,J=19.3,5.3Hz,2H),0.83-0.72(m,2H).

[0071] Example 3 This example prepares compound 3a / 3b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine-6-yl)-N-((3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide), and the specific process is as follows. [ka] Crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL), and then compound 3-1 (65.0 mg, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were added sequentially at room temperature. The reaction mixture was allowed to react at 25°C for 1 hour with stirring. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was removed by vacuum distillation to remove the solvent. The resulting crude product was purified by liquid chromatography, and then separated by SFC to obtain compound 3a (25.0 mg, 0.06 mmol, purity: 97.0%) and compound 3b (22.0 mg, 0.05 mmol, purity: 100.0%). SFC division conditions: Column specification: 3μm, 150mm*3mm. Mobile Phase:A:CO2B:EtOH / 0.1%DEA, Flow Rate:1mL / min Column Temperature:40℃.[P1, 3.541min;P2, 5.085min]. 3a: MS-ESI calculated value [M+H] + 403.2, measured value 403.2. 3b: MS-ESI calculated value [M+H] + 403.2, measured value 403.2. 3a:1H NMR(400MHz,DMSO)δ8.35(t,J=12.7Hz,1H),8.28(s,1H),7.57(t,J=9.3Hz,1H),7.55-7.43(m,2H),7.37-7.18(m,3H),4 .89(d,J=75.0Hz,2H),3.24-2.93(m,3H),2.73(dd,J=9.2,5.7Hz,1H),2.27(s,3H),1.73(s,1H),0.86(d,J=4.4Hz,1H). 3b:1H NMR(400MHz,DMSO)δ8.36-8.29(m,1H),8.26(s,1H),7.57(dd,J=13.0,11.8Hz,1H),7.53-7.44(m,2H),7.35-7.17(m,3H),4.84( dd,J=53.0,37.4Hz,2H),3.23-2.94(m,3H),2.65(dd,J=9.3,5.6Hz,1H),2.27(s,3H),1.72-1.61(m,1H),0.76(d,J=4.8Hz,1H).

[0072] Test Example 1 In this study, enzyme activity was evaluated by monitoring the oxidation of cofactors NADH / NADPH using a microplate reader.

[0073] The compound was dissolved in DMSO and added to a 384-well plate using ECHO665. The compound was diluted 3-fold or 4-fold to produce a total of 10 doses, with two parallel overlapping wells for each concentration. The final concentration of DMSO in each well was also adjusted to 1%. Next, the FabI protein solution was added. The proteins were prepared in a buffer of 100 mmol / L PBS, 0.05% Tween-20, 150 mmol / L NaCl, pH 6.5, so that the final concentrations of SaFabI and EcFabI proteins were 15 nmol / L and 9 nmol / L, respectively. 5 μL each of the prepared 15 nmol / L SaFabI and 9 nmol / L EcFabI was added to the 384-reaction plate, centrifuged at 1000 rpm for 1 minute, and then the plate was pre-incubated in a thermostat shaker at 30°C for 20 minutes. Simultaneously, the substrates trans-octenoyl-CoA, NADPH, trans-dodecenoyl-CoA, and NADH were diluted in 100 mmol / L PBS, 0.05% Tween-20, 150 mmol / L NaCl, and pH 6.5 buffer to concentrations of 300 μmol / L, 300 μmol / L, 600 μmol / L, and 150 μmol / L, respectively. For the SaFabI protein, 5 μL of 300 μmol / L trans-octenoyl-CoA and 5 μL of 300 μmol / L NADPH were added to initiate the reaction. The reaction plate was immediately placed on a microplate reader, and fluorescence signals (Ex 340 nm / Em 460 nm) were collected every 0.5 minutes. The collection time was at least 10 minutes. Similarly, 5 μL of 600 μmol / L trans-dodecenoyl-CoA and 5 μL of 150 μmol / L NADH were added to initiate each EcFabI reaction. The reaction plates were immediately placed on a microplate reader, and fluorescence signals (Ex 340 nm / Em 460 nm) were collected every 0.5 minutes. The collection time was at least 10 minutes. The reaction rate (fluorescence signal per minute) for each well was calculated from the fluorescence values. The inhibitory effect of the compounds on proteins was calculated using these reaction rates.Next, IC of enzyme activity inhibition by the compound was performed using GraphPad Prism 6 by log(inhibitor) vs. response-variable slope mode fitting. 50 The following was calculated. The fitting equation is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC) 50 -X)*HillSlope)), where Y represents the known percentage of residual enzyme activity and X represents the known concentration of the compound after logarithmization.

[0074] The in vitro enzymatic activity of the compound of this application has been demonstrated by the above tests, showing excellent inhibitory activity against the FaBI enzymes of Staphylococcus aureus and Escherichia coli.

[0075] [Table 1]

[0076] Test Example 2 In this study, the minimum inhibitory concentration (MIC) of the compound was tested.

[0077] Using the agar plate 2-fold dilution method, experimental drug concentrations were diluted 2-fold in the range of 0.008 μg / mL to 128 μg / mL. Samples were collected and dissolved in DMSO to prepare 2 mL of a 1.92 mg / mL solution. A control sample was prepared to 1.92 mg / mL with sterile distilled water. 1 mL of the prepared drug solution was added to a sterile Petri dish, and 14 mL of MHA medium at approximately 60°C was added and mixed uniformly. 1 mL of sterile distilled water was added for a 2-fold dilution, resulting in final drug concentrations of 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, and 0.008 μg / mL (of these, the final concentrations of samples 2, 4, and 9 were diluted starting from 128 μg / mL), and the samples were prepared for use. The prepared bacterial suspension was inoculated into petri dishes containing drug-containing MHA medium using a multi-point inoculation device. The amount of inoculation at each inoculation point was approximately 10 4CFU was defined as the limiting factor (CFU). A sterile control group (1 mL of DMOS + 14MHA medium and 1 mL of sterile distilled water + 14MHA medium) was also prepared. After incubating the petri dishes in an incubator at 37°C for 16-20 hours, bacterial growth at each inoculation site was observed and the MIC value was determined.

[0078] Regarding the in vitro antibacterial activity of the compound in this application, the above tests showed excellent antibacterial activity against all Staphylococcus aureus strains, including susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Staphylococcus aureus (VRSA). It also showed some antibacterial activity against Escherichia coli, but its antibacterial activity against Klebsiella pneumoniae and Acinetobacter baumannii was weak.

[0079] [Table 2]

[0080] The antimicrobial spectrum of compound 1b was tested according to the minimum inhibitory concentration test method described above. The results showed that compound 1b exhibited excellent antimicrobial activity against Staphylococcus aureus, hemolytic Staphylococcus, Staphylococcus hominis, and Moraxella catarrhalis. It also showed good antimicrobial activity against Haemophilus influenzae.

[0081] [Table 3]

[0082] Test Example 3 In this study, the pharmacokinetic properties of the compound were tested in rats.

[0083] Twelve healthy adult female SD rats (purchased from Charles River) (average weight approximately 180-220g) were divided into four groups of three rats each. Two groups received the drug via tail vein injection, and the other two groups received it intragastricly. Compound 1b was dissolved in (5% DMSO-30% PEG400-65% H2O) solvent, and Debio-1450 was dissolved in physiological saline. Both solutions formed stable, clear solutions and were prepared for use. The animals were fasted for 12 hours prior to administration and resumed normal feeding 2 hours after administration. Subsequently, blood samples of approximately 200-400 μL were collected from the jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (intravenous administration), and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours (intragastric administration). Whole blood was collected at each time point, placed in anticoagulation tubes containing K2EDTA, and stored in an incubator with an ice pack. Within 15 minutes, all samples were centrifuged at 4,600 r / min at 4°C for 5 minutes to separate the plasma. The concentrations of compounds in rat plasma were measured by LC / MS / MS, and pharmacokinetic parameters were calculated based on the drug concentration-time curve. The results are shown in Table 4, Figure 1, and Figure 2.

[0084] [Table 4]

[0085] The pharmacokinetic properties of the compound of this application were tested using the above-described test. The experimental results showed that the compound of this application exhibited excellent pharmacokinetic properties in rats after intravenous or oral administration, and C max Furthermore, it was shown to be superior to the Debio-1450 in terms of AUC.

[0086] Test Example 4 In this study, the in vivo efficacy of the compound was tested in mice (a systemic infection model).

[0087] Ninety healthy adult male Balb / c mice (purchased from Charles River) were selected and divided into 10 groups: one negative control group (9 mice, inoculated with bacteria and administered a solvent), one positive control group (9 mice, vancomycin), one linezolid test group (9 mice), three groups of compound 1a (high, medium, and low doses, 3 x 9 mice), three groups of Debio-1450 (high, medium, and low doses, 3 x 9 mice), and one Debio-1452 test group (9 mice). All animals underwent a 3-4 day quarantine period before the study. The bacterial strain inoculated in this study was methicillin-resistant Staphylococcus aureus (NRS384), with an inoculation dose of 1.0E+08 CFU / mouse, administered via the tail vein. The compounds were administered 30 minutes after inoculation. The solvents for compound 1a and Debio-1452 were 5% DMSO-30% PEG400-65% H2O. Debio-1450 was administered orally as a single dose using an isotonic glucose solution (immediately prepared) as the solvent. The specific administration regimens are shown in Table 5.

[0088] [Table 5]

[0089] The above tests validated the in vivo efficacy of the compound of this application. As shown in Figure 3, the compound of this application showed a clear protective effect on mice compared to the negative control group after oral administration, and the protective effect increased with increasing dose. Compared to the control compounds linezolid and Debio-1450, compound 1a showed significantly superior efficacy.

[0090] The embodiments described above are preferred embodiments of the present application, but the embodiments of the present application are not limited to those described above. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principles of the protection of the present application shall all be deemed equivalent substitutions and shall be within the scope of the protection of the present application.

Claims

1. Compounds represented by formula I, their stereoisomers, their deuterated compounds, their isotope-labeled derivatives, their pharmaceutically acceptable salts, their prodrugs or solvates. 【Chemistry 1】 Equation I (Here, X is O, CR Ｘ１ R Ｘ２ , NR Ｘ１ Selected from S, Y is O, -CH ２ -, NR Ｙ , -O-CH ２ -, -CH ２ -O-, -NR Ｙ -CH ２ -, -CH ２ -NR Ｙ - is selected from R Ｘ１ , R Ｘ２ These are, independently, hydrogen and -C. １～６ Alkyl, halogen-substituted C １～６ Selected from alkyl groups, R Ｙ is hydrogen, -C １～６ Alkyl, halogen-substituted C １～６ Alkyl alkyl group, -C ０～２ Alkylene-C(O)R Ｙ１ , -C ０～２ Alkylene-C(O)NR Ｙ１ R Ｙ２ , -C ０～２ Alkylene-NR Ｙ１ R Ｙ２ , -C ０～２ Alkylene-NR Ｙ１ C(O)R Ｙ２ , -C ０～２ Alkylene-(3-10 membered cycloalkyl group), -C ０～２ Alkylene-(3-10 member heterocycloalkyl group), -C ０～２ Alkylene-(6-10 membered aromatic ring), -C ０～２ Selected from alkylenes (5-10 membered aromatic heterocycles), R Ｙ１ , R Ｙ２ These are, independently, hydrogen and -C. １～６ Alkyl, halogen-substituted C １～６ Selected from alkyl groups, R １ These are hydrogen, halogen, cyano group, nitro group, and -C １～６ Alkyl, halogen-substituted C １～６ Alkyl alkyl group, -C ０～２ Alkylene-OR １１ , -C ０～２ Alkylene-C(O)R １１ , -C ０～２ Alkylene-C(O)NR １１ R １２ , -C ０～２ Alkylene-NR １１ R １２ , -C ０～２ Alkylene-NR １１ C(O)R １２ , -C ０～２ Alkylene-(3-10 membered cycloalkyl group), -C ０～２ Alkylene-(3-10 member heterocycloalkyl group), -C ０～２ Alkylene-(6-10 membered aromatic ring), -C ０～２ Selected from alkylenes (5-10 membered aromatic heterocycles), R １１ , R １２ These are, independently, hydrogen, halogen, and -C. １～６ Alkyl, halogen-substituted C １～６ Alkyl alkyl group, -C ０～２ Alkylene-(3-10 membered cycloalkyl group), -C ０～２ Alkylene-(3-10 member heterocycloalkyl group), -C ０～２ Alkylene-(6-10 membered aromatic ring), -C ０～２ Selected from alkylenes (5-10 membered aromatic heterocycles), R ２ These are hydrogen, halogen, cyano group, nitro group, and -C １～６ Alkyl, halogen-substituted C １～６ Alkyl alkyl group, -C ０～２ Alkylene-OR ２１ , -C ０～２ Alkylene-C(O)R ２１ , -C ０～２ Alkylene-C(O)NR ２１ R ２２ , -C ０～２ Alkylene-NR ２１ R ２２ , -C ０～２ Alkylene-NR ２１ C(O)R ２２ , -C ０～２ Alkylene-(3-10 membered cycloalkyl group), -C ０～２ Alkylene-(3-10 member heterocycloalkyl group), -C ０～２ Alkylene-(6-10 membered aromatic ring), -C ０～２ Selected from alkylenes (5-10 membered aromatic heterocycles), R ２１ , R ２２ each independently represent hydrogen, halogen, -C １～６ alkyl group, halogen-substituted -C １～６ alkyl group, -C ０～２ alkylene-(3- to 10-membered cycloalkyl group), -C ０～２ alkylene-(3- to 10-membered heterocycloalkyl group) R ３ is hydrogen, halogen, cyano group, nitro group, hydroxy group, -C １～６ alkyl group, halogen-substituted -C １～６ alkyl group, -C ０～２ alkylene-OR ３１ , -C ０～２ alkylene-C(O)R ３１ , -C ０～２ alkylene-C(O)NR ３１ R ３２ , -C ０～２ alkylene-NR ３１ R ３２ , -C ０～２ alkylene-NR ３１ C(O)R ３２ , -C ０～２ alkylene-(3- to 10-membered cycloalkyl group), -C ０～２ alkylene-(3- to 10-membered heterocycloalkyl group), -C ０～２ alkylene-(6- to 10-membered aromatic ring), -C ０～２ alkylene-(5- to 10-membered aromatic heterocycle), is selected from the group consisting of R ３１ , R ３２ These are, independently, hydrogen, halogen, and -C. １～６ Alkyl, halogen-substituted C １～６ Alkyl alkyl group, -C ０～２ Alkylene-NR ３３ R ３４ , -C ０～２ Alkylene-(3-10 membered cycloalkyl group), -C ０～２ Alkylene-(3-10 member heterocycloalkyl group), -C ０～２ Alkylene-(6-10 membered aromatic ring), -C ０～２ Selected from alkylenes (5-10 membered aromatic heterocycles), R ３３ , R ３４ These are, independently, hydrogen, halogen, and -C. １～６ Alkyl, halogen-substituted C １～６ Selected from alkyl groups, R ４ is hydrogen, -C １～６ Alkyl, halogen-substituted C １～６ Selected from alkyl groups, m is selected from 0, 1, or 2, and n is selected from 1 or 2. Here, a C value of 0 indicates that the group in question does not exist.

2. The compound represented by formula I is the compound represented by formula II as described in claim 1, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate. 【Chemistry 2】 Formula II (Here, the above R １ , R ２ , R ３ , R ４ X and n are as defined in claim 1.

3. The compound represented by formula I is the compound represented by formula III as described in claim 1, a stereoisomer thereof, a deuterated compound thereof, an isotope-labeled derivative thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof. 【Transformation 3】 Formula III (Here, the above R １ , R ２ , R ３ , R ４ (X, m, and n are as defined in claim 1.)

4. The compound represented by formula I is the compound represented by formula IV as described in claim 1, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate. 【Chemistry 4】 Formula IV (Here, the above R １ , R ２ , R ３ , R ４ X and n are as defined in claim 1.

5. The compound represented by formula I is the compound represented by formula V as described in claim 1, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate. 【Transformation 5】 Formula V (Here, the above R １ , R ２ , R ３ , R ４ , R Ｙ X and n are as defined in claim 1.

6. R ３ is, -C ０～２ Alkylene-OR ３１ , -C ０～２ Alkylene-NR ３１ R ３２ , -C ０～２ Alkylene-NR ３１ C(O)R ３２ Selected from ,- (3-6 member heterocycloalkyl groups), R ３１ , R ３２ These are, independently, hydrogen and -C. １～３ Alkyl alkyl group, -C ０～２ Alkylene-NR ３３ R ３４ Selected from, R ３３ , R ３４ These are, independently, hydrogen and -C. １～３ A compound represented by formula I as described in claim 1, selected from alkyl groups, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate.

7. R ３ is, -NH ２ ,formula 【Transformation 6】 A compound represented by formula I according to claim 1, characterized by being selected from the groups represented by , its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate.

8. The compound represented by formula I is selected from the following compounds, characterized in that it is the compound represented by formula I as described in claim 1, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate. 【Transformation 7】 【change】

9. A pharmaceutical composition comprising a compound represented by formula I as described in any one of claims 1 to 8, a stereoisomer thereof, a deuterated compound thereof, an isotope-labeled derivative thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof.

10. Use of a compound represented by formula I according to any one of claims 1 to 8, its stereoisomer, its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or solvate, or the pharmaceutical composition according to claim 9, in the preparation of a drug for treating and / or preventing a FabI enzyme-mediated disease.

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