FabI enzyme inhibitor and application thereof

Abstract

The invention discloses a FabI enzyme inhibitor and application thereof, the FabI enzyme inhibitor is a compound as shown in a formula I, and a new choice is provided for clinical screening and / or preparation of drugs for treating diseases related to FabI enzyme activity.

Description

A FabI enzyme inhibitor and its application Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a FabI enzyme inhibitor and its application. Background Art

[0002] Fatty acid synthase (FAS) participates in the entire biosynthetic pathway for saturated fatty acids in all organisms. Each bacterial fatty acid biosynthesis cycle consists of four steps: First, malonyl-ACP condenses with acetyl-CoA, catalyzed by β-ketoacyl-ACP synthase; second, the ketoate is reduced by NADPH-dependent β-ketoacyl-ACP reductase; third, β-hydroxyacyl-ACP dehydratase dehydrates the ketoate to produce trans-2-enoyl-ACP; and fourth, NADH-dependent enoyl-ACP reductase (FabI) ​​converts trans-2-enoyl-ACP to an acyl-ACP with two additional carbon atoms. This cycle is repeated, ultimately yielding palmitoyl-ACP (C16). FabI is a key regulatory enzyme in fatty acid biosynthesis. Therefore, inhibiting FabI activity can block bacterial fatty acid biosynthesis, thereby inhibiting bacterial growth and reproduction, potentially playing a therapeutic role in bacterial infections.

[0003] There are currently some compounds with FabI enzyme inhibitory activity, but with the increasing number of patients affected by multiple bacterial infections and drug resistance, there is still a need to further develop new drugs for the treatment of bacterial infections.

[0004] Summary of the Invention

[0005] The present application aims to solve at least one of the above-mentioned technical problems existing in the prior art. To this end, the purpose of the present application is to provide a FabI enzyme inhibitor and its application.

[0006] In order to achieve the above objectives, the technical solutions adopted in this application are:

[0007] In the first aspect of the present application, a compound of formula I, or a stereoisomer thereof, or a deuterated compound thereof, an isotope-labeled derivative thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof is provided:

[0008] Wherein, X is selected from O, CR X1 R X2 NR X1 , S;

[0009] Y is selected from O, -CH2-, NR Y 、-O-CH2-、-CH2-O-、-NR Y-CH2-, -CH2-NR Y -;

[0010] R X1 、R X2 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0011] R Y Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0012] R Y1 、R Y2 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0013] R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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), -C 0～2Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0014] R 11 、R 12 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0015] R 2 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0016] R 21 、R 22 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl);

[0017] R 3 Selected from hydrogen, halogen, cyano, nitro, hydroxyl, -C 1～6 Alkyl, halogen-substituted -C1～6 Alkyl, -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-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0018] R 31 、R 32 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-NR 33 R 34 、-C 0～2 Alkylene-(3-10 membered cycloalkyl), -C 0～2 Alkylene-(3-10 membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle);

[0019] R 33 、R 34 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0020] R 4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0021] m is selected from 0, 1 or 2; n is selected from 1 or 2;

[0022] Wherein, when C is 0, it means that the group does not exist.

[0023] In some embodiments of the present application, R 1 Selected from hydrogen, -C 1～3 Alkyl, -C0～2 Alkylene-NR 11 R 12 , -(3- to 6-membered cycloalkyl).

[0024] In some embodiments of the present application, R 1 Selected from hydrogen, methyl, cyclopropyl, -NH2.

[0025] In some embodiments of the present application, R 2 Selected from halogen, -C 1～3 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl).

[0026] In some embodiments of the present application, R 2 Selected from hydrogen, methyl, halogen, cyclopropyl.

[0027] In some embodiments of the present application, R 3 Selected from -C 0～2 Alkylene-OR 31 、-C 0～2 Alkylene-NR 31 R 32 、-C 0～2 Alkylene-NR 31 C(O)R 32 , -(3- to 6-membered heterocycloalkyl);

[0028] R 31 、R 32 are independently selected from hydrogen, -C 1～3 Alkyl, -C 0～2 Alkylene-NR 33 R 34 ;

[0029] R 33 、R 34 are independently selected from hydrogen, -C 1～3 alkyl.

[0030] In some embodiments of the present application, R 3 Selected from -NH2,

[0031] In some embodiments of the present application, R 4 Selected from hydrogen and methyl.

[0032] In some embodiments of the present application, R X1 、R X2 are independently selected from hydrogen and methyl.

[0033] In some embodiments of the present application, the R YSelected from hydrogen, methyl, -C(O)R Y1 In some embodiments of the present application, the R Y1 Selected from hydrogen, -C 1～3 alkyl.

[0034] In some embodiments of the present application, the compound represented by formula I is represented by formula II:

[0035] Among them, the R 1 、R 2 、R 3 、R 4 , X, and n are as defined above.

[0036] In some embodiments of the present application, the compound represented by Formula I is represented by Formula III:

[0037] Among them, the R 1 、R 2 、R 3 、R 4 , X, m, n are as defined above.

[0038] In some embodiments of the present application, the compound represented by Formula I is represented by Formula IV:

[0039] Among them, the R 1 、R 2 、R 3 、R 4 , X, and n are as defined above.

[0040] In some embodiments of the present application, the compound represented by Formula I is represented by Formula V:

[0041] Among them, the R 1 、R 2 、R 3 、R 4 、R Y , X, and n are as defined above.

[0042] In some embodiments of the present application, the compound represented by Formula I is selected from the following compounds:

[0043] The second aspect of the present application provides a pharmaceutical composition comprising the compound of Formula I, its stereoisomers, its deuterated compounds, its isotope-labeled derivatives, its pharmaceutically acceptable salts, its prodrugs or its solvates.

[0044] In some embodiments of the present application, the above-mentioned pharmaceutical composition further includes a pharmaceutically acceptable carrier and / or excipient and / or vehicle.

[0045] The pharmaceutical compositions of the present application are suitable for a variety of routes of administration and can be formulated into any pharmaceutically acceptable dosage form. For example, the pharmaceutical compositions can be administered to patients or subjects requiring such treatment via oral, parenteral, rectal, or transpulmonary administration. For oral administration, the pharmaceutical compositions can be formulated into oral preparations, such as conventional oral solid preparations such as tablets, capsules, pills, granules, or oral liquid preparations such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, lubricants, and the like can be added to these oral preparations. For parenteral administration, the pharmaceutical compositions can also be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. These injections can be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, the pharmaceutical compositions can be formulated into suppositories. For transpulmonary administration, the pharmaceutical compositions can be formulated into inhalation preparations, aerosols, powder sprays, or sprays.

[0046] Pharmaceutically acceptable adjuvant refers to a substance that is non-toxic, compatible with the active ingredient and otherwise biologically applicable to organisms. The selection of specific adjuvants will depend on the mode of administration or disease type and state for treating a particular patient. Examples of pharmaceutically acceptable adjuvants include, but are not limited to, solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coatings, flavoring agents, and antioxidants, etc., which are conventional in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.

[0047] The third aspect of the present application provides a compound of formula I, its stereoisomers, its deuterated compounds, its isotope-labeled derivatives, its pharmaceutically acceptable salts, its prodrugs or solvates, or the use of the above-mentioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases mediated by the Fabl enzyme.

[0048] In some embodiments of the present application, the present application provides effective FabI enzyme inhibitors that can be used to treat diseases caused by organisms that require FabI as their main reductase, including but not limited to one or more of the following organisms: Francisella tularensis, Staphylococcus aureus, Bacillus anthracis, Plasmodium falciparum, Yersinia pestis, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus saprophyticus, Clostridium pertussis, Clostridium jejuni, Brucella, Brucella, Legionella pneumococcus, Neisseria gonorrhoeae, Neisseria meningitidis, Rickettsia rickettsii, Salmonella enterica, Salmonella, Vibrio cholerae, Chlamydia trachomatis, Chlamydia trachomatis pneumonia, Chlamydia pneumoniae, Chlamydia psittaci, Mycobacterium tuberculosis, Mycoplasma, Mycobacterium tuberculosis, Mycoplasma pneumonia and Listeria monocytogenes.

[0049] The fourth aspect of the present application provides a method for treating and / or preventing a disease mediated by the FabI enzyme, comprising administering an effective amount of a compound of Formula I according to any of the foregoing schemes, its stereoisomers, deuterated compounds, isotope-labeled derivatives, pharmaceutically acceptable salts, prodrugs, or solvates, or the pharmaceutical composition thereof. The disease is as described above.

[0050] The method of the present application can be a combination therapy in combination with other therapies known in the art for treating specific diseases or indications. The other therapies include the administration of other active drugs, which can be administered simultaneously, separately or sequentially with the compound of the present application or a pharmaceutical composition comprising the same.

[0051] The other therapies may also include physical or indirect therapies, examples of which are surgery, laser therapy, endocrine therapy (also known as hormone therapy), etc. Specifically, the above-mentioned other therapies can be administered simultaneously with the administration of the compound of the present application or a pharmaceutical composition containing the same, or the two therapies can be used at an interval of time.

[0052] The compounds and derivatives provided in this application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0053] Definitions of terms used in this application: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0054] "Substitution" means that the hydrogen atoms in a molecule are replaced by other different atoms or groups; or the lone pair of electrons in the atoms in the molecule are replaced by other atoms or groups. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0055] “Can be further substituted” means that “substitution” can but does not have to occur, and the description includes situations where it occurs or does not occur.

[0056] "Multiple" refers to a number of two or more, and thus the term "substituted by multiple groups" as described in this application refers to substitution by two or more groups. The specific number of substituents is affected by the number of substitutable sites of the substituted group and steric hindrance, and generally refers to substitution by two, three, four, five or six groups, and more preferably substitution by two or three groups.

[0057] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0058] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be 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. Alkyl groups may also be part of other groups, such as -O(C 1～6 alkyl).

[0059] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0060] The -C0~4 alkylene group in the present application can be a C0 alkylene group, a C1 alkylene group (for example, -CH2-), a C2 alkylene group (for example, -CH2CH2-, etc.), a C3 alkylene group or a C4 alkylene group; the C0 alkylene group means that the group here does not exist and is connected in the form of a chemical bond, and A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0061] "Alkenyl" refers to a straight or branched chain hydrocarbon group having at least one site of vinyl unsaturation (>C=C<). For example, C a-bAlkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0062] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon radicals having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0063] As used herein, "cycloalkyl" refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused rings). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and polycyclic alkyl rings such as bicyclopropyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, etc., wherein each ring in the polycyclic alkyl ring may be attached to the same carbon atom, for example They can also be connected to adjacent and / or spaced carbon atoms, for example

[0064] As used herein, "heterocycloalkyl" or "heterocycle" refers to a saturated or non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It generally refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system of multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heterocycloalkyl groups of monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl, etc. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems include etc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system include Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl. The term "heterocycloalkyl" also includes partially saturated cyclic groups formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, wherein the attachment point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. Examples include

[0065] As used herein, "aromatic ring" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having multiple carbon atoms. Additionally, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0066] As used herein, "aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; a heteroatom is a nitrogen atom, an oxygen atom, a sulfur atom, or the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heterocyclic aryl groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0067] The "halogen" described in the present application refers to fluorine, chlorine, bromine or iodine.

[0068] The "halogen-substituted alkyl" mentioned in this application refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen; for example, a halogen-substituted C 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0069] The “-OR”, “-NR”, “-NRR” and the like described in this application mean that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0070] The oxygen atom in "-C(O)R", "-S(O)2R" and the like described in the present application is connected to the carbon atom or the sulfur atom via a double bond.

[0071] In the present application, the oxygen atom in "-C(O)R", "-S(O)2R", etc. is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond; for example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0072] The "oxo" described in this application refers to =O, that is, an oxygen atom replaces two hydrogen atoms or lone pairs of electrons through a double bond.

[0073] The “-” in the group description of this application, It is used to describe the position of the substitution group. For example refers to the tetrahydropyrrole ring passing through The position forms a spiral ring with other rings in the structure.

[0074] The "deuterated compound" of the present application refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0075] "Stereoisomers" include enantiomers and diastereomers, as well as cis-trans isomers and tautomers.

[0076] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0077] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0078] The "prodrug" described in this application refers to a compound that is rapidly converted in vivo to the parent compound of the above formula, which can be converted into the compound of this application by chemical or biochemical methods in an in vivo or in vitro environment, such as by hydrolysis in the blood.

[0079] The compounds of the present application can exist in unsolvated and solvated forms, including hydrate forms. In general, the solvated forms are equivalent to the unsolvated forms and are also encompassed within the scope of the present application.

[0080] In certain embodiments, one or more compounds of the present invention may be used in combination with one another. Compounds of the present invention may also be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately, or sequentially.

[0081] In this application, when any variable appears more than once in the composition or structure of a compound, its definition in each case is independent, and the substituents may be the same or different. 11 Substitute, where each R 11 Are independent of each other.

[0082] Obviously, based on the above content of this application, in accordance with common technical knowledge and customary means in this field, without departing from the above basic technical ideas of this application, various other forms of modifications, replacements or changes can be made.

[0083] The beneficial effects of the present application are as follows: compared with existing FabI inhibitors under clinical development, the FabI enzyme inhibitors of the present application have better drug properties, can be directly administered in the form of the original drug, and have better drug exposure in the body; in terms of antibacterial spectrum, compared with existing FabI inhibitors under clinical development, the antibacterial spectrum of the compounds of the present application is broader, such as Moraxella catarrhalis, a common pathogen of community infection; in terms of in vivo efficacy, compared with FabI inhibitors under clinical development, the compounds of the present application have better in vivo efficacy. In summary, the present application provides a new option for clinical screening and / or preparation of drugs for diseases related to FabI enzyme activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] FIG1 shows the pharmacokinetic test results of compound 1a of the present application in rats.

[0085] Figure 2 shows the pharmacokinetic test results of Debio-1450 in rats.

[0086] FIG3 shows the results of in vivo efficacy tests of the compounds of the present application in mice. DETAILED DESCRIPTION

[0087] The present invention is further described in detail below using specific examples. Unless otherwise specified, the raw materials, reagents, and apparatus used in the examples and comparative examples are available from conventional commercial sources or by conventional methods. Unless otherwise specified, all experimental and testing methods are conventional in the art.

[0088] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0089] LC-MS analysis was performed using a Shimadzu LC-MS2020 (ESI) liquid chromatography-mass spectrometer. HPLC analysis was performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reverse-phase preparative chromatograph. Thin-layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254. The specifications used for thin-layer chromatography separation and purification products were 0.4 mm to 0.5 mm. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0090] The known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0091] Unless otherwise specified, reactions were carried out under a nitrogen atmosphere. Unless otherwise specified, solutions are aqueous solutions. Unless otherwise specified, reactions were performed at room temperature. Unless otherwise specified, M is moles per liter.

[0092] Example 1

[0093] In this example, compound 1a / 1b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthyridin-6-yl)-N-((3,7-dimethylbenzofuran-2-yl)methyl)-N-methylacrylamide) was prepared by the following process:

[0094] first step

[0095] Compound 1-1 (6.0 g, 29.5 mmol) was dissolved in dichloromethane (200.0 mL), and active 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 completion of the reaction as monitored by TLC, the mixture was filtered and the solvent removed by distillation under reduced pressure. The resulting crude product 1-2 (5.0 g, 24.9 mmol, yield: 84.3%) was used directly in the next step.

[0096] MS-ESI calculated value [M+H] + 202.0, measured value 202.0.

[0097] Step 2

[0098] Compound 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 and reacted at 120°C for 2 hours. The reaction was monitored by LCMS. After completion, the mixture was filtered and the filter cake was washed with ethyl acetate (20 x 3 mL) to obtain crude product 1-3 (5.8 g, 19.5 mmol, yield: 78.4%), which was used directly in the next step.

[0099] MS-ESI calculated value [M+H] + 298.0, measured value 298.0.

[0100] Step 3

[0101] Trimethylsulfoxide iodide (8.0 g, 40.0 mmol) was dissolved in dimethylsulfoxide (150.0 mL), and sodium hydride (2.4 g, 60.0 mmol) was added. The mixture was stirred at 25°C under nitrogen for 1 hour, and then compound 1-3 (5.8 g, 19.5 mmol) was added and reacted for 3 hours. After the reaction of the raw materials was complete, the reaction solution was poured into a saturated aqueous ammonium chloride solution (500.0 mL) to quench the reaction, and extracted with ethyl acetate (200.0 mL*3). The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The obtained filtrate was distilled under reduced pressure to remove the solvent to obtain a crude product 1-4 (4.5 g, 14.5 mmol, yield: 74.2%), which was directly used in the next step.

[0102] MS-ESI calculated value [M+H] + 312.0, measured value 312.0.

[0103] Step 4

[0104] 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 stirred at room temperature for 2 hours. After the reaction, an appropriate amount of dilute hydrochloric acid was added to adjust the pH to less than 6. 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 distilled under reduced pressure to remove the solvent, yielding crude product 1-5 (2.9 g, 10.2 mmol, yield: 70.4%), which was used directly in the next step.

[0105] MS-ESI calculated value [M+H] + 284.0, measured value 284.0.

[0106] Step 5

[0107] Compound 1-5 (2.9 g, 10.2 mmol) was added to toluene (45.0 mL), followed by diphenylphosphoryl azide (4.2 g, 15.4 mmol), triethylamine (3.1 g, 30.7 mmol), and tert-butyl alcohol (1.1 g, 15.4 mmol). The reaction mixture was stirred at 100°C for 4 hours. After the reaction, the toluene was removed by distillation under reduced pressure. The 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, measured value 355.0.

[0108] Step 6

[0109] 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 (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 allowed to proceed at 100°C for 3 hours. Upon completion, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (50.0 mL x 3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then distilled under reduced pressure to remove the solvent and obtain the crude compound. The crude product was purified by column chromatography to obtain compound 1-7 (1.0 g, 2.5 mmol, yield: 58.8%).

[0110] MS-ESI calculated value [M+H] + 402.2, measured value 402.2.

[0111] Step 7

[0112] 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 stirred at room temperature for 1 hour. After the reaction, the resulting solution was filtered and the solvent was removed by distillation under reduced pressure to obtain the crude product 1-8 (2.0 g).

[0113] MS-ESI calculated value [M+H] + 246.1, measured value 246.1.

[0114] Step 8

[0115] The crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL). Compound 1-9 (70.0 mg, 0.4 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were then added sequentially at room temperature. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, 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, and filtered. The solvent was removed by distillation under reduced pressure from the filtrate. The crude product was purified by liquid chromatography and then resolved by SFC to obtain compound 1a (30.0 mg, 0.07 mmol) with a purity of 100.0%. Compound 1b (26.5 mg, 0.06 mmol), purity: 100.0%.

[0116] SFC separation conditions: Column specification: 3μm, 150mm*3mm.

[0117] Mobile Phase: A: CO2 B: EtOH / 0.1% DEA, Flow Rate: 1mL / min Column Temperature: 40℃. [P1, 2.834min; P2, 3.718min].

[0118] 1a: MS-ESI calculated value [M+H] + 417.2, measured value 417.2.

[0119] 1b: MS-ESI calculated value [M+H] + 417.2, measured value 417.2.

[0120] 1a:1H NMR (400MHz, DMSO) δ8.34 (d, J = 12.9 Hz, 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).

[0121] 1b:1H NMR(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=36.2 Hz, 3H), 2.24 (t, J = 7.4Hz, 3H), 1.71 (d, J = 5.1Hz, 1H), 0.87 (d, J = 4.1Hz, 1H).

[0122] Example 2

[0123] In this example, compound 2a / 2b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthyridin-6-yl)-N-((7-cyclopropyl-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide) was prepared by the following process:

[0124] The crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL). Compound 2-1 (80.0 mg, 0.4 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were then added sequentially at room temperature. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, 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, and filtered. The solvent was removed by distillation under reduced pressure from the filtrate. The crude product was purified by liquid chromatography and then resolved by SFC to afford compound 2a (35.0 mg, 0.08 mmol) with a purity of 96.0%. Compound 2b (30.5 mg, 0.07 mmol), purity: 96.0%.

[0125] SFC separation conditions: Column specification: 3μm, 150mm*3mm.

[0126] Mobile Phase: A: CO2 B: EtOH / 0.1% DEA, Flow Rate: 1mL / min Column Temperature: 40℃. [P1, 3.897min; P2, 4.780min].

[0127] 2a: MS-ESI calculated value [M+H] + 443.2, measured value 443.2.

[0128] 2b: MS-ESI calculated value [M+H] + 443.2, measured value 443.2.

[0129] 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).

[0130] 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).

[0131] Example 3

[0132] In this example, compound 3a / 3b (chemical name: (E)-3-(1a-amino-2-oxa-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthyridin-6-yl)-N-((3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide) was prepared by the following process:

[0133] The crude product 1-8 (300.0 mg) was dissolved in N,N-dimethylformamide (3.0 mL). Compound 3-1 (65.0 mg, 0.4 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (154.6 mg, 0.4 mmol), and N,N-diisopropylethylamine (95.0 mg, 0.7 mmol) were then added sequentially at room temperature. The reaction mixture was stirred at 25°C for 1 hour. After completion of the reaction, water (2 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (10.0 mL*3). The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by liquid chromatography and then resolved by SFC to obtain compound 3a (25.0 mg, 0.06 mmol) with a purity of 97.0%. Compound 3b (22.0 mg, 0.05 mmol), purity: 100.0%.

[0134] SFC separation conditions: Column specification: 3μm, 150mm*3mm.

[0135] Mobile Phase: A: CO2 B: EtOH / 0.1% DEA, Flow Rate: 1mL / min Column Temperature: 40℃. [P1, 3.541min; P2, 5.085min].

[0136] 3a: MS-ESI calculated value [M+H] + 403.2, measured value 403.2.

[0137] 3b: MS-ESI calculated value [M+H] + 403.2, measured value 403.2.

[0138] 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).

[0139] 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).

[0140] Test Example 1

[0141] In this assay, enzyme activity was assessed by monitoring the oxidation of the cofactor NADH / NADPH using a microplate reader.

[0142] Compounds were dissolved in DMSO and added to a 384-well plate using ECHO665. The compounds were diluted 3-fold or 4-fold for a total of 10 dose points, with two replicates per concentration. The final DMSO content in each reaction well was 1%. FabI protein solution was then added. The proteins were prepared in a 100 mmol / L PBS buffer containing 0.05% Tween-20 and 150 mmol / L NaCl, pH 6.5, to a final concentration of 15 nmol / L SaFabI and 9 nmol / L EcFabI, respectively. 5 μL of the 15 nmol / L SaFabI and 9 nmol / L EcFabI solutions were added to the 384-well plate, centrifuged at 1000 rpm for 1 minute, and the plate was pre-incubated on a 30°C shaker for 20 minutes. Simultaneously, the substrates trans-octenoyl-CoA, NADPH, trans-dodecenoyl-CoA, and NADH were diluted in a 100 mmol / L buffer. PBS, 0.05% Tween-20, 150mmol / L NaCl, pH 6.5, and the concentrations were 300μmol / L, 300μmol / L, 600μmol / L, and 150μmol / L, respectively. For SaFabI protein, 5μL 300μmol / L trans-octenoyl-CoA and 5μL 300μmol / L NADPH were added to start the reaction, and the reaction plate was immediately placed in a microplate reader to collect the fluorescence signal (Ex340 nm / Em460 nm) every 0.5 minutes, and the collection time was not less than 10 minutes. Similarly, 5μL 600μmol / L trans-dodecenoyl-CoA and 5μL 150μmol / L NADH were added to start each reaction of EcFabI, and the reaction plate was immediately placed in a microplate reader to collect the fluorescence signal (Ex340 nm / Em460 The fluorescence intensity was collected every 0.5 minutes, and the collection time was not less than 10 minutes. The reaction rate of each well (fluorescence signal per minute) was calculated by the fluorescence value. The inhibitory effect of the compound on the protein was calculated using the reaction rate. The IC value of the compound on the enzyme activity inhibition was then calculated using the log (inhibitor) vs. response–Variable slope model in GraphPad Prism 6. 50 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 concentration of the known compound after Log.

[0143] The in vitro enzymatic activity of the compound of the present application is shown by the above-mentioned test to have excellent inhibitory activity against the FabI enzyme of Staphylococcus aureus and Escherichia coli.

[0144] Table 1 Evaluation of SaFabI & EcFabI enzyme activities

[0145] Test Example 2

[0146] In this test example, the minimum inhibitory concentration (MIC) of the compound was tested.

[0147] The agar plate two-fold dilution method was used to set the experimental drug concentration in the range of 0.008μg / mL to 128μg / mL. The sample was dissolved in DMSO to a 2mL solution with a concentration of 1.92mg / mL. The control was prepared with sterile distilled water to 1.92mg / mL. 1mL of the prepared drug solution was added to a sterile plate, and then 14mL of MHA medium at about 60℃ was added. Mix well and add 1mL of sterile distilled water to dilute the drug by folds to make the final concentration of the drug 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.008μg / mL (among which the final concentrations of samples 2, 4 and 9 were diluted from 128μg / mL) for later use. The prepared bacterial solution was inoculated on the drug-containing MHA medium plate using a multi-point inoculator, with an inoculum size of about 10 at each point. 4 CFU. Set up sterile control groups (1 mL DMOS + 14MHA medium and 1 mL sterile distilled water + 14MHA medium). Place the plate in an incubator at 37°C for 16-20 hours, then observe each inoculation point for bacterial growth and determine its MIC value.

[0148] The in vitro antibacterial activity of the compounds of the present application was shown by the above-mentioned tests. In addition to excellent antibacterial activity against Staphylococcus aureus, including sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Staphylococcus aureus (VRSA), the compounds exhibited certain activity against Escherichia coli, but had weaker activity against Klebsiella pneumoniae and Acinetobacter baumannii.

[0149] Table 2 Minimum inhibitory concentration MIC (μg / mL)

[0150] The antibacterial spectrum of compound 1b was tested using the aforementioned minimum inhibitory concentration (MIC) test method. The results showed that compound 1b exhibited excellent antibacterial activity against Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, and Moraxella catarrhalis. It also exhibited significant antibacterial activity against Haemophilus influenzae.

[0151] Table 3 Antimicrobial spectrum test MIC (μg / mL) of compound 1b

[0152] Test Example 3

[0153] In this test example, the pharmacokinetic test of the compound was conducted in rats.

[0154] Twelve healthy adult female Sprague-Dawley rats (purchased from Vital River) weighing an average of 180-220 g were divided into four groups of three rats each. Two groups received the drug via tail vein injection, while the other two groups received the drug via oral gavage. Compound 1b was dissolved in a solvent (5% DMSO-30% PEG400-65% H2O), and Debio-1450 was dissolved in saline. Both solutions formed stable, clear solutions for later use. Animals were fasted for 12 hours before dosing and resumed normal feeding 2 hours after dosing. Blood samples were collected via the jugular vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h (intravenous administration) and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h (oral gavage). Approximately 200-400 μL of blood was collected. Whole blood was collected at each time point and placed in tubes containing K2EDTA for anticoagulation and stored in an insulated container with ice packs. All samples were centrifuged at 4600 rpm and 4°C for 5 minutes within 15 minutes to separate the plasma. Compound concentrations in rat plasma were determined using LC / MS / MS, and pharmacokinetic parameters were calculated based on drug concentration-time curves. The results are shown in Table 4, Figures 1, and 2.

[0155] Table 4 Pharmacokinetic parameters of compound 1b / Debio-1450 in rats after oral administration

[0156] The pharmacokinetic properties of the compounds of the present application were tested by the above experiments. The experimental results showed that the compounds of the present application showed excellent pharmacokinetic characteristics in rats after intravenous injection or oral administration, and compared with Debio-1450 in C max , AUC performance is better.

[0157] Test Example 4

[0158] In this test example, the compound was tested for its efficacy in mice (systemic infection model).

[0159] Ninety healthy adult male Balb / c mice (purchased from Vital River) were selected and divided into 10 groups: a negative control group (nine mice inoculated with bacteria and given a vehicle), a positive control group (nine mice given vancomycin), a linezolid test group (nine mice), three high-, medium-, and low-dose test groups (3 x 9 mice) of compound 1a, three high-, medium-, and low-dose test groups (3 x 9 mice), and one Debio-1452 test group (9 mice). All animals were tested after a 3-4 day quarantine period. The inoculation strain for this test was methicillin-resistant Staphylococcus aureus (NRS384), the inoculation dose was 1.0E+08 CFU / mouse, and the inoculation site was the tail vein. The compounds were administered half an hour after inoculation. The solvent for 1a and Debio-1452 was 5% DMSO-30% PEG400-65% H2O, while Debio-1450 was prepared in an isotonic glucose solution (prepared immediately). A single oral dose was used. The specific dosage regimen is shown in Table 5:

[0160] Table 5 Dosage regimen for systemic infection efficacy model

[0161] The in vivo efficacy of the compounds of the present application was verified in the aforementioned tests. The experimental results, shown in Figure 3, demonstrate that after oral administration, the compounds of the present application exhibited a significant protective effect in rats compared to the negative control group, and this protective effect increased with increasing dose. Compared to the reference compounds linezolid and Debio-1450, compound 1a demonstrated significantly superior efficacy to linezolid and Debio-1450.

[0162] The above embodiments are preferred implementation modes of the present application, but the implementation modes of the present application are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the protection essence and principles of the present application should be equivalent replacement methods and are included in the protection scope of the present application.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a deuterated compound thereof, an isotope-labeled derivative thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof: in, X is selected from O, CR X1 R X2 NR X1 , S; Y is selected from O, -CH2-, NR Y 、-O-CH2-、-CH2-O-、-NR Y -CH2-, -CH2-NR Y -; R X1 , R X2 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; R Y Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R Y1 , R Y2 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 11 , R 12 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 2 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 21 , R 22 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl); R 3 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -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), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 31 , R 32 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-NR 33 R 34 , -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); R 33 , R 34 are independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; R 4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl; m is selected from 0, 1 or 2; n is selected from 1 or 2; Wherein, when C is 0, it means that the group does not exist.

2. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: The compound shown in formula I is shown in formula II: Among them, the R 1 , R 2 , R 3 , R 4 , X, n as defined in claim 1.

3. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: The compound shown in formula I is shown in formula III: Among them, the R 1 , R 2 , R 3 , R 4 , X, m, n are as defined in claim 1.

4. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: The compound shown in formula I is shown in formula IV: Among them, the R 1 , R 2 , R 3 , R 4 , X, n as defined in claim 1.

5. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: The compound represented by formula I is represented by formula V: Among them, the R 1 , R 2 , R 3 , R 4 , R Y , X, n as defined in claim 1.

6. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: R 3 Selected from -C 0～2 Alkylene-OR 31 , -C 0～2 Alkylene-NR 31 R 32 , -C 0～2 Alkylene-NR 31 C(O)R 32 , -(3- to 6-membered heterocycloalkyl); R 31 , R 32 are independently selected from hydrogen, -C 1～3 Alkyl, -C 0～2 Alkylene-NR 33 R 34 ; R 33 , R 34 are independently selected from hydrogen, -C 1～3 alkyl.

7. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: R 3 Selected from -NH2, 8. The compound of formula I according to claim 1, or its stereoisomer, or its deuterated compound, its isotope-labeled derivative, its pharmaceutically acceptable salt, its prodrug or its solvate, characterized in that: The compound represented by formula I is selected from the following compounds:

9. A pharmaceutical composition comprising a compound of formula I as claimed 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 of formula I as claimed in 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 as claimed in claim 9 in the preparation of a medicament for treating and / or preventing a disease mediated by the Fabl enzyme.

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