Cyclic peptide compound as well as preparation method and application thereof

Abstract

The invention discloses a cyclic peptide compound as well as a preparation method and application thereof. Specifically, the invention discloses a compound as shown in a formula (I), and a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. The compound provided by the invention is an antibiotic and can be used for preparing a medicine for treating and / or preventing diseases related to gram-negative bacteria.

Description

Technical Field

[0001] This invention pertains to the field of medicinal chemistry, specifically relating to a cyclic peptide compound, its preparation method, and its uses. Background Technology

[0002] Acinetobacter baumannii is a Gram-negative, aerobic, non-fermenting bacterium that has been considered an emerging pathogen in recent years, with very limited treatment options. This bacterium is listed as part of the so-called "ESKAPE" group of pathogens on the Centers for Disease Control and Prevention's (CDC) list of serious threats. These pathogens are currently the leading cause of most hospital-acquired infections and are highly resistant to antimicrobial agents.

[0003] Acinetobacter baumannii is commonly found in intensive care and surgical wards. Extensive antibiotic use has led to resistance selection against all known antimicrobial agents, and it can cause a variety of infections, including bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections. Acinetobacter baumannii exhibits an unusual ability to upregulate and acquire resistance determinants and demonstrates environmental persistence, making this organism a frequent cause of infection outbreaks and a hospital-acquired pathogen.

[0004] Treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections becomes extremely difficult, if not impossible, due to resistance to most available antibiotics, particularly carbapenems, resulting in high mortality rates and increased morbidity and length of stay in intensive care units.

[0005] The Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) defines Acinetobacter baumannii as "a prime example of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline." Therefore, there is an urgent need to identify compounds suitable for treating diseases and infections caused by Acinetobacter baumannii.

[0006] Recently, Claudia et al. (Nature 2024, 625, 566-571) reported cyclic peptide compounds for the treatment of Gram-negative bacteria such as Acinetobacter baumannii, but there remains a high unmet need for improved compounds suitable for treating diseases and infections caused by Acinetobacter baumannii, as the microorganisms proliferate very rapidly and are prone to developing resistance (J. Med. Chem. 2024, 67, 10, 7759-7787).

[0007] Therefore, there is an urgent need in the field for a cyclic peptide compound that is effective, safe, and unlikely to induce drug resistance to meet the clinical needs for treating Gram-negative bacteria (such as Acinetobacter baumannii). Summary of the Invention

[0008] To address the aforementioned problems, this invention provides a novel cyclic peptide compound with good efficacy, high safety, and low likelihood of inducing drug resistance, its preparation method, pharmaceutical compositions containing it, and its use in the preparation of medicaments for treating bacterial infections and diseases.

[0009] In a first aspect of the invention, a compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs are provided. (I) Where X is Se or S; L is , or ; And does not contain the following structures: .

[0010] In a preferred embodiment, the compound is selected from the group consisting of: .

[0011] In a second aspect of the present invention, a method for preparing a compound as described in the first aspect of the present invention is provided, comprising the following steps: S6. In the presence of a palladium catalyst, compound III and compound A undergo a Suzuki or Ulmann coupling reaction to give compound II; Where X is S or Se; R1 is B(OH)2R a -、B(OR b )2R a -; Among them, each R b Independently for C 1-4 Alkyl, or two ORs b Together with the boron atoms they are attached to, they form 4-7 membered heterocyclic groups; R a Selected from the following group: C 6-10 aryl, 5-7 quinone heteroaryl, C 4-7 Subcarbonyl cycloalgide, 4-7 membered subheterocyclic cycloalgide; The palladium catalyst is selected from the group consisting of: di(tri-tert-butylphosphine)palladium, tetra-triphenylphosphine palladium, chloro(2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylylene](3-chloropyridyl)palladium(II)dichloride, [2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-... [-aminoethyl)phenyl]palladium(II), bis(triphenylphosphine)palladium(II), bis[tris(2-tolyl)phosphine]palladium, bis(tricyclohexylphosphine)palladium(II), bis(dibenzylacetone)palladium(O), [1,2-bis(diphenylphosphine)ethane]palladium(II), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II), 1,1′-bis(dicyclohexylphosphine)ferrocenepalladium(II), 1,1′-bis(diisopropylphosphine)ferrocenepalladium(II), or combinations thereof; II I S7. In the presence of acid A, compound II undergoes a deprotection reaction to give compound I; Wherein, acid A is selected from the group consisting of hydrochloric acid, organic solutions of hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, or combinations thereof.

[0012] In another preferred embodiment, compound A is selected from the group consisting of: , .

[0013] In another preferred embodiment, step S6 is performed in the presence of base A; The base A is selected from the group consisting of potassium phosphate, potassium carbonate, sodium carbonate, potassium fluoride, sodium acetate, potassium acetate, or combinations thereof.

[0014] In another preferred embodiment, step S6 is carried out in the presence of solvent A, wherein solvent A is a mixed solution of an organic solvent and water; The organic solvent is selected from the group consisting of dioxane, tetrahydrofuran, methanol, ethanol, n-propanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or combinations thereof.

[0015] In another preferred embodiment, in step S6, the volume ratio of the organic solvent to water is (2~10):1, preferably (2~8):1, and more preferably (4~7):1.

[0016] In another preferred embodiment, in step S6, the molar ratio of compound III to compound A is 1:(1~10), preferably 1:(1~8), more preferably 1:(1~4).

[0017] In another preferred embodiment, in step S6, the temperature of the coupling reaction is 70~120 °C, preferably 80~110 °C, and more preferably 80~90 °C.

[0018] In another preferred embodiment, in step S6, the coupling reaction takes 6 to 20 hours, preferably 8 to 18 hours, and more preferably 10 to 14 hours.

[0019] In another preferred embodiment, in step S7, the deprotection reaction is carried out in the presence of solvent B; Solvent B is selected from the group consisting of tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, isopropanol, 1,4-dioxane, or combinations thereof.

[0020] In another preferred embodiment, the solvent of the organic solution of hydrogen chloride is solvent B.

[0021] In another preferred embodiment, in step S7, the temperature of the deprotection reaction is 2~30 °C.

[0022] In another preferred embodiment, in step S7, the temperature of the deprotection reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0023] In another preferred embodiment, in step S7, the temperature of the deprotection reaction is 2~20 °C, preferably 5~15 °C, and more preferably 8~12 °C.

[0024] In another preferred embodiment, in step S7, the time for the deprotection reaction is 1 to 10 h, preferably 1 to 8 h, and more preferably 1 to 4 h.

[0025] In a preferred embodiment, compound III is prepared by the following steps: S5. In the presence of condensing agent A, compound IV undergoes an intramolecular condensation dehydration reaction to give compound III; The condensing agent A is selected from the group consisting of: EDCI / HOBt, HATU / DIEA, HBTU / DIEA, EEDQ, TCFH / NMI, BOPCI / DIEA, TSTU / TEA, PyBOP / DIEA, T3P / TEA, T4P / TEA, DPPA / TEA, or combinations thereof.

[0026] In another preferred embodiment, in step S5, the molar ratio of compound IV to EDCI is 1:(2~10), preferably 1:(2~8), and more preferably 1:(2~6).

[0027] In another preferred embodiment, in step S5, the molar ratio of compound IV to HOBt is 1:(2~10), preferably 1:(2~8), and more preferably 1:(2~6).

[0028] In another preferred embodiment, in step S5, the temperature of the intramolecular condensation dehydration reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0029] In another preferred embodiment, in step S5, the intramolecular condensation dehydration reaction takes 1 to 8 hours, preferably 1 to 6 hours, and more preferably 1 to 4 hours.

[0030] In another preferred embodiment, step S5 is performed in the presence of solvent C; The solvent C is selected from the group consisting of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof.

[0031] In a preferred embodiment, compound IV is prepared by the following steps: VII V IV S4-1. In the presence of sodium borohydride acetate and / or sodium cyanoborohydride, compound VII undergoes a reductive ammoniation reaction with compound VI to give compound V; S4-2. In the presence of tetrabutylammonium fluoride, compound V undergoes a deprotection reaction to give compound IV.

[0032] In another preferred embodiment, in step S4-1, the reductive amination reaction is carried out in the presence of a Lewis acid; The Lewis acid is selected from the group consisting of: acetic acid, tartaric acid, titanium tetrachloride, titanium tetraisopropoxy, titanium tetraethoxy, and boron trifluoride ether.

[0033] In another preferred embodiment, in step S4-1, the reductive amination reaction is carried out in the presence of solvent D; The solvent D is selected from the group consisting of: 1,2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran, anhydrous methanol, and anhydrous N,N-dimethylformamide.

[0034] In another preferred embodiment, in step S4-1, the molar ratio of compound VII to compound VI is 1: (1~10), preferably 1: (1~8), and more preferably 1: (1~4).

[0035] In another preferred embodiment, in step S4-1, the molar ratio of compound VII to sodium borohydride acetate or sodium cyanoborohydride is 1: (1~10), preferably 1: (1~8), and more preferably 1: (2~6).

[0036] In another preferred embodiment, in step S4-1, the reaction temperature of the reductive ammoniation reaction is 20~60 ℃, preferably 30~50 ℃, and more preferably 35~45 ℃.

[0037] In another preferred embodiment, in step S4-1, the reaction time of the reductive ammoniation reaction is 1 to 10 h, preferably 1 to 8 h, and more preferably 2 to 5 h.

[0038] In another preferred embodiment, step S4-1 includes the following steps: Lewis acid, solvent D and compound VII react at 20~60 °C for 2~5 h to obtain reaction solution 1; Sodium borohydride acetate was added to reaction solution 1, and the reaction was continued at 20-60 °C for 2-5 h to obtain compound V.

[0039] In another preferred embodiment, in step S4-2, the deprotection reaction is carried out in the presence of solvent E; The solvent E is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, methanol, ethanol, dichloromethane, or combinations thereof.

[0040] In another preferred embodiment, in step S4-2, the reaction temperature of the deprotection reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0041] In another preferred embodiment, in step S4-2, the reaction time for the deprotection reaction is 5-25 h, preferably 5-20 h, and more preferably 10-15 h.

[0042] In a preferred embodiment, compound VIII is prepared by the following steps: X VIII VII S3-1. In the presence of condensing agent B, compound X and compound IX undergo a condensation reaction to obtain compound VIII; S3-2. In the presence of base B, compound VIII undergoes a deprotection reaction to give compound VII.

[0043] In another preferred embodiment, in step S3-1, the condensing agent B is selected from the group consisting of: DIEA / HATU, EDCI / HOBt, HBTU / DIEA, EEDQ, TCFH / NMI, BOPCI / DIEA, TSTU / TEA, PyBOP / DIEA, T3P / TEA, T4P / TEA, DPPA / TEA, or combinations thereof.

[0044] In another preferred embodiment, in step S3-1, the molar ratio of compound VIII to HATU is 1:(0.1~10), preferably 1:(1~5), more preferably 1:(1~2).

[0045] In another preferred embodiment, in step S3-1, the molar ratio of compound VIII to DIEA is 1: (0.1~10), preferably 1: (1~8), more preferably 1: (1~4).

[0046] In another preferred embodiment, in step S3-1, the temperature of the condensation reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0047] In another preferred embodiment, in step S3-1, the condensation reaction takes 5 to 25 hours, preferably 8 to 20 hours, and more preferably 10 to 14 hours.

[0048] In another preferred embodiment, in step S3-2, the base B is selected from the group consisting of diethylamine, ammonia, concentrated sodium hydride, piperidine, ethanolamine, cyclohexylamine, morpholine, or combinations thereof.

[0049] In another preferred embodiment, in step S3-2, the molar ratio of compound VIII to base B is 1:(2~20), preferably 1:(5~15), and more preferably 1:(8~12).

[0050] In another preferred embodiment, in step S3-2, the temperature of the deprotection reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0051] In another preferred embodiment, in step S3-2, the deprotection reaction takes 5 to 25 hours, preferably 8 to 20 hours, and more preferably 10 to 14 hours.

[0052] In a preferred embodiment, compound X is prepared by the following steps: S2-1. In the presence of an acylation catalyst and a dehydrating agent, compound X-2 and 2-(trimethylsilyl)ethanol undergo an acylation reaction to give compound X-1; S2-2. In the presence of a debenzylating catalyst, compound X-1 undergoes a debenzylating reaction to give compound X.

[0053] In another preferred embodiment, in step S2-1, the acylation reaction catalyst is selected from the group consisting of 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, or combinations thereof.

[0054] In another preferred embodiment, in step S2-1, the molar ratio of compound X-2 to the acylation reaction catalyst is (1~20): 1, preferably (5~15): 1, more preferably (8~12): 1.

[0055] In another preferred embodiment, in step S2-1, the dehydrating agent is selected from the group consisting of DCC, DIC, EDC, EDCI, or combinations thereof.

[0056] In another preferred embodiment, in step S2-1, the molar ratio of compound X-2 to the dehydrating agent is 1: (0.1~10), preferably 1: (1~8), and more preferably 1: (1~3).

[0057] In another preferred embodiment, in step S2-1, the temperature of the acylation reaction is 20~30 °C, preferably 22~28 °C, and more preferably 23~27 °C.

[0058] In another preferred embodiment, in step S2-1, the acylation reaction takes 5 to 25 hours, preferably 8 to 20 hours, and more preferably 10 to 14 hours.

[0059] In another preferred embodiment, in step S2-2, the debenzylating catalyst is selected from the group consisting of Pd / C, Pd(OH)2 / C, palladium chloride, palladium acetate, or combinations thereof.

[0060] In another preferred embodiment, in step S2-2, the molar ratio of compound X-1 to the debenzylidene catalyst is (1~10):1, preferably (1~8):1, more preferably (1~5):1.

[0061] In another preferred embodiment, in step S2-2, the debenzylation reaction is carried out under a hydrogen atmosphere or with a reagent that can provide a hydrogen source; The reagent that can provide a hydrogen source is selected from the group consisting of: formic acid, ammonium formate, boric acid / water, triethylsilane, hydrazine hydrate, cyclohexadiene, and nitroene.

[0062] In another preferred embodiment, in step S2-2, the pressure of the debenzylation reaction is 5 to 25 psi, preferably 10 to 20 psi, and more preferably 12 to 17 psi.

[0063] In another preferred embodiment, in step S2-2, the debenzylation reaction takes 5-25 h, preferably 8-20 h, and more preferably 10-14 h.

[0064] In a preferred embodiment, compound VI is prepared by the following steps: Where X is S or Se; S1-1. In the presence of base C, compound VI-4 undergoes a substitution reaction with 2-bromo-6-fluorobenzonitrile to give compound VI-3; S1-2. In the presence of a reducing agent, compound VI-3 undergoes a reduction reaction to give compound IV-2; S1-3. In the presence of base D, compound VI-2 and compound C undergo a substitution reaction to give compound VI-1; S1-4. In the presence of an oxidizing agent, compound VI-1 undergoes an oxidation reaction to yield compound VI.

[0065] In another preferred embodiment, in step S1-1, the base C is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide potassium hydroxide, or combinations thereof.

[0066] In another preferred embodiment, in step S1-1, the reaction is carried out in the presence of solvent F; The solvent F is selected from the group consisting of N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, or combinations thereof.

[0067] In another preferred embodiment, in step S1-1, the molar ratio of compound VI-4 and 2-bromo-6-fluorobenzonitrile is 1: (1~10), preferably 1: (1~8), and more preferably 1: (1~3).

[0068] In another preferred embodiment, in step S1-1, the temperature of the substitution reaction is 60~120 °C, preferably 70~110 °C, and more preferably 80~100 °C.

[0069] In another preferred embodiment, in step S1-1, the substitution reaction takes 10-40 h, preferably 15-30 h, and more preferably 15-25 h.

[0070] In another preferred embodiment, in steps S1-2, the reducing agent is selected from the group consisting of: boron dimethyl sulfide complex (BH3-Me2S), boron tetrahydrofuran, boron pyridine complex, boron trimethylamine complex, lithium aluminum hydride, sodium borohydride / nickel dichloride hexahydrate, sodium borohydride / cobalt dichloride hexahydrate, sodium borohydride / lithium chloride, sodium borohydride / iodine, sodium borohydride / indium trichloride, Raney nickel / hydrogen, or combinations thereof.

[0071] In another preferred embodiment, in steps S1-2, the reducing agent is a boronane dimethyl sulfide complex (BH3-Me2S).

[0072] In another preferred embodiment, in step S1-2, the temperature of the reduction reaction is 20~50 ℃, preferably 25~40 ℃, and more preferably 30~40 ℃.

[0073] In another preferred embodiment, in step S1-2, the reduction reaction time is 1-10 h, preferably 1-5 h, and more preferably 1-2 h.

[0074] In another preferred embodiment, in steps S1-2, the reducing agent is lithium aluminum hydride.

[0075] In another preferred embodiment, in step S1-2, the temperature of the reduction reaction is -10~10 ℃, preferably -5~5 ℃, and more preferably -2~2 ℃.

[0076] In another preferred embodiment, in step S1-2, the reduction reaction time is 10-25 h, preferably 12-20 h, and more preferably 14-28 h.

[0077] In another preferred embodiment, in steps S1-3, the base D is selected from the group consisting of triethylamine, diisopropylethylamine, tricyclohexylamine, 1,8-diazobisspirocyclo[5.4.0]undecene-7-ene, 1,5,7-triazabicyclo[4.4.0]decene-5-ene, or combinations thereof.

[0078] In another preferred embodiment, in steps S1-3, the temperature of the substitution reaction is 20~30 °C, preferably 22~28 °C, and more preferably 23~27 °C.

[0079] In another preferred embodiment, in steps S1-3, the substitution reaction takes 1 to 10 hours, preferably 1 to 5 hours, and more preferably 1 to 3 hours.

[0080] In another preferred embodiment, in steps S1-4, the oxidant is selected from the group consisting of MnO2, Desmond-Martin oxidant, Jones reagent, PCC, PDC, IBX, dimethyl sulfoxide / oxalyl chloride, dimethyl sulfoxide / acetic anhydride, dimethyl sulfoxide / DCC, or combinations thereof.

[0081] In another preferred embodiment, in steps S1-4, the oxidant is MnO2.

[0082] In another preferred embodiment, in steps S1-4, the molar ratio of compound VI-1 to oxidant is (2~20), preferably 1:(5~15), more preferably 1:(8~12).

[0083] In another preferred embodiment, in steps S1-4, the temperature of the oxidation reaction is 60~120 ℃, preferably 70~110 ℃, and more preferably 80~100 ℃.

[0084] In another preferred embodiment, in steps S1-4, the oxidation reaction takes 10-40 h, preferably 15-30 h, and more preferably 15-25 h.

[0085] In another preferred embodiment, in steps S1-4, the oxidant is a Des Martin oxidant.

[0086] In another preferred embodiment, in steps S1-4, the molar ratio of compound VI-1 to the oxidant is (1~10), preferably 1:(1~5), more preferably 1:(1~2).

[0087] In another preferred embodiment, in steps S1-4, the temperature of the oxidation reaction is 20~30 ℃, preferably 22~28 ℃, and more preferably 23~27 ℃.

[0088] In another preferred embodiment, in steps S1-4, the oxidation reaction takes 1 to 10 hours, preferably 1 to 5 hours, and more preferably 1 to 3 hours.

[0089] In a third aspect of the invention, a pharmaceutical composition is provided, the composition comprising: (i) the compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof; and (ii) One or more pharmaceutically acceptable carriers, excipients and / or excipients.

[0090] In a fourth aspect of the invention, the use of a compound as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect of the invention, for the preparation of a medicament for the prevention and / or treatment of infectious diseases caused by Gram-negative bacteria is provided. Preferably, the Gram-negative bacterium is Acinetobacter baumannii.

[0091] In a fifth aspect of the invention, an intermediate compound is provided, said compound being selected from the group consisting of: .

[0092] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0093] Through long-term and in-depth research and extensive screening, the inventors have developed for the first time a novel cyclic peptide compound that is highly effective, safe, and unlikely to induce drug resistance. This compound can be used to prepare drugs for treating infections and diseases caused by bacteria. Based on this, the inventors completed this invention.

[0094] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials described herein may be used in the practice or testing of this invention, suitable methods and materials are described below.

[0095] Features, integers, properties, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims or abstract) and / or all steps of any method or process so disclosed may be combined in any combination, unless at least some of such features and / or steps are mutually exclusive combinations. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any new feature or any new combination of features disclosed in this specification (including any appended claims or abstract), or to any new step or any new combination of steps of any method or process so disclosed.

[0096] All publications, patent applications, patents and other references mentioned in this article are incorporated herein by reference in their entirety.

[0097] Unless otherwise stated, the nomenclature used in this application is based on the IUPAC systematic nomenclature, and IUPAC chemical names are generated using InDraw.

[0098] Active ingredients As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0099] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0100] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that allows for free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0101] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0102] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0103] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium (2H), are preferred in certain cases due to their excellent metabolic stability, which offers advantages in some therapies, such as increasing half-life or reducing dosage in vivo. Isotope-labeled compounds can be prepared using general methods by replacing non-isotopic reagents with readily available isotope-labeling reagents, as described in the examples.

[0104] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0105] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0106] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0107] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0108] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0109] As used herein, the term "hydrate" refers to a complex of a compound of formula (I) coordinated with water molecules in a specific ratio.

[0110] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0111] Pharmaceutical Compositions and Administration Another aspect of the present invention provides pharmaceutical compositions or medicaments comprising the compounds of the present invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, and methods for preparing said compositions and medicaments using the compounds of the present invention.

[0112] Because the compounds of the present invention can inhibit Gram-negative bacteria (such as Acinetobacter baumannii) and are used to treat diseases and infections caused by Gram-negative bacteria (such as Acinetobacter baumannii), the compounds of the present invention, their stereoisomers, their optical isomers, their pharmaceutically acceptable salts, their crystal forms, their isotopic derivatives, their prodrugs, their metabolites, their solvates or hydrates thereof, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) infections and disease-related diseases caused by Gram-negative bacteria (such as Acinetobacter baumannii).

[0113] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0114] The composition is formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the condition, the site of delivery of the drug, the method of administration, the timing of administration, and other factors known to the medical practitioner.

[0115] The compounds of the present invention can be administered by any suitable manner, including oral, topical (including sublingual and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, and, if local treatment is required, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0116] In a preferred embodiment, a pharmaceutical composition comprising one or more compounds of the present invention is provided, wherein the pharmaceutical composition is suitable for intravenous administration.

[0117] The compounds of this invention can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical preparations, such as diluents, carriers, pH adjusters, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, antioxidants, and other active agents. They may also contain other substances with therapeutic value.

[0118] Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004), Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al., Remington: The Science and Practice of Pharmacy (2000), Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005), PharmaceuticalPress, Chicago.

[0119] The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives to provide an elegant appearance for the medicament (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to facilitate the preparation of the pharmaceutical product (i.e., the pharmaceutical preparation).

[0120] The dosage of the compounds of this invention can vary over a wide range, and of course, can be adjusted according to individual needs in each specific case. Generally, when administered intravenously, a daily dose of approximately 1-1000 mg of the compound of general formula (I) per person should be appropriate, although the above upper limit may be exceeded if necessary.

[0121] An example of a suitable intravenous dosage form is a sterile aqueous solution containing about 1 mg to about 500 mg of the compound of the present invention. Such a sterile aqueous solution for intravenous administration can be obtained, for example, by dissolving 1 mg to about 500 mg of the compound of the present invention in water (e.g., about 50 mL) and adjusting the pH to 4-8, preferably about 7, by adding an aqueous sodium hydroxide solution. This process is accomplished by terminal sterilization using methods known in the art.

[0122] Examples of aerosol formulations can be prepared by dissolving, for example, 10 to 100 mg of the compound of the invention in a suitable buffer solution, such as phosphate buffer, and, if necessary, by adding a tonic agent, such as a salt like sodium chloride. The solution can be filtered, for example, using a 0.2 μm filter to remove impurities and contaminants.

[0123] use Compounds of formula (I) and their pharmaceutically usable salts have valuable pharmacological properties for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, especially species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0124] Compounds of formula (I) and their pharmaceutically acceptable salts exhibit activity as antibiotics, particularly as antibiotics against species of Acinetobacter, more particularly as antibiotics against Acinetobacter baumannii, and most particularly as pathogen-specific antibiotics against Acinetobacter baumannii.

[0125] Compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e. as antimicrobial drug components, suitable for the treatment and prevention of bacterial infections, especially bacterial infections caused by species of the genus Acinetobacter, and even more particularly bacterial infections caused by Acinetobacter baumannii.

[0126] The compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0127] One aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof as defined above and one or more pharmaceutically acceptable excipients.

[0128] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0129] Another aspect of the invention relates to compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, used as therapeutic active substances, particularly as therapeutic active substances for the treatment or prevention of infections and diseases caused by pathogens, especially bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0130] Another aspect of the invention relates to compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0131] Another aspect of the invention relates to a method for treating or preventing infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, the method comprising administering a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, to a subject.

[0132] Another aspect of the invention relates to the use of compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, especially Acinetobacter baumannii, particularly bacteremia, pneumonia, meningitis, urinary tract infections and wound infections.

[0133] Another aspect of the invention relates to the use of compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment or prevention of infections and diseases caused by pathogens, particularly bacteria, more particularly species of the genus Acinetobacter, and most particularly Acinetobacter baumannii, especially bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections. Such medicaments include compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof.

[0134] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of infections and diseases caused by Gram-negative bacteria.

[0135] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of infections and diseases caused by “ESKAPE” pathogens (Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae, and Escherichia coli) or combinations thereof.

[0136] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for treating hospital-acquired infections.

[0137] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of infections and diseases caused by multidrug-resistant (MDR) bacteria, particularly MDR Acinetobacter baumannii.

[0138] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment of infections and diseases caused by carbapenem-resistant bacteria, particularly carbapenem-resistant Acinetobacter baumannii.

[0139] The main advantages of this invention are that the compounds of this invention have good efficacy, high safety, and are not prone to drug resistance, which can meet the clinical needs for treating Gram-negative bacteria (such as Acinetobacter baumannii).

[0140] Example The invention will be more fully understood by referring to the following embodiments. However, they should not be construed as limiting the scope of the invention.

[0141] Unless otherwise specified, experimental methods in the following examples were generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are weight percentages and parts by weight.

[0142] Unless otherwise stated, all examples and intermediates were prepared under a nitrogen atmosphere.

[0143] The room temperature is 25±2℃. Example 1. Synthesis of 2-(trimethylsilyl)ethyl(2-bromo-6-((3-formylpyridin-2-yl)seleno)benzyl)carbamate (VIa) Step 1: 2-[(3-carboxypyridin-2-yl)diselenoyl]pyridine-3-carboxylic acid (VIa-5) At 0 °C, selenium powder (3.20 g, 40.6 mmol) was suspended in ethanol (100 mL), sodium borohydride (1.62 g, 42.8 mmol) was added, and the mixture was stirred for 10 minutes until the reaction stopped exothermically and the reaction solution became colorless and transparent. The reaction solution was heated to 80 °C and stirred for 3 hours, then cooled to room temperature. 2-chloropyridine-3-carboxylic acid (4.00 g, 25.4 mmol) was added, and the mixture was heated to 80 °C and stirred for 18 hours. The mixture was filtered while hot, and the filtrate was poured into ice water. The pH was adjusted to 4 with 1 N hydrochloric acid, and the mixture was filtered again. The filter cake was collected and dried to give the title compound VIa-5 (1.80 g, yellow solid).

[0144] LCMS (ESI, m / z): 402 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 13.95 (s, 2H), 8.59 (dd, 2H), 8.26 (dd,2H), 7.35 (dd, 2H). Step 2: 2-Hydroselenonicotinic acid (VIa-4) Compound VIa-5 (4.00 g, 9.95 mmol) was dispersed in water (20 mL) at 25 °C, and sodium hydroxide (1 M, 30.0 mL, 29.8 mmol) and hydrazine hydrate (11.4 mL, 198.9 mmol, 85% wt) were added. The mixture was then stirred at 80 °C for 12 hours. The reaction solution was cooled to room temperature, added to ice water, and the pH was adjusted to 4 with 1 N hydrochloric acid. The mixture was then filtered, and the filter cake was collected and dried to obtain the target compound VIa-4 (1.50 g, yellow solid).

[0145] LCMS (ESI, m / z): 201 [M+H] + . 1 H NMR (400 MHz, DMSO- d6)δ14.70 (s, 1H), 13.86 (s, 1H), 8.28 (dd,1H), 8.10 (dd, 1H), 7.24 (dd, 1H). Step 3: 2-((3-bromo-2-cyanophenyl)vinyl)nicotinic acid (VIa-3) Sodium hydride (1.60 g, 40.1 mmol) was dispersed in N,N-dimethylacetamide (30.0 mL) at 0 °C. 2-Bromo-6-fluorobenzene-1-onitrile (5.90 g, 29.7 mmol) was added, followed by a solution of compound VIa-4 (3.00 g, 14.8 mmol) in N,N-dimethylacetamide (30.0 mL). The mixture was stirred at 90 °C for 18 hours. Water (60.0 mL) was added to the mixture, and extraction was performed with petroleum ether / ethyl acetate (V / V = 10 / 1, 60.0 mL). The aqueous phase was adjusted to pH 3–4 with hydrochloric acid (2 mol / L), filtered, and the filter cake was dissolved in acetonitrile (350 mL). The mixture was heated to 90 °C, stirred for 30 minutes, filtered while hot, and the filtrate was concentrated under reduced pressure to give the title compound VIa-3 (4.00 g, yellow solid).

[0146] LCMS (ESI, m / z): 382 [M+H] + . 1H NMR (400 MHz, DMSO- d6)δ 14.09 (s, 1H), 8.47 (dd, 1H), 8.32 (dd,1H), 7.95 (dd, 1H), 7.91-7.86 (m, 1H), 7.67-7.58 (m, 1H), 7.39-7.33 (m, 1H). Step 4: (2-((2-(aminomethyl)-3-bromophenyl)vinyl)pyridin-3-yl)methanol (VIa-2) The mixture of compound VIa-3 (4.50 g, 11.7 mmol) and boronane dimethyl sulfide complex (BH3-Me2S) (10 M, 45.0 mL, 450 mmol) was heated to 35 °C, stirred for 1 hour, cooled to 0 °C, and the mixture was slowly poured into MeOH (150 mL). The reaction mixture (VIa-2) was used directly in the next step.

[0147] LCMS (ESI, m / z): 373 [M+H] + . Step 5: 2-(trimethylsilyl)ethyl(2-bromo-6-((3-(hydroxymethyl)pyridin-2-yl)vinyl)benzyl)carbamate (VIa-1) At 0 °C, triethylamine (TEA) (4.80 mL, 34.6 mmol) and compound C, 2-(trimethylsilyl)ethyl[(2,5-dioxotetrahydro-1H-pyrrolo-1-yl)oxy]carbamate (2.70 g, 10.4 mmol), were added to a methanol (150 mL) solution of the above compound VIa-2. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (600 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography. The crude product was eluted with dichloromethane / ethyl acetate (1:0-3:1) to give the title compound VIa-1 (1.60 g, yellow oil).

[0148] LCMS (ESI, m / z): 517 [M+H] + . 1H NMR (400 MHz, DMSO- d6)δ 8.20 (dd, 1H), 7.76-7.70 (m, 1H), 7.67(dd, 1H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.17 (t, 2H), 5.51 (s, 1H), 4.52 (dd,4H), 4.01 (t, 2H), 0.90 (d, 2H), 0.00 (s, 9H). Step 6: 2-(trimethylsilyl)ethyl(2-bromo-6-((3-formylpyridin-2-yl)acetyl)benzyl)carbamate (VIa) Compound VIa-1 (1.60 g, 3.10 mmol) was dissolved in toluene (50.0 mL) solution, and manganese dioxide (2.40 g, 27.9 mmol) was added. The mixture was stirred at 90 °C for 18 hours, cooled, and filtered. The filter cake was washed three times with dichloromethane, and the filtrate was concentrated under reduced pressure to obtain the target compound VIa (1.40 g, yellow oil).

[0149] LCMS (ESI, m / z): 515 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.47 (dd, 1H), 8.38 (dd,1H), 7.73 (dd, 1H), 7.63 (dd, 1H), 7.44 (dd, 1H), 7.25-7.21 (m, 1H), 7.05 (s,1H), 4.39 (d, 2H), 4.03-3.92 (m, 2H), 0.92-0.83 (m, 2H), 0.00 (s, 9H). Example 2. Synthesis of 2-(trimethylsilyl)ethyl[({2-bromo-6-[(3-carboxypyridin-2-yl)thio]phenyl}methyl)amino]carbamate (VIb) Step 1: 2-(3-bromo-2-cyanophenyl)thionicotinic acid (VIb-3) At 0 °C, 2-mercaptonicotinic acid (10.0 g, 64.4 mmol) was added to a mixture of sodium hydride (5.16 g, 129 mmol) and N,N-dimethylacetamide (300 mL), and the mixture was stirred at 0 °C for 30 min. Then, 2-bromo-6-fluorobenzonitrile (15.4 g, 77.3 mmol) was added, and the mixture was stirred at 90 °C for 24 h. Water (300 mL) was added to the mixture. Extraction was performed with petroleum ether / ethyl acetate (v / v = 10 / 1, 300 mL). The pH of the aqueous phase was adjusted to 3–4 with hydrochloric acid (2 mol / L). The mixture was filtered and concentrated under reduced pressure with toluene (to remove water, three times, 500 mL each time) to give the title compound VIb-3 (14.5 g, yellow solid).

[0150] LCMS (ESI, m / z): 335 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6)δ 13.86 (s, 1H), 8.46 (dd, 1H), 8.32 (dd,1H), 7.97 (dd, 1H), 7.80 (dd, 1H), 7.69 (t, 1H), 7.33 (dd, 1H). Step 2: (2-((2-(aminomethyl)-3-bromophenyl)thio)pyridin-3-yl)methanol (VIb-2) At 0 °C, aluminum trichloride (11.9 g, 89.5 mmol) was added to a tetrahydrofuran (150 mL) solution of compound VIb-3 (10.0 g, 22.4 mmol). The mixture was stirred at room temperature for 15 minutes, cooled to -10 °C, and then lithium aluminum hydride solution (2.5 M, 35.8 mL, 89.5 mmol) was slowly added dropwise over one hour. After the addition was complete, the mixture was stirred at 0 °C for 16 hours. Water (17 mL) was added dropwise to the mixture at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. A 15% sodium hydroxide solution (17 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 30 minutes. After filtration, the filter cake was dissolved in methanol (500 mL), stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated under vacuum to obtain the title compound VIb-2 (17.0 g, yellow solid), which was used directly in the next step.

[0151] LCMS (ESI, m / z): 325 [M+H] + . Step 3: 2-(trimethylsilyl)ethyl(2-bromo-6-((3-(hydroxymethyl)pyridin-2-yl)thio)benzyl)carbamate (VIb-1) Compound C (2.71 g, 10.4 mmol) was added to a mixture of compound VIb-2 (17.0 g, 10.45 mmol) and triethylamine (TEA) (15 mL, 108.21 mmol) in tetrahydrofuran / water (300 mL, V / V = 1 / 1) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature for 2 hours. The reaction mixture was diluted with water (300 mL) and dichloromethane (300 mL), extracted with dichloromethane (300 mL × 2), the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / methanol, to give the title compound VIb-1 (3.00 g, yellow solid).

[0152] LCMS (ESI, m / z): 469 [M+H] + . 1 H NMR (400 MHz, CDCl3)δ 8.21 (d, 1H), 7.72 (dd, 1H), 7.66 (d, 1H), 7.56 (d, 1H), 7.19 (d, 1H), 7.07 (dd, 1H), 5.33 (s, 1H), 4.81 (s, 2H), 4.07-3.97 (m, 2H), 2.98 (s, 1H), 0.88 (t, 2H), 0.00 (s, 9H). Step 4: 2,2,2-Trichloroethyl (2-bromo-6-((3-formylpyridin-2-yl)thio)benzyl)carbamate (VIb) At 0 °C, a solution of compound VIb-1 (1.60 g, 3.41 mmol) in dichloromethane (20 mL) was added with Dys-Martin oxidant (1.45 g, 3.41 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and dichloromethane (10 mL). The mixture was extracted with dichloromethane (15 mL × 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with dichloromethane / methanol as eluent to give the title compound VIb (1.10 g, yellow oil).

[0153] LCMS (ESI, m / z): 467 [M+H] + . 1 H NMR (400 MHz, CDCl3)δ 10.27 (s, 1H), 8.35 (d, 1H), 8.02 (dd, 1H), 7.64 (d, 1H), 7.46 (d, 1H), 7.17-7.10 (m, 2H), 4.64 (d, 2H), 4.39-4.31 (m,1H), 4.05-3.93 (m, 2H), 0.86-0.79 (m, 2H), -0.07 (s, 9H). Example 3. N 2 -((S)-2-(Fmoc)amino)-5-((Boc)amino)pentanoyl)-N 6 Synthesis of -(Boc)-L-lysine (IX) Step 1: N-Fmoc-N'-Boc-L-ornithine pentafluorophenol ester (IX-1) N-Fmoc-N'-Boc-L-ornithine (22.0 g, 48.4 mmol) and pentafluorophenol (10.0 g, 54.3 mmol) were dissolved in a mixture of tetrahydrofuran (250 mL) and ethyl acetate (250 mL). N,N'-dicyclohexylcarboimide (11.7 g, 56.9 mmol) was added in portions, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (500 mL × 3). The organic layers were combined, washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound IX-1 (32.0 g, 51.6 mmol, white solid).

[0154] LCMS (ESI, m / z): 521 [M-100+H] + . Step 2: N 2 -((S)-2-(Fmoc)amino)-5-((Boc)amino)pentanoyl)-N 6 -(Boc)-L-L-lysine (IX) Compound IX-1 (12.7 g, 51.6 mmol) was dissolved in water (200 mL), and sodium carbonate (5.47 g, 51.6 mmol) was added. The mixture was stirred for 5 minutes, and then a tetrahydrofuran solution (200 mL) of compound B (32.0 g, 51.6 mmol) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 6 hours. The mixture was adjusted to pH 3 with 10% tartaric acid solution, and then concentrated. The residue was dissolved in water and extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / methanol (1:0–10:1) to give the title compound IX (35.0 g, white solid).

[0155] LCMS (ESI, m / z): 583 [M-100+H] + . 1 HNMR (400 MHz, DMSO-d6)δ 12.53 (s, 1H), 8.03 (d, 1H), 7.89 (d, 2H), 7.73 (dd, 2H), 7.47 (d, 1H), 7.42 (t, 2H), 7.32 (td, 2H), 6.76 (dt, 2H), 4.24(m, 3H), 4.14 (m, 1H), 4.02 (m, 1H), 2.89 (m, 4H), 1.75-1.39 (m, 8H), 1.38(s, 9H), 1.35 (s, 9H), 1.28 (m, 2H). Example 4. Synthesis of N-methyl-L-tryptophan-2-(trimethylsilyl)ethyl ester (IV) Step 1: N-Benzyl-N-Methyl-L-Tryptophan (X-2) Compound X-3, namely L-tryptophan (50.0 g, 245 mmol) and benzaldehyde (26.0 mL, 257 mmol), was dissolved in methanol (500 mL) at 25 °C. Sodium cyanoborohydride (30.8 g, 490 mmol) was then added in portions. The reaction was carried out for 3 hours, and the reaction was monitored by LCMS until it was complete. Paraformaldehyde (23.2 g, 734 mmol) was then added, followed by sodium cyanoborohydride (30.8 g, 490 mmol) in portions. The reaction was carried out overnight. Finally, the mixture was concentrated, and the residue was slurried with ethyl acetate (500 mL) and filtered to give the title compound X-2 (55.0 g, white solid).

[0156] LCMS (ESI, m / z): 309 [M+H] + . 1 HNMR (400 MHz, DMSO CDCl3-d6)δ 12.23 (br, 1H), 10.82 (s, 1H), 7.42(d, 1H), 7.36-7.20 (m, 6H), 7.11 (d, 1H), 7.08-7.01 (m, 1H), 6.97-6.90 (m,1H), 3.87 (d, 1H), 3.77-3.62 (m, 2H), 3.21 (dd, 1H), 3.02 (dd, 1H), 2.33 (s,3H). Step 2: N-Benzyl-N-Methyl-L-Tryptophan-2-(Trimethylsilyl)ethyl ester (X-1) Compound X-2 (50.0 g, 162 mmol) and 2-(trimethylsilyl)ethanol (28.8 g, 243 mmol) were dissolved in dichloromethane (500 mL). 4-Dimethylaminopyridine (DMAP) (1.98 g, 16.2 mmol) was added, and the mixture was cooled to 0 °C. N,N'-dicyclohexylcarboimide (DCC) (40.1 g, 195 mmol) was added in portions, and the reaction was stirred at 25 °C for 12 hours. The mixture was quenched with water (500 mL), extracted with dichloromethane (300 mL × 3), and the organic phases were combined, washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / n-hexane (1:20–1:1) to give the title compound X-1 (45.0 g, yellow oil).

[0157] LCMS (ESI, m / z): 409 [M+H] + ; 1 H-NMR (400 MHz, CDCl3 CDCl3-d)δ 7.96 (s, 1H), 7.50 (d, 1H), 7.34 (d,1H), 7.31-7.21 (m, 6H), 7.20-7.14 (m, 1H), 7.10-7.05 (m, 1H), 7.04 (d, 1H),4.20-4.09 (m, 2H), 3.88 (d, 1H), 3.74 (ddd, 1H), 3.66 (d, 1H), 3.34 (dd, 1H),3.10 (dd, 1H), 2.38 (s, 3H), 0.92 (m, 2H), 0.00 (s, 9H). Step 3: N-Methyl-L-tryptophan-2-(trimethylsilyl)ethyl ester (X) Compound X-1 (27.0 g, 66.1 mmol) was dissolved in methanol (300 mL) at 25 °C, and palladium hydroxide on carbon (Pd(OH)2 / C) (Pd 20% on carbon, nominally 50% water) (3.71 g, 26.4 mmol) was added. The reaction mixture was stirred for 12 hours under a hydrogen atmosphere and a reaction pressure of 15 psi. The reaction mixture was filtered and concentrated under reduced pressure to give the target compound X (19.0 g, a yellow oil).

[0158] LCMS (ESI, m / z): 319 [M+H] + . 1 H-NMR (400 MHz, CDCl3-d)δ 8.10 (s, 1H), 7.61 (d, 1H), 7.34 (d, 1H), 7.18 (t, 1H), 7.11 (t, 1H), 7.06 (s, 1H), 4.12 (pd, 2H), 3.56-3.43 (m, 1H), 3.13 (qd, 2H), 2.37 (s, 3H), 0.90-0.79 (m, 2H), -0.00 (s, 9H). Example 5. 2-(trimethylsilyl)ethyl N α -(N 2 -((S)-2-amino-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (VII) X VIII VII Step 1: 2-(trimethylsilyl)ethyl N α -(N 2 -((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (VIII) Compound X (14.7 g, 46.2 mmol) and compound IX (31.5 g, 46.2 mmol) were dissolved in N,N-dimethylformamide (400 mL). At room temperature, diisopropylethylamine (DIEA) (21.3 mL, 132 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (25.1 g, 65.9 mmol) were added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with water (1000 mL), extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane / tetrahydrofuran / methanol (1:0:0-10:5:1) as the eluent to give the target compound III-1 (25.0 g, yellow oil).

[0159] LCMS (ESI, m / z): 883 [M-100+H] + . 1HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.91-7.86 (m, 2H), 7.70 (t,1H), 7.50 (d, 1H), 7.41 (dd, 2H), 7.29 (d, 2H), 7.13 (d, 1H), 7.03 (t, 1H),6.94 (t, 1H), 6.73 (t, 1H), 6.66 (t, 1H), 5.12 (dd, 1H), 4.56 (td, 1H), 4.26-4.10 (m, 5H), 4.05-3.96 (m, 1H), 3.23 (ddd, 2H), 2.86 (s, 5H), 2.76-2.65 (m,2H), 1.54 (ddd, 2H), 1.35 (t, 18H), 1.25-0.77 (m, 10H), -0.00 (s, 10H). Step 2: 2-(trimethylsilyl)ethyl N α -(N 2 -((S)-2-amino-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (VII) Compound VIII (24.0 g, 24.4 mmol) was dissolved in dichloromethane (200 mL) at 25 °C, and diethylamine (26.8 g, 244 mmol) was added. The reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0-10:1) as the eluent to give title compound VII (18.0 g, yellow oil).

[0160] LCMS (ESI, m / z): 761 [M+H] + ; 1HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.97 (d, 1H), 7.47 (d, 1H), 7.28 (t, 1H), 7.10 (d, 1H), 7.02 (t, 1H), 6.93 (t, 1H), 6.68 (dd, 2H), 5.09(dd, 1H), 4.55 (dd, 1H), 4.19-4.08 (m, 2H), 3.28-3.22 (m, 1H), 3.13 (dd, 2H), 2.82 (d, 5H), 2.72 (dd, 2H), 2.26 (s, 2H), 1.61-1.40 (m, 2H), 1.34 (d, 18H),1.20-0.78 (m, 10H), 0.00 (s, 9H). Example 6. 2-(trimethylsilyl)ethyl N α -(N 2 -((S)-2-((2-((3-bromo-2-((((2,2,2-trichloroethoxy)carbonyl)amino)methyl)phenyl)seleno)pyridin-3-yl)methyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (IIIa) Step 1: 2-(trimethylsilyl)ethyl N α -(N2-((S)-2-((2-((3-bromo-2-((((2,2,2-trichloroethoxy)carbonyl)amino)methyl)phenyl)seleno)pyridin-3-yl)methyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (Va) Compound VIIa (10.0 g, 13.1 mmol) and compound VIa (7.43 g, 14.5 mmol) were dissolved in a mixed solution of 1,2-dichloroethane (100 mL) and acetic acid (2.25 mL, 39.4 mmol). The mixture was stirred at 40 °C for 3 hours, and then sodium borohydride acetate (8.35 g, 39.4 mmol) was added. The reaction was stirred at 40 °C for 2 hours. The reactants were diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane / tetrahydrofuran / methanol (1:0:0-70:10:1) as the eluent to give the target compound Va (15.3 g, yellow oil).

[0161] LCMS (ESI, m / z): 1261 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 10.83 (s, 1H), 8.16 (dd, 1H), 8.09 (d, 1H), 7.67 (d, 1H), 7.58 (dd, 2H), 7.53 (d, 1H), 7.32 (d, 1H), 7.18-7.11 (m, 3H),7.05 (dd, 2H), 6.97 (t, 1H), 6.70 (d, 2H), 5.13 (dd, 1H), 4.65 (dd, 1H), 4.53(d, 2H), 4.15 (dd, 2H), 3.73 (d, 1H), 3.59-3.46 (m, 1H), 3.30-3.27 (m, 1H),3.22 (dd, 1H), 3.04 (s, 1H), 2.91 (d, 5H), 2.81-2.72 (m, 2H), 1.54-1.40 (m,4H), 1.36 (d, 19H), 1.23-1.11 (m, 4H), 0.96-0.85 (m, 6H). Step 2: N α -(N 2 -((S)-2-(((2-((2-(aminomethyl)-3-bromophenyl)selenoyl)pyridin-3-yl)methyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α -Methyl-L-tryptophan (IVa) Compound Va (15.0 g, 2.04 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylamine fluoride (119 mL, 119 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0-10:1) as the eluent to give the target compound IVa (11.0 g, yellow oil).

[0162] LCMS (ESI, m / z): 1017 [M+H] + . Step 3: Tert-butyl (4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-17-bromo-7-(3-(tert-butoxycarbonylamino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecene-10-yl]butyl)carbamate (IIIa) At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (8.31 g, 43.4 mmol) and 1-hydroxybenzotriazole (HOBt) (5.86 g, 43.3 mmol) were dissolved in dichloromethane (25 mL) and stirred for 30 minutes. Then, a dichloromethane (25 mL) solution of compound IVa (11 g, 10.8 mmol) was slowly added dropwise, and stirring was continued at room temperature for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0-10:1) as the eluent to give the target compound IIIa (10.0 g, yellow oil).

[0163] LCMS (ESI, m / z): 995 [M+H] + . Example 7. Tert-butyl(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-17-bromo-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecano[pyrido][1,4]thiazine[5,8,11,14]tetraazacycloheptadecene-10-yl)butyl)carbamate (IIb) Step 1: 2-(trimethylsilyl)ethyl N α -(N 2 -((S)-2-((2-((3-bromo-2-((((2,2,2-trichloroethoxy)carbonyl)amino)methyl)phenyl)thio)pyridin-3-yl)methyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan ester (Vb) Compound VIIb (2.00 g, 2.63 mmol) and compound VIb (1.47 g, 3.15 mmol) were dissolved in a mixed solution of 1,2-dichloroethane (25 mL) and acetic acid (0.45 mL, 7.88 mmol). The mixture was stirred at 40 °C for 3 hours, and then sodium borohydride acetate (1.67 g, 7.88 mmol) was added. The reaction was continued to be stirred at 40 °C for 2 hours. The reactants were diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane / tetrahydrofuran / methanol (1:0:0-70:10:1) as the eluent to give the target compound Vb (3.10 g, yellow oil).

[0164] LCMS (ESI, m / z): 1213 [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 10.81 (s, 1H), 8.16 (dd, 1H), 8.08 (d, 1H),7.74-7.66 (m, 2H), 7.52 (d, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 7.22 (t, 1H),7.18-7.10 (m, 2H), 7.05 (t, 1H), 6.95 (dd, 2H), 6.70 (dt, 2H), 5.11 (dd, 1H),4.64 (td, 1H), 4.44 (d, 2H), 4.19-4.08 (m, 2H), 4.04-3.94 (m, 2H), 3.68 (dd,2H), 3.30-3.17 (m, 2H), 3.06 (s, 1H), 2.92 (d, 5H), 2.80-2.72 (m, 2H), 1.53-1.40 (m, 4H), 1.38-1.34 (m, 18H), 1.24-1.10 (m, 4H), 0.95-0.83 (m, 6H), -0.00 (s, 9H), -0.01 (s, 9H). Step 2: N α -(N 2 -((S)-2-(((2-(2-(aminomethyl)-3-bromophenyl)thio)pyridin-3-yl)methyl)amino)-5-((tert-butoxycarbonyl)amino)pentanoyl)-N 6 -(tert-Butoxycarbonyl)-L-L-Lysyl)-N α 1-Methyl-L-tryptophan (IVb) Compound Vb (2.50 g, 2.04 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylamine fluoride (20.4 mL, 20.4 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0-10:1) as the eluent to give the title compound IVb (2.00 g, yellow oil).

[0165] LCMS (ESI, m / z): 967 [M+H] + . Step 3: tert-butyl(4-((7S,10S,13S)-13-((1H-indol-3-yl)methyl)-17-bromo-7-(3-((tert-butoxycarbonyl)amino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzo[pyrido][1,4]thiazine[5,8,11,14]tetraazacycloheptadecene-10-yl)butyl)carbamate (IIIb) At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.58 g, 8.26 mmol) and 1-hydroxybenzotriazole (HOBt) (1.12 g, 8.26 mmol) were dissolved in dichloromethane (25 mL) and stirred for 30 minutes. Then, a dichloromethane (25 mL) solution of compound IVb (2.00 g, 1.97 mmol) was slowly added dropwise, and stirring was continued at room temperature for 2 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0–10:1) as the eluent to give the title compound IIIb (1.8 g, yellow oil).

[0166] LCMS (ESI, m / z): 949. [M+H] + . 1H NMR (400 MHz, DMSO-d6)δ 10.75 (s, 1H), 8.39 (d, 1H), 8.22 (dd, 1H), 7.86 (t, 1H), 7.81 (dd, 1H), 7.65 (dd, 1H), 7.57 (d, 1H), 7.32-7.19 (m, 4H),7.09 (d, 1H), 7.06-7.00 (m, 1H), 6.93 (dd, 1H), 6.77 (t, 1H), 6.68 (t, 1H),5.42 (dd, 1H), 4.53 (q, 1H), 4.41 (d, 2H), 3.66 (d, 1H), 3.41 (dd, 1H), 3.21(dd, 1H), 3.15-3.02 (m, 5H), 2.88 (dd, 2H), 2.72 (dd, 2H), 1.38 (t, 21H),1.22 (dd, 3H), 1.11 (dd, 2H), 0.83 (dt, 1H), 0.72-0.54 (m, 1H). Example 8. Synthesis of 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecene-17-yl]benzoic acid (I-1) Step 1: 2-Methyl-2-propyl ({3-[(11S, 14S, 17S)-14-(2,2-dimethyl-4-oxo-5-aza-3-oxaza-9-yl)-17-(1H-indol-3-ylmethyl)-16-methyl-22-(4-{[(2-methylpropyl-2-yl)oxy]carbonyl}phenyl)-12,15,18-trioxo-4,10,13,16,19-pentaza-2-thiatricyclo[19.4.0.03,8]tetracos-1(21),3(8),4,6,22,24-hexen-11-yl]propyl}amino)carbamate (IIa-1) Compound IIIa (9.00 g, 9.03 mmol) and 4-tert-butoxycarbonylphenylboronic acid (4.01 g, 18.1 mmol) were dissolved in a mixture of dioxane (50.0 mL) and water (10.0 mL). Potassium phosphate (5.75 g, 27.1 mmol) and bis(tri-tert-butylphosphine)palladium (1.38 g, 2.71 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 12 hours. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane / methanol (1:0–10:1) as the eluent. The product was further purified by high-performance preparative liquid chromatography (column: Waters-Xbridge-C18-10µm-19*250mm; mobile phase A: 10 mM ammonium bicarbonate / The crude product was purified by water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient B: 60%~95%, 12 min) to give the title compound IIa-1 (1.30 g, white solid).

[0167] LCMS (ESI, m / z): 1095 [M+H] + . 1H NMR (400 MHz, DMSO- d6)δ 10.76 (s, 1H), 8.37 (d, 1H), 8.21 (dd,1H), 7.95 (dt, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.28 (t, 2H), 7.24-7.14 (m,2H), 7.08 (ddd, 2.9 Hz, 2H), 7.03 (dd, 1H), 6.93 (t, 1H), 6.76 (t, 1H), 6.69(t, 1H), 5.63-5.54 (m, 1H), 5.47 (dt, 1H), 4.61 (dt, 1H), 4.27-4.11 (m, 2H),3.67-3.56 (m, 1H), 3.52-3.39 (m, 1H), 3.20-3.03 (m, 6H), 2.88 (dd, 2H), 2.73(dd, 2H), 2.38-2.16 (m, 5H), 2.00-1.89 (m, 1H), 1.78-1.65 (m, 1H), 1.43 (d,10H), 1.38 (dd, 23H), 1.31-1.08 (m, 6H), 0.96-0.81 (m, 1H), 0.71 (tdd, 1H). Step 2: 4-[(4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecene-17-yl]benzoic acid (I-1) Compound IIa-1 (700 mg, 0.64 mmol) was dissolved in tetrahydrofuran (1.00 mL), and concentrated hydrochloric acid (1.00 mL) was slowly added dropwise at room temperature. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) (column: Waters-SunFire-C18-10µm-19*250mm; mobile phase A: 0.05% hydrochloric acid / water, mobile phase B: acetonitrile; flow rate: 25, B%: 0-95%, 15 min) to obtain the target compound I-1 (353 mg, 3 HCl, light brown solid).

[0168] LCMS (ESI, m / z): 840 [M+H] + . 1 H NMR (400 MHz, MeOD)δ 8.97 (d, 1H), 8.55 (dd, 1H), 8.42 (dd, 1H), 8.09 (d, 2H), 7.61 (dd, 2H), 7.43 (d, 2H), 7.38 (d, 1H), 7.24 (ddd, 3H), 7.13(s, 1H), 7.10 (t, 1H), 6.99 (t, 1H), 5.60 (dd, 1H), 4.63-4.49 (m, 3H), 4.40(d, 1H), 4.21-4.13 (m, 2H), 3.28-3.17 (m, 5H), 3.02-2.95 (m, 2H), 2.71-2.52(m, 2H), 2.14-1.97 (m, 2H), 1.89-1.71 (m, 2H), 1.49-1.29 (m, 4H), 1.20 (qd,1H), 1.08-0.93 (m, 1H), 0.87-0.71 (m, 1H). Example 9. Synthesis of 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecane-17-yl]cyclohexyl-3-en-1-carboxylic acid (I-2) Step 1: tert-Butoxycarbonylmethyl 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-(tert-Butoxycarbonylamino)butyl)-7-(3-(tert-Butoxycarbonylamino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecane-17-yl]cyclohexyl-3-en-1-carboxylate (IIa-2) Compound IIIa (500 mg, 0.50 mmol) and pinacol ester of 1-tert-butoxycarbonylcyclohexyl-3-ene-4-boronic acid (200 mg, 0.65 mmol) were dissolved in a mixture of dioxane (5.00 mL) and water (1.00 mL). Potassium phosphate (210 mg, 1.50 mmol) and bis(tri-tert-butylphosphine)palladium (30.0 mg, 0.05 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 12 hours. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0–10:1) as the eluent. The product was further purified by high-performance preparative liquid chromatography (column: Waters-Xbridge-C18-10µm-19*250mm; mobile phase A: 10). mM ammonium bicarbonate / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: B 60%~95%, 12 min), yielded the title compound IIa-2 (150 mg, white solid).

[0169] LCMS (ESI, m / z): 1099 [M+H] + . 1H NMR (400 MHz, DMSO- d6)δ 10.76 (s, 1H), 8.37 (d, 1H), 8.21 (dd,1H), 7.95 (dt, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.28 (t, 2H), 7.24-7.14 (m,2H), 7.08 (ddd, 2H), 7.03 (dd, 1H), 6.93 (t, 1H), 6.76 (t, 1H), 6.69 (t, 1H),5.63-5.54 (m, 1H), 5.47 (dt, 1H), 4.61 (dt, 1H), 4.27-4.11 (m, 2H), 3.67-3.56(m, 1H), 3.52-3.39 (m, 1H), 3.20-3.03 (m, 6H), 2.88 (dd, 2H), 2.73 (dd, 2H), 2.38-2.16 (m, 5H), 2.00-1.89 (m, 1H), 1.78-1.65 (m, 1H), 1.43 (d, 10H), 1.38(dd, 23H), 1.31-1.08 (m, 6H), 0.96-0.81 (m, 1H), 0.71 (tdd, 1H). Step 2: 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]seleno[5,8,11,14]tetraazacycloheptadecane-17-yl]cyclohexyl-3-en-1-carboxylic acid (I-2) Compound IIa-2 (200 mg, 0.18 mmol) was dissolved in tetrahydrofuran (1.00 mL), and concentrated hydrochloric acid (1.00 mL) was slowly added dropwise at room temperature. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (HPLC) (column: Waters-SunFire-C18-10µm-19*250mm; mobile phase A: 0.05% hydrochloric acid / water, mobile phase B: acetonitrile; flow rate: 25, B%: 0-95, 15 min) to obtain the target compound I-2 (103 mg, 3 HCl, light brown solid).

[0170] LCMS (ESI, m / z): 843 [M+H] + . 1 H NMR (400 MHz, DMSO-d6)δ 10.94 (s, 1H), 10.63 (s, 1H), 9.48 (d, 1H), 9.26 (d, 1H), 8.39 (d, 1H), 8.19 (d, 2H), 8.08 (s, 3H), 8.00 (s, 3H), 7.63(d, 1H), 7.36 (dd, 2H), 7.16 (dd, 1H), 7.12 (t, 2H), 7.09-7.06 (m, 1H), 7.03(d, 1H), 6.93 (t, 1H), 5.62 (s, 1H), 5.51 (ddd, 1H), 4.51 (dd, 1H), 4.35-4.23(m, 2H), 4.21-4.14 (m, 1H), 4.00-3.92 (m, 2H), 3.16 (d, 4H), 3.08-3.00 (m,1H), 2.86-2.77 (m, 2H), 2.60-2.54 (m, 3H), 2.38-2.22 (m, 4H), 2.06-1.96 (m,2H), 1.88-1.79 (m, 1H), 1.74-1.67 (m, 1H), 1.61 (dt, 2H), 1.39-1.29 (m, 2H),1.19 (d, 1H), 0.97 (dd, 2H), 0.82 (ddd, 1H). Example 10. Synthesis of 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]thiazine[5,8,11,14]tetraazacycloheptadecene-17-yl]cyclohexyl-3-en-1-carboxylic acid (I-3) Step 1: tert-butyl(4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-17-bromo-7-(3-(tert-butoxycarbonylamino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]thiazine[5,8,11,14]tetraazacycloheptadecene-10-yl]butyl)carbamate (IIIb) Compound IIb (100 mg, 0.10 mmol) and pinacol 1-tert-butoxycarbonylcyclohexyl-3-ene-4-boronic acid (63.9 mg, 0.21 mmol) were dissolved in dioxane (0.80 mL) and water (0.20 mL). Potassium carbonate (43.01 mg, 0.31 mmol) and bis(tri-tert-butylphosphine)palladium (5.30 mg, 0.01 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction was monitored until complete, and the mixture was concentrated under reduced pressure. The crude product was purified by high performance preparative liquid chromatography (column: Waters-Xbridge-C18 -10µm-19*250mm; mobile phase A: 10 mM ammonium bicarbonate / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: B 60%~95%, 12 min) to obtain the target compound I-3-1 (40 mg, white solid).

[0171] LCMS (ESI, m / z): 1051 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6)δ 8.46 (d, 1H), 8.19-8.13 (m, 1H), 7.89 (dt,1H), 7.78 (d, 1H), 7.57 (dd, 1H), 7.30 (d, 1H), 7.26 (dd, 2H), 7.18-7.11 (m,2H), 7.09 (s, 1H), 7.02 (t, 1H), 6.93 (t, 1H), 6.77 (t, 1H), 6.69 (t, 1H),5.56 (dt, 1H), 5.48-5.39 (m, 1H), 4.67-4.58 (m, 1H), 4.12 (qd, 2H), 3.63 (dd,1H), 3.45-3.37 (m, 1H), 3.16 (t, 4H), 3.10-3.03 (m, 1H), 2.89 (dd, 2H), 2.74(dd, 2H), 2.35-2.17 (m, 5H), 1.98-1.90 (m, 1H), 1.76-1.67 (m, 1H), 1.43 (d,11H), 1.37 (d, 20H), 1.27-1.21 (m, 2H), 1.17-1.10 (m, 2H), 0.92-0.84 (m, 1H), 0.69 (ddd, 1H). Step 2: 4-[(11S,14S,17S)-14-(4-aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3-ylmethyl)-16-methyl-12,15,18-trione-4,10,13,16,19-pentaza-2-thionecyclic[19.4.0.03,8]pentacarbon-1(21),3(8),4,6,22,24-hexen-22-yl]benzoic acid (I-3) Compound I-3-1 (110 mg, 0.10 mmol) was dissolved in dichloromethane (1.00 mL) at 25 °C, and then trifluoroacetic acid (1.00 mL) was added. The mixture was stirred at 10 °C for 2 hours, concentrated under reduced pressure, and the crude product was purified by high performance preparative liquid chromatography (column: Waters-Xbridge-C18-10µm-19*250mm; mobile phase A: 10mM ammonium bicarbonate / water; mobile phase B: acetonitrile; B% 5-95, 14 min) to obtain the target compound I-3 (61.5 mg, white solid).

[0172] LCMS (ESI, m / z): 795 [M+H] + . 1 H NMR (400 MHz, MeOD-d4)δ 8.36 (dd, 1H), 7.87 (d, 1H), 7.58 (d, 1H),7.39-7.30 (m, 2H), 7.10 (ddd, 4H), 6.98 (t, 1H), 6.73 (dd 1H), 5.76-5.69 (m,1H), 5.67 (s, 1H), 4.52-4.38 (m, 2H), 4.28 (dd, 1H), 3.91 (d, 1H), 3.53-3.40(m, 2H), 3.17 (t, 5H), 2.89-2.64 (m, 2H), 2.53-2.42 (m, 2H), 2.41-2.31 (m,3H), 2.26 (dt, 1H), 2.15-2.05 (m, 1H), 1.86-1.71 (m, 1H), 1.44 (ddd, 9H), 0.95-0.79 (m, 1H), 0.61-0.42 (m, 1H). Comparative Example 1. Synthesis of 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecano[pyrido][1,4]thiazine[5,8,11,14]tetraazacycloheptadecenyl]benzoic acid (I-4) Step 1: tert-Butoxycarbonyl-4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-(tert-Butoxycarbonylamino)butyl)-7-(3-(tert-Butoxycarbonylamino)propyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrobenzopyrido[3,2-p][1]thiazine[5,8,11,14]tetraazacycloheptadecene-17-yl]benzoate (I-4-1) Compound IIb (1.80 g, 1.87 mmol) and 2-methylpropane-2-ol 4-(dihydroxyboryl)benzoate (1.14 g, 3.73 mmol) were dissolved in a mixture of dioxane (15.0 mL) and water (3.00 mL). Potassium carbonate (0.77 g, 5.60 mmol) and bis(tri-tert-butylphosphine)palladium (0.10 g, 0.19 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 12 hours. The reaction mixture was cooled, filtered, and the filtrate was diluted with ethyl acetate, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography with dichloromethane / methanol (1:0-10:1) as the eluent to obtain the product. It was then further purified by high performance preparative liquid chromatography (column: Waters-Xbridge-C18-10µm-19*250mm; mobile phase A: 10 mM ammonium bicarbonate / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: B 60%~95%, 12 min) to obtain the title compound I-4-1 (0.66 g white solid).

[0173] LCMS (ESI, m / z): 1047 [M+H] + . 1H NMR (400 MHz, DMSO- d6)δ 10.80 (s, 1H), 8.47 (d, 1H), 8.26 (s, 1H),8.21-8.17 (m, 1H), 7.93 (d, 2H), 7.80 (d, 1H), 7.61 (d, 1H), 7.54 (d, 2H),7.44 (d, 1H), 7.43 (s, 1H), 7.35-7.26 (m, 2H), 7.18 (dd, 1H), 7.15 (d, 1H),7.04 (t, 1H), 6.94 (t, 1H), 6.77 (t, 1H), 6.69 (t, 1H), 5.51 (dd, 1H), 4.64(q, 1H), 4.17 (dd, 1H), 3.82 (dd, 1H), 3.68-3.62 (m, 1H), 3.43 (d, 1H), 3.22-3.11 (m, 5H), 3.05 (dd, 1H), 2.89 (dd, 2H), 2.74 (dd, 2H), 1.57 (s, 9H), 1.42(d, 2H), 1.38 (s, 9H), 1.36 (s, 10H), 1.34-1.21 (m, 4H), 1.15 (ddd, 2H),0.92-0.83 (m, 1H), 0.69 (dt, 1H). Step 2: Synthesis of 4-[(7S,10S,13S)-13-((1H-indol-3-yl)methyl)-10-(4-aminobutyl)-7-(3-aminopropyl)-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecano[pyrido][1,4]thiazine[5,8,11,14]tetraazacycloheptadecenyl]benzoic acid (I-4, hydrochloride) Compound I-4-1 (1.00 g, 0.96 mmol) was dissolved in tetrahydrofuran (2.00 mL), and concentrated hydrochloric acid (2.00 mL) was slowly added dropwise at room temperature, while the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated. The crude product was purified by reverse preparative chromatography (column: Waters-SunFire-C18-10µm-19*250mm; mobile phase A: 0.05% hydrochloric acid / water, mobile phase B: acetonitrile; flow rate: 25, gradient: B% 0-95, 15 min) to give the target compound I-4 (755 mg, 3 HCl, pale brown solid).

[0174] LCMS (ESI, m / z): 791 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6)δ 10.99 (s, 1H), 10.83 (s, 1H), 9.58 (s, 1H), 9.36 (d, 1H), 8.37-8.31 (m, 2H), 8.12 (d, 4H), 8.00 (d, 5H), 7.63 (d, 1H),7.57 (d, 2H), 7.48-7.45 (m, 2H), 7.36 (t, 2H), 7.29-7.26 (m, 1H), 7.13 (d,1H), 7.04 (d, 1H), 6.94 (t, 1H), 5.50 (dd, 1H), 4.56 (d, 1H), 4.30 (dd, 1H),4.14 (s, 2H), 3.92 (s, 2H), 3.82 (d, 2H), 3.13 (s, 3H), 3.10 (d, 1H), 2.87-2.79 (m, 2H), 2.58-2.54 (m, 1H), 2.08 (t, 1H), 1.93-1.84 (m, 1H), 1.68-1.59(m, 2H), 1.32 (td, 3H), 1.15-1.05 (m, 1H), 1.01-0.92 (m, 1H), 0.81-0.70 (m,1H). CNMR (101 MHz, DMSO-d6)δ 172.5, 169.8, 167.2, 167.0, 155.9, 149.4,145.1, 142.9, 137.9, 137.2, 136.2, 136.1, 132.1, 130.1, 129.8, 129.6, 129.3,128.1, 127.0, 126.3, 123.2, 121.0, 120.6, 118.6, 118.2, 111.4, 109.8, 59.4,55.4, 49.7, 48.7, 45.1, 38.2, 38.1, 31.0, 29.9, 26.9, 26.5, 24.6, 22.7, 21.6. Example 1. Antimicrobial susceptibility test The minimum inhibitory concentration (MIC) method in microbroth was used in this experiment to determine the in vitro antimicrobial activity of the compound.

[0175] For MIC determination, a stock solution of the compound was prepared freshly at 10x the desired highest concentration (i.e., 1280 mg / L) by reconstructing the dried compound in 50:50 water:DMSO.

[0176] Untreated polystyrene 96-well microtiter plates were used to prepare groups containing compounds serially diluted twice to twice the final test concentration (e.g., from 64 to 0.06 μg / ml) in cationic-regulated Mueller Hinton broth medium (CAMHB).

[0177] Inoculum was prepared using the "direct colony suspension method". Colonies of Acinetobacter baumannii ATCC19606 or clinical isolates were suspended in saline solution, adjusted to 0.5 McFarland, diluted 100-fold in CAMHB broth, and 50 μl was added to each well (final concentration per well: ~5 x 10⁵ CFU / ml and final volume per well: 100 μl). The microtiter plate was sealed and incubated at 35 ± 2 °C.

[0178] After 2 hours of incubation, the MIC value was read and recorded as the lowest concentration of antimicrobial agent that inhibited more than or equal to 80% of microbial growth (as detected by naked eye or using a microtiter plate densitometer (OD 600nm)).

[0179] Table 1 provides the minimum inhibitory concentrations (MIC, ug / mL) obtained against Acinetobacter baumannii strains ATCC19606 and ATCC 17978. Example 2. In vivo pharmacokinetic studies of some embodiments of the present invention. Test compound Compounds of the present invention: I-1 (Example 8), I-4 (Comparative Example 1); Sample preparation Table 2: Sample Configuration Information laboratory animals Species: Healthy male ICR (Institute of Cancer Research) mice (SPF grade), weighing 18-22g.

[0180] Source: Experimental Animal Management Department, Shanghai Institute of Family Planning Science; animals transferred from the experimental institution's animal reserve.

[0181] Quantity: 6 males; Animal selection: randomly grouped into groups of 3. Administration method and blood collection time Weigh the patient before administration and calculate the dosage based on their body weight. Administer via intravenous injection, gavage, or oral administration.

[0182] Following intravenous administration (2 mg / kg), 0.2 ml of blood was collected from the jugular vein of mice at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was anticoagulated with EDTA-K2 and placed on ice after collection.

[0183] Sample processing steps 1) Sample preparation: Take 10 µL of plasma sample and mix it with 90 µL of (acetonitrile:methanol=1:1) containing 20 ng / mL of internal standard (IS).

[0184] 2) Protein precipitation: Mix the mixture in a vortex mixer for 5 minutes, then centrifuge at 4000 rpm for 15 minutes.

[0185] 3) Transfer of supernatant: Transfer 50 µL of the supernatant and mix it with 50 µL of water.

[0186] 4) Analysis: The mixture was injected into LC-MS / MS for analysis.

[0187] Data processing Pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 7.0 software based on blood drug concentration data at different time points, and AUC was provided. 0-int C max T max T 1 / 2 Parameters such as oral bioavailability (F%) were also analyzed. The results are shown in Table 3 below.

[0188] Table 3 As can be seen from the data comparison in Table 3, compared with the positive control compound I-4, compound I-1 has a higher Cmax. t Compared to I-4, I-1 showed a 3.13-fold and 2.98-fold increase in AUC, respectively, a 29.8-fold increase in in vivo half-life, and a 37.8% decrease in metabolic clearance. In summary, in intravenous pharmacokinetic studies, I-1 achieved significant pharmacokinetic improvements over I-4, particularly in systemic exposure and clearance, laying a solid foundation for future drug development.

[0189] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, in, X is either Se or S; L is... And does not contain the following structures:

2. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

3. A method for preparing the compound as described in claims 1 and 2, characterized in that, Includes the following steps: S6. In the presence of a palladium catalyst, compound III and compound A undergo a Suzuki or Ulmann coupling reaction to give compound II; Where X is S or Se; R1 is B(OH)2R a -, B(OR b )2R a -; Among them, each R b Independently for C 1-4 Alkyl, or two ORs b Together with the boron atoms they are attached to, they form 4-7 membered heterocyclic groups; R a Selected from the following group: C 6-10 aryl, 5-7 quinone heteroaryl, C 4-7 Subcarbonyl cycloalgide, 4-7 membered subheterocyclic cycloalgide; The palladium catalyst is selected from the group consisting of: di(tri-tert-butylphosphine)palladium, tetra-triphenylphosphine palladium, chloro(2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylylene](3-chloropyridyl)palladium(II)dichloride, [2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-... [-aminoethyl)phenyl]palladium(II), bis(triphenylphosphine)palladium(II), bis[tris(2-tolyl)phosphine]palladium, bis(tricyclohexylphosphine)palladium(II), bis(dibenzylacetone)palladium(O), [1,2-bis(diphenylphosphine)ethane]palladium(II), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II), 1,1′-bis(dicyclohexylphosphine)ferrocenepalladium(II), 1,1′-bis(diisopropylphosphine)ferrocenepalladium(II), or combinations thereof; S7. In the presence of acid A, compound II undergoes a deprotection reaction to give compound I; Wherein, acid A is selected from the group consisting of hydrochloric acid, organic solutions of hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, or combinations thereof.

4. The preparation method according to claim 3, characterized in that, Compound III was prepared by the following steps: S5. In the presence of condensing agent A, compound IV undergoes an intramolecular condensation dehydration reaction to obtain compound III; The condensing agent A is selected from the group consisting of: EDCI / HOBt, HATU / DIEA, HBTU / DIEA, EEDQ, TCFH / NMI, BOPCI / DIEA, TSTU / TEA, PyBOP / DIEA, T3P / TEA, T4P / TEA, DPPA / TEA, or combinations thereof.

5. The preparation method according to claim 4, characterized in that, Compound IV was prepared by the following steps: S4-1. In the presence of sodium borohydride acetate and / or sodium cyanoborohydride, compound VII undergoes a reductive ammoniation reaction with compound VI to give compound V; S4-2. In the presence of tetrabutylammonium fluoride, compound V undergoes a deprotection reaction to give compound IV.

6. The preparation method according to claim 5, characterized in that, Compound VIII is prepared by the following steps: S3-1. In the presence of condensing agent B, compound X and compound IX undergo a condensation reaction to obtain compound VIII; S3-2. In the presence of base B, compound VIII undergoes a deprotection reaction to give compound VII.

7. The preparation method according to claim 6, characterized in that, The compound X is prepared by the following steps: S2-1. In the presence of an acylation catalyst and a dehydrating agent, compound X-2 and 2-(trimethylsilyl)ethanol undergo an acylation reaction to give compound X-1; S2-2. In the presence of a debenzylidene catalyst, compound X-1 undergoes a debenzylidene reaction to give compound X.

8. The preparation method according to claim 5, characterized in that, The compound VI is prepared by the following steps: Where X is S or Se; S1-1. In the presence of base C, compound VI-4 undergoes a substitution reaction with 2-bromo-6-fluorobenzonitrile to give compound VI-3; S1-2. In the presence of a reducing agent, compound VI-3 undergoes a reduction reaction to give compound IV-2; S1-3. In the presence of base D, compound VI-2 and compound C undergo a substitution reaction to give compound VI-1; S1-4. In the presence of an oxidizing agent, compound VI-1 undergoes an oxidation reaction to yield compound VI.

9. A pharmaceutical composition, characterized in that, The composition comprises: (i) the compounds as described in claims 1 and 2, or pharmaceutically acceptable salts thereof; and (ii) One or more pharmaceutically acceptable carriers, excipients and / or excipients.

10. The use of the compound as claimed in claims 1 and 2, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as claimed in claim 8, characterized in that, Used to prepare drugs for the prevention and / or treatment of infectious diseases caused by Gram-negative bacteria; Preferably, the Gram-negative bacterium is Acinetobacter baumannii.

11. An intermediate compound, characterized in that, The compounds are selected from the group consisting of:

Images