Benzoheterocycle-containing cyclic peptides against acinetobacter baumannii and use thereof

Abstract

The present application relates to a kind of anti-acinetobacter baumannii containing benzoheterocyclic ring peptide and its application. Specifically related to the compound shown in formula (I), its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug and preparation method, and in the preparation for treating or preventing the use in the preparation of drug caused by acinetobacter baumannii infection and the disease caused by acinetobacter baumannii. (I)

Description

Technical Field

[0001] This invention relates to a class of benzo[a]heterocyclic cyclic peptides containing anti-Acinetobacter baumannii and their applications. Specifically, it relates to carboxylic acid substituent compounds of formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or prodrugs, methods for their preparation, and their use in the preparation of medicaments for the treatment or prevention of infections and diseases caused by Acinetobacter baumannii. Background Technology

[0002] Acinetobacter baumannii (scientific name: Acinetobacter baumannii Commonly known as AB bacteria, this is a Gram-negative bacterium, a strictly aerobic, non-lactose-fermenting opportunistic pathogen. It lacks flagella, has low mobility, but is extremely resilient and widely found in nature. Furthermore, this bacterium has strong adhesive properties, easily adhering to various medical materials. It is also present on the skin (25%) and pharynx (7%) of healthy individuals, as well as in the conjunctiva, saliva, gastrointestinal tract, and vaginal secretions. It has been identified as an ESKAPE pathogen (Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp., Enterococcus faecalis, Staphylococcus aureus), a group of pathogens causing most nosocomial infections with high antibiotic resistance.

[0003] Treatment of Acinetobacter baumannii infection has always been a major clinical challenge because Acinetobacter baumannii readily develops resistance to various disinfectants and antibiotics, significantly impacting critically ill patients and those in ICUs. The widespread prevalence of carbapenem-resistant Acinetobacter baumannii (CRAB), multidrug-resistant Acinetobacter baumannii (MDR-AB), and multidrug-resistant Acinetobacter baumannii (XDR-AB) has become a nightmare for both doctors and patients. Therefore, the development of drugs to treat infections and diseases caused by Acinetobacter baumannii is urgently needed. Summary of the Invention

[0004] The first aspect of the present invention provides a compound of formula (I), its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, (I) R1 is -(CH2) m -C 6-12 Aryl, -(CH2) m -5-12 heteroaryl groups or -(CH2) m -3-12-membered heterocyclic alkyl; the C 6-12 Aryl, 5-12-membered heteroaryl, and 3-12-membered heterocyclic alkyl groups are each independently and optionally divided by g R. a replace; Each R a They are, independently, H, D, halogen, OH, NH2, CN, COOH, and C.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; Q1 and Q2 are independently a single bond, -O-, -C(=O)-, and -C, respectively. 1-3 Alkyl-, -C 3-6 Cycloalkyl- or -3-8-membered heterocycloalkyl-, wherein the -C 1-3 Alkyl-, -C 3-6 Cycloalkyl or 3-8-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; Each R b They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. R2, R3, R4, and R7 are independently H and C, respectively. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; R5 and R6 are independently H, D, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is N or CR x5 ; X6 is either N or CR x6 ; X7 is either N or CR x7 ; R x1 R x2 R x3 and R x4 They can be independently H, D, F, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. c replace; R x5 R x6 and R x7They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. d replace; R x8 and R x9 They can be independently H, D, F, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. e replace; Each R c R d and R e They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 alkyl; L1 is a single bond or -C(R8R9)-; R8 represents H, D, F, Cl, Br, OH, NH2, CN, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 81 replace; R9 represents H, D, F, Cl, Br, OH, NH2, CN, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 91 replace; Each R 81 They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. Each R 91 They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. Ring A is C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkenyl or 3-12 membered heterocyclic alkenyl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-8 The cycloalkenyl and 3-12 membered heterocyclic alkenyl groups are optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 10 replace; Each R 10 They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C.1-6 alkyl; Each m is independently 1, 2, 3, or 4; g is 1, 2, 3, or 4; h, h', r, and r' are each independently 0, 1, 2, or 3; The 5-12-membered heteroaryl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-12-membered heterocyclic alkyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-8-membered heterocyclic alkyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-12-membered heterocyclic alkenyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms.

[0005] In an optional embodiment of the present invention, R1 is -(CH2). m -5-10 heteroaryl, wherein the 5-10 heteroaryl is optionally surrounded by g R a Substitution; preferably, one or two ring atoms in the 5-10 membered heteroaryl group are N, and the rest are carbon atoms.

[0006] In an optional embodiment of the present invention, R1 is -(CH2). m -benzo5-membered heteroaryl, wherein the benzo5-membered heteroaryl is optionally surrounded by g R a Substitution; preferably, one or two ring atoms in the benzo5-membered heteroaryl group are N, and the rest are carbon atoms.

[0007] In an optional embodiment of the present invention, the above-mentioned R a H or C, independently respectively 1-3 alkyl.

[0008] In an optional embodiment of the present invention, the above-mentioned R a They can be H or CH3 independently, respectively.

[0009] In an optional embodiment of the present invention, the above-mentioned R1 is .

[0010] In an optional embodiment of the present invention, the above-mentioned R1 is .

[0011] In an optional embodiment of the present invention, the above-mentioned R1 is or .

[0012] In an optional embodiment of the present invention, the above-mentioned R1 is .

[0013] In an optional embodiment of the present invention, R2 is C. 1-3 Alkyl or C 1-3 Deuterated alkyl groups.

[0014] In an optional embodiment of the present invention, R2 is C. 1-3 alkyl.

[0015] In an optional embodiment of the present invention, R2 is CH3 or CD3; In an optional embodiment of the present invention, R2 is CH3.

[0016] In an optional embodiment of the present invention, Q1 and Q2 are each independently a single bond, -O-, -C(=O)-, -CH2-, cyclopropyl, cyclobutyl, or oxacyclobutyl, wherein the -CH2-, cyclopropyl, cyclobutyl, and oxacyclobutyl groups are optionally separated by 1, 2, 3, or 4 R groups. b replace.

[0017] In an optional embodiment of the present invention, the above-mentioned R b They are H, F, Cl, Br, OH, NH2, CN, and COOH, respectively.

[0018] In an optional embodiment of the present invention, Q1 and Q2 are independently a single bond, -O-, -C(=O)-, -CH2-, -CF2-, etc. , or .

[0019] In an optional embodiment of the present invention, Q1 is a single bond, -O-, -C(=O)-, -CH2-, or -CF2-.

[0020] In an optional embodiment of the present invention, Q1 is a single bond or -CH2-.

[0021] In an optional embodiment of the present invention, Q2 is a single bond or -CH2-.

[0022] In an optional embodiment of the present invention, h is 0, 1 or 2.

[0023] In an optional embodiment of the present invention, h' is 0, 1 or 2.

[0024] In an optional embodiment of the present invention, r is 0, 1 or 2.

[0025] In an optional embodiment of the present invention, the above r' is 0, 1 or 2.

[0026] In an optional embodiment of the present invention, the above for , or .

[0027] In an optional embodiment of the present invention, the above for .

[0028] In an optional embodiment of the present invention, the above for or .

[0029] In an optional embodiment of the present invention, the above for .

[0030] In an optional embodiment of the present invention, the above-mentioned R c R d and R e They can be H, F, Cl, Br, OH, NH2, CN or COOH, respectively.

[0031] In an optional embodiment of the present invention, the above-mentioned R x1 R x2 R x3 and R x4 They can be H, F, or Cl, respectively.

[0032] In an optional embodiment of the present invention, the above-mentioned R x1 R x2 R x3 and R x4 Each is independently represented by H.

[0033] In an optional embodiment of the present invention, X1 is N or CR. x1 .

[0034] In an optional embodiment of the present invention, X2 is CR. x2 .

[0035] In an optional embodiment of the present invention, X3 is CR. x3 .

[0036] In an optional embodiment of the present invention, X4 is N.

[0037] In one optional embodiment of the present invention for or .

[0038] In one optional embodiment of the present invention for .

[0039] In an optional embodiment of the present invention, the above-mentioned R x5 R x6 and R x7 They can be H, F, or Cl, respectively.

[0040] In an optional embodiment of the present invention, the above-mentioned R x5 R x6 and R x7 Each is independently represented by H.

[0041] In an optional embodiment of the present invention, X5 is CR. x5 .

[0042] In an optional embodiment of the present invention, X6 is N or CR. x6 .

[0043] In an optional embodiment of the present invention, X7 is CR. x7 .

[0044] In one optional embodiment of the present invention for , .

[0045] In one optional embodiment of the present invention for .

[0046] In an optional embodiment of the present invention, the above-mentioned R x8 and R x9 They can be H, F, or Cl, respectively.

[0047] In an optional embodiment of the present invention, the above-mentioned R x8 and R x9 Each is independently represented by H.

[0048] In an optional embodiment of the present invention, R3, R4 and R7 are respectively independently H and C. 1-3 Alkyl or C 1-3 Deuterated alkyl groups.

[0049] In an optional embodiment of the present invention, R3, R4 and R7 are each independently H.

[0050] In an optional embodiment of the present invention, R5 and R6 are respectively independently H or C. 1-3 alkyl.

[0051] In an optional embodiment of the present invention, R5 and R6 are each independently H.

[0052] In an optional embodiment of the present invention, R8 is H, D, F, Cl, Br, OH, NH2, CN, or C.1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 81 replace.

[0053] In an optional embodiment of the present invention, R8 is H, F, Cl or CH3.

[0054] In an optional embodiment of the present invention, R9 is H, D, F, Cl, Br, OH, NH2, CN, or C. 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 91 replace.

[0055] In an optional embodiment of the present invention, R9 is H, F, Cl or CH3.

[0056] In an optional embodiment of the present invention, L1 is a single bond.

[0057] In an optional embodiment of the present invention, the above compound has the structural formula (I-1): (Ⅰ-1), in, X1, X2, X3, X4, X5, X6, X7, R a R2, R8, R9, R x8 R x9 Rings A, Q1, Q2, g, h, h', r, and r' are as defined in this invention.

[0058] In an optional embodiment of the present invention, the ring A is C. 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl or 5-6 membered heterocyclic alkenyl, wherein the C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 The cycloalkenyl or 5-6 membered heterocyclic alkenyl group is optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 10 replace.

[0059] In an optional embodiment of the present invention, the aforementioned ring A is a 5-6 membered heterocyclic alkyl group; the 5-6 membered heterocyclic alkyl group is optionally surrounded by 1, 2, 3 or 4 R groups. 10 Substitution; preferably, the ring atoms in the 5-6 membered heterocyclic alkyl group are O and / or S, for example O, and the remainder are carbon atoms.

[0060] In an optional embodiment of the present invention, the above for E1, E2, and E3 are each independently -C(R) 10 )2-, -O-, -S- or -NR10 -

[0061] In an optional embodiment of the present invention, the above-mentioned R 10 They can be H, F, D, Cl, Br, OH, NH2, CN, COOH or CH3, respectively.

[0062] In an optional embodiment of the present invention, the above-mentioned R 10 They can be H, F, Cl, or Br, respectively.

[0063] In an optional embodiment of the present invention, E1, E2 and E3 are independently -CH2-, -CF2-, -CHF-, -O- or -S-, respectively.

[0064] In an optional embodiment of the present invention, E1, E2 and E3 are independently -CH2-, -CF2- or O, respectively.

[0065] In an optional embodiment of the present invention, E1, E2 and E3 are each independently -CF2- or O.

[0066] In an optional embodiment of the present invention, E1 and E3 are each independently -CH2- or O.

[0067] In an optional embodiment of the present invention, E1 and E3 are each independently O.

[0068] In an optional embodiment of the present invention, E2 is -CF2-.

[0069] In an optional embodiment of the present invention, the above compound has the structural formula (I-2): (Ⅰ-2), in, E1, E2, E3, X1, X2, X3, X4, X5, X6, X7, R a R2, R x8 R x9 Q1, Q2, h, h', r and r' are as defined in this invention.

[0070] In an optional embodiment of the present invention, the above for , , or .

[0071] In an optional embodiment of the present invention, the above for or .

[0072] In an optional embodiment of the present invention, the above for .

[0073] In an optional embodiment of the present invention, the above-mentioned compound has the structural formula (I-3): (Ⅰ-3), in, R a It is H or CH3; R2 is CH3 or CD3; X1 is CH or N; X2 is CH or N; X3 is CH or N; X4 is CH or N; X5 is CH or N; X6 is CH or N; X7 is CH or N; R x8 and R x9 They can be H, F, or Cl, respectively. Q1 is a single bond, -O-, -C(=O)-, -CH2-, or -CF2-; Q2 is a single bond or -CH2-; E1, E2 and E3 are independently -CH2-, -CF2-, -CHF-, -O- or -S-, respectively; g is 1; h is 0, 1, or 2; h' can be 0, 1, or 2; r is 0, 1, or 2; r' can be 0, 1, or 2.

[0074] In an optional embodiment of the present invention, the above-mentioned compound is selected from any of the following compounds or their tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs: , , , and .

[0075] In an optional embodiment of the present invention, the above-mentioned compound is selected from any of the following compounds or their tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs: , , , and .

[0076] In an optional embodiment of the invention, the pharmaceutically acceptable salt comprises hydrochloride or formate.

[0077] In a second aspect, the present invention provides a pharmaceutical composition characterized in that it comprises the above-described compound or its tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs.

[0078] In an optional embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0079] In an optional embodiment of the present invention, the amount of the above-mentioned compound or its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs used is a therapeutically effective amount.

[0080] In a third aspect, the present invention provides for the use of the compounds described in the first aspect above, or their tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical compositions described in the second aspect of the present invention, in the preparation of medicaments for the treatment or prevention of infections and / or diseases caused by Acinetobacter baumannii.

[0081] In an optional embodiment of the present invention, the drug for infection and / or disease caused by Acinetobacter baumannii is a drug for infection and / or disease caused by carbapenem-resistant Acinetobacter baumannii (CRAB).

[0082] In a fourth aspect, the present invention provides a method for treating or preventing infections and / or diseases caused by Acinetobacter baumannii using the compounds described in the first aspect above, or tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical compositions described in the second aspect of the present invention.

[0083] In an optional embodiment of the present invention, the infection and / or disease caused by Acinetobacter baumannii is an infection and / or disease caused by carbapenem-resistant Acinetobacter baumannii (CRAB).

[0084] In an optional embodiment of the present invention, the carbapenem-resistant Acinetobacter baumannii is resistant to one or more of the following: ampicillin / sulbactam, levofloxacin, tobramycin, cefepime, ceftazidime, imipenem, trimethoprim-sulfamethoxazole, gentamicin, ceftriaxone, ciprofloxacin, piperacillin / tazobactam, meropenem, amikacin, cefoperazone / sulbactam, and minocycline.

[0085] In a fifth aspect, the present invention provides for the use of the compound described in the first aspect above, or its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect of the present invention, in the preparation of a medicament against Acinetobacter baumannii.

[0086] In a sixth aspect, the present invention provides the use of the compounds described in the first aspect above, or their tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical compositions described in the second aspect of the present invention, in the preparation of a medicament against carbapenem-resistant Acinetobacter baumannii (CRAB).

[0087] Terms and Definitions

[0088] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0089] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0090] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0091] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0092] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0093] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0094] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0095] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0096] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0097] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0098] When the bonds of the chiral carbon in the formulas of this invention are depicted as linear, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. Examples of racemic or enantiomerically pure compounds in this document are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds denote the absolute configuration of a stereocenter.

[0099] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0100] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0101] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( The absolute configuration of a solid center is represented by a straight solid line key ( ). ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0102] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0103] In examples of the present invention, the proton can occupy two or more positions in the cyclic form of the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazolium, and 1H- and 2H-pyrazole. The tautomer form can be in equilibrium or spatially fixed in one form through appropriate substitution. For example:

[0104] Due to resonance, the hydrogen atom of nitrogen in tetrazolium can be on any of the four nitrogen atoms.

[0105] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), iodine-125 (125I) or C-14 (14C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0106] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0107] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0108] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups.

[0109] Unless otherwise specified, the terms “optional” or “optionally” refer to events or conditions described below that may but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0110] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0111] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. For example, R1 can be substituted by g Rs. a Replacement, when g is 2, 3 or 4, each R a These are independent options, and they can be the same or different.

[0112] Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds. Additionally, when polycyclic (fused, spirocyclic, or bridged) rings are substituted with substituents, it means that a hydrogen atom on each ring can potentially be substituted.

[0113] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0114] Unless otherwise specified, the term "C"1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0115] The term "halogenated" is used interchangeably with the term "halogenated" when used alone or as part of other substituents.

[0116] Unless otherwise specified, "halogenated alkyl" or "halogen-substituted alkyl" means a saturated aliphatic hydrocarbon group comprising a specific number of carbon atoms, branched and straight-chained and substituted with one or more halogens.

[0117] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to an alkyl group consisting of 1 to 6 carbon atoms that is attached to the rest of the molecule by one oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

[0118] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to an alkyl group consisting of 1 to 3 carbon atoms that is attached to the rest of the molecule by one oxygen atom. The C 1-3 Alkoxy groups include C 1-2 C 2-3 C3 and C2 alkoxy groups, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0119] Unless otherwise specified, the term "C" 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-12 Cycloalkyl groups include C 3-10 C 3-8 C3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0120] Unless otherwise specified, the term "C" 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. The C 3-8 Cycloalkyl groups include C 3-6 C 3-5 C 4-8 C 4-6 C 4-5 C 5-8 Or C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0121] Unless otherwise specified, the term "C" 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which can be monocyclic or bicyclic. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0122] Unless otherwise specified, the term "C" 3-8 "Cycloalkenyl" alone or in combination with other terms refers to a partially unsaturated cyclic group consisting of 3 to 8 ring atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings, and any ring in this system is non-aromatic.

[0123] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0124] Unless otherwise specified, the term "3-12 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 3 to 12 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with respect to "3-12 membered heterocyclic alkyl," the heteroatom may occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. For example, 3-12 membered heterocyclic alkyl groups include, but are not limited to, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 3-10-membered, 3-8-membered, 4-6-membered, etc. Examples of “3-12 membered heterocyclic alkyl” include, but are not limited to, oxetyl, aziridine, oxetyl, thioheterocyclic, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, and hexahydropyridazinyl.

[0125] Unless otherwise specified, the term "4-8 membered heterocyclic alkyl" or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, with respect to "6-8 membered heterocyclic alkyl," the heteroatom may occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. For example, 4-8 membered heterocyclic alkyl groups include, but are not limited to, 4-, 5-, 6-, 7-, 8-, and 4-6 membered groups. Examples of 4-8 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, and hexahydropyridazinyl.

[0126] Unless otherwise specified, the term "3-12 membered heterocyclic alkenyl" on its own or in combination with other terms refers to a partially unsaturated cyclic group consisting of 3 to 12 ring atoms comprising at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings, and any ring in this system is non-aromatic.

[0127] Unless otherwise specified, the terms "5-12-membered heteroaryl ring" and "5-12-membered heteroaryl" are used interchangeably in this invention. The term "5-12-membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic, or fused tricyclic system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-12-membered heteroaryl group can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-12-membered heteroaryl groups include 5-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered, and 6-membered heteroaryl groups, etc. Examples of the 5-12 heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), and thiazolyl (including 2-thiazolyl, 4-thiazolyl, etc.). (e.g., azole and 5-thiazolyl), furanyl (including 2-furanyl and 3-furanyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1-pyridyl), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl), benzothiazolyl (including 5-benzothiazolyl), purinyl, benzimidazolyl (including 2-benzimidazolyl), benzoxazolyl, indole (including 5-indole), isoquinolinyl (including 1-isoquinolinyl and 5-isoquinolinyl), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl), or quinolinyl (including 3-quinolinyl and 6-quinolinyl).

[0128] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" are used interchangeably in this invention. The term "5-6-membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6-membered heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl, and 5-isooxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), and furanyl (including 2-furanyl and 3-furanyl). Thiophene (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0129] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0130] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0131] Unless otherwise specified, the term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0132] Unless otherwise specified, the term “therapeutic effective amount” means the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0133] The term "treatment" and other similar synonyms used in this article include the following meanings: (i) To prevent the occurrence of diseases or conditions in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it; (ii) To suppress a disease or symptom, that is, to curb its development; (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or (iv) To alleviate the symptoms caused by the disease or condition.

[0134] The abbreviations in this invention are defined as follows: DCM represents dichloromethane; DMF represents... N , N - Dimethylformamide; Fmoc represents 9-fluorenylmethoxycarbonyl; Boc represents tert-butyloxycarbonyl; Trp represents tryptophan; Pip represents piperidine; DIEA represents N,N-diisopropylethylamine; Lys represents lysine; Orn represents ornithine; HATU represents benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; NMP represents N-methylpyrrolidone; MTBE represents methyl tert-butyl ether; HFIP represents hexafluoroisopropanol; 2-CTCreisn represents 2-chlorotriphenylmethyl chloride resin; DMAP represents 4-dimethylaminopyridine; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride.

[0135] Beneficial effects

[0136] According to embodiments of the present invention, the present invention has at least one of the following technical effects: This invention provides a novel compound, its tautomers, stereoisomers, and pharmaceutically acceptable salts, which exhibit good antibacterial activity against Acinetobacter baumannii and carbapenem-resistant Acinetobacter baumannii, excellent pharmacokinetic properties, good efficacy and drug-likeness, and good safety. These compounds can be used to effectively treat or prevent infections and diseases caused by Acinetobacter baumannii and carbapenem-resistant Acinetobacter baumannii. The compounds of this invention have a strong inhibitory effect on Acinetobacter baumannii and carbapenem-resistant Acinetobacter baumannii. Detailed Implementation

[0137] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0138] Preparation of 3-{[(7S,10S,13S)-17-bromo-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylpyridino[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadec-13-yl]methyl}-1H-indole-1-carboxylic acid tert-butyl ester (intermediate A1):

[0139] The synthesis steps are as follows: Table 1:

[0140] 1.1 Operating Steps: 1.1.1 Weigh 60 g of 2-CTC reisn (1.197 mmol / g) and add it to the reactor. Add 10 V DCM to swell the resin, add amino acids (10 g), and 4.0 eq. DIEA. Stir for 3 h, then add MeOH and stir for 0.5 h.

[0141] 1.1.2 Drain and rinse 6 times with 10V DMF, each time with nitrogen agitation for 30 seconds.

[0142] 1.1.3 Add 10V 20% Pip / DMF to the reactor (1st: 10min; 2nd: 10min) 2.

[0143] 1.1.4 After the reaction was completed, the resin was washed 6 times with 10V DMF. The ninhydrin / tetrachlorobenzoquinone test was positive.

[0144] 1.1.5 Weigh 3.0 eq amino acids, 4.0 eq DIEA, and 10 VDMF and add them to the reactor. Then add 3 eq HATU and N2 and agitate for 1 hour.

[0145] 1.1.6 After the reaction was completed, the ninhydrin / tetrachlorobenzoquinone test was negative. The reaction solution was removed, and the resin was washed 6 times with 10V DMF.

[0146] 1.1.7 Repeat steps 1.1.2-1.1.5 according to Table 1 to condense the above amino acids 1-3 in sequence.

[0147] 1.1.8 Wash the resin twice with MeOH and twice with MTBE, then dry the resin to a fine sand-like state to obtain compound A1-4.

[0148] 1.2 Reductive amination:

[0149] 1.2.1 Weigh the peptide resin (A1-4) and place it in a flask. Add 10V of 49.7% trimethyl orthoformate / 49.7% NMP / 0.6% acetic acid and 1.5 eq of compound A1-5. Stir at room temperature for 3 hours. Add 10 eq of Na(CN)BH3 and stir at room temperature for 10 hours (if the reaction is not complete, the time needs to be extended).

[0150] 1.2.2 Drain and rinse 6 times with 10V DMF, each time with nitrogen agitation for 30 seconds.

[0151] 1.2.3 Add 10V 20% Pip / DMF to the reactor (1st: 10min; 2nd: 10min) 2.

[0152] 1.2.4 After the reaction was completed, the resin was washed 6 times with 10V DMF. The ninhydrin / tetrachlorobenzoquinone test was positive.

[0153] 1.2.5 Wash the resin twice with MeOH and twice with MTBE, then dry the resin to a fine sand-like state to obtain compound A1-6.

[0154] 1.3 Cutting, pyrolysis, and condensation closure: 1.3.1 Weigh the peptide resin (compound A1-6) into a centrifuge tube, add 10V 30% HFIP / 70% DCM reagent, lyse at room temperature for 2.5 hours, and filter. Dry the filtrate by rotary evaporation to obtain the crude product.

[0155] 1.3.2 The crude product was dissolved in 10V DMF, and 1.5 eq HATU and 2 eq DIEA were added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched in ice water, extracted three times with ethyl acetate, and three times with saturated brine. After drying with anhydrous sodium sulfate, the product was concentrated and evaporated to dryness. The intermediate product A1 was obtained by column chromatography (EA:PE = 80%~100%).

[0156] Example 1: Preparation of target compound 1

[0157] 4-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylpyrido[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl}-2,3-dihydro-1-benzofuran-7-carboxylic acid (Target compound 1)

[0158] The synthetic route for compound 1 is shown below:

[0159] Step 1: Synthesis of methyl 4-bromo-2-[(prop-2-en-1-yl)oxy]benzoate (compounds 1-2)

[0160] Methyl 4-bromo-2-hydroxybenzoate (5 g, 21.6 mmol) and potassium carbonate (6 g, 43.2 mmol) were dissolved in N,N-dimethylformamide (60 mL), and 3-bromo-1-propene (5.2 g, 43.2 mmol) was added. The mixture was reacted at 40°C for 3 hours. The reaction solution was diluted with water (400 mL), extracted with ethyl acetate (150 mL × 3), and the organic layers were combined. The organic phase was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give compounds 1-2.

[0161] LC-MS, M / Z (ESI): 271.1 [M+H] +

[0162] Step 2: Synthesis of methyl 4-bromo-2-hydroxy-3-(prop-2-en-1-yl)benzoate (compounds 1-3)

[0163] Compounds 1-2 (3.5 g, 12.9 mmol) were dissolved in... N In methylpyrrolidone (35 mL), the mixture was heated to 190°C under argon protection and stirred for 6 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Purification was performed by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) to give compounds 1-3 (2.1 g, yield: 60.0%).

[0164] LC-MS, M / Z (ESI): 271.0 [M+H] +

[0165] Step 3: Synthesis of methyl 4-bromo-2-hydroxy-3-(2-oxoethyl)benzoate (compounds 1-4)

[0166] Compounds 1-3 (2.1 g, 7.7 mmol) were dissolved in tetrahydrofuran (42 mL) and water (14 mL). Under argon protection, potassium osmium tetroxide dihydrate (285 mg, 0.8 mmol) and sodium periodate (6.6 g, 30.8 mmol) were added, and the reaction was carried out at 20°C for 2 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to give compounds 1-4.

[0167] LC-MS, M / Z (ESI): 273.0 [M+H] +

[0168] Step 4: Synthesis of methyl 4-bromo-2-hydroxy-3-(2-hydroxyethyl)benzoate (compounds 1-5)

[0169] Compounds 1-4 (1.6 g, 5.8 mmol) were dissolved in anhydrous methanol (30 mL), and sodium borohydride (439 mg, 11.6 mmol) was added at 0°C. The mixture was then heated to 20°C and reacted for 2 hours. Saturated ammonium chloride (30 mL) and water (30 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1) to give compounds 1-5.

[0170] LC-MS, M / Z (ESI): 274.9 [MH] -

[0171] Step 5: Synthesis of methyl 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylate (compounds 1-6)

[0172] Compounds 1-5 (1.3 g, 4.7 mmol) and triphenylphosphine (2.47 g, 9.4 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to 0°C. Diisopropyl azodicarboxylate (1.9 g, 9.4 mmol) was added under argon protection, and the reaction was carried out at 20°C for 2 hours. The reaction mixture was diluted with water (60 mL), extracted with ethyl acetate (20 mL × 3), and the organic layers were combined. The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Purification by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 3:1) yielded compounds 1-6.

[0173] LC-MS, M / Z (ESI): 258.7 [M+H] +

[0174] Step 6: Synthesis of 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid (compounds 1-7)

[0175] Compounds 1-6 (1 g, 3.9 mmol) were dissolved in tetrahydrofuran (15 mL), methanol (5 mL), and water (5 mL), and reacted at 20°C for 5 hours. The reaction mixture was diluted with water (50 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to give compounds 1-7.

[0176] LC-MS, M / Z (ESI): 244.7 [M+H] +

[0177] Step 7: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-2,3-dihydro-1-benzofuran-7-carboxylic acid (compounds 1-8)

[0178] Compounds 1-7 (500 mg, 2.1 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (790 mg, 4.2 mmol) were dissolved in dioxane (5 mL). Potassium acetate (1.07 g, 4.8 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (150 mg, 0.2 mmol) were added. The mixture was purged three times with argon gas and heated to 100°C for 16 hours. The reaction mixture was diluted with water (50 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 0:1) to give compounds 1-8.

[0179] LC-MS, M / Z (ESI): 290.9 [M+H] +

[0180] Step 8: Synthesis of 4-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylpyridino[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl]-2,3-dihydro-1-benzofuran-7-carboxylic acid (compounds 1-9)

[0181] Intermediate A1 (300 mg, 0.29 mmol) and compounds 1-8 (165 mg, 0.57 mmol) were dissolved in dioxane (5 mL) and water (1 mL). Potassium carbonate (140 mg, 1.02 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (38 mg, 0.06 mmol) were added. The mixture was purged three times with argon and heated to 100°C for 16 hours. The reaction solution was diluted with water (50 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compounds 1-9.

[0182] LC-MS, M / Z (ESI): 1133.5 [M+H] +

[0183] Step 9: Synthesis of Compound 1

[0184] Compounds 1-9 (220 mg, 0.19 mmol) were dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added. The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was dissolved in water (5 mL) and stirred for 16 hours. The aqueous solution was then concentrated to dryness under reduced pressure. The crude product was then purified by preparative separation (chromatographic column: YMC-Triart Prep C18 7μm 30mm). (40 cm; Mobile phase A: 0.05% hydrochloric acid; Mobile phase B: acetonitrile; Flow rate: 42 ml / min) to obtain the hydrochloride salt of compound 1.

[0185] LC-MS, M / Z (ESI): 832.8 [M+H] +

[0186] Example 2: Preparation of target compound 2

[0187] 7-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylpyridino[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl}-2,2-difluoro-2H-1,3-benzodioxacyclopenten-4-carboxylic acid (Target compound 2)

[0188] The synthetic route for compound 2 is shown below:

[0189] Step 1: Synthesis of 7-bromo-2,2-difluoro-2H-1,3-benzodioxane-4-carboxylic acid (compound 2-2)

[0190] Under argon protection, diisopropylamine (212.5 mg, 2.1 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to -90°C, and n-butyllithium (0.85 mL, 2.1 mmol) was added. The reaction mixture was stirred at -90°C for 15 minutes, followed by the addition of a solution of 4-bromo-2,2-difluoro-2H-1,3-benzodioxane (compound 2-1) (500 mg, 2.1 mmol) in anhydrous tetrahydrofuran (2 mL), and stirred at -90°C for 1 hour. The reaction mixture was then poured into dry ice and stirred for 15 minutes. The mixture was diluted with water (50 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (1 M). Extraction was performed with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to give compound 2-2.

[0191] LC-MS, M / Z (ESI): 280.7 [M+H] +

[0192] Step 2: Synthesis of 7-borono-2,2-difluoro-2H-1,3-benzodioxane-4-carboxylic acid (compounds 2-3)

[0193] Compound 2-2 (230 mg, 0.82 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborane (417 mg, 1.64 mmol) were dissolved in dioxane (5 mL). Potassium acetate (241 mg, 2.46 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (62 mg, 0.08 mmol) were added. The mixture was purged three times with argon gas and heated to 100°C for 16 hours. The reaction mixture was diluted with water (50 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 0:1) to give compound 2-3.

[0194] LC-MS, M / Z (ESI): 244.8 [MH] -

[0195] Step 3: Synthesis of 7-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylpyridino[2,3-b][1,5,8,11,14]benzothiotetraazacycloheptadecen-17-yl]-2,2-difluoro-2H-1,3-benzodioxacyclopenten-4-carboxylic acid (compound 2-4)

[0196] Intermediate A1 (300 mg, 0.29 mmol) and compounds 2-3 (143 mg, 0.58 mmol) were dissolved in dioxane (5 mL) and water (1 mL). Potassium carbonate (140 mg, 1.02 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (38 mg, 0.06 mmol) were added. The mixture was purged three times with argon and heated to 100°C for 16 hours. The reaction solution was diluted with water (50 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 2-4.

[0197] LC-MS, M / Z (ESI): 1171.6 [M+H] +

[0198] Step 4: Synthesis of Compound 2

[0199] Compound 2-4 (200 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added. The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was dissolved in water (5 mL) and stirred for 16 hours. The aqueous solution was then concentrated to dryness under reduced pressure. The crude product was then purified by preparative separation (chromatographic column: YMC-Triart Prep C18 7μm 30mm). (40 cm; Mobile phase A: 0.05% hydrochloric acid; Mobile phase B: acetonitrile; Flow rate: 42 ml / min) to obtain the hydrochloride salt of compound 2.

[0200] LC-MS, M / Z (ESI): 871.5 [M+H]+

[0201] Example 3: Preparation of target compound 3

[0202] 7-{(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-13-[(1H-indol-3-yl)methyl]-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrodipyrido[2,3-b:4',3'-p][1,5,8,11,14]thiotetraazacycloheptadecen-17-yl}-2,2-difluoro-2H-1,3-benzodioxane-penten-4-carboxylic acid (target compound 3)

[0203] The synthetic route for compound 3 is shown below:

[0204] Step 1: Tert-butyl 3-{[(7S,10S,13S)-17-bromo-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecyldipyrido[2,3-b:4',3'-p][1,5,8,11,14]thiotetraazacycloheptadecen-13-yl]methyl}-1H-indole-1-carboxylic acid ester (compound 3-1) was prepared according to the method for intermediate A1.

[0205] Step 2: Synthesis of 7-[(7S,10S,13S)-10-{4-[(tert-butoxycarbonyl)amino]butyl}-7-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-12-methyl-8,11,14-trioxo-5,6,7,8,9,10,11,12,13,14,15,16-dodecylhydrodipyrido[2,3-b:4',3'-p][1,5,8,11,14]thiotetraazacycloheptadecen-17-yl]-2,2-difluoro-2H-1,3-benzodioxane-penten-4-carboxylic acid (compound 3-2)

[0206] Compounds 3-1 (600 mg, 0.58 mmol) and 2-3 (286 mg, 1.16 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Potassium carbonate (280 mg, 2.04 mmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (72 mg, 0.12 mmol) were added. The mixture was purged three times with argon and heated to 100°C for 16 hours. The reaction solution was diluted with water (50 mL) and the pH was adjusted to 7 with dilute hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (20 mL × 3), the organic layers were combined, washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1) to give compound 3-2.

[0207] LC-MS, M / Z (ESI): 1172.6 [M+H] +

[0208] Step 3: Synthesis of Compound 3

[0209] Compound 3-2 (120 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.6 mL) was added. The mixture was stirred at 20°C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was dissolved in water (5 mL) and stirred for 16 hours. The aqueous solution was then concentrated to dryness under reduced pressure. The crude product was then purified by preparative separation (chromatographic column: YMC-Triart Prep C18 7μm 30mm). (40 cm; Mobile phase A: 0.05% hydrochloric acid; Mobile phase B: acetonitrile; Flow rate: 42 ml / min) to obtain the hydrochloride salt of compound 3.

[0210] LC-MS, M / Z (ESI): 872.0 [M+H] +

[0211] Example 4: Preparation of target compound 4

[0212] 7-{(13S,16S,19S)-16-(4-aminobutyl)-19-(3-aminopropyl)-13-[(1H-indol-3-yl)methyl]-14-methyl-12,15,18-trioxo-10,11,12,13,14,15,16,17,18,19,20,21-dodecylhydropyrazino[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecen-9-yl}-2,2-difluoro-2H-1,3-benzodioxacyclopenten-4-carboxylic acid (Target compound 4)

[0213] The synthetic route for compound 4 is shown below:

[0214]

[0215] Step 1: Tert-butyl 3-{[(13S,16S,19S)-9-bromo-16-{4-[(tert-butyloxycarbonyl)amino]butyl}-19-{3-[(tert-butyloxycarbonyl)amino]propyl}-14-methyl-12,15,18-trioxo-10,11,12,13,14,15,16,17,18,19,20,21-dodecylhydropyrazino[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecen-13-yl]methyl}-1H-indole-1-carboxylic acid ester (compound 4-1) was prepared according to the method for intermediate A1.

[0216]

[0217] LC-MS,M / Z(ESI):1050.4,1052.4[M+H] +

[0218] Step 2: Synthesis of tert-butyl 3-({(13S,16S,19S)-16-{4-[(tert-butyloxycarbonyl)amino]butyl}-19-{3-[(tert-butyloxycarbonyl)amino]propyl}-9-[2,2-difluoro-7-(methoxycarbonyl)-2H-1,3-benzodioxane-4-yl]-14-methyl-12,15,18-trioxo-10,11,12,13,14,15,16,17,18,19,20,21-dodecylhydropyrazino[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecene-13-yl}methyl)-1H-indole-1-carboxylic acid ester (compound 4-2)

[0219] Compound 4-1 (100 mg, 0.1 mmol), methyl 2,2-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2H-1,3-benzodioxane-4-carboxylate (compound 4-4) (65.2 mg, 0.19 mmol), Pd(dtbpf)Cl2 (6.46 mg, 0.01 mmol), potassium carbonate (39.40 mg, 2.85 mmol), toluene (8 mL), and water (0.4 mL) were added sequentially to a 50 mL single-necked flask. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was complete, the mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 1:0-9:1) to obtain product compound 4-2.

[0220] LC-MS, M / Z (ESI): 1186.50 [M+H] +

[0221] Step 3: Synthesis of 7-[(13S,16S,19S)-16-{4-[(tert-butoxycarbonyl)amino]butyl}-19-{3-[(tert-butoxycarbonyl)amino]propyl}-13-{[1-(tert-butoxycarbonyl)-1H-indol-3-yl]methyl}-14-methyl-12,15,18-trioxo-10,11,12,13,14,15,16,17,18,19,20,21-dodecylhydropyrazino[2,3-b][1,5,8,11,14]benzothiatetrazene-9-yl]-2,2-difluoro-2H-1,3-benzodioxane-penten-4-carboxylic acid (compound 4-3)

[0222] Compound 4-2 (110 mg, 0.09 mmol), methanol (2 mL), tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (7.78 mg, 0.19 mmol) dissolved in water (1 mL) were added sequentially to a 50 mL single-necked flask. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the organic solvent was evaporated to dryness, and water (3 mL), pH adjusted to 6 with 1N hydrochloric acid, and ethyl acetate (3 mL) were added. 3) Extraction: The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 1:0-8:1) to obtain product compound 4-3.

[0223] LC-MS, M / Z (ESI): 1172.50 [M+H] +

[0224] Step 4: Synthesis of target compound 4

[0225] Compound 4-3 (80 mg, 0.07 mmol) and dichloromethane (5 mL) were added sequentially to a 50 mL single-necked flask. The mixture was cooled to 0°C in an ice bath, and trifluoroacetic acid (1 mL) was added. The reaction was carried out at 0°C for 10 min, followed by reaction at room temperature for 2 h. The reaction mixture was evaporated to dryness, and water (5 mL) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the crude product was concentrated. The crude product was then subjected to reverse-phase chromatography (column: YMC-Triart Prep C18, S-12nm, S-7μm, 50mm). 40 cm; Solvent: A = water + 0.1% formic acid, B = acetonitrile; gradient: 5%-95%, 17 min) to obtain the formate salt of product target compound 4.

[0226] LC-MS, M / Z (ESI): 872.39 [M+H] +

[0227] The preparation methods for the following compounds are the same as those in Examples 1-4: Table 2

[0228]

[0229] Biological testing: Test Example 1: Determination of Minimum Inhibitory Concentration (MIC) of Antibiotics The in vitro antibacterial activity of antibiotics was tested using a minimum inhibitory concentration (MIC) assay, with Acinetobacter baumannii as the test bacterium. Acinetobacter baumannii The test compound (ATCC19606) was purchased from Beijing Beina Chuanglian Biotechnology Research Institute, catalog number BNCC337173; the culture medium was sterile cation-regulated MH II broth (BD, catalog number 212322). The test compound was dissolved in cation-regulated MH II broth to prepare a working solution at a maximum concentration of 64 μg / mL. This solution was then serially diluted twofold with the culture medium. The diluted media were transferred to sterile 96-well plates, 100 μL per well, with control wells containing no compound. Subsequently, Acinetobacter baumannii was prepared to a final concentration of ~1×10⁻⁶ using the culture medium. 6A working solution of CFU / mL was added to each well of a 96-well plate, 100 μL per well. Blank wells containing neither the compound nor bacteria were also included. After mixing, the 96-well plate was incubated at 37 ℃ for 16 hours. After incubation, the 96-well plate was transferred to a microplate reader (Molecular Devices, SpectraMax iD5) to measure the absorbance at OD600 of each well. The bacterial growth inhibition rate at different compound concentrations was calculated. The lowest concentration at which the compound showed an inhibition rate ≥80% was defined as the minimum inhibitory concentration (MIC) of that compound.

[0230] Table 3: Minimum inhibitory concentrations of the compounds of this invention against Acinetobacter baumannii

[0231] Testing revealed that the compound of this invention has a strong inhibitory effect on Acinetobacter baumannii.

[0232] Test Example 2: MIC detection of antibiotics against clinically resistant strains

[0233] The clinical strains used in this test were all carbapenem-resistant Acinetobacter baumannii. Acinetobacter baumannii (CRAB) All clinical strains tested were obtained from the Shanghai Public Health Clinical Center, the First Affiliated Hospital of Jilin University, and the Phage Research Institute of the Second Affiliated Hospital of Hainan Medical University. Each number corresponds to an independent isolate. The tolerance of each clinical strain is shown in Tables 4 and 5, where R represents tolerance, I represents moderate tolerance, S represents sensitivity, and / represents undetectable. The tolerance test method refers to "Standards for the Implementation of Antimicrobial Susceptibility Testing; 18th Edition Informational Supplement", "M100S: Performance Standards for Antimicrobial Susceptibility Testing", and "M100-S25: ​​Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement".

[0234] Clinical strains ABb25035696 and ABb25037663 were derived from sputum of patients with pulmonary infections at the Shanghai Public Health Clinical Center; clinical strain AB250831SE000021 was derived from ascites of patients with abdominal infections at the First Affiliated Hospital of Jilin University; and clinical strain AB033038 was derived from sputum of patients with pulmonary infections at the Second Affiliated Hospital of Naval Medical University.

[0235] The bacterial culture medium was sterile cationic-regulated MH II broth (BD, catalog number 212322), supplemented with 20% (v / v) human serum (GeminiBio, SKU 100-512-100). The test compound was dissolved in the culture medium to prepare a working solution at a maximum concentration of 64 μg / mL. This solution was then serially diluted twofold with the culture medium. The diluted solution was transferred to sterile 96-well plates, 100 μL per well, with control wells containing the compound. Subsequently, the clinical strain was prepared to a final concentration of ~1×10⁻⁶ using the culture medium. 6 The working solution (CFU / mL) was added to each well of a 96-well plate at a concentration of 100 μL. Blank wells containing neither the compound nor bacteria were also included. After mixing, the 96-well plate was incubated at 37 °C for 16 hours. After incubation, the 96-well plate was transferred to a microplate reader (Molecular Devices, SpectraMax iD5) to measure the absorbance at OD600 of each well. The inhibition rate of bacterial growth at different compound concentrations was calculated. The lowest concentration at which the compound achieved an inhibition rate ≥80% was defined as the minimum inhibitory concentration (MIC) of the compound. The test results are shown in Table 6.

[0236] Table 4: Explanation of Drug Resistance of Strains

[0237] Table 5: Description of Drug Resistance of Strains

[0238] Table 6: Minimum inhibitory concentrations of compounds against clinically resistant Acinetobacter baumannii

[0239] The results are shown in Table 6. The compounds of this invention have a strong inhibitory effect on carbapenem-resistant Acinetobacter baumannii.

[0240] Test Example 3: Plasma Precipitation MEC Analysis

[0241] (1) Human plasma preparation: Blood was collected from healthy volunteers into heparin sodium collection tubes. The tubes were inverted and mixed multiple times to prevent clotting. The plasma was centrifuged at 2500 g at room temperature for 10 min. The supernatant was then transferred to a new centrifuge tube for later use. (2) Weigh approximately 10 mg of compound 3 hydrochloride and add an appropriate amount of PBS solution to prepare a stock solution with a concentration of 5 mM. (3) Using PBS as a diluent, prepare a series of working solutions with final concentrations of 4000, 3600, 3200, 2800, 2400, 2000, 1600, 1200 and 800 μM, with 500 μL for each concentration; (4) For each compound, use one 96-well plate. According to the following plate design, transfer 50 μL of the diluted compound solution from the previous step into a new 96-well flat-bottom culture plate. The blank control group is replaced with an equal volume of PBS instead of the working solution of the test compound. (5) Add fresh human plasma into each well sequentially, 50 μL per well, and mix on a mixer for 2 min. (6) Detect the absorbance of each well at OD362 nm using an ELISA reader; (7) MEC determination: The highest compound concentration corresponding to the difference between the OD value of each well and the baseline value OD(0) is ≥0.05, which is the minimum effect concentration (MEC) of the compound on human plasma.

[0242] Table 7: Minimum Effective Concentration (MEC) of Plasma Precipitation in Human Blood

[0243] The results are shown in Table 7. The compounds of the present invention have excellent safety.

Claims

1. The compound shown in formula (Ⅰ), （Ⅰ）， Its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs, R1 is -(CH2) m -C 6-12 Aryl, -(CH2) m -5-12 heteroaryl groups or -(CH2) m -3-12-membered heterocyclic alkyl; the C 6-12 Aryl, 5-12-membered heteroaryl, and 3-12-membered heterocyclic alkyl groups are each independently and optionally divided by g R. a replace; Each R a They are, independently, H, D, halogen, OH, NH2, CN, COOH, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; Q1 and Q2 are independently a single bond, -O-, -C(=O)-, and -C, respectively. 1-3 Alkyl-, -C 3-6 Cycloalkyl- or -3-8-membered heterocycloalkyl-, wherein the -C 1-3 Alkyl-, -C 3-6 Cycloalkyl or 3-8-membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; Each R b They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. R2, R3, R4, and R7 are independently H and C, respectively. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; R5 and R6 are independently H, D, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is N or CR x4 ; X5 is either N or CR x5 ; X6 is either N or CR x6 ; X7 is either N or CR x7 ; R x1 R x2 R x3 and R x4 They can be independently H, D, F, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. c replace; R x5 R x6 and R x7 They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. d replace; R x8 and R x9 They can be independently H, D, F, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 Alkyl, the C 1-6 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. e replace; Each R c R d and R e They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 alkyl; L1 is a single bond or -C(R8R9)-; R8 represents H, D, F, Cl, Br, OH, NH2, CN, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 81 replace; R9 represents H, D, F, Cl, Br, OH, NH2, CN, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally surrounded by 1, 2, 3 or 4 R groups. 91 replace; Each R 81 They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. Each R 91 They can be H, D, F, Cl, Br, OH, NH2, CN, or COOH, respectively. Ring A is C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-8 Cycloalkenyl or 3-12 membered heterocyclic alkenyl, wherein the C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-8 The cycloalkenyl and 3-12 membered heterocyclic alkenyl groups are optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 10 replace; Each R 10 They can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH, or C. 1-6 alkyl; Each m is independently 1, 2, 3, or 4; g is 1, 2, 3, or 4; h, h', r, and r' are each independently 0, 1, 2, or 3; The 5-12-membered heteroaryl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-12-membered heterocyclic alkyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-8-membered heterocyclic alkyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms; the 3-12-membered heterocyclic alkenyl group has 1, 2, 3, or 4 ring atoms independently selected from O, S, and N heteroatoms, with the remainder being carbon atoms.

2. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: (1a) R1 is -(CH2) m -5-10 heteroaryl, wherein the 5-10 heteroaryl is optionally surrounded by g R a Substitution; preferably, one or two ring atoms in the 5-10 membered heteroaryl group are N, and the remainder are carbon atoms; (2a) Each R a H or C, independently respectively 1-3 alkyl; (3a) R2 is C 1-3 Alkyl or C 1-3 Deuterated alkyl; preferably C 1-3 alkyl; (4a) Q1 and Q2 are independently single bonds, -O-, -C(=O)-, -CH2-, cyclopropyl, cyclobutyl, or oxacyclobutyl, respectively, wherein the -CH2-, cyclopropyl, cyclobutyl, and oxacyclobutyl groups are optionally separated by 1, 2, 3, or 4 R groups. b replace; (5a) Each R b They can be independently H, F, Cl, Br, OH, NH2, CN, or COOH; (6a)R c R d and R e They can be independently H, F, Cl, Br, OH, NH2, CN, or COOH; (7a)R x1 R x2 R x3 and R x4 They can be H, F, or Cl, respectively, independently. (8a) X1 is N or CR x1 ; (9a)X2 is CR x2 ; (10a)X3 is CR x3 ; (11a) X4 is N; (12a)R x5 R x6 and R x7 Each can be independently H, F, or Cl; preferably H; (13a)X5 is CR x5 ; (14a) X6 is N or CR x6 ; (15a)X7 is CR x7 ; (16a)R x8 and R x9 Each can be independently H, F, or Cl; preferably H; (17a) R3, R4 and R7 are H and C respectively. 1-3 Alkyl or C 1-3 Deuterated alkyl groups; (18a) R5 and R6 are independently H or C. 1-3 alkyl; (19a) Ring A is C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 Cycloalkenyl or 5-6 membered heterocyclic alkenyl, wherein the C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 3-6 The cycloalkenyl and 5-6 membered heterocyclic alkenyl groups are optionally surrounded by 1, 2, 3, 4, 5 or 6 R groups. 10 Substitution; preferably, ring A is a 5-6 membered heterocyclic alkyl group; the 5-6 membered heterocyclic alkyl group is optionally replaced by 1, 2, 3 or 4 R groups. 10 Substitution; more preferably, the cyclic atom in the 5-6 membered heterocyclic alkyl group is O and / or S, for example O, and the remainder is carbon atom; (20a) Each R 10 Each of the following can be independently H, F, D, Cl, Br, OH, NH2, CN, COOH or CH3; preferably H, F, Cl or Br.

3. The compound according to any one of claims 1-2, characterized in that, The compound satisfies one or more of the following conditions: (1b) R1 is -(CH2) m -benzo5-membered heteroaryl, wherein the benzo5-membered heteroaryl is optionally surrounded by g R a Substitution; preferably, one or two ring atoms in the benzo5-membered heteroaryl group are N, and the remainder are carbon atoms; (2b) Each R a They can be H or CH3 independently, respectively; (3b) R2 is CH3 or CD3; (4b) Q1 and Q2 are independently single bonds, -O-, -C(=O)-, -CH2-, -CF2-, respectively. , or ; (5b) h is 0, 1, or 2; (6b) h' is 0, 1, or 2; (7b) r is 0, 1, or 2; (8b) r' is 0, 1, or 2; (9b)R x1 R x2 R x3 and R x4 Each is independently represented by H; (10b) R3, R4 and R7 are each independently H; (11b) R5 and R6 are each independently H; (12b) for E1, E2, and E3 are each independently -C(R) 10 )2-, -O-, -S- or -NR 10 - 4. The compound according to any one of claims 1-3, characterized in that, The compound satisfies one or more of the following conditions: (1c) R1 is ; (2c) Q1 is a single bond, -O-, -C(=O)-, -CH2- or -CF2-; preferably a single bond or -CH2-; (3c) Q2 is a single bond or -CH2-; (4c) R8 is H, D, F, Cl, Br, OH, NH2, CN or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 81 replace; (5c) R9 is H, D, F, Cl, Br, OH, NH2, CN or C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. 91 replace; (6c) E1, E2 and E3 are independently -CH2-, -CF2-, -CHF-, -O- or -S-; preferably -CH2-, -CF2- or O.

5. The compound according to any one of claims 1-4, characterized in that, The compound satisfies one or more of the following conditions: (1d)R1 is or ; (2d) R8 is H, F, Cl or CH3; (3d) R9 is H, F, Cl or CH3; (4d) L1 is a single bond; (5d) for , ,or Preferred ; (6d) for or Preferred ; (7d) for or ; (8d) for or .

6. The compound according to any one of claims 1-5, characterized in that, The compound has the structural formula (Ⅰ-1): （Ⅰ-1）。 7. The compound according to any one of claims 1-6, characterized in that, The compound has the structural formula (Ⅰ-2): （Ⅰ-2）。 8. The compound according to claim 7, characterized in that, for , , or ; Preferred or .

9. The compound according to any one of claims 1-8, characterized in that, The compound has the structural formula (Ⅰ-3): （Ⅰ-3）， in, R a It is H or CH3; R2 is CH3 or CD3; X1 is CH or N; X2 is CH or N; X3 is CH or N; X4 is CH or N; X5 is CH or N; X6 is CH or N; X7 is CH or N; R x8 and R x9 They can be H, F, or Cl, respectively, independently. Q1 is a single bond, -O-, -C(=O)-, -CH2-, or -CF2-; Q2 is a single bond or -CH2-; E1, E2, and E3 are independently -CH2-, -CF2-, -CHF-, -O-, or -S-, respectively; g is 1; h is 0, 1, or 2; h' can be 0, 1, or 2; r is 0, 1, or 2; r' can be 0, 1, or 2.

10. The compound according to claim 1, characterized in that, It is selected from any of the following compounds or their tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs: , , , and .

11. The compound according to claim 10, characterized in that, Selected from any of the following compounds or their tautomers, stereoisomers, pharmaceutically acceptable salts, or prodrugs: , , , and ; Preferably, the pharmaceutically acceptable salt comprises hydrochloride or formate.

12. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1-11 or its tautomers, stereoisomers, pharmaceutically acceptable salts or prodrugs; preferably, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient.

13. Use of the compound or its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 12 in the preparation of a medicament, according to any one of claims 1-11; The drug is used to treat or prevent infections and / or diseases caused by Acinetobacter baumannii; preferably, it is used to treat or prevent infections and / or diseases caused by carbapenem-resistant Acinetobacter baumannii (CRAB). Alternatively, the drug may be a drug used to prepare an anti-Acinetobacter baumannii drug.

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