Cephalosporin antimicrobial compounds and methods for preparing the same

Abstract

FIELD OF THE DISCLOSURE The present disclosure relates to cephalosporin antibacterial compounds and methods for preparing the same. The cephalosporin antibacterial compounds can exhibit antibacterial activity against a wide variety of bacteria, including gram-negative bacteria.

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and specifically to cephalosporin-based antimicrobial compounds and methods for preparing them. [Background technology]

[0002] The development of antifungal therapies remains an ongoing challenge facing modern society. Antimicrobial agents include various chemically synthesized drugs such as antibiotics, sulfonamides, imidazoles, nitroimidazoles, and quinolones. Among these, β-lactam antibiotics are of paramount importance, and to date, several types of β-lactamase agents have been reported in the literature and are commercially available, already becoming clinically significant antimicrobial agents. However, the problem of drug resistance to β-lactamase agents is becoming increasingly serious, with more and more bacteria producing β-lactamase and acquiring drug resistance by degrading β-lactamase agents.

[0003] According to the Ambler molecular classification, β-lactamases are mainly divided into four types. Specifically, these include type A (TEM, SHV, CTX-M, KPC, etc.), type B (IMP, VIM, L-1, etc.), type C (AmpC), and type D (OXA, etc.). Within these types, types A, C, and D are mainly serine-β-lactamases, while type B is classified as a metallobe-β-lactamase. Both types have different mechanisms for hydrolyzing β-lactamase drugs.

[0004] The emergence of Gram-negative bacteria that develop strong drug resistance to β-lactamase agents (including cephalosporins and carbapenems) presents a major clinical challenge. This drug resistance is caused by the production of serine β-lactamases of type A or D and metallobe β-lactamases of type B, which extend the substrate spectrum of these bacteria. Although metallobe β-lactamases are known to be one of the causes of multidrug resistance in Gram-negative bacteria, there is a need to develop cephalosporin compounds that have more effective antibacterial activity, particularly those effective against Gram-negative bacteria that produce multiple types of β-lactamases. This is currently a major challenge in the field of antimicrobial research.

[0005] According to a literature report (Antimicrob Agents Chemother. 1982, 22(2), 181-185.), cephalosporin compounds containing a catechol group in their molecule have high antibacterial activity against Gram-negative bacteria. This action is due to the interaction of the catechol group in the molecule with extracellular Fe. 3+ The compound forms a chelate, which allows the Fe on the cell membrane to 3+ The goal is to effectively bind to the bacterial cell via a transport system (tonB-dependent transport system). This Trojan horse strategy leads to higher concentrations in the periplasmic space (the narrow space between the outer membrane and the cell wall), and by binding to the receptor, it inhibits bacterial cell wall synthesis. Therefore, compounds having catechol or similar structures in the 3- or 7-position side chain of the cephalosporin skeleton have already been studied (European Patent No. 0416410). Cefiderocol is a novel siderophore cephalosporin (International Publication No. 2010 / 050468, International Publication No. 2017 / 216765, Eur. J Med. Chem. 2018, 155, 847-868), and the FDA (U.S. Food and Drug Administration) has already approved Shionogi & Co.'s Fetroja (cefiderocol) for the treatment of complicated urinary tract infections (cUTIs), including kidney infections caused by susceptible Gram-negative bacteria, in patients aged 18 years and older. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] European Patent No. 416410 [Patent Document 2] International Publication No. 2010 / 050468 [Patent Document 3] International Publication No. 2017 / 216765 [Patent Document 4] Chinese Patent Publication No. 106661052 [Patent Document 5] International Publication No. 2016 / 035847 [Non-patent literature]

[0007] [Non-Patent Document 1] Antimicrob Agents Chemother. 1982, 22(2), 181-185. [Non-Patent Document 2] Eur. J Med. Chem. 2018, 155, 847-868 [Non-Patent Document 3] “Protective Groups in Organic Synthesis”, 5Th Ed. TW Greene & PGM Wuts [Non-Patent Document 4] Angewandte Chemie International Edition, 2010, 49, 7208-7212 [Overview of the project] [Problems that the invention aims to solve]

[0008] The purpose of this disclosure is to provide a cephalosporin-based antimicrobial compound that can exhibit an effective antimicrobial spectrum against various types of bacteria, including Gram-negative bacteria. [Means for solving the problem]

[0009] This disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, [ka] Eventually, X is N, CH, or C-Cl. T is S, S=O, CH2, or O. E is [ka] R1 and R2 are each independently selected from hydrogen, halogen, phenyl group, alkylthio group, or optionally an alkyl group substituted with a carbamoyl group, and R 11 and R 12 Each of these is independently selected from a hydrogen atom, a carboxyl group, or an alkyl group optionally substituted with a carbamoyl group, and m refers to an integer from 1 to 5. F is a single bond, A is a C1-C6 alkylidene group, a C2-C6 alkenylene group, or a C2-C6 alkynylene group. R5 is independently selected from halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. G1 is [ka] And, R1' and R2' are each independently selected from a hydrogen atom, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 haloalkyl group, and C1-C6 haloalkoxy group. R3 is [ka] These are C1-C6 alkyl groups substituted with R3’ is selected from a hydrogen atom, a hydroxy group, a C1-C6 alkyl group, and a C1-C6 alkoxy group. Among them, the above alkyl group and alkoxy group are optionally substituted with one or more substituents selected from a C1-C6 alkyl group, a halogen, a hydroxy group, a sulfhydryl group, -NR i R j ,

Chemical formula

[0010] In some embodiments, E is [ka] R1 and R2 are each independently selected from hydrogen, a halogen, or an alkyl group optionally substituted with a carbamoyl group.

[0011] In some embodiments, A is a C1-C6 alkylidene group.

[0012] In some embodiments, R1' and R2' are both hydrogen atoms.

[0013] In some embodiments, x refers to an integer between 3 and 6.

[0014] In some embodiments, R3 is [ka] Selected from C3-C6 alkyl groups substituted with [the appropriate compound].

[0015] In some embodiments, [ka] teeth [ka] And R nEach of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and r independently represents an integer from 0 to 5, preferably [ka] And r independently refers to an integer from 0 to 3, more [ka] That is the case.

[0016] In some embodiments, R3' is a hydrogen atom or [ka] Selected from C1-C6 alkyl groups substituted with a hydrogen atom or [ka] These are C3-C6 alkyl groups that have been substituted with [the specified compound].

[0017] In some embodiments, [ka] teeth [ka] And R n Each of these is independently selected from C1-C6 alkyl groups, hydroxyl groups, and halogens, and r independently represents an integer from 0 to 5, preferably [ka] And r independently refers to an integer from 0 to 3, more [ka] That is the case.

[0018] In some embodiments, the compound represented by formula I above is [ka] Alternatively, it is selected from the medicinal salts thereof.

[0019] In some embodiments, the compound [ka] Alternatively, it is selected from the medicinal salts thereof.

[0020] The "alkyl group" described in this disclosure is preferably a C1-C6 alkyl group.

[0021] The "alkylene group" described in this disclosure is preferably a C1-C6 alkylene group.

[0022] The "alkenylene group" described in this disclosure is preferably a C2-C6 alkenylene group.

[0023] The "alkylylene group" described in this disclosure is preferably a C2-C6 alkylylene group.

[0024] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0025] The "alkylsulfanil group" described in this disclosure is preferably a C1-C6 alkylsulfanil group.

[0026] The "cycloalkyl group" described herein is preferably a cycloalkyl group having 3 to 12 members, more preferably 3 to 6 members.

[0027] The “condensed cycloalkyl group” described herein is preferably a condensed cycloalkyl group having 6 to 14 members, more preferably 7 to 10 members.

[0028] The "heterocyclyl group" described herein is preferably a heterocyclyl group with 3 to 12 members, more preferably a heterocyclyl group with 3 to 6 members.

[0029] The “condensed heterocyclyl group” described herein is preferably a 6- to 14-membered, more preferably 7- to 10-membered condensed heterocyclyl group.

[0030] The “aryl group” described herein is preferably a 6- to 14-membered, more preferably a 6- to 10-membered aryl group.

[0031] The “condensed ring aryl group” described herein is preferably an 8- to 14-membered, more preferably an 8- to 12-membered condensed ring aryl group.

[0032] The "heteroaryl group" described herein is preferably a 5- to 12-membered heteroaryl group, more preferably a 5- to 8-membered heteroaryl group.

[0033] The “condensed heteroaryl group” described herein is preferably a 5- to 14-membered, more preferably 5- to 12-membered condensed heteroaryl group.

[0034] In some embodiments, the compounds described herein have a Z configuration.

[0035] This disclosure further provides pharmaceutical compositions comprising at least one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vector, diluent, or excipient.

[0036] In some embodiments, the unit dose of the above pharmaceutical composition is 0.001 to 1000 mg.

[0037] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of the compound. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the compound. In some embodiments, the pharmaceutical composition contains 1% to 99% of the compound. In some embodiments, the pharmaceutical composition contains 2% to 98% of the compound.

[0038] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% to 99.99% of pharmaceutically acceptable vectors, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable vectors, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable vectors, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable vectors, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable vectors, diluents, or excipients.

[0039] This disclosure further provides uses of the compounds described herein or their medicinal salts for the prevention and treatment of pathogenic diseases in mammals, including humans. These uses include, for example, respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, meningomyelia, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

[0040] This disclosure further provides uses for the compounds described herein or their medicinal salts for the prevention and treatment of diseases caused by Gram-negative bacteria. The above Gram-negative bacteria are preferably intestinal Gram-negative bacteria (such as Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, and Proteus), Gram-negative bacteria that reside in the respiratory system (such as Haemophilus and Moraxella), and non-fermenting Gram-negative bacteria (such as Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, and Acinetobacter).

[0041] This disclosure further provides uses for the compounds described herein or their medicinal salts for the prevention and treatment of diseases caused by Gram-positive bacteria.

[0042] This disclosure further provides a method for treating the above-mentioned diseases in mammals, which may be human or non-human mammals, and includes administering to the mammal, for therapeutic purposes, a compound or medicinal salt thereof described in this disclosure, or a pharmaceutical composition thereof.

[0043] This disclosure further provides reagent kits comprising the compounds described herein or their pharmaceutically acceptable salts, or pharmaceutical compositions.

[0044] Tests conducted using methods publicly known in this field (e.g., International Publication No. 2010 / 050468) showed that the compounds relating to this disclosure exhibit inhibitory activity against Gram-negative bacteria and exhibit excellent efficacy.

[0045] Explanation of terms: Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0046] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, and preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl This includes n-octyl groups, 2,3-dimethylpentyl groups, 2,4-dimethylpentyl groups, 2,2-dimethylpentyl groups, 3,3-dimethylpentyl groups, 2-ethylpentyl groups, 3-ethylpentyl groups, n-octyl groups, 2,3-dimethylhexyl groups, 2,4-dimethylhexyl groups, 2,5-dimethylhexyl groups, 2,2-dimethylhexyl groups, 3,3-dimethylhexyl groups, 4,4-dimethylhexyl groups, 2-ethylhexyl groups, 3-ethylhexyl groups, 4-ethylhexyl groups, 2-methyl-2-ethylpentyl groups, 2-methyl-3-ethylpentyl groups, n-nonyl groups, 2-methyl-2-ethylhexyl groups, 2-methyl-3-ethylhexyl groups, 2,2-diethylpentyl groups, n-decyl groups, 3,3-diethylhexyl groups, 2,2-diethylhexyl groups, and various branched isomers thereof.More preferably, the alkyl group contains 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may or may not be substituted, and if substituted, the substituent may be substituted at any available connection site, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0047] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, and is a linear or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, and more preferably containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylene groups may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available connection site.

[0048] The term "alkenylene group" includes linear alkenyl groups having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one double bond at any position, such as vinylidene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentadienyldene, hexenylene, and hexadienylene groups.

[0049] The term "alkynylene group" refers to a linear alkylylene group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one triple bond at any position, and includes, for example, ethynylene group, propynylene group, butynylene group, pentynylene group, hexynylene group, and the like.

[0050] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings.

[0051] The term "spirocycloalkyl group" refers to a polycyclic group with 5 to 20 members, in which monocyclic rings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl groups are classified into monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferably, they are 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0052] The term "condensed cycloalkyl group" refers to a 5-20 member, all-carbon polycyclic group in which each ring in the system shares one adjacent pair of carbon atoms with the other rings in the system, and which may contain one or more double bonds, but none of which have a fully conjugated π-electron system. Preferably, they are 6-14 member, more preferably 7-10 member. Depending on the number of constituent rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 5-member / 5-member or 5-member / 6-member bicyclic alkyl groups. Non-limiting examples of condensed cycloalkyl groups are: [ka] Includes.

[0053] The term "crosslinked cycloalkyl group" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, it has 6-14 members, more preferably 7-10 members. Depending on the number of rings it comprises, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyl group, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] Includes.

[0054] The above cycloalkyl ring may be condensed with an aryl group, a heteroaryl group, or a heterocycloalkyl ring, of which the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptanyl group, and the like. The cycloalkyl group may be optionally substituted or not substituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0055] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). m The heteroatoms are selected from (where m is an integer from 0 to 2), but do not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrazolyl group, dihydropyrrolyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, etc., with piperidinyl group and pyrrolidinyl group being preferred. Polycyclic heterocyclyl groups include heterocyclyl groups of spiro rings, fused rings, and bridging rings.

[0056] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group with 5 to 20 members, in which monocyclic rings share one atom (called a spiro atom), and one or more of these ring atoms are nitrogen, oxygen, or S(O).m The heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group, or a polyspiroheterocyclyl group depending on the number of spiroatoms shared between the rings, preferably a monospiroheterocyclyl group and a bisspiroheterocyclyl group. More preferably it is a 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0057] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group with 5 to 20 members, in which each ring in the system shares one pair of adjacent atoms with the other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more of the ring atoms are nitrogen, oxygen, or S(O). m The heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that make up the group, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0058] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, in which any two rings share two atoms that are not directly bonded, and which may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and of which one or more ring atoms are nitrogen, oxygen, or S(O) m The heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that make up the group, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging heterocyclyl groups are: [ka] Includes.

[0059] The above heterocyclyl ring may be condensed with an aryl group, a heteroaryl group, or a cycloalkyl ring, of which the ring linked to the parent structure is a heterocyclyl group, and a non-limiting example thereof is: [ka] This includes, among others.

[0060] The heterocyclyl group may be optionally substituted or left unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0061] The term "aryl group" refers to a 6-14 member all-carbon monocyclic or condensed polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-10 membered, such as the phenyl group and the naphthyl group. The above aryl ring may be condensed with a heteroaryl, heterocyclyl, or cycloalkyl ring, of which the ring linked to the parent structure is an aryl ring, and non-limiting examples include: [ka] Includes, The aryl group may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups, with a phenyl group being preferred.

[0062] The term "fused ring aryl group" may refer to an aromatic, unsaturated fused ring structure containing 8 to 14 ring atoms, formed by the sharing of two or more adjacent atoms between two or more cyclic structures, with 8 to 12 ring atoms being preferred. Examples include fully unsaturated fused ring aryl groups such as naphthalene and phenanthrene, and further, partially saturated fused ring aryl groups such as benzo-3 to 8-membered saturated monocyclic cycloalkyl groups and benzo-3 to 8-membered partially saturated monocyclic cycloalkyl groups. Specific examples include, for example, 2,3-dihydro-1H-indenyl, IH-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0063] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12 members, for example, an imidazolyl group, furanyl group, thienyl group, thiazolyl group, pyrazolyl group, oxazolyl group, pyrrolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, thiadiazolyl group, pyrazinyl group, etc., preferably an imidazolyl group, pyrazolyl group, pyrimidinyl group, or thiazolyl group, and more preferably a pyrazolyl group or thiazolyl group. The heteroaryl ring may be condensed with an aryl, heterocyclyl, or cycloalkyl ring, of which the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples include: [ka] Includes.

[0064] The heteroaryl group may be optionally substituted or left unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0065] The term "condensed heteroaryl group" refers to an aromatic, unsaturated condensed ring structure that contains 5 to 14 ring atoms (including at least one heteroatom), and is formed by two or more cyclic structures sharing two adjacent atoms. It may also contain oxo-substitutable carbon, nitrogen, and sulfur atoms, and is preferably a "5-12 membered condensed heteroaryl group," a "7-12 membered condensed heteroaryl group," a "9-12 membered condensed heteroaryl group," etc. For example, a benzofuranyl group, These include benzoisofuranyl group, benzothiophenyl group, indolyl group, isoindolyl group, benzoxazolyl group, benzimidazolyl group, indazolyl group, benzotriazolyl group, quinolyl group, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl group, acridinyl group, phenantridinyl group, benzopyridazinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, phenazinyl group, pteridinyl group, prinyl group, naphthylidinyl group, phenazinyl group, and phenothiazinyl group.

[0066] The condensed heteroaryl group may be optionally substituted or left unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0067] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), of which the definition of alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. Alkoxy groups may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0068] The term "alkylthio group" refers to -S-(alkyl group) and -S-(unsubstituted cycloalkyl group), of which the definition of alkyl group is as described above. Non-limiting examples of alkylthio groups include methylthio group, ethylthio group, propylthio group, butylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, and cyclohexylthio group. Alkylthio groups may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0069] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxyl group, and among these, alkyl groups are defined as described above.

[0070] The term "haloalkyl group" refers to an alkyl group substituted with a halogen, and the alkyl group is defined as described above.

[0071] The term "deuterated alkyl group" refers to an alkyl group substituted with a deuterium atom, and the alkyl group is defined as described above.

[0072] The term "hydroxyl group" refers to the -OH group.

[0073] The term "oxo" refers to an =O group. For example, a carbon atom and an oxygen atom are linked by a double bond, forming a ketone or aldehyde group.

[0074] The term "thio" refers to the =S group. For example, a carbon atom and a sulfur atom are linked by a double bond to form a thiocarbonyl group -C(S)-.

[0075] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0076] The term "amino group" refers to -NH2.

[0077] The term "cyano group" refers to -CN.

[0078] The term "nitro group" refers to -NO2.

[0079] The term "carboxyl group" refers to -C(O)OH.

[0080] The term "aldehyde group" refers to -CHO.

[0081] The term "carboxylic acid ester group" refers to -C(O)O (alkyl group) or -C(O)O (cycloalkyl group), of which alkyl groups and cycloalkyl groups are defined as described above.

[0082] The term "acyl halogen" refers to compounds that contain the group -C(O)-halogen.

[0083] "Carboxylic protecting groups" are groups used to protect carboxyl groups, as known in this field, as described in the literature ("Protective Groups in Organic Synthesis", 5 Th The carboxyl protecting group in Ed. TW Greene & PGM Wuts is referenced, and as an example, preferably the carboxyl protecting group is substituted or unsubstituted C 1-10 Linear or branched alkyl groups, substituted or unsubstituted C 2-10 A linear or branched alkenyl or alkynyl group, substituted or unsubstituted C 3-8 A cyclic alkyl group, substituted or unsubstituted C 5-10 an aryl group or heteroaryl group, or (C 1-8 It may also be an alkyl group or aryl group, or a 3-silyl group, preferably C 1-6 A linear or branched alkyl group, more preferably C 1-4 These are linear or branched alkyl groups. Examples include methyl, ethyl, allyl, isopentenyl, and trimethylsilylethyl groups.

[0084] "Amino protecting groups" are groups applied to the protection of amino groups, as known in this field, as described in the literature ("Protective Groups in Organic Synthesis", 5 Th The amino protecting group in (Ed. TW Greene & PGM Wuts) is referenced, and preferably the amino protecting group is a (C) such as a formyl group, acetyl group, or benzoyl group. 1-10 It may be an alkyl or aryl)acyl group, (C 1-6 Alkyl alkyl group or C 6-10 It may also be an aryl)sulfonyl group, such as Boc or Cbz (C 1-6 Alkoxy group or C 6-10It may be an aryloxy)carbonyl group, or a substituted or unsubstituted alkyl group such as a trityl group (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB), or a benzyl group (Bn).

[0085] "Hydroxy protecting groups" are groups known in this field that are applied to the protection of hydroxyl groups, as seen in the reference ("Protective Groups in Organic Synthesis", 5 Th The hydroxy protecting group in Ed. TW Greene & PGM Wuts is referenced. For example, preferably the hydroxy protecting group is a triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc. (C 1-10 It may also be an alkyl or aryl)3-silane group, C 1-10 It may be an alkyl group or a substituted alkyl group, preferably an alkyl group substituted with an alkoxy group or an aryl group, more preferably C 1-6 C substituted with an alkoxy group 1-6 C substituted with alkyl or phenyl groups 1-6 Alkyl alkyl groups, most preferably C 1-4 C substituted with an alkoxy group 1-4 Alkyl groups include, for example, methyl group, tert-butyl group, allyl group, benzyl group, methoxymethyl group (MOM), ethoxyethyl group, 2-tetrahydropyranyl group (THP), and (C) groups such as formyl group, acetyl group, and benzoyl group. 1-10 It may also be an alkyl or aryl acyl group, (C 1-6 Alkyl or C 6-10 It may also be an aryl)sulfonyl group, (C 1-6 Alkoxy or C 6-10 It may also be an aryloxy carbonyl group.

[0086] The term "leaving group" refers to an atom or functional group that is removed from a larger molecule in a chemical reaction. Typical leaving groups include halogens, substituted sulfonyloxy groups, phosphoryloxy groups, amino groups, and Ri R j N-, cyano group, R m There are S- and others.

[0087] The substituted sulfonyloxy group may be a C1-C6 alkylsulfonyloxy group, a perfluoroC1-C6 alkylsulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, or the like.

[0088] Specific examples of C1-C6 alkylsulfonyloxy groups include C1-C6 linear or branched alkylsulfonyloxy groups, such as methylsulfonyloxy groups, ethylsulfonyloxy groups, n-propylsulfonyloxy groups, isopropylsulfonyloxy groups, n-butylsulfonyloxy groups, tert-butylsulfonyloxy groups, n-pentylsulfonyloxy groups, and n-hexylsulfonyloxy groups.

[0089] Specific examples of perfluoroC1-C6 alkylsulfonyloxy groups include C1-C6 linear or branched perfluoroalkylsulfonyloxy groups, such as trifluoromethylsulfonyloxy, 1,1,2,2,2-pentafluoro-1-ethylsulfonyloxy, 1,1,2,2,3,3,3-heptafluoro-1-propylsulfonyloxy, and 1,1,2,2,3,3,4,4,4-nonafluoro-1-butylsulfonyloxy.

[0090] Examples of arylsulfonyloxy groups include phenylsulfonyloxy groups and naphthylsulfonyloxy groups having 1 to 3 substituents on a benzene ring, optionally selected from the group consisting of a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkyl group, a nitro group, and a halogen atom. Specific examples of optionally substituentd phenylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-tolylsulfonyloxy, 2-nitrophenylsulfonyloxy, and 3-chlorophenylsulfonyloxy. Specific examples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy and β-naphthylsulfonyloxy.

[0091] Examples of aralkylsulfonyloxy groups include C1-C6 linear or branched alkylsulfonyloxy groups substituted with a phenyl group (which optionally has 1-3 substituents selected from C1-C6 linear or branched alkyl groups, C1-C6 linear or branched alkyl groups, nitro groups, and halogen atoms on the benzene ring), and C1-C6 linear or branched alkylsulfonyloxy groups substituted with a naphthyl group. Specific examples of alkylsulfonyloxy groups substituted with a phenyl group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-xylylsulfonyloxy, and 3-chlorobenzylsulfonyloxy. Specific examples of alkylsulfonyloxy groups substituted with a naphthyl group include α-naphthylmethylsulfonyloxy and β-naphthylmethylsulfonyloxy.

[0092] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the expression includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may or may not be present, and the expression includes both cases in which the heterocyclyl group is substituted with an alkyl group and cases in which the heterocyclyl group is not substituted with an alkyl group.

[0093] "Substitution" means that one or more hydrogen atoms in a group, preferably five or fewer, more preferably one to three hydrogen atoms, are substituted by a number of substituents that correspond to each other independently. Of course, substituents can only be located at their chemically possible sites, and those skilled in the art can determine possible or impossible substitutions with little effort (by experiment or theory).

[0094] In the chemical structure of the compounds described in this disclosure,

number

number

number

number

number

[0095] Tautomers are structural isomers of organic compounds that are readily interconverted by a chemical reaction called tautomerism. Such reactions always involve the transfer of hydrogen atoms or protons, with the transformation of single bonds and adjacent double bonds. Some common tautomer pairs are keto-enols and lactam-lactims. An example of lactam-lactim equilibrium is between A and B, as shown below. [ka]

[0096] All compounds in this disclosure can be described as either type A or type B. All tautomer forms are within the scope of this disclosure. The nomenclature of the compounds does not exclude any tautomer.

[0097] Any isotope-labeled derivatives of the compounds described herein or their pharmaceutically acceptable salts are covered herein. Atoms that can be isotoped include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Each of these is an isotope. 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 It can be substituted with I, etc. Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to be deuterium with an abundance at least 3000 times higher than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium is incorporated). [Modes for carrying out the invention] [Examples]

[0098] The preparation of the compounds and medicinal salts described in this disclosure will be further explained below, along with examples, but these examples are not intended to limit the scope of this disclosure.

[0099] In the examples provided herein, experimental methods for which specific conditions are not explicitly stated were generally conducted under normal conditions or conditions recommended by the raw material or product manufacturers. Reagents for which specific sources are not explicitly stated are commercially available, standard reagents.

[0100] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (LCMS). The NMR shift (δ) was 10 -6 The values ​​are expressed in units of ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The stereochemistry of the optical isomers (isomers) of the compound can be further confirmed by measuring the single crystal parameters.

[0101] For HPLC measurements, Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-pressure liquid chromatographs (ACQUITY UPLC BEH C18 1.7UM 2.1×50 mm column, Ultimate XB-C18 3.0×150 mm column, or Xtimate C18 2.1×30 mm column) were used.

[0102] A Waters SQD2 mass spectrometer was used for the MS measurements, scanning in positive / negative ion mode with a mass scan range of 100–1200.

[0103] For measurements of chiral HPLC analysis, Chiralpak IC-3 100×4.6 mm ID, 3 μm, Chiralpak AD-3 150×4.6 mm ID, 3 μm, Chiralpak AD-3 50×4.6 mm ID, 3 μm, Chiralpak AS-3 150×4.6 mm ID, 3 μm, Chiralpak AS-3 100×4.6 mm ID, 3 μm, ChiralCel OD-3 150×4.6 mm ID, 3 μm, Chiralcel OD-3 100×4.6 mm ID, 3 μm, ChiralCel OJ-H 150×4.6 mm ID, 5 μm, Chiralcel OJ-3 150×4.6 mm ID, 3 μm columns were used.

[0104] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications for silica gel plates used in thin-layer chromatography (TLC) were 0.15 to 0.2 mm, and the specifications for the separation and purification of products by thin-layer chromatography were 0.4 to 0.5 mm.

[0105] For the flash column purification system, Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) was used.

[0106] For normal-phase column chromatography, silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh from Yantai Huanghai was commonly used as a vector, or pre-packed ultra-high purity normal-phase silica gel columns from Changzhou Sandai (40-63 μm, 60, 12 g, 25 g, 40 g, 80 g, or other specifications) were used.

[0107] For reverse-phase column chromatography, Changzhou Sandai pre-packed ultra-high purity C18 silica gel columns (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g, or other specifications) were commonly used.

[0108] For the high-pressure column purification system, Waters AutoP was used, along with either a Waters XBridge BEH C18 OBD Prep Column (130 Å, 5 μm, 19×150 mm) or an Atlantis T3 OBD Prep Column (100 Å, 5 μm, 19×150 mm).

[0109] For chiral preparative columns, DAIEL CHIRALPAK IC (250×30 mm, 10 μm) or Phenomenex-Amylose-1 (250×30 mm, 5 μm) were used.

[0110] The known starting materials in this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as Shanghai Taitan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemicals.

[0111] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0112] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 L.

[0113] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 L.

[0114] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0115] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0116] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0117] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0118] Unless otherwise specified in the examples, the reaction temperature is 20°C to 30°C at room temperature.

[0119] The reaction process in the examples was monitored by thin-layer chromatography (TLC). The developing solvents used in the reaction, the eluent system for column chromatography to purify the compounds, and the developing solvent system for thin-layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, D: petroleum ether / ethyl acetate / methanol, and E: petroleum ether / tetrahydrofuran system. The volume ratio of the solvents was adjusted according to the polarity of the compounds, but it may also be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid. Example 1:

[0120] [ka] [ka] Step 1 Compound 1-1 (synthesized by the method described in Chinese Patent Publication No. 106661052, 1.5 g, 3.50 mmol) was dissolved in DMF (35 mL) and DMTMM (1.55 g, 5.26 mmol) and DIEA (905 mg, 7.0 mmol) were added. After protecting the reaction with argon and substituting three times, 1-A (525 mg, 7.0 mmol) was added to the reaction mixture and the reaction was allowed to proceed at room temperature for 2 hours with stirring. The reaction mixture was gradually added to water, and the solid product was allowed to precipitate. The solid product obtained by filtration was dissolved in DCM, extracted, and separated. The organic phase was then washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain product 1-2 (1.6 g, yield 94%). LC / MS (ESI): m / z 486.1 [M+H] +

[0121] Step 2 A 10 mL solution of oxalyl chloride (1.05 g, 8.24 mmol) in DCM was cooled to -78°C in a dry ice / acetone bath. Under argon protection, DMSO (1.29 g, 16.5 mmol) was added dropwise, and the reaction was carried out with stirring. A 6 mL solution of 1-2 (1.6 g, 3.30 mmol) in DCM was gradually added dropwise to the reaction mixture, and stirring was continued at -78°C. Et3N (3.34 g, 33.0 mmol) was then added, and the mixture was stirred at -78°C. The reaction was then gradually raised to 0°C until the reaction was complete. After quenching the reaction with H2O, the mixture was extracted with DCM, the organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain product 1-3 (1.28 g, 80% yield). LC / MS (ESI): m / z 484.0 [M+H] +

[0122] Step 3 To a solution of substrates 1-3 (1.28 g, 2.65 mmol) in DCM (26 mL), 1-B (605 mg, 5.30 mmol) was added. The reaction mixture was cooled in an ice bath, and then NaBH(OAc)3 (1.68 g, 7.95 mmol) was added. The reaction was carried out with stirring while the temperature was raised to room temperature. After the reaction was complete, the reaction mixture was quenched with NaHCO3, extracted with DCM, and the organic phase was washed sequentially with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel flash chromatography to obtain product 1-4 (735 mg, 48% yield). LC / MS (ESI): m / z 582.1 [M+H] +

[0123] Step 4 To a solution of 1-1 (650 mg, 1.51 mmol) in DMF (13 mL), HATU (961 mg, 2.52 mmol) and DIEA (490 mg, 3.78 mmol) were added. The reaction was protected with argon and stirred at room temperature. After adding 1-4 (735 mg, 1.26 mmol) to the reaction mixture, the reaction was continued with stirring at room temperature. The reaction mixture was gradually added to water, filtered, and dried by suction to obtain product 1-5 (1.2 g, 96% yield). LC / MS (ESI): m / z 992.1 [M+H] +

[0124] Step 5 Compounds 1-5 (546 mg, 0.55 mmol), compound 1-6 (398 mg, 0.5 mmol, synthesized by the method described in International Publication No. 2016 / 035847), and sodium iodide (225 mg, 1.5 mmol) were added to N,N-dimethylformamide (1.5 mL) and reacted with stirring. After the reaction was complete, the reaction flask was cooled in an ice bath, and PBr3 (360 mg, 1.33 mmol) was added and reacted with stirring. After the reaction was complete, the reaction mixture was added dropwise to an aqueous solution of NaHSO3, filtered, and the filter cake was washed with clean water and dried under vacuum to obtain 1.13 g of crude products 1-7. LC / MS (ESI): m / z 1737.1[M] +

[0125] Step 6 Compounds 1-7 (1.13 g, 0.5 mmol) were added to anisole (2 mL) and trifluoroacetic acid (8 mL), and the mixture was reacted at room temperature. Methyl tert-butyl ether was added, the mixture was stirred, and then filtered. The filtered cake was rinsed with MTBE and dried to obtain 600 mg of crude product. After fractionation by HPLC, 4 mg of compound 1 was obtained. HRMS: 979.1874 [M+H] + 1H-NMR (400 MHz,DMSO-d6)δ: 1.44(s,3H),1.46 (s,3H),1.66-2.06(m,6H),2.93-3.88 (m,14H),3.04-3.05 (m,2H),4.00-4.03 (m,2H),4.82-5.13 (m,1H),5.18(d,1H),5.74 (dd,1H),6.54 (d,1H),6.60 (d,1H),6.73-6.85 (m,3H),7.28(s,2H),8.05-8.33 (m,1H),9.46(br s,2H),10.26(br s,2H). Example 2

[0126] [ka] [ka] Step 1 Add 2-1 (30.3 g, 174.1 mmol, 1.0 eq), 2,4-dimethoxybenzaldehyde (29.5 g, 177.6 mmol, 1.02 eq), methanol (300 mL), and anhydrous sodium sulfate (24.7 g, 174.1 mmol, 1.0 eq) to a reaction flask and react at room temperature with stirring. Then, cool the reaction mixture in an ice bath, add sodium borohydride (3.3 g, 87.0 mmol, 0.5 eq) in several batches, react with stirring for 5 minutes, and continue reacting at room temperature with stirring until complete. Add glacial acetic acid (3.3 mL), stir, filter, and wash with ethyl acetate. Concentrate the filtrate, add water and ethyl acetate to the residue, stir to separate the layers, and extract the aqueous phase with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 2-2, totaling 58.0 g (yield: 102.8%). MS m / z 325.1[M+H] +

[0127] Step 2 2-2 (2.0 g, 6.2 mmol, 1.0 eq), S-epoxypropane (0.54 g, 9.3 mmol, 1.5 eq), and EtOH (20 mL) were added to a reaction flask and heated to 60°C to allow the reaction to proceed. The reaction was monitored by LC-MS to ensure that the starting materials had reacted completely. The reaction mixture was concentrated, and the crude product was purified by column chromatography to obtain a total of 1.2 g of product 2-3, with a yield of 51.1%. MS m / z 383.2[M+H] +

[0128] Step 3 2-3 (1.2 g, 3.2 mmol, 1.0 eq), DCM (20 mL), and TEA (0.65 g, 6.4 mmol, 2.0 eq) were added to the reaction flask and cooled in an ice bath. MsCl (0.54 g, 4.7 mmol, 1.5 eq) was gradually added dropwise, and the reaction was carried out with stirring. The complete reaction of the starting materials was monitored by LC-MS. The reaction mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 2-4 (1.34 g), which was used directly in the next step. MS m / z 461.1[M+H] +

[0129] Step 4 The crude product of 2-4 (1.34 g, 3.2 mmol, 1.0 eq), tetrahydropyrrole (0.56 g, 8.0 mmol, 2.5 eq), MeCN (15 mL), and potassium carbonate (0.66 g, 4.8 mmol, 1.5 eq) were added to a reaction flask and reacted while stirring at 40°C. The reaction was monitored by LC-MS to ensure that the starting materials had reacted completely. Water (30 mL) and EA (30 mL) were added to the reaction mixture and the mixture was stirred to separate the layers. The aqueous phase was washed with EA, the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain 2-5 (0.66 g, two-step yield: 48.5%). MS m / z 436.1[M+H] +

[0130] Step 5 2-5 (600 mg, 1.38 mmol) and TFA (10 mL) were added to the reaction flask and dissolved. The mixture was heated to 60°C and reacted until complete. The reaction mixture was concentrated to dryness, MTBE (10 mL) was added, and the mixture was slurryed. The supernatant was poured out, and most of the solvent was removed from the resulting oily substance 2-6 under vacuum. This was then used directly in the next step of the reaction. MS m / z 186.1[M+H] +

[0131] Step 6 The crude products of 2-6 and 1-1 (1.31 g, 3.05 mmol) were dissolved in DCM (15 mL) and stirred at 0°C. DIPEA (2.02 mL, 12.22 mmol) and HATU (1.39 g, 3.67 mmol) were added. The reaction mixture was allowed to rise naturally to room temperature and continued until complete. After adding water (10 mL), the mixture was separated, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude products were separated by chromatography column (DCM:MeOH = 10:1) to obtain a total of 0.85 g of 2-7. MS m / z 1006.3 [M+H] +

[0132] Step 7 1-6 (720 mg, 0.904 mmol), 2-7 (650 mg, 0.645 mmol), sodium iodide (0.406 g, 2.71 mmol), and boric acid (17 mg, 0.271 mmol) were added to the reaction flask. After replacing the air with argon three times, NMP (2.1 mL) was added. The reaction mixture was allowed to react at room temperature until complete. The reaction mixture was used directly in the next step without further treatment. MS m / z 1767.5 [M] +

[0133] Step 8 After adding NMP (0.7 mL) to the above reaction mixture, the reaction mixture was cooled to 0°C, phosphorus trichloride (0.103 mL, 1.17 mmol) was added, and the reaction was kept warm at 0°C until the reaction was complete. 5% sodium bisulfite aqueous solution (20 mL) was added to the reaction mixture, and it was slurryed in an ice bath. The mixture was filtered, the filtered cake was dissolved in DCM (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, yielding a total of 1.21 g of 2-9. MS m / z 1751.4 [M] +

[0134] Step 9 Compounds 2-9 (1.21 g, 0.69 mmol) were dissolved in anisole (0.2 mL) and trifluoroacetic acid (0.8 mL) and reacted at room temperature until the reaction was complete. After cooling to 0°C, MTBE (20 mL) was added, and the mixture was slurryed in an ice bath. The mixture was filtered, the filter cake was rinsed with MTBE, and then dried to obtain 0.82 g of crude product. Further fractionation by reverse-phase HPLC yielded a total of 107 mg of compound 2. MS m / z 993.1 [M+H] + Example 3

[0135] [ka] [ka] Step 1 Add 3-1 (3.7 g, 28.0 mmol) (synthesized according to the known literature Angewandte Chemie International Edition, 2010, 49, 7208-7212), 1-1 (26.4 g, 61.6 mmol), and DCM (316 mL) to a reaction flask. Stir to dissolve and cool in an ice bath. Add DIPEA (11.9 g, 92.4 mmol) and DMTMM (23.2 g, 84.0 mmol). Heat to room temperature and stir until the reaction is complete. Filter, wash the filtrate with water, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The crude product was purified by silica gel flash chromatography to obtain product 3-2 (21.8 g, 82% yield). LC / MS (ESI): m / z 953.1 [M+H] + 1 H-NMR (400 MHz,CDCl3) δ: 1.63-1.94 (m,4H),3.19-3.27 (m,3H),3.42-3.47 (m,2H),3.61-3.65 (m,1H),3.67-3.82 (m,14H),3.90-3.97 (m,1H),4.88-5.04 (m,8H),6.77-6.97 (m,12H),7.22-7.40 (m,8H).

[0136] Step 2 3-2 (21.7 g, 22.75 mmol) and DCM (217 mL) were added to the reaction flask, purged with nitrogen gas, and cooled in an ice bath. TEA (8.06 g, 79.63 mmol) was added dropwise. MsCl (7.82 g, 68.25 mmol) was dissolved in 8 mL of DCM and gradually added dropwise to the reaction system. After the addition was complete, the mixture was stirred in an ice bath until the reaction was complete. Water was added to quench the reaction, and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The solution was separated, and the organic phase was collected. The aqueous phase was extracted with DCM, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain product 3-3 (24.0 g, 102%). LC / MS (ESI): m / z 1031.2 [M+H] +

[0137] Step 3 3-3 (23.9 g, 22.75 mmol) and THF (240 mL) were added to the reaction flask, stirred and dissolved. LiBr (5.93 g, 68.25 mmol) was added. After the addition was complete, the temperature was raised to 60 o °C and the reaction was carried out with stirring. After the reaction was completed, it was concentrated to remove the solvent, water was added, extracted with EA, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. It was concentrated to dryness to obtain the product 3-4 (22.2 g, yield 94%). LC / MS (ESI): m / z 1015.2 [M+H] +

[0138] Step 4 3-4 (22.1 g, 21.73 mmol) and ACN (442 mL) were added to the reaction flask, stirred and dissolved, and further K2CO3 (10.51 g, 76.06 mmol) and pyrrolidine (4.64 g, 65.19 mmol) were added respectively. After the addition was complete, the temperature was raised to 60 o °C and the reaction was carried out with stirring. After the reaction was completed, it was concentrated to remove the solvent, water was added, and extracted with a mixed solvent of DCM:MeOH = 10:1. The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by normal-phase silica gel column to obtain the product 3-5 (16.2 g, yield 74%). LC / MS (ESI): m / z 1006.3 [M+H] + 1 1H-NMR (400 MHz, DMSO-d6) δ: 1.50 - 1.65 (m, 4H), 1.74 - 1.89 (m, 4H), 2.21 - 2.38 (m, 3H), 2.69 - 2.9l (m, 3H), 2.99 - 3.16 (m, 4H), 3.60 - 3.68 (m, 2H), 3.70 - 3.77 (m, 12H), 4.81 - 5.16 (m, 8H), 6.81 - 7.45 (m, 20H), 8.16 - 8.34 (m, 1H).

[0139] Step 5 1-6 (5.4 g, 6.78 mmol), 3-5 (8.2 g, 8.14 mmol), NaI (3.05 g, 20.34 mmol) and boric acid (136 mg, 2.03 mmol) were added to the reaction flask, and the flask was purged with argon three times. NMP (27 mL) was added in an ice-water bath. After the addition was complete, the temperature was raised to room temperature and the mixture was stirred until the reaction was complete. The reaction solution was used directly in the next reaction without further purification. LC / MS (ESI): m / z 1767.9 [M] + (The ion flow with the strongest response)

[0140] Step 6 The reaction solution obtained in the previous step was cooled to 0 o °C. Phosphorus trichloride (1.58 g, 11.53 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out with stirring while maintaining the temperature at 0 o °C until completion. Water was added to dilute the reaction solution, and the mixture was filtered to obtain 14 g of the crude product of 3-7, which was dried by suction and used directly in the next step. LC / MS (ESI): m / z 1751.5 [M] + (The ion flow with the strongest response)

[0141] Step 7 The above-mentioned crude product of 3-7 was dissolved in anisole (28 mL) and trifluoroacetic acid (112 mL) and reacted at room temperature. After the reaction was complete, it was cooled to 0 °C, MTBE (200 mL) was added, slurried in an ice-water bath, and filtered. The filter cake was washed with MTBE and then dried to obtain 8 g of the crude product. Further preparative separation was carried out by reverse-phase HPLC to obtain the product, compound 3 (3.37 g, yield 50%). LC / MS (ESI): m / z 993.2 [M+H] + 1H-NMR (400 MHz,DMSO-d6) δ: 1.44-1.46 (m,6H),1.59-2.20 (m,8H),2.83-3.89 (m,16H),4.87-5.19 (m,2H),5.68-5.79 (m,1H),6.53-6.64 (m,1H),6.67-6.84 (m,4H),7.30 (s,2H),8.30 (s,1H),9.42 (br s,3H),10.14 (br s,2H). Biological evaluation

[0142] The present disclosure will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure. Test Example 1: Antifungal Activity Test

[0143] 1. The test compound was dissolved in sterile saline, vortexed and shaken to mix uniformly, and then gradient-diluted with sterile saline to a total of 11 concentration points. The test concentration range was 32 to 0.031 μg / mL, with 2 wells per concentration. In addition, wells without the drug were set up as growth controls.

[0144] 2. A 4 μL dilution was added to a 196 μL bacterial suspension in a 96-well plate (bacterial count in the suspension was 2-8 × 10⁶). 5 (Colony-forming units / mL).

[0145] 3. After incubation at 36°C for 24 hours, the MIC value was visually measured.

[0146] The method for detecting the minimum inhibitory concentration (MIC) was performed in accordance with the guidelines of the Clinical Laboratory Standards Institute (CLSI). [Table 1-1] [Table 1-2] Test Example 2: Pharmacokinetic study of the test compound in cynomolgus monkeys

[0147] 1. Sample placement An appropriate amount of each test compound was precisely weighed into a container. Under an ice bath, 0.9% sodium chloride injection and 0.2 M NaOH solution were added until the test compound was completely dissolved, and a sample solution with a concentration of 2 mg / mL was prepared, which was stored at 2 - 8 °C for use.

[0148] 2. Test animals Species and race: Cynomolgus monkeys Animal level: Conventional Animal origin: Guangxi Xiongsen Primate Experimental Animal Breeding and Development Co., Ltd. Animal use license number: SYXK (Su) 2019 - 0012

[0149] 3. Test method Six cynomolgus monkeys were selected, with half males and half females. They were randomly divided into 3 groups, with 1 animal / sex per group. The samples were administered to the cynomolgus monkeys by single intravenous injection, and the dosage for each was 10 mg / kg. For the animals in each group, blood samples were collected at the time points of before administration, 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h after the end of administration. The test detected the concentration of each test compound in the plasma of cynomolgus monkeys by the LC - MS / MS method, and the lower limit of quantification of the plasma sample analysis method was 1 μg / mL for all. The plasma concentration data were analyzed by the non - compartmental model method (NCA) of the pharmacokinetic data analysis software WinNonlin to calculate the pharmacokinetic parameters and examine the pharmacokinetic characteristics of the test compounds in the cynomolgus monkeys after administration. The results are as shown in the following table.

[0150]

Table 2

[0151] The compound according to the present disclosure is superior to cefiderocol in terms of Cmax and AUC. Test Example 3: Pharmacokinetic test of the test compound in ICR mice

[0152] 1. Sample placement The dosing formulation was prepared on ice. An appropriate amount of the test compound was accurately weighed, 90% by volume of physiological saline was gradually added, and ultrasonic stirring was performed in an ice bath until there were no large particles. After thorough and uniform mixing, 1 M NaOH solution was added little by little in several portions using a pipette. After visually observing that all of the test sample had dissolved, the pH value was measured and the volume was made up to the final volume to obtain a dosing formulation at the target concentration for subcutaneous injection.

[0153] 2. Test Animals Species and Strain: ICR mice Animal Level: SPF grade Animal Origin: Medicilon / MPI Animal Bank: 999M - 018

[0154] 3. Test Methods The test sample was administered by subcutaneous injection, and the dosing schedule was as shown in the following table.

[0155]

Table 3 - 1

Table 3 - 2

[0156] Subcutaneous injection: For each gender, 3 animals per time point. Blood samples were collected 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, for a total of 9 time points. The collected blood samples were placed in EDTA - K2 anticoagulant collection tubes. The collected whole blood was placed on ice, and the plasma was centrifuged within 1 hour (centrifugation at 6800 g for 6 minutes, at 2 - 8°C). After centrifugation, the plasma was transferred to a centrifuge tube with a plasma stabilizer added (plasma: concentrated phosphoric acid = 100:0.2, for example, 1 μL of 10% concentrated phosphoric acid was added to 50 μL of plasma). Detailed clinical observations were performed on all animals at each blood collection point before and after administration, and the symptoms of adverse events in the animals were recorded.

[0157] Test Results: The pharmacokinetic data for each group were as follows.

[0158] [Table 4]

[0159] The exposure level of the compound related to this disclosure in mice is 4.2 times that of cefiderocol.

Claims

1. A compound represented by formula I or a medicinal salt thereof, 【Chemistry 1】 Eventually, X is N, CH, or C-Cl, T is S, S=O, CH ２ or O, E is 【Chemistry 2】 And among them, R １ and R ２ Each is independently selected from hydrogen, halogen, phenyl group, alkylthio group, or optionally an alkyl group substituted with a carbamoyl group, R １１ and R １２ Each of these is independently selected from a hydrogen atom, a carboxyl group, or an alkyl group optionally substituted with a carbamoyl group, and m refers to an integer from 1 to 5. F is a single bond, A is C １ ~C ６ an alkylidene group, C ２ ~C ６ an alkenylene group or C ２ ~C ６ an alkynylene group, R ５ These are, independently, halogen, hydroxyl group, and C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Selected from haloalkoxy groups, G １ teeth 【Transformation 3】 And, R １ ', R ２ ' are, independently, a hydrogen atom, a halogen, a hydroxyl group, and C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Selected from haloalkoxy groups, R ３ teeth, 【Chemistry 4】 C replaced by １ ~C ６ It is an alkyl group, R ３ ' is a hydrogen atom, a hydroxyl group, C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Selected from alkoxy groups, of which the alkyl group and alkoxy group are optionally C １ ~C ６ Alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR ｉ R ｊ , 【Transformation 5】 , oxo, thio, -C(O)R ｋ , -C(O)OR ｋ , -C(S)R ｋ , nitro group, cyano group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Substituted with one or more substituents selected from alkylsulfanil groups, R ｍ Each is independently a hydrogen atom, C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Selected from alkoxy groups, hydroxyl groups, 6-10 membered aryl groups, and 5-8 membered heteroaryl groups, of which the alkyl group, alkoxy group, aryl group, and heteroaryl group are optionally C １ ~C ６ Alkyl group, halogen, hydroxyl group, sulfhydryl group, amino group, carboxyl group, nitro group, cyano group, C １ ~C ６ Substituted with one or more substituents selected from alkoxy groups, R ４ These are, independently, halogen, hydroxyl group, sulfhydryl group, and -NR ｉ R ｊ Selected from, R ｉ , R ｊ These are, independently, a hydrogen atom, a hydroxyl group, and C. １ ~C ６ Alkyl alkyl group, C １ ~C ６ Selected from alkoxy groups, R ｋ Each is independently a hydrogen atom, C １ ~C ６ Alkyl alkyl group, C １ ~C ６ Haloalkyl group, hydroxyl group, C １ ~C ６ Alkoxy group, -NR ｉ R ｊ Selected from, of which the alkyl group, haloalkyl group, and alkoxy group are optionally C １ ~C ６ Alkyl group, halogen, hydroxyl group, sulfhydryl group, -NR ｉ R ｊ , oxo, thio, carboxyl group, nitro group, cyano group, C １ ~C ６ Alkoxy group, C １ ~C ６ Substituted with one or more substituents selected from alkylsulfanyl groups, 3-6 membered cycloalkyl groups, 3-6 membered heterocyclyl groups, 6-10 membered aryl groups, and 5-8 membered heteroaryl groups, p refers to an integer between 0 and 5. q refers to an integer between 0 and 5. x refers to an integer between 3 and 8. n refers to an integer between 0 and 3. A compound represented by formula I or a medicinal salt thereof.

2. A is C １ ~C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is an alkylidene group.

3. R １ ', R ２ The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein all of the atoms are hydrogen atoms.

4. x refers to an integer from 3 to 6, the compound according to any one of claims 1 to 3 or a medicinal salt thereof.

5. R ３ is 【Transformation 6】 C replaced by ３ ~C ６ A compound selected from alkyl groups, according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. [Request Item 6] [Chemistry 7] teeth 【Transformation 8】 And R ｎ Each of them is independently C １ ~C ６ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein r is selected from alkyl groups, hydroxyl groups, and halogens, and r independently refers to an integer from 0 to 5. 【Request Item 7】 【Chemistry 9】 teeth 【Chemistry 10】 The compound or medicinal salt thereof according to claim 6, wherein r independently refers to an integer from 0 to 3. 【Request Item 8】 【Chemistry 11】 teeth 【Chemistry 12】 The compound according to claim 6 or a medicinal salt thereof.

9. R ３ ' is a hydrogen atom or 【Chemistry 13】 C replaced by １ ~C ６ The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, selected from an alkyl group. 【Request Item 10】 【Chemistry 14】 teeth 【Chemistry 15】 And R ｎ Each of them is independently C １ ~C ６ A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein r is selected from alkyl groups, hydroxyl groups, and halogens, and r independently refers to an integer from 0 to 5. 【Request Item 11】 【Chemistry 16】 teeth 【Chemistry 17】 The compound according to claim 10 or a medicinal salt thereof, wherein r independently refers to an integer from 0 to 3. 【Request Item 12】 【Chemistry 18】 teeth 【Chemistry 19】 The compound according to claim 10 or a medicinal salt thereof.

13. The compound represented by formula I is 【Chemistry 20】 A compound according to any one of claims 1 to 12, or a medicinal salt thereof, selected from the above. 【Request Item 14】 【Chemistry 21】 A compound according to claim 1 or a medicinal salt thereof, selected from the medicinal salts thereof.

15. An isotopic substitution of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14.

16. The isotopic substitution according to claim 15, wherein the isotopic substitution is a deuterium atom substitution.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or an isotope substitution according to claim 15 or 16, and a pharmaceutically acceptable diluent or excipient.

18. The pharmaceutical composition according to claim 17 for preventing and treating diseases caused by Gram-negative bacteria.

19. The pharmaceutical composition according to claim 18, wherein the disease is selected from respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, meningomyelinitis, otitis media, enteritis, sinusitis, wound infections, and opportunistic infections.

20. The Gram-negative bacteria include Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, Haemophilus, Moraxella, Pseudomonas aeruginosa, and Pseudomonas other than Pseudomonas. The pharmaceutical composition according to claim 18, wherein the genera are Aeruginosa, Stenotropomonas, Burkholderia, or Acinetobacter.

21. The pharmaceutical composition according to claim 17 for preventing and treating diseases caused by pathogenic bacteria in mammals.

Images