A cephalosporin antibacterial compound and its preparation method

Abstract

This disclosure relates to a cephalosporin antibacterial compound and a method for preparing the same. This cephalosporin antibacterial compound exhibits antibacterial activity against a variety of bacteria, including Gram-negative bacteria.

Description

[0001] This application is a divisional application of the invention patent application with application number 202280007952.9, application date January 12, 2022, entitled "A cephalosporin antibacterial compound and its preparation method". Technical Field

[0002] This disclosure pertains to the pharmaceutical field, specifically relating to a cephalosporin antibacterial compound and its preparation method. Background Technology

[0003] The development of antibacterial treatment regimens remains a continuous challenge for society today. Antibacterial drugs include various synthetic antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, and other chemically synthesized drugs. Among these, β-lactam antibiotics are a very important class. To date, numerous β-lactamase drugs have been reported in the literature or are already on the market, making them extremely important antibacterial agents in clinical practice. However, the problem of resistance to β-lactam drugs is becoming increasingly serious, with a growing number of bacteria acquiring resistance by producing β-lactamases that degrade these drugs.

[0004] According to the Ambler molecular classification, β-lactamases are mainly divided into four categories. 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.). Among these types, types A, C, and D are mainly serine-β-lactamases, while type B is mainly metallo-β-lactamases. Both types have different mechanisms for hydrolyzing β-lactamase drugs.

[0005] The emergence of Gram-negative bacteria highly resistant to β-lactamases (including cephalosporins and carbapenems) has caused significant problems in clinical applications. This resistance arises from the production of type A or D serine β-lactamases and type B metallo-β-lactamases, which extend their substrate spectrum. Metallo-β-lactamases are known to be one of the causes of multidrug resistance in Gram-negative bacteria; however, developing cephalosporin compounds with more effective antibacterial activity, especially against Gram-negative bacteria that produce multiple β-lactamases, remains a challenge in the field of antimicrobial drug research.

[0006] According to literature reports (Antimicrob Agents Chemother. 1982, 22(2), 181–185.), cephalosporin compounds containing catechol groups in their molecules exhibit high activity against Gram-negative bacteria. This activity is attributed to the interaction between the catechol groups in the molecule and extracellular Fe... 3+ Formation of integrase, allowing compounds to pass through the Fe on the cell membrane 3+ The transport system (tonB-dependent transport system) effectively binds to the bacterial cell, and this Trojan horse strategy results in higher concentrations in the periplasmic space (the narrow space between the outer membrane and the cell wall), where it binds to receptors and inhibits bacterial cell wall synthesis. Therefore, compounds with catechol or similar structures at the 3- or 7-position side chains of the cephalosporin skeleton have been investigated (EP0416410B1). Cefiderocol is a novel siderophore cephalosporin (WO2010050468, WO2017216765, Eur. J Med. Chem. 2018, 155, 847-868.), and the FDA (Food and Drug Administration) has approved Shionogi Pharmaceuticals' Fetroja (cefiderocol) for the treatment of complicated urinary tract infections (cUTI) in patients aged 18 years and older, including kidney infections caused by susceptible Gram-negative bacteria. Summary of the Invention

[0007] The purpose of this disclosure is to provide a cephalosporin antibacterial compound that exhibits an effective antibacterial spectrum against a variety of bacteria, including Gram-negative bacteria.

[0008] This disclosure provides, in one aspect, a compound of formula I or a pharmaceutically acceptable salt thereof.

[0009]

[0010] in,

[0011] X is N, CH, or C-Cl;

[0012] T is S, S=O, CH2, or O;

[0013] E is , or R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio, or alkyl groups optionally substituted with carbamoyl groups, R 11 and R 12 Each is independently selected from hydrogen, carboxyl, or alkyl groups optionally substituted with carbamoyl, and m refers to an integer from 1 to 5;

[0014] F represents a single bond;

[0015] A is a C1-C6 alkylene group, a C2-C6 alkenyl subgroup, or a C2-C6 alkynyl subgroup;

[0016] R5 is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0017] G1 is ,

[0018] R1' and R2' are each independently selected from hydrogen atoms, halogens, hydroxyl groups, C1~C6 alkyl groups, C1~C6 alkoxy groups, C1~C6 haloalkyl groups, and C1-C6 haloalkoxy groups;

[0019] R3 is the Substituted C1-C6 alkyl groups;

[0020] R3' is selected from hydrogen atom, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, wherein the alkyl or alkoxy group is optionally selected from C1-C6 alkyl group, halogen, hydroxyl group, mercapto group, -NR group. i R j , Oxygenation, thioation, -C(O)R k -C(O)OR k -C(S)R k It is substituted by one or more substituents selected from nitro, cyano, C1-C6 alkoxy and C1-C6 alkyl thioether;

[0021] R m Each of the following is independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, 6 to 10 aryl and 5 to 8 heteroaryl, wherein the alkyl, alkoxy, aryl and heteroaryl are optionally substituted by one or more substituents selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, amino, carboxyl, nitro, cyano and C1-C6 alkoxy;

[0022] R4 groups are independently selected from halogens, hydroxyl groups, thiol groups, and -NR groups. i R j ;

[0023] R i R j Each is independently selected from hydrogen atom, hydroxyl group, C1~C6 alkyl group, and C1~C6 alkoxy group;

[0024] R k Each is independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, -NR i R jThe alkyl, haloalkyl, and alkoxy groups thereon are optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, and -NR groups. i R j It is substituted by one or more of the following substituents: oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl and 5- to 8-membered heteroaryl.

[0025] p refers to an integer from 0 to 5;

[0026] q refers to an integer from 0 to 5;

[0027] x refers to an integer from 3 to 8;

[0028] n refers to an integer from 0 to 3.

[0029] In the formula, "C" represents a carbon atom.

[0030] In some implementations, E is R1 and R2 are each independently selected from hydrogen, halogen, or alkyl groups optionally substituted with carbamoyl groups.

[0031] In some embodiments, A is a C1-C6 alkylene group.

[0032] In some implementations, R1' and R2' are both hydrogen atoms.

[0033] In some implementations, x refers to an integer from 3 to 6.

[0034] In some implementations, R3 is selected from the... Substituted C3-C6 alkyl groups.

[0035] In some implementations, for R n Each is independently selected from C1-C6 alkyl, hydroxyl, and halogen compounds; r independently refers to an integer from 0 to 5, preferably. r independently refers to an integer from 0 to 3, more preferably as .

[0036] In some embodiments, R3' is selected from hydrogen atoms or atoms that are... Substituted C1-C6 alkyl groups, preferably with hydrogen atoms or with... Substituted C3-C6 alkyl groups.

[0037] In some implementations, for R n Each is independently selected from C1-C6 alkyl, hydroxyl, and halogen compounds; r independently refers to an integer from 0 to 5, preferably. r independently refers to an integer from 0 to 3, more preferably as .

[0038] In some embodiments, the compound represented by Formula I is selected from...

[0039]

[0040] Or its medicinal salt.

[0041] In some embodiments, the compound is selected from...

[0042]

[0043] Or its medicinal salt.

[0044] The "alkyl" referred to in this disclosure is preferably a C1-C6 alkyl.

[0045] The "alkylene" described in this disclosure is preferably a C1-C6 alkylene.

[0046] The "sub-alkenyl" described in this disclosure is preferably a C2-C6 sub-alkenyl.

[0047] The "sub-chain alkynyl" described in this disclosure is preferably a C2-C6 sub-chain alkynyl.

[0048] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0049] The "alkyl thioether group" described in this disclosure is preferably a C1-C6 alkyl thioether group.

[0050] The "cycloalkyl" in this disclosure is preferably 3 to 12-membered, and more preferably 3 to 6-membered cycloalkyl.

[0051] The "fused cycloalkyl" described in this disclosure is preferably a 6- to 14-membered fused cycloalkyl, more preferably a 7- to 10-membered fused cycloalkyl.

[0052] The "heterocyclic group" described in this disclosure is preferably a 3- to 12-membered heterocyclic group, and more preferably a 3- to 6-membered heterocyclic group.

[0053] The "fused heterocyclic group" described in this disclosure is preferably a 6- to 14-membered fused heterocyclic group, and more preferably a 7- to 10-membered fused heterocyclic group.

[0054] The "aryl" in this disclosure is preferably 6 to 14 methyl groups, and more preferably 6 to 10 methyl groups.

[0055] The "fused-ring aryl" group described in this disclosure is preferably 8 to 14 quinones, and more preferably 8 to 12 quinones.

[0056] The "heteroaryl" as described in this disclosure is preferably 5 to 12 quinones, and more preferably 5 to 8 quinones.

[0057] The "heterogeneous aryl" described in this disclosure is preferably 5 to 14 quinones, and more preferably 5 to 12 quinones.

[0058] In some embodiments, the compounds described in this disclosure are Z-configured.

[0059] This disclosure also provides a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0060] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0061] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0062] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0063] This disclosure also provides the use of the compounds described herein or their pharmaceutically acceptable salts for the prevention and treatment of diseases caused by pathogens in mammals, including humans. Such uses include, for example, airway infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomeningomyelia, otitis media, enteritis, empyema, wound infections, opportunistic infections, etc.

[0064] This disclosure also provides for the use of the compounds described herein or their pharmaceutically acceptable salts for the prevention and treatment of diseases caused by Gram-negative bacteria. The Gram-negative bacteria mentioned are preferably Gram-negative intestinal bacteria (Escherichia coli, Klebsiella, Serratia, Enterobacter, Citrobacter, Morganella, Providencia, Proteus, etc.), Gram-negative bacteria residing in the respiratory system (Haemophilus, Moraxella, etc.), and non-fermenting glucose Gram-negative bacteria (Pseudomonas aeruginosa, Pseudomonas other than P. aeruginosa, Stenotrophomonas, Burkholderia, Acinetobacter, etc.).

[0065] This disclosure also provides for the use of the compounds described herein or their pharmaceutically acceptable salts for the prevention and treatment of diseases caused by Gram-positive bacteria.

[0066] This disclosure further provides a method for treating the above-mentioned diseases in mammals, which may be human or non-human mammals, for therapeutic purposes, comprising administering to the mammal the compounds described in this disclosure or their pharmaceutically acceptable salts, or pharmaceutical compositions.

[0067] This disclosure further provides a kit comprising the compounds described herein or their pharmaceutically acceptable salts, or pharmaceutical compositions.

[0068] According to test methods known in the art (e.g., WO2010050468), the compound disclosed herein was found to have inhibitory activity against Gram-negative bacteria, with excellent results.

[0069] Terminology Explanation:

[0070] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0071] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0072] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene 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. Alkylenes can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linking point.

[0073] The term "alkenyl" refers to a linear alkenyl 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 double bond at any position, including, for example, vinylene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentenylene, hexenylene, hexadienylene, etc.

[0074] The term "subchain ynyl" includes linear subchain ynyl 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 triple bond at any position, including, for example, ethynylene, propynylene, butynylene, pentylyne, hexynylene, etc.

[0075] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein 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, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0076] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0077] .

[0078] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0079] .

[0080] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include: .

[0081] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0082] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m The heteroatom (where m is an integer from 0 to 2) excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl or pyrrolidinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0083] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 member monocyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m The ring atoms are (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are 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-membered, more preferably 7 to 10-membered. Spirocyclic groups are classified into monospirocyclic, bispirocyclic, or multispirocyclic groups according to the number of shared spiroatoms between rings, preferably monospirocyclic and bispirocyclic groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0084] .

[0085] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0086]

[0087] .

[0088] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0089] .

[0090] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0091] wait.

[0092] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0093] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0094]

[0095] and ;

[0096] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group, preferably phenyl.

[0097] The term "fused-ring aryl" can refer to an unsaturated aromatic fused-ring structure containing 8-14 ring atoms, formed by two or more ring structures sharing two adjacent atoms. Preferably, it contains 8-12 ring atoms. Examples include fully unsaturated fused-ring aryl groups such as naphthalene and phenanthrene, as well as partially saturated fused-ring aryl groups such as benzo[3-8] saturated monocyclic cycloalkyl groups and benzo[3-8] partially saturated monocyclic cycloalkyl groups, specifically 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0098] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 12-membered, such as imidazolyl, furanyl, thiophenel, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0099] .

[0100] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0101] The term "fused aryl" can refer to an unsaturated aromatic fused ring structure containing 5-14 ring atoms (including at least one heteroatom) formed by two or more ring structures sharing two adjacent atoms. The carbon, nitrogen, and sulfur atoms can be substituted with oxygen. Preferably, it includes "5-12 fused aryl", "7-12 fused aryl", "9-12 fused aryl", etc., such as benzofuranyl, benzoisofuranyl, benzothiopheneyl, indole, isoindole, benzoxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinel, phenanthridinel, benzopyridinyl, phthalazinyl, quinazolinyl, quinoxalinyl, quinoxalinyl, phenazinyl, pteridinel, purinel, naphthidyl, phenazine, phenothiazine, etc.

[0102] The fused heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0103] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0104] The term "alkathio" refers to -S- (alkyl) and -S- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkathio groups include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, and cyclohexylthio. Alkathio groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkathio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkathio, and heterocycloalkathio.

[0105] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0106] The term "halogenated alkyl" refers to an alkyl group that has been substituted with a halogen, wherein the alkyl group is as defined above.

[0107] The term “deuterated alkyl” refers to an alkyl group that has been replaced by a deuterium atom, wherein the alkyl group is as defined above.

[0108] The term "hydroxyl group" refers to the -OH group.

[0109] The term "oxo" refers to the =O group. For example, a carbon atom is connected to an oxygen atom by a double bond, forming a ketone or aldehyde group.

[0110] 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)-.

[0111] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0112] The term "amino" refers to -NH2.

[0113] The term "cyano" refers to -CN.

[0114] The term "nitro" refers to -NO2.

[0115] The term "carboxyl group" refers to -C(O)OH.

[0116] The term "aldehyde group" refers to -CHO.

[0117] The term "carboxylic acid ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0118] The term "acyl halide" refers to a compound containing a -C(O)-halogen group.

[0119] "Carboxyl protecting group" is a suitable group known in the art for the protection of carboxyl groups; see reference ("Protective Groups in Organic Synthesis", 5). Th As an example, the carboxyl protecting group in Ed. TW Greene & PGMWuts, preferably, can be a substituted or unsubstituted C. 1-10 Straight-chain or branched alkyl, substituted or unsubstituted C 2-10 Straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3-silyl; preferably C 1-6 Straight-chain or branched alkyl groups, more preferably C 1-4 Straight-chain or branched alkyl groups. For example, methyl, ethyl, allyl, isopentenyl, trimethylsilylethyl, etc.

[0120] "Amino protecting group" is a suitable group known in the art for amino protection, see reference ("Protective Groups in Organic Synthesis", 5). Th The amino protecting group in Ed. TW Greene & PGMWuts, preferably, the amino protecting group can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C6-10 Aryloxy)carbonyl, such as Boc or Cbz; can also be substituted or unsubstituted alkyl, such as triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0121] "Hydroxy protecting group" is a suitable group known in the art for the protection of hydroxyl groups, see reference ("Protective Groups in Organic Synthesis", 5). Th The hydroxyl protecting group in Ed. TW Greene & PGMWuts. As an example, preferably, the hydroxyl protecting group can be (C 1-10 Alkyl or aryl) 3-silyl, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl-substituted alkyl, more preferably C 1-6 alkoxy-substituted C 1-6 alkyl or phenyl substituted C 1-6 Alkyl group, C is the most preferred. 1-4 alkoxy-substituted C 1-4 Alkyl groups, such as methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 Alkyl or aromatic acyl group, such as formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; or (C 1-6 Alkoxy or C 6-10 Aryloxy)carbonyl.

[0122] The term "leaving group" refers to an atom or functional group that is released from a larger molecule during a chemical reaction. Representative leaving groups include halogens, substituted sulfonyloxy groups, phosphoryloxy groups, amino groups, and R-terminal groups. i R j N-, cyano, R m S-etc.

[0123] The substituted sulfonyloxy group can be C1~C6 alkylsulfonyloxy, perfluorinated C1~C6 alkylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, etc.

[0124] Specific examples of C1-C6 alkylsulfonyloxy groups include C1-C6 straight-chain or branched alkylsulfonyloxy groups, such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy, and n-hexylsulfonyloxy.

[0125] Specific examples of perfluoroC1-C6 alkylsulfonyloxy groups include C1-C6 straight-chain 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.

[0126] Examples of arylsulfonyloxy groups include phenylsulfonyloxy and naphthylsulfonyloxy groups, which optionally have 1 to 3 substituents on the benzene ring, selected from the group consisting of a C1-C6 straight-chain or branched alkyl group, a C1-C6 straight-chain or branched alkyl group, a nitro group, and a halogen atom. Specific examples of phenylsulfonyloxy groups optionally having substituents include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-tolylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and so on. Specific examples of naphthylsulfonyloxy groups include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, and so on.

[0127] Examples of aralkylsulfonyloxy groups include: C1-C6 straight-chain or branched alkylsulfonyloxy groups substituted with a phenyl group (which optionally has 1 to 3 substituents selected from C1-C6 straight-chain or branched alkyl groups, C1-C6 straight-chain or branched alkyl groups, nitro groups, and halogen atoms on the benzene ring); and C1-C6 straight-chain or branched alkylsulfonyloxy groups substituted with a naphthyl group. Specific examples of phenyl-substituted alkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methylbenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc. Specific examples of naphthyl-substituted alkylsulfonyloxy groups include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

[0128] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0129] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.

[0130] In the chemical structure of the compounds described in this disclosure, the bond " "No configuration specified, i.e., key" "can be " "or" , or both contain " "and" "Two configurations. In the chemical structure of the compounds described in this disclosure, the bond " "No configuration is specified, which means it can be Z configuration or E configuration, or both configurations at the same time."

[0131] Tautomers are structural isomers of organic compounds that readily interconvert through a chemical reaction called tautomerization. This reaction often results in the migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomer pairs are keto-enol and lactam-lactamimide. An example of a lactam-lactamimide equilibrium is between A and B as shown below.

[0132]

[0133] All compounds in this disclosure can be classified as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0134] This disclosure covers any isotopically labeled derivatives of the compounds described herein or their pharmaceutically acceptable salts. Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. They can be labeled with isotopes. 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 I, etc. are used instead. Unless otherwise stated, when a position is specifically designated as deuterium (D), the position shall be understood as having a deuterium abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation). Detailed Implementation

[0135] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts described in this disclosure, but these examples are not intended to limit the scope of this disclosure.

[0136] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0137] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (LCMS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The spatial configurations of the optical isomers (isomers) of the compounds were further confirmed by measuring single-crystal parameters.

[0138] HPLC determinations were performed using a Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high performance liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column, or Ultimate C18 2.1*30mm column).

[0139] MS measurements were performed using a Waters SQD2 mass spectrometer in positive / negative ion mode, with a mass scan range of 100–1200.

[0140] Chiral HPLC analysis was performed using the following columns: Chiralpak IC-3 100×4.6mm ID, 3µm; Chiralpak AD-3 150×4.6mm ID, 3µm; Chiralpak AD-3 50×4.6mm ID, 3µm; Chiralpak AS-3 150×4.6mm ID, 3µm; Chiralpak AS-3 100×4.6mm ID, 3µm; ChiralCel OD-3 150×4.6mm I.D., 3µm; Chiralcel OD-3 100×4.6mm ID, 3µm; ChiralCel OJ-H 150×4.6mm ID, 5µm; and Chiralcel OJ-3 150×4.6mm ID, 3µm.

[0141] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0142] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0143] Normal column chromatography generally uses Yantai Huanghai silica gel of 100~200 mesh, 200~300 mesh or 300~400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0144] Reversed-phase column chromatography generally uses Changzhou Santai pre-packed ultrapure C18 silica gel columns (20-45μm, 100 Å, 40g, 80g, 120g, 220g or other specifications).

[0145] The high-pressure column purification system uses Waters AutoP, in conjunction with Waters XBridge BEH C18 OBDPrep Column, 130 Å, 5 µm, 19 mm x 150 mm, or Atlantis T3 OBD Prep Column, 100 Å, 5 µm, 19 mm x 150 mm.

[0146] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0147] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0148] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0149] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0150] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0151] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0152] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0153] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0154] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0155] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0156] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC 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 solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0157] Example 1:

[0158]

[0159]

[0160] Step 1

[0161] DMF (35 mL) solution of compound 1-1 (synthesized according to patent CN106661052A, 1.5 g, 3.50 mmol) was mixed with DMTMM (1.55 g, 5.26 mmol) and DIEA (905 mg, 7.0 mmol). After purging the reaction solution three times under argon protection, 1-A (525 mg, 7.0 mmol) was added to the above reaction solution, and the reaction was stirred at room temperature for 2 h. The reaction solution was slowly added to water, and a solid product gradually precipitated. The filtered solid product was dissolved in DCM, extracted, and separated. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain product 1-2 (1.6 g, 94% yield).

[0162] LC / MS (ESI): m / z 486.1 [M+H] +

[0163] Step 2

[0164] A solution of oxalyl chloride (1.05 g, 8.24 mmol) in DCM (10 mL) was cooled to -78 °C using a dry ice / acetone bath. Under argon protection, DMSO (1.29 g, 16.5 mmol) was added dropwise with stirring. A solution of 1-2 (1.6 g, 3.30 mmol) in DCM (6 mL) was slowly added dropwise to the above reaction solution, and stirring 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 slowly raised to 0 °C until completion. The reaction was quenched with H2O, and the mixture was extracted with DCM. The organic phase was washed successively 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 chromatography to obtain products 1-3 (1.28 g, 80% yield).

[0165] LC / MS (ESI): m / z 484.0 [M+H] +

[0166] Step 3

[0167] 1-B (605 mg, 5.30 mmol) was added to a 26 mL solution of DCM containing substrates 1-3 (1.28 g, 2.65 mmol). After cooling the reaction solution in an ice-water bath, NaBH(OAc)3 (1.68 g, 7.95 mmol) was added. The reaction was stirred at room temperature. After the reaction was complete, the reaction solution was quenched with NaHCO3 solution, then extracted with DCM. The organic phase was washed successively 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 chromatography to obtain product 1-4 (735 mg, yield 48%).

[0168] LC / MS (ESI): m / z 582.1 [M+H] +

[0169] Step 4

[0170] Add HATU (961 mg, 2.52 mmol) and DIEA (490 mg, 3.78 mmol) to a 13 mL solution of DMF containing 1-1 (650 mg, 1.51 mmol). Protect the reaction mixture with argon and stir at room temperature. Add 1-4 (735 mg, 1.26 mmol) to the above reaction mixture and stir again at room temperature. Slowly add the reaction mixture to water, filter, and dry under vacuum to obtain product 1-5 (1.2 g, 96% yield).

[0171] LC / MS (ESI): m / z 992.1 [M+H] +

[0172] Step 5

[0173] Compounds 1-5 (546 mg, 0.55 mmol), compounds 1-6 (synthesized according to patent WO2016035847, 398 mg, 0.5 mmol), and sodium iodide (225 mg, 1.5 mmol) were added to N,N-dimethylformamide (1.5 mL), and the mixture was stirred. After the reaction was complete, the reaction flask was cooled in an ice-water bath, and PBr3 (360 mg, 1.33 mmol) was added, followed by 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 water and dried under vacuum to obtain 1.13 g of crude product 1-7.

[0174] LC / MS (ESI): m / z 1737.1 [M] +

[0175] Step 6

[0176] Compounds 1-7 (1.13 g, 0.5 mmol) were added to anisole (2 mL) and trifluoroacetic acid (8 mL) and reacted at room temperature. Methyl tert-butyl ether was then added, and the mixture was stirred and filtered. The filter cake was washed with MTBE and dried to give 600 mg of crude product. HPLC analysis yielded 4 mg of compound 1.

[0177] HRMS: 979.1874 [M+H] +

[0178] 1 H-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).

[0179] Example 2:

[0180]

[0181]

[0182] Step 1

[0183] 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 stir at room temperature. Then cool the reaction mixture in an ice-water bath, add sodium borohydride (3.3 g, 87.0 mmol, 0.5 eq.) in portions, stir for 5 min, and then stir at room temperature 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. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain product 2-2, totaling 58.0 g (yield: 102.8%).

[0184] MS m / z 325.1 [M+H] +

[0185] Step 2

[0186] 2-2 (2.0 g, 6.2 mmol, 1.0 eq), S-propylene oxide (0.54 g, 9.3 mmol, 1.5 eq), and EtOH (20 mL) were added to a reaction flask and heated to 60 °C. The reaction mixture was monitored by LC-MS to ensure complete reaction of the starting materials. The reaction solution was concentrated, and the crude product was purified by column chromatography to obtain 1.2 g of product 2-3, yield: 51.1%.

[0187] MS m / z 383.2 [M+H] +

[0188] Step 3

[0189] Add 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) to a reaction flask, cool in an ice-water bath, and slowly add MsCl (0.54 g, 4.7 mmol, 1.5 eq) while stirring. Monitor the reaction mixture by LC-MS to ensure complete reaction. Wash the reaction solution with water and saturated sodium chloride solution, dry to anhydrous sodium sulfate, and concentrate to obtain crude 2-4 (1.34 g), which can be used directly in the next reaction step.

[0190] MS m / z 461.1 [M+H] +

[0191] Step 4

[0192] Crude product 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 heated to 40 °C with stirring. The reaction mixture was monitored by LC-MS to ensure complete reaction of the starting material. 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, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 2-5 (0.66 g, two-step yield: 48.5%).

[0193] MS m / z 436.1 [M+H] +

[0194] Step 5

[0195] Dissolve 2-5 (600 mg, 1.38 mmol) and TFA (10 mL) in a reaction flask, and heat to 60°C until the reaction is complete. Concentrate the reaction solution to dryness, add MTBE (10 mL), slurry, and decant the supernatant. Remove most of the solvent from the resulting oily substance 2-6 under vacuum and use it directly in the next reaction step.

[0196] MS m / z 186.1 [M+H] +

[0197] Step 6

[0198] Crude products 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 until completion. 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 product was separated by column chromatography (DCM:MeOH = 10:1) to obtain 0.85 g of 2-7.

[0199] MS m / z 1006.3 [M+H] +

[0200] Step 7

[0201] Add 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) to the reaction flask. After purging the air three times with argon, add NMP (2.1 mL). Let the reaction solution react at room temperature until completion. The reaction solution is used directly in the next step without further treatment.

[0202] MS m / z 1767.5 [M] +

[0203] Step 8

[0204] After adding 0.7 mL of NMP to the above reaction solution, the reaction solution was cooled to 0°C. Then, 0.103 mL of phosphorus trichloride (1.17 mmol) was added, and the reaction was maintained at 0°C until completion. Next, 20 mL of a 5% sodium bisulfite aqueous solution was added to the reaction solution, and the mixture was stirred in an ice-water bath. The mixture was filtered, and the filter cake was dissolved in 20 mL of DCM, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 1.21 g of 2-9.

[0205] MS m / z 1751.4 [M] +

[0206] Step 9

[0207] Compound 2-9 (1.21 g, 0.69 mmol) was 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 stirred in an ice-water bath. The mixture was filtered, and the filter cake was washed with MTBE and dried to obtain 0.82 g of crude product. Further analysis by reverse HPLC yielded 107 mg of compound 2.

[0208] MS m / z 993.1 [M+H] +

[0209] Example 3:

[0210]

[0211]

[0212] Step 1

[0213] Add 3-1 (3.7 g, 28.0 mmol) (synthesized according to the method described in Angewandte Chemie International Edition, 2010, 49, 7208–7212), 1-1 (26.4 g, 61.6 mmol), and DCM (316 mL) to the reaction flask, stir to dissolve, and cool in an ice-water 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 to anhydrous sodium sulfate, filter again, and concentrate to dryness. Purify the crude product by silica gel chromatography to obtain product 3-2 (21.8 g, 82% yield).

[0214] LC / MS (ESI): m / z 953.1 [M+H] +

[0215] 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).

[0216] Step 2

[0217] Add 3-2 (21.7 g, 22.75 mmol) and DCM (217 mL) to the reaction flask, purge with nitrogen, and cool in an ice-water bath. Add TEA (8.06 g, 79.63 mmol) dropwise. Dissolve MsCl (7.82 g, 68.25 mmol) in 8 mL of DCM and slowly add it dropwise to the reaction system. After the addition is complete, stir in an ice-water bath until the reaction is finished. Quench the reaction with water, and adjust the pH to 8 with a saturated NaHCO3 aqueous solution. Separate the liquid and collect the organic phase. Extract the aqueous phase with DCM, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to dryness to obtain product 3-3 (24.0 g, yield 102%).

[0218] LC / MS (ESI): m / z 1031.2 [M+H] +

[0219] Step 3

[0220] Add 23.9 g (22.75 mmol) of 3-3 and 240 mL of THF to the reaction flask and stir to dissolve. Add LiBr (5.93 g, 68.25 mmol). After the addition is complete, heat to 60°C. o C. Stir the reaction. After the reaction is complete, concentrate to remove the solvent, add water, extract with EA, combine the organic phases, dry with anhydrous sodium sulfate, and filter. Concentrate to dryness to obtain product 3-4 (22.2 g, yield 94%).

[0221] LC / MS (ESI): m / z 1015.2 [M+H] +

[0222] Step 4

[0223] Add 3-4 (22.1 g, 21.73 mmol) and ACN (442 mL) to the reaction flask, stir to dissolve, then add K2CO3 (10.51 g, 76.06 mmol) and pyrrolidine (4.64 g, 65.19 mmol), respectively. After the additions are complete, heat to 60°C. o C. Stir the reaction. After the reaction is complete, concentrate to remove the solvent, add water, and extract with a mixed solvent of DCM:MeOH = 10:1. Combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the crude product by normal-phase silica gel column chromatography to obtain product 3-5 (16.2 g, yield 74%).

[0224] LC / MS (ESI): m / z 1006.3 [M+H] +

[0225] 1 H-NMR (400 MHz, DMSO-d6) δ: 1.50-1.65 (m, 4H), 1.74-1.89 (m, 4H), 2.21-2.38 (m, 3H), 2.69-2.91 (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).

[0226] Step 5

[0227] Add 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) to the reaction flask, purging the argon atmosphere three times. Add 27 mL of NMP under an ice-water bath. After the addition is complete, bring the mixture to room temperature and stir until the reaction is complete. The reaction solution can be directly added to the next reaction step without further purification.

[0228] LC / MS (ESI): m / z 1767.9 [M] + (The strongest ion flow)

[0229] Step 6

[0230] Cool the reaction solution obtained in the previous step to 0°C. o C. Slowly add phosphorus trichloride (1.58 g, 11.53 mmol), maintaining a constant temperature at 0°C after addition. o C. Stir the reaction mixture until complete. Dilute the reaction solution with water, filter to obtain 14 g of crude product 3-7, dry under vacuum and use directly in the next step.

[0231] LC / MS (ESI): m / z 1751.5 [M] + (The strongest ion flow)

[0232] Step 7

[0233] The crude products 3-7 were dissolved in anisole (28 mL) and trifluoroacetic acid (112 mL) and reacted at room temperature. After the reaction was complete, the mixture was cooled to 0°C, MTBE (200 mL) was added, and the mixture was stirred in an ice-water bath and filtered. The filter cake was washed with MTBE and dried to obtain 8 g of crude product. Further analysis by reverse HPLC yielded product compound 3 (3.37 g, 50% yield).

[0234] LC / MS (ESI): m / z 993.2 [M+H]+

[0235] 1 H-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).

[0236] Biological evaluation

[0237] The present disclosure is further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0238] Test Example 1: Antifungal Activity Test

[0239] 1. Dissolve the test compound in sterile physiological saline, vortex to mix, and then perform 2-fold serial dilutions with sterile physiological saline. A total of 11 concentration points were tested. The test concentration range was 32–0.031 μg / mL, with duplicate wells per concentration. An additional well without the drug was included as a growth control.

[0240] 2. Add 4 μL of diluent to 196 μL of bacterial suspension in a 96-well plate (the bacterial count in the suspension should be 2-8 × 10⁻⁶). 5 Colony forming units / mL).

[0241] 3. After incubation at 36℃ for 24 hours, visually observe and read the MIC value.

[0242] The determination of the minimum inhibitory concentration (MIC) should be performed in accordance with the guidelines of the Clinical Laboratory Standards Institute (CLSI).

[0243]

[0244]

[0245] Test Example 2: Pharmacokinetic Test of the Test Compound in Cynomolgus Monkeys

[0246] 1. Sample preparation

[0247] Accurately weigh appropriate amounts of the test compound into containers, add 0.9% sodium chloride injection and 0.2 M NaOH solution under ice bath until the test compound is completely dissolved, prepare a sample solution with a concentration of 2 mg / mL, and store at 2~8°C for later use.

[0248] 2. Experimental animals

[0249] Species and strains: Crab-eating macaques

[0250] Animal rating: Common

[0251] Animal source: Guangxi Xiongsen Primate Laboratory Animal Breeding and Development Co., Ltd.

[0252] Animal Use Permit Number: SYXK (Su) 2019-0012

[0253] 3. Test methods

[0254] Six cynomolgus macaques (half male and half female) were randomly divided into three groups, with one animal per group (sex). Each group received a single intravenous infusion of the test samples at a dose of 10 mg / kg. Blood samples were collected from each group before administration and at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 8 h after administration. The concentrations of each test compound in the cynomolgus macaque plasma were determined using LC-MS / MS, with a limit of quantitation (LOQ) of 1 μg / mL for all plasma samples. The plasma concentration data were analyzed using the non-compartmental aggregator (NCA) method in WinNonlin software to calculate pharmacokinetic parameters and investigate the pharmacokinetic characteristics of the test compounds in the cynomolgus macaques after administration. The results are shown in the table below.

[0255]

[0256] The disclosed compound is superior to cefdil in terms of Cmax and AUC.

[0257] Test Example 3: Pharmacokinetic Test of the Test Compound in ICR Mice

[0258] 1. Sample preparation

[0259] Prepare the drug formulation on ice. Accurately weigh an appropriate amount of the test compound and slowly add 90% physiological saline. Sonicate the mixture in an ice-water bath until no large particles remain. After thorough mixing, add 1M NaOH solution in small amounts several times using a pipette. Once the test sample is visibly dissolved, measure the pH value and bring the volume to the final volume to obtain the drug formulation of the target concentration, which is then used for subcutaneous injection.

[0260] 2. Experimental animals

[0261] Species and strains: ICR mice

[0262] Animal rating: SPF

[0263] Animal source: Medicipua Reserve Animal Bank: 999M-018

[0264] 3. Test methods

[0265] The test sample was administered via subcutaneous injection, and the dosing regimen is shown in the table below.

[0266]

[0267] Subcutaneous injection administration: 3 animals of each sex at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration, for a total of 9 time points. The collected blood samples were placed in EDTA-K2 anticoagulant blood collection tubes. The collected whole blood was placed on ice and centrifuged for 1 hour to separate the plasma (centrifugation force 6800g, centrifugation 6 min, 2-8 ºC). The centrifuged plasma was transferred to centrifuge tubes pre-added with plasma stabilizer (plasma:concentrated phosphate = 100:0.2, e.g., 50uL plasma to 1uL of 10% concentrated phosphate). All animals underwent detailed clinical observation at each blood collection point before and after administration, and adverse reaction symptoms were recorded.

[0268] Experimental results: The pharmacokinetic data for each group are shown below.

[0269]

[0270] The disclosed compound was exposed at levels 4.2 times higher in mice than cefdil.

Claims

1. The compound shown in Formula I or a pharmaceutically acceptable salt thereof, in, X is N, CH, or C-Cl; T is S, S=O, CH2, or O; E is , or R1 and R2 are each independently selected from hydrogen, halogen, phenyl, alkylthio, or alkyl groups optionally substituted with carbamoyl groups, R 11 and R 12 Each is independently selected from hydrogen, carboxyl, or alkyl groups optionally substituted with carbamoyl, and m refers to an integer from 1 to 5; F represents a single bond; A is a C1-C6 alkylene group, a C2-C6 alkenyl subgroup, or a C2-C6 alkynyl subgroup; R5 is independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. G1 is , R1' and R2' are each independently selected from hydrogen atoms, halogens, hydroxyl groups, C1~C6 alkyl groups, C1~C6 alkoxy groups, C1~C6 haloalkyl groups, and C1-C6 haloalkoxy groups; R3 is the Substituted C1-C6 alkyl groups; R3' is selected from hydrogen atom, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, wherein the alkyl or alkoxy group is optionally selected from C1-C6 alkyl group, halogen, hydroxyl group, mercapto group, -NR group. i R j , Oxygenation, thioation, -C(O)R k -C(O)OR k -C(S)R k It is substituted by one or more substituents selected from nitro, cyano, C1-C6 alkoxy and C1-C6 alkyl thioether; R m Each of the following is independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, 6 to 10 aryl and 5 to 8 heteroaryl, wherein the alkyl, alkoxy, aryl and heteroaryl are optionally substituted by one or more substituents selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, amino, carboxyl, nitro, cyano and C1-C6 alkoxy; R4 groups are independently selected from halogens, hydroxyl groups, thiol groups, and -NR groups. i R j ; R i R j Each is independently selected from hydrogen atom, hydroxyl group, C1~C6 alkyl group, and C1~C6 alkoxy group; R k Each is independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy, -NR i R j The alkyl, haloalkyl, and alkoxy groups thereon are optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, and -NR groups. i R j It is substituted by one or more of the following substituents: oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 6- to 10-membered aryl and 5- to 8-membered heteroaryl. p refers to an integer from 0 to 5; q refers to an integer from 0 to 5; x refers to an integer from 3 to 8; n refers to an integer from 0 to 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a C1-C6 alkylene group.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein R1' and R2' are both hydrogen atoms.

4. The compound or its pharmaceutically acceptable salt according to any one of claims 1-3, wherein x refers to an integer from 3 to 6.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from... Substituted C3-C6 alkyl groups.

6. The compound or its pharmaceutically acceptable salt according to any one of claims 1-5, wherein... for R n Each is independently selected from C1-C6 alkyl, hydroxyl, and halogen compounds; r independently refers to an integer from 0 to 5, preferably. r independently refers to an integer from 0 to 3, more preferably as .

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R3' is selected from hydrogen atoms or atoms that are... Substituted C1-C6 alkyl groups.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1-7, wherein... for R n Each is independently selected from C1-C6 alkyl, hydroxyl, and halogen compounds; r independently refers to an integer from 0 to 5, preferably. r independently refers to an integer from 0 to 3, more preferably as .

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is selected from... 。 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... Or its medicinal salt.

11. An isotope-substituted derivative of the compound according to any one of claims 1-10 or a pharmaceutically usable salt thereof, preferably wherein the isotope substitution is deuterium substitution.

12. A pharmaceutical composition comprising the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof or an isotopic substitute of claim 11, and a pharmaceutically acceptable carrier, diluent or excipient.

13. The compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, the isotope-substituted product of claim 11, or the pharmaceutical composition of claim 12, for use in the preparation of a treatment for the prevention and treatment of diseases caused by Gram-negative bacteria, preferably from airway infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, pneumonia, myelomeningomyelitis, otitis media, enteritis, empyema, wound infections, and opportunistic infections, wherein the Gram-negative bacteria are preferably *Escherichia coli* (E. coli). The following bacteria are listed: *C. coli*, *Klebsiella*, *Serratia*, *Enterobacter*, *Citrobacter*, *Morganella*, *Providencia*, *Proteus*, *Haemophilus*, *Moraxella*, *Pseudomonas aeruginosa*, *Pseudomonas other than *P. aeruginosa*, *Stenotrophomonas*, *Burkholderia*, or *Acinetobacter*.

14. The use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof, the isotope substitute of claim 11, or the pharmaceutical composition of claim 12 in the preparation of a drug for the prevention and treatment of diseases caused by pathogens in mammals.

15. The following compounds or their salts, 。

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