Boric acid derivatives as β-lactamase inhibitors

Abstract

The boric acid derivatives of β-lactamase inhibitors of formula I or pharma- ceutically acceptable salts thereof and their stereoisomers, rotamers or tautomers or deuterated compounds are applicable to the treatment of bacterial infections. JPEG2024514055000059.jpg42170

Description

[Technical Field]

[0001] This disclosure belongs to the pharmaceutical field and specifically relates to boric acid derivatives as β-lactamase inhibitors. [Background technology]

[0002] Beta-lactam antibiotics are among the most widely used and effective antimicrobial agents clinically. The most important antibiotics currently available are compounds containing several beta-lactam rings, including penicillins, penems, carbapenems, cephalosporins, monocyclic lactams, and sulfactams. These beta-lactam antibiotics inhibit cell wall biosynthesis by binding to a protein called penicillin-binding protein (PBP), which is essential for the synthesis of peptidoglycan, a major component of the cell walls of Gram-negative and Gram-positive bacteria.

[0003] Although β-lactam antibiotics remain extremely important worldwide, resistance to β-lactamase antibiotics in various infectious pathogens reduces their therapeutic effectiveness against bacterial infections. The most prominent drug resistance mechanism is the production of A, C, and D type β-lactamases, which have serine residues in their active site. These enzymes can degrade β-lactam antibiotics and inactivate their antibacterial activity. Type A β-lactamases are primarily substrate-specific to penicillin-based drugs, while type C β-lactamases are primarily substrate-specific to cephalosporin-based drugs. Commercially available β-lactamase inhibitors include clavulanic acid, sulbactam, and tazobactam. These inhibitors are mainly effective against type A β-lactamase-producing bacteria and are used in combination with penicillin-based antibiotics. However, to date, more than 250 types of β-lactamases have been reported. Of these, aside from the spread of type C β-lactamases and extended-spectrum β-lactamases (ESBLs) belonging to types A and D, the fact that KPC-2, which belongs to type A and further breaks down carbapenems, the final barrier to β-lactam antibiotics, is also a cause for concern.

[0004] In recent years, novel β-lactamase inhibitors such as QPX-7728 and VNRX-5133 have become a hot spot in development. WO2014107536, WO2014089365, WO2018005662, and WO2019226931 describe the development of a series of β-lactamase inhibitors to improve drug resistance to existing β-lactamase inhibitors. [ka] [Overview of the Initiative]

[0005] This disclosure aims to provide boric acid derivatives as β-lactamase inhibitors applicable to the treatment of bacterial infections.

[0006] One aspect of the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, tautomer or deuterium compound thereof,

Chemical formula

[0007] B is a boron atom.

[0008] In one embodiment, R k These are independently hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, hydroxyl groups, and -NR groups. i R j Selected from among, of which the alkyl groups, alkoxy groups, and haloalkyl groups are optionally C1-C6 alkyl groups, halogens, hydroxyl groups, mercapto groups, and -NR groups. i R j It is substituted with one or more substituents selected from oxy groups, thio groups, carboxyl groups, nitro groups, cyano groups, C1-C6 alkoxy groups, C1-C6 alkylthioether groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups.

[0009] In one embodiment, the compound represented by formula I is the compound represented by formula I-1 or I-2, [ka] .

[0010] Of these, rings B and C are independently and arbitrarily selected from a ring system consisting of a carbocyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, a spirocarbocyclic ring, a spiroheterocyclic ring, a fused carbocyclic ring, a fused heterocyclic ring, a fused aromatic ring, and a fused heteroaromatic ring. Y2' is selected from CR5 or N. Y3' is selected from CR5' or N. R5 and R5' are each independently substituted with hydrogen or optionally substituted alkyl groups, alkenyl groups, alkynyl groups, halogens, deuterium, hydroxyl groups, mercapto groups, or -NR i R j , -C(O)R k , -C(O)OR k ,-S(O)R k , -S(O)OR k ,-S(O)(O)R k , -S(O)(O)OR k ,-C(S)R k The group is selected from the following: nitro group, cyano group, alkoxy group, alkylthioether group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0011] In one embodiment, the ring system formed by R6 together with at least one of R5 and R5' and an adjacent carbon atom, or ring B, ring C, independently, [ka] From this ring system, one was selected, Y is independently selected from CH2, NH, O, and S. R a , R b These are each independently and optionally substituted C1-C6 alkyl groups, halogens, deuterium, hydroxyl groups, mercapto groups, and -NR groups. i R j , oxy group, thio group, -C(O)R k , -C(O)OR k ,-S(O)R k , -S(O)OR k ,-S(O)(O)R k , -S(O)(O)OR k,-C(S)R k A group selected from the following: nitro group, cyano group, C1-C6 alkoxy group, C1-C6 alkylthioether group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclyl group, 7-10 membered condensed cycloalkyl group, 7-10 membered condensed heterocyclyl group, 6-10 membered aryl group, 5-10 membered heteroaryl group, 8-12 membered condensed ring aryl group, and 5-12 membered condensed heteroaryl group. n is selected from 1, 2, 3, 4, 5, or 6. m and p are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0012] In one embodiment, R1 and R2 are independently substituted with hydrogen or optionally substituted with a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a halogen, deuterium, a hydroxyl group, or -NR i R j The group is selected from C1-C6 alkoxy groups.

[0013] In one embodiment, ring A is selected from a 3- to 12-membered, more preferably 3- to 6-membered carbon ring or heteroring that is optionally substituted.

[0014] In one embodiment, R3 is independently and optionally substituted with -C(O)OR k and are selected from carboxylic acid isosteres that are optionally substituted.

[0015] In one embodiment, the carboxylic acid isostere may be selected from tetrazole, -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from hydrogen, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, 3- to 6-membered cycloalkyl groups, 6- to 10-membered aryl groups, 5- to 10-membered heteroaryl groups, and 3- to 6-membered heterocyclyl groups.

[0016] In one embodiment, the compound [ka] or a pharmaceutically acceptable salt thereof, or selected from its stereoisomers, rotational isomers, tautomers, or deuterium compounds, Of these, Y is independently selected from CH2, NH, O, and S; n is independently selected from 1, 2, 3, 4, 5, or 6; and X1 is independently selected from F, Cl, and Br.

[0017] In one embodiment, the compound [ka] Alternatively, a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, selected from these.

[0018] In one embodiment, the compound [ka] Alternatively, a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, selected from these.

[0019] In one embodiment, the pharmaceutically acceptable salt is selected from alkali metal salts or ammonium salts. In one embodiment, the pharmaceutically acceptable salt is a sodium salt, and includes disodium salts.

[0020] In one embodiment, the compound is [ka] Alternatively, it may be selected from its stereoisomers, rotational isomers, tautomers, or deuterium compounds.

[0021] In one embodiment, the compound is [ka] Alternatively, it may be selected from its stereoisomers, rotational isomers, tautomers, or deuterium compounds.

[0022] The "alkyl group" described in this disclosure is preferably a C1-C6 alkyl group.

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

[0024] The "alkynyl group" described in this disclosure is preferably a C2-C6 alkynyl group.

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

[0026] The "alkenylene group" described in this disclosure is preferably a C2-C6 alkenylene group.

[0027] The "alkylylene group" described in this disclosure is preferably a C2-C6 alkylylene group.

[0028] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0029] The "alkylthioether group" described in this disclosure is preferably a C1-C6 alkylthioether group.

[0030] The "cycloalkyl group" described herein is preferably a cycloalkyl group having 3 to 12 members, more preferably 3 to 6 members.

[0031] The “condensed cycloalkyl group” described herein is preferably a condensed cycloalkyl group having 6 to 14 members, more preferably 7 to 10 members.

[0032] The "heterocyclyl group" described herein is preferably a 3- to 12-membered, more preferably 3- to 6-membered heterocyclyl group.

[0033] The “condensed heterocyclyl group” described herein is preferably a condensed heterocyclyl group having 6 to 14 members, more preferably 7 to 10 members.

[0034] The “aryl group” described herein is preferably a 6- to 14-membered, more preferably 6- to 10-membered aryl group.

[0035] The "fused ring aryl group" described herein is preferably an 8- to 14-membered, more preferably 8- to 12-membered fused ring aryl group.

[0036] The "heteroaryl group" described herein is preferably a 5- to 12-membered heteroaryl group, more preferably a 5- to 10-membered heteroaryl group.

[0037] The “condensed heteroaryl group” described herein is preferably a 5- to 14-membered, more preferably 5- to 12-membered condensed heteroaryl group.

[0038] The "optionally substituted" group described in this disclosure is an alkyl group (preferably a C1-C6 alkyl group), a halogen, deuterium, a hydroxyl group, a mercapto group, or -NR. i R j , oxy group, thio group, -C(O)R k , -C(O)OR k ,-S(O)R k , -S(O)OR k ,-S(O)(O)R k , -S(O)(O)OR k ,-C(S)R kIt may also be substituted with one or more substituents selected from nitro groups, cyano groups, alkoxy groups (preferably C1-C6 alkoxy groups), alkylthioether groups (preferably C1-C6 alkylthioether groups), alkenyl groups (preferably C2-C6 alkenyl groups), alkynyl groups (preferably C2-C6 alkynyl groups), cycloalkyl groups (preferably 3- to 6-membered cycloalkyl groups), heterocyclyl groups (preferably 3- to 6-membered heterocyclyl groups), condensed cycloalkyl groups (preferably 7- to 10-membered condensed cycloalkyl groups), condensed heterocyclyl groups (preferably 7- to 10-membered condensed heterocyclyl groups), aryl groups (preferably 6- to 10-membered aryl groups), heteroaryl groups (preferably 5- to 10-membered heteroaryl groups), condensed ring aryl groups (preferably 8- to 12-membered condensed ring aryl groups), and condensed heteroaryl groups (preferably 5- to 12-membered condensed heteroaryl groups). i , R j and R k As stated above, the group of selectable substituents for each "optionally substituted" group may be homologous or different.

[0039] This disclosure further provides pharmaceutical compositions comprising at least one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof, or stereoisomers, rotational isomers, tautomers or deuterium compounds thereof, and a pharmaceutically acceptable vector, diluent or excipient.

[0040] In one embodiment, the unit dose of the above pharmaceutical composition is 0.001 mg to 1000 mg.

[0041] In one embodiment, the pharmaceutical composition contains 0.01% to 99.99% of the compound based on the total weight of the composition. In another embodiment, the pharmaceutical composition contains 0.1% to 99.9% of the compound. In yet another embodiment, the pharmaceutical composition contains 0.5% to 99.5% of the compound. In yet another embodiment, the pharmaceutical composition contains 1% to 99% of the compound. In yet another embodiment, the pharmaceutical composition contains 2% to 98% of the compound.

[0042] In one embodiment, 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 one embodiment, the pharmaceutical composition contains 0.1% to 99.9% of pharmaceutically acceptable vectors, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 0.5% to 99.5% of pharmaceutically acceptable vectors, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 1% to 99% of pharmaceutically acceptable vectors, diluents, or excipients. In one embodiment, the pharmaceutical composition contains 2% to 98% of pharmaceutically acceptable vectors, diluents, or excipients.

[0043] This disclosure further provides uses for the treatment of bacterial infections of the compounds described herein or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterium compounds. Examples of bacterial organisms include Gram-positive bacteria, Gram-negative bacteria, aerobic bacteria, and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, and Mycobacterium. This includes Proteus, Campylobacter, Citrobacter, Nisseria, Bacillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, and other organisms.

[0044] Further examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, and Salmonella typhimurium. Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris Providencia vulgaris, Providencia alcalifaciens, Providencia letgeriBordetella rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter hae molyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae Haemophilus parahae molyticus, Haemophilus parahae molyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella hae molytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrioparahae Legionella pneumophilapneumophila), Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactia agalactiae), Streptococcus pyogenes, Enterococcus faecalisThis includes Staphylococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus hae molyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

[0045] The compounds described herein or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterium compounds, may be used in combination with one or more other antibiotics for the treatment of bacterial infections. These other antibiotics include, for example, β-lactam antibiotics.

[0046] This disclosure further provides a method for treating bacterial infections in mammals, the mammals may be human or non-human mammals, and includes administering to the mammal, for therapeutic purposes, a compound described in this disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer or deuterium compound thereof, or a pharmaceutical composition.

[0047] This disclosure further provides reagent kits comprising the compounds described herein or pharmaceutically acceptable salts thereof, or stereoisomers, rotational isomers, tautomers or deuterium compounds thereof, or pharmaceutical compositions.

[0048] Explanation of terms: Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0049] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, 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 point, 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, mercapto 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.

[0050] 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 substituents may be substituted at any available connection point.

[0051] 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, and includes, for example, vinylidene group, allylene group, propenylene group, butenylene group, prenylene group, butadienylene group, pentenylene group, pentadienyldene group, hexenylene group, hexadienylene group, and the like.

[0052] The term "alkynylene group" includes linear alkylylene 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, such as ethynylene, propynylene, butynylene, pentynylene, and hexynylene groups.

[0053] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents, where a 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. "Carbocyclic" refers to the ring system within a cycloalkyl group.

[0054] 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, they have 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. "Spirocarbocyclic ring" refers to the ring system within a spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0055] The term "condensed cycloalkyl group" refers to a 5- to 20-membered, 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, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. "Condensed carbon ring" refers to the ring system in a condensed cycloalkyl group. Non-limiting examples of condensed cycloalkyl groups are: [ka] Includes.

[0056] The term "crosslinked cycloalkyl group" refers to a 5- to 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 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, crosslinked cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] Includes.

[0057] 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, mercapto 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.

[0058] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic 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. "Heterocyclic" refers to the ring system in the heterocyclyl group.

[0059] 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 there are no rings with 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. "Spiroheterocycle" refers to the ring system in the spiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0060] 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-member / 5-member or 5-member / 6-member bicyclic fused heterocyclyl group. "Fused heterocycle" refers to the ring system in the fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0061] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group with 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.

[0062] 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.

[0063] 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, mercapto 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.

[0064] The term "aryl group" 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 members, such as the phenyl group and the naphthyl group. The above aryl ring may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, of which the ring linked to the parent structure is the aryl ring. "Aromatic ring" refers to the ring system in the aryl group. Non-limiting examples of aryl groups are: [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, mercapto 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.

[0065] The term "fused ring aryl group" refers 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. "Fused aromatic ring" refers to the ring system within the fused ring aryl group. Specific examples of fused ring aryl groups include, for example, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0066] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 12-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, and pyrazinyl groups, preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl groups, and more preferably pyrazolyl or thiazolyl groups. The heteroaryl ring may be fused to an aryl group, heterocyclyl group, or cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring. "Heteroaromatic ring" refers to the ring system within a heteroaryl group. Non-limiting examples of heteroaryl groups include: [ka] Includes.

[0067] 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, mercapto 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 "condensed heteroaryl group" refers to an aromatic, unsaturated condensed ring structure containing 5 to 14 ring atoms (including at least one heteroatom), 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- to 12-membered condensed heteroaryl group," a "7- to 12-membered condensed heteroaryl group," a "9- to 12-membered condensed heteroaryl group," etc., such as benzofuranyl. These include groups such as 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, naphthilidinyl group, phenazinyl group, and phenothiazinyl group. "Fused heteroaromatic ring" refers to the ring system in a fused heteroaryl group.

[0069] 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, mercapto 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.

[0070] 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, mercapto 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.

[0071] 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, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0072] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxyl group, and among these, alkyl groups are defined as described above.

[0073] The term "haloalkyl group" refers to an alkyl group substituted with a halogen, and the alkyl group is defined as described above.

[0074] The term "deuterated alkyl group" refers to an alkyl group substituted with a deuterium atom, and the alkyl group is defined as described above.

[0075] The term "hydroxyl group" refers to the -OH group.

[0076] The term "oxy group" 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.

[0077] The term "thio group" refers to the =S group. For example, a carbon atom and a sulfur atom are linked by a double bond to form a thiocarbonyl-C(S)-.

[0078] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0079] The term "amino group" refers to -NH2.

[0080] The term "cyano group" refers to -CN.

[0081] The term "nitro group" refers to -NO2.

[0082] The term "carboxyl group" refers to -C(O)OH.

[0083] The term "aldehyde group" refers to -CHO.

[0084] 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.

[0085] The term "acyl halogen" refers to compounds that contain the group -C(O)-halogen.

[0086] The term "sulfonyl group" refers to -S(O)(O)-.

[0087] The term "sulfinyl group" refers to -S(O)-.

[0088] An "isoster," as a chemical group, is another chemical group that exhibits similar or analogous properties. For example, tetrazole is an isoster of a carboxylic acid because, even though the two have quite different molecular formulas, tetrazole simulates the properties of a carboxylic acid. Tetrazole is one of many possible isosteric substitutions of carboxylic acids. Other foreseeable carboxylic acid isosteres include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from, for example, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups as defined herein. Carboxylic acid isosteres may also include 5- to 7-membered carbon rings or heterocycles, where the heterocycles include any combination of CH2, O, S, or N in any chemically stable oxidation state, and where one or more atoms in the ring structure are optionally substituted at one or more positions. As expected, when chemical substituents are added to a carboxyl isosterella, it should be expected that the compound retains the properties of the carboxyl isosterella. As expected, when a carboxyl isosterella is selectively substituted with one or more parts chosen from the R as defined above, the degree of substitution and the site of substitution should be chosen so as not to remove the carboxylic acid isosterella properties of the compound. Similarly, if one or more R substituents impair the carboxylic acid isosterella properties of the compound, it should be expected that the position of such substituents in the carbocyclic or heterocyclic carboxylic acid isosterella is not a substitution located at a site that completes the carboxylic acid isosterella properties of the compound or at a site that completes one or more atoms.

[0089] "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 this description 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.

[0090] "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).

[0091] In the chemical structure of the compound described in this disclosure, [ka] The combination " does not have a specified placement, that is, " [ka] The combination " is " [ka] " or " [ka] It could be " or " [ka] " and " [ka] It may simultaneously include two configurations of "」. In the chemical structure of the compounds described in the present disclosure, "

Chemical formula

[0092] The present disclosure further includes isotopically labeled compounds of the compounds of the present application, which are the same as those described herein but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be bonded to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. For example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, <F 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and so on.

[0093] <0000F581>The compounds of the present disclosure can include non-natural ratios of atomic isotopes in one or more atoms constituting the compounds. For example, the compounds may be labeled with radioactive isotopes such as tritium (3H), iodine 125 (125I), or C-14 ( 14 C). Also, for example, hydrogen may be replaced with deuterium to form a deuterated agent. The bond composed of deuterium and carbon is stronger than the bond composed of ordinary hydrogen and carbon. Compared with the non-deuterated agent, the deuterated agent has advantages such as reducing toxicity and side effects, enhancing the stability of the agent, improving the therapeutic effect, and extending the biological half-life of the agent. All conversions of the isotope compositions of the compounds according to the present application are included within the scope of the present application regardless of the presence or absence of radioactivity.

[0094] Furthermore, relatively heavy isotopes (for example, deuterium ( 2 Substitution with H)) can provide several therapeutic benefits resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose demand), and may therefore be preferable in some cases, where the deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium. [Modes for carrying out the invention]

[0095] The preparation of the compounds and pharmaceutically acceptable salts described herein will be further explained below, along with examples, but these examples are not intended to limit the scope of this disclosure.

[0096] 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.

[0097] The NMR shift (δ) is 10 -6 The unit is expressed as ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d). 6 The internal standards are deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated acetonitrile (CD3CN), with tetramethylsilane (TMS) being the internal standard.

[0098] For mass spectrometry (MS) measurements, a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer was used.

[0099] HPLC measurements were performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-performance liquid chromatographs (Ultimate XB-C18 3.0×150 mm column or Xtimate C18 2.1×30 mm column).

[0100] For chiral HPLC analysis and measurements, 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, and for thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications for silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography were 0.4 mm to 0.5 mm.

[0101] Column chromatography typically used silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh from Yantai Huanghai as the vector.

[0102] For chiral preparative columns, DAIEL CHIRALPAK IC (250×30 mm, 10 μm) or Phenomenex-Amylose-1 (250×30 mm, 5 μm) were used.

[0103] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf150 (TELEDYNE ISCO) was used.

[0104] Kinase mean inhibition rate and IC 50 A plate reader, NovoStar (BMG GmbH, Germany), was used to measure the values.

[0105] The known starting materials relating to this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Dalui Chemicals.

[0106] In the examples, unless otherwise specified, all reactions can be carried out in an argon or nitrogen atmosphere.

[0107] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 L.

[0108] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 L.

[0109] 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.

[0110] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0111] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0112] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0113] Unless otherwise specified in the examples, the reaction temperature is 20°C to 30°C at room temperature.

[0114] Thin-layer chromatography (TLC) was used to monitor the progress of the reaction in the examples. The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, 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, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvents was adjusted according to the polarity of the compound, but it may also be adjusted by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0115] The meanings of the abbreviations used in the following experiment are as follows:

[0116] DCM: Dichloromethane, DIPEA: N,N-Diisopropylethylamine, CH3CN: Acetonitrile, MeOH: Methanol, THF: Tetrahydrofuran, NaOH: Sodium hydroxide, TsOH: p-Toluene sulfonic acid. Example 1

[0117] [ka] [ka] Step 1 Under nitrogen gas protection, compound 1a (5 g, 32.86 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to 0°C. Sodium hydride (2.1 g, 52.50 mmol) was added in several portions, and the reaction was carried out with stirring. Bromomethyl methyl ether (6.15 g, 49.22 mmol) was then added dropwise to the reaction system. After the reaction was complete, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 2 / 1) and concentrated to obtain the title compound 1b (4.39 g, yield 68%).

[0118] Step 2 Compound 1c (5.0 g, 25.48 mmol) and tetramethylethylenediamine (3.6 g, 31.25 mmol) were dissolved in 50 mL of tetrahydrofuran, purged with nitrogen gas, and cooled to -78°C. n-butyllithium (15 mL, 37.5 mmol) was added dropwise to the reaction and stirred. Crushed dry ice (11 g, 250 mmol) was added to the reaction and stirred, and the temperature was gradually raised to room temperature. The reaction was quenched with 1 mol / L hydrochloric acid solution (100 mL), trifluoroacetic acid (3 mL) was added and stirred at room temperature, then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) and concentrated to obtain the title compound 1c (6.3 g, 100% yield). MS (ESI) m / z 195.2 [MH] -

[0119] Step 3 Compound 1c (3.9 g, 19.88 mmol) was dissolved in 40 mL of N,N-dimethylformamide at room temperature, and N-bromosuccinimide (3.18 g, 17.89 mmol) was added to the reaction in several portions, and the mixture was stirred at room temperature. Water (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1), concentrated, and the title compound 1d (3.9 g, yield 71.3%) was obtained. MS (ESI) m / z 275.2,277.2 [M+H] +

[0120] Step 4 Compound 1d (3.0 g, 10.90 mmol) and trifluoroacetic acid (8 mL) were added to a reaction flask and heated to 70°C. Acetone (3.8 g, 65.44 mmol) and anhydrous trifluoroacetic acid (4.6 g, 21.71 mmol) were gradually added to the reaction simultaneously using two injection pumps. The mixture was stirred at 70°C, and after the reaction was complete, it was cooled to room temperature, concentrated, saturated sodium bicarbonate solution (150 mL) was added, and the mixture was extracted with ethyl acetate. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 1 / 1) and concentrated to obtain the title compound 1e (1.97 g, yield 57.6%). MS (ESI) m / z 315.2,317.2 [M+H] +

[0121] Step 5 Compound 1e (1.97 g, 6.25 mmol), acrylic acid (0.68 g, 9.38 mmol), palladium acetate (210 mg, 0.94 mmol), triethylamine (1.9 g, 18.75 mmol), and tris(2-tolyl)phosphine (571 mg, 1.89 mmol) were dissolved in N,N-dimethylformamide (8 mL). After purging with nitrogen gas, the mixture was microwaved at 100°C for 5 hours. After cooling to room temperature, the mixture was filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1). The mixture was then concentrated to obtain the title compound 1f (1.4 g, yield 73.1%). MS (ESI) m / z 307.4 [M+H] +

[0122] Step 6 Compound 1f (1.5 g, 4.90 mmol) was dissolved in 20 mL of chloroform at room temperature, purged with nitrogen gas, and then cooled to 0°C. Liquid bromine (2.0 mL, 5.36 mmol) was added dropwise to the reaction at 0°C within 5 minutes, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in N,N-dimethylformamide (20 mL), and cooled to 0°C. Triethylamine (1.19 mL, 8.58 mmol) was added dropwise to the reaction at 0°C within 2 minutes, the mixture was gradually heated to room temperature, stirred for 12 hours, water (50 mL) was added, the organic phase was extracted three times with ethyl acetate (50 mL), washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 7 / 3) and concentrated to obtain 1 g (310 mg, yield 18.6%) of the title compound. MS (ESI) m / z 340.9, 342.9 [M+H] +

[0123] Step 7 1 g (310 mg, 1.03 mmol) of the compound, bis[(+)-pinandiolate]diborone (553 mg, 1.54 mmol), potassium acetate (202 mg, 2.06 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (115 mg, 0.15 mmol) were dissolved in 1,4-dioxane (8 mL), purged with nitrogen gas, and reacted at 60°C for 2 hours. After cooling to room temperature, the mixture was filtered, concentrated, and the crude product was purified by column chromatography (eluted with n-hexane / ethyl acetate = 1 / 1) and concentrated to obtain 1 h (210 mg, yield 51%) of the title compound. MS (ESI) m / z 441.5 [M+H] +

[0124] Step 8 Dichloromethane (3 mL) was added to a 25 mL reaction flask, purged with nitrogen gas, and then cooled to -78°C. At -78°C, diethylzinc n-hexane solution (2.2 mL, 2.2 mmol) and diiodomethane (876 mg, 3.26 mmol) were added dropwise to the reaction flask, and the mixture was stirred at -78°C for 20 minutes. Compound 1i (120 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL) and added dropwise to the reaction within 5 minutes. After the addition was complete, the mixture was stirred at -78°C for 1 hour, gradually raised to room temperature, and stirred at room temperature for 18 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL), extracted three times with ethyl acetate (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) and concentrated to obtain the title compound 1i (52 mg, 42% yield). MS (ESI) m / z 455.5 [M+H] +

[0125] Step 9 Compound 1i (100 mg, 0.22 mmol) was dissolved in 0.5 mL of 1,4-dioxane at room temperature, and sodium hydroxide solution (3 mol / L, 0.5 mL) was added. The mixture was reacted with stirring. The temperature was then lowered to 0°C, and triethylsilane (30.4 mg, 0.26 mmol), isobutylboric acid (33.7 mg, 0.33 mmol), and trifluoroacetic acid (0.8 mL) were added in sequence. The temperature was gradually raised to room temperature to allow the reaction to proceed. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by C18 reverse-phase column chromatography [water (0.1% trifluoroacetic acid) / acetonitrile = 1 / 1]. After lyophilization, a pair of enantiomers, title compound 1 (12.3 mg, yield 21.3%), was obtained. 1H NMR (400 MHz, DMSO-d6) δ 6.85 (s, 1H), 4.19 (dq, J = 8.9, 3.1 Hz, 4H), 4.12 (d, J = 9.7 Hz, 1H), 2.16 (td, J = 7.9, 4.0 Hz, 1H), 1.24 MS (ESI) m / z 263.3 [M+H] + Example 2

[0126] [ka] [ka] Step 1 Under nitrogen gas protection, compound 2a (5 g, 28.7 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled to 0°C. Sodium hydride (1.7 g, 43.0 mmol) was added in several portions, and the reaction was carried out with stirring at 0°C. Subsequently, bromomethyl methyl ether (2.8 mL, 34.5 mmol) was added dropwise to the reaction system and the reaction was continued. After the reaction was complete, water (100 mL) was added to quench the reaction, the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 3 / 1), concentrated, and the title compound 2b (4.5 g, yield 72%) was obtained. MS (ESI) m / z 219.3 [M+H] +

[0127] Step 2 Compound 2b (4.5 g, 20.6 mmol) and tetramethylethylenediamine (4.6 mL, 30.9 mmol) were dissolved in 50 mL of tetrahydrofuran, purged with nitrogen gas, and cooled to -78°C. n-butyllithium (13.2 mL, 33.0 mmol) was added dropwise to the reaction, and the reaction was continued with stirring. Crushed dry ice (11 g, 250 mmol) was added to the reaction, and the reaction was continued with stirring at -78°C. The temperature was then gradually raised to room temperature, the reaction was quenched with 1 mol / L hydrochloric acid solution (100 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature. Extraction with ethyl acetate was performed, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1), concentrated, and the title compound 2c (2.5 g, 55% yield) was obtained. MS (ESI) m / z 217.2 [MH] -

[0128] Step 3 Compound 2c (2.5 g, 11.5 mmol) was dissolved in 40 mL of DCM at room temperature, and N-bromosuccinimide (2.2 g, 12.6 mmol) was added to the reaction in several portions, and the reaction was carried out at room temperature with stirring. After the reaction was complete, water (50 mL) was added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1), concentrated to obtain the title compound 2d (2.8 g, yield 82%). MS (ESI) m / z 296.2,297.2 [M+H] +

[0129] Step 4 Intermediate 2d (2.8 g, 9.4 mmol) was dissolved in 20 mL of THF, and the mixture was reacted in an ice bath with the addition of sodium hydride (0.56 mL, 28.3 mmol) and stirring. BnBr (3.4 mL, 28.3 mmol) was gradually added to the reaction mixture, and stirring continued. After the reaction was complete, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the solution was removed under reduced pressure. Compound 2e (2.0 g, 44% yield) was obtained by column chromatography (n-hexane / ethyl acetate = 7 / 1). MS (ESI) m / z 477.2,479.2 [M+H] +

[0130] Step 5 Compound 2e (2 g, 4.2 mmol), acrylic acid (0.9 mL, 13.8 mmol), palladium acetate (0.1 g, 0.46 mmol), triethylamine (3.8 mL, 27.7 mmol), and tris(2-tolyl)phosphine (0.28 g, 0.92 mmol) were dissolved in N,N-dimethylformamide (8 mL). After purging with nitrogen gas, the mixture was microwaved at 100°C, cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1). The mixture was then concentrated to obtain the title compound 2f (2.1 g, 54% yield). MS (ESI) m / z 469.4 [M+H] +

[0131] Step 6 Compound 2f (1.1 g, 2.4 mmol) was dissolved in 20 mL of chloroform at room temperature, purged with nitrogen gas, and cooled to 0°C. Liquid bromine (1.0 mL, 2.6 mmol) was added dropwise to the reaction at 0°C, and the mixture was stirred at 0°C. The reaction mixture was concentrated under reduced pressure, dissolved in N,N-dimethylformamide (20 mL), cooled to 0°C, triethylamine (0.6 mL, 4.3 mmol) was added dropwise, and the mixture was gradually heated to room temperature while stirring. After the reaction was complete, water (50 mL) was added, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane / ethyl acetate = 10 / 1), concentrated, and yielded 2 g (400 mg, 32% yield) of the title compound. MS (ESI) m / z 503.2, 505.2 [M+H] +

[0132] Step 7 Two g (400 mg, 0.79 mmol) of the compound, bis[(+)-pinandiolate]diborone (427 mg, 1.19 mmol), potassium acetate (156 mg, 1.59 mmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (117.9 mg, 0.16 mmol) were dissolved in 8 mL of 1,4-dioxane, purged with nitrogen gas, and reacted at 60°C. After the reaction was complete, the mixture was cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (n-hexane / ethyl acetate = 2 / 1) and concentrated to obtain 2h (300 mg, 62% yield) of the title compound. MS (ESI) m / z 603.4 [M+H] +

[0133] Step 8 Dichloromethane (6 mL) was added to a 25 mL reaction flask, purged with nitrogen gas, and then cooled to -78°C. At -78°C, diethylzinc n-hexane solution (19.9 mL, 19.9 mmol) and diiodomethane (2.68 mL, 33.2 mmol) were added dropwise to the reaction flask, and the reaction was carried out with stirring at -78°C. Compound 2h (400 mg, 0.66 mmol) was dissolved in dichloromethane (6 mL) and added dropwise to the reaction, and the reaction was carried out with stirring at -78°C. The temperature was then gradually raised to room temperature and the reaction was carried out. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 9 / 1), concentrated to obtain the title mixture 2i (40 mg, yield 9.7%). MS (ESI) m / z 617.3 [M+H] +

[0134] Step 9 Compound 2i (10 mg, 0.016 mmol) was dissolved in 2 mL of dichloromethane at room temperature, and a solution of boron tribromide in dichloromethane (0.2 mL, 1 M) was added. The mixture was stirred at -78°C. The temperature was then gradually raised to room temperature. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by C18 reverse-phase column chromatography (water (0.1% trifluoroacetic acid) / acetonitrile = 1 / 1), and lyophilized to obtain a pair of enantiomers, the title compound 2 (2 mg, 43% yield). 1 H NMR (400 MHz, DMSO-d6) δ 6.83 (s, 1H), 2.20-2.24 (m, 1H), 1.21-1.15 (m, 1H), 0.75-0.96(m, 2H); MS (ESI) m / z 285.5 [M+H] + Example 3

[0135] [ka] [ka] Step 1 [ka] 250 mL of DMF was added to the reaction flask, and under N2 protection, NaH (15.6 g, 3900 mmol, 1.8 eq, 60% wt) was added in several portions. 50 mL of DMF solution 3-1 (29.5 g, 216.9 mmol, 1.0 eq) (prepared according to reference J. Am. Chem. Soc. 1948, 70, 3619) was gradually added dropwise over an ice bath. After the addition was complete, the mixture was kept in the ice bath and stirred for 10 minutes. MOMBr (43.4 g, 347 mmol, 1.6 eq) was gradually added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred until the reaction was complete. Water was gradually added to quench the reaction, and the mixture was diluted with 250 mL of ethyl acetate and 250 mL of water. The aqueous phase was extracted with ethyl acetate, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was analyzed by silica gel column chromatography to obtain approximately 25.8 g of 3-2. 1 H NMR (400 MHz, CDCl3) δ 7.07-7.05 (d, J = 8.4 Hz, 1H), 6.53-6.51 (m, 2H), 5.13 (s, 2H), 4.59-4.55 (t, J = 8.8 Hz, 2H ), 3.47 (s, 3H), 3.16-3.12 (t, J = 8.8 Hz, 2H).

[0136] Step 2 [ka] Add 3-2 (25.8 g, 143 mmol, 1.0 eq) and TMDPA (20.0 g, 172 mmol, 1.2 eq) to a reaction flask, purge with nitrogen gas, add anhydrous THF (258 mL, 10 V), and cool the system to below -65°C. Add 1.6 M n-BuLi (143 mL, 229 mmol, 1.6 eq) dropwise under N2 protection, control the temperature to below -65°C, and stir at -65°C for 1 hour after the addition is complete. Wash dry ice (20 eq) with anhydrous THF and add it to the reaction mixture in several batches, controlling the reaction temperature to below -30°C. The reaction was quenched by adding 200 mL of saturated citric acid solution in an ice bath, followed by liquid-liquid separation. The aqueous phase was extracted with EA / THF (1:1) (150 mL x 3), the organic phase was combined, washed with saturated NaCl solution (150 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was slurryed with 400 mL of PE / EA (3:1) for 1 hour, filtered, and approximately 24.4 g of 3-3 was obtained, with a yield of 76.0%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 12.82 (br, 1H), 7.19-7.16 (d, J = 8.4 Hz, 1 H), 6.60-6.58 (d, J = 8.4 Hz, 1 H), 5.14 (s, 2H), 4.59-4.55 (t, J = 8.8 Hz, 2H), 3.37 (s, 3H), 3.14-3.09 (t, J = 8.8 Hz, 2H).

[0137] Step 3 [ka] 3-3 (22.2 g, 98.8 mmol, 1.0 eq) was weighed and added to the reaction flask, EtOH (330 mL, 15 V) was added, and TfOH (23.7 g, 158 mmol, 1.6 eq) was added in an ice bath. The mixture was stirred for 20 minutes while still in the ice bath. The reaction mixture was diluted with 300 mL of ethyl acetate and 300 mL of saturated NaCl solution, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum and dried to obtain crude product 3-4. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.48 (br, 2H), 7.28-7.26 (d, J = 8.0 Hz, 1 H), 6.36-6.34 (d, J = 8.0 Hz, 1 H), 4.63-4.58 (t, J = 8.8 Hz, 2H), 3.09-3.05 (t, J = 8.8 Hz, 2H).

[0138] Step 4 [ka] Weighed 3-4 (26.0 g, 144 mmol, 1.0 eq) and added it to the reaction flask. Add EtOH (260 mL, 10 V) and TfOH (26.0 g, 173 mmol, 1.2 eq), and refluxed overnight. Add 260 mL of EtOH and continue refluxing overnight. Dilute the reaction mixture with HCl (300 mL) and saturated NaCl solution (300 mL), separate the solutions, extract the aqueous phase with HCl (200 mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain approximately 13.2 g of 3-5, and the two-step yield was 64%. 1 1H NMR (400 MHz, DMSO-d 6) δ 10.60 (br, 1H), 7.25-7.23 (d, J = 8.0 Hz, 1 H), 6.38-6.36 (d, J = 8.0 Hz, 1 H), 4.63-4.59 (t, J = 8.8 Hz, 2H), 4.34-4.29 (q, J = 7.2 Hz,2H), 3.10-3.05 (t, J = 8.8 Hz, 2H), 1.31-1.27 (t, J = 7.2 Hz, 3H).

[0139] Step 5 [ka] Compounds 3-5 (13.2 g, 63.5 mmol, 1.0 eq) were weighed and placed in a reaction flask. DMF (132 mL, 10 V) and t-BuOK (9.26 g, 82.5 mmol, 1.3 eq) were added, and 2-bromo-1,1-diethoxyethane (15.0 g, 76.2 mmol, 1.2 eq) was added dropwise in an ice bath. After the addition was complete, the temperature was raised to 140°C and the mixture was stirred overnight. The reaction mixture was diluted with siRNA (200 mL) and H₂O (200 mL), separated, the aqueous phase was extracted with siRNA (100 mL x 2), the organic phase was added, the organic phase was washed sequentially with H₂O (200 mL x 2) and saturated NaCl solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain approximately 9.00 g of 3-6, with a yield of 43.8%. 1H NMR (400 MHz, CDCl3) δ 7.12-7.09 (m, 1H), 6.39-6.37 (d, J = 8.4 Hz, 1H), 4.81-4.78 (t, J = 5.2 Hz, 1H), 4.67-4.62 (t,J = 8.8 Hz, 2H), 4.39-4.33 (q, J = 7.2 Hz, 2H), 4.00-3.99 (d, J = 5.2 Hz, 2H), 3.79-3.71 (m, 2H), 3.66-3.58 (m, 2H), 3.16-3.11 (m, 2H), 1.39-1.35 (t, J = 14.0 Hz, 3H), 1.25-1.21 (t, J = 6.8 Hz, 6H).

[0140] Step 6 [ka] Add 3-6 (9.80 g, 30.2 mmol, 1.0 eq), 98 mL of DCE (10 V), and 2.38 g of Amberlyst 15 (25% wt) to a reaction flask and reflux until the reaction was complete. Filter by suction, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography to obtain approximately 4.51 g of product 3-7, with a yield of 64.3%. 1 H NMR (400 MHz, CDCl3) δ 7.62-7.61 (d, J = 2.0Hz, 1H), 7.47-7.46 (m, 1H), 6.67-6.66 (d, J = 2.4 Hz, 1H), 4.80-4.76 (t, J = 8.4 Hz, 2H), 4.50-4.51 (q, J = 6.8 Hz, 2H), 3.30-3.25 (m, 2H), 1.46-1.42 (t, J = 7.2 Hz, 3H).

[0141] Step 7 [ka] Nickel chloride (0.505 g, 3.88 mmol, 0.2 eq) was weighed and placed in a reaction flask. Tetrahydrofuran (22.5 mL, 5 V) was added, followed by tri-n-octylphosphine (3.20 g, 7.78 mmol, 0.4 eq). The flask was then purged with nitrogen gas, and the mixture was refluxed for 1 hour before being cooled to room temperature. 3-7 (4.51 g, 19.4 mmol, 1.0 eq) was weighed and placed in a separate reaction flask. Tetrahydrofuran (67.5 mL, 15 V) was added, followed by bis(pinacolate)diborone (7.41 g, 29.2 mmol, 1.5 eq), potassium carbonate (7.24 g, 54.5 mmol, 2.7 eq), and cesium carbonate (1.90 g, 5.83 mmol, 0.3 eq). Finally, the catalyst system prepared with nickel chloride / tri-n-octylphosphine was added, the mixture was purged with nitrogen gas, and the reaction was carried out under reflux for 2 hours. The reaction system was cooled to 0°C-5°C, MTBE (199 mL, 15 V) and deionized water (199 mL, 15 V) were added, and the pH was adjusted to 1 with 6 N hydrochloric acid. The mixture was then kept warm at 0°C-5°C and stirred for 30 minutes. The mixture was separated into layers, the aqueous phase was extracted once with MTBE (132 mL, 10 V), the organic phase was combined, dried over anhydrous sodium sulfate, filtered by suction, and concentrated under vacuum to obtain the crude product. The crude product was purified by C18 reversed-phase preparative column chromatography, the positive components were collected and concentrated, 6 N hydrochloric acid was added to adjust the pH to 1-2, and further extracted with methyl tert-butyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated and dried to obtain 4.14 g of 3-8, with a yield of 82.1%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.99 (br, 1H), 7.78-7.75 (d, J = 12.0 Hz, 1 H ), 7.48 (s, 1H), 6.00-5.97 (d, J = 12.0 Hz, 1 H), 4.73-4.69 (t, J = 17.2 Hz, 2 H), 4.39-4.33 (q, J = 7.2 Hz, 2 H), 3.28-3.24 (t, J = 8.8 Hz, 2 H), 1.37-1.33 (t, J = 7.2 Hz, 3 H).

[0142] Step 8 [ka] The reaction flask was purged with argon, 55.7 mL (4.0 eq) of 1 M diethylzinc n-hexane solution was added, and the reaction system was cooled to -40°C. Diiodomethane (29.8 g, 111 mmol, 8.0 eq) was dissolved in 9 mL of dichloromethane, and the diethylzinc n-hexane solution was gradually added dropwise using a syringe, while stirring continued at -40°C for 30 minutes. Trifluoroacetic acid (6.35 g, 55.7 mmol, 4.0 eq) was dissolved in 9 mL of dichloromethane, and the above solution was gradually added dropwise using a syringe, while stirring continued at -40°C for 30 minutes. 3-8 (3.62 g, 13.9 mmol, 1.0 eq) was dissolved in 12.5 mL of dichloromethane, and the above system was gradually added dropwise using a syringe. After the addition was complete, the temperature was gradually increased and the reaction was continued for 3 hours. The reaction was quenched with 1 M hydrochloric acid, the system was diluted with 25 mL of dichloromethane, the organic phase was separated, the aqueous phase was further extracted with 25 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum, and then parried by HPLC to obtain 1.42 g of 3-9, with a yield of 37.3%. After chiral resolution of the racemic mixture 3-9, approximately 320 mg of 3-9-1 and approximately 300 mg of 3-9-2 were obtained. Single-configuration compound 3-9-1: Chiral HPLC analysis: Retention time 2.832 minutes, chiral purity >99% (Column: ChiralPak IG, 250 × 30 mm ID, 10 μm, Mobile phase: A: CO2, B: Methanol (0.1% NH3H2O)) Single-configuration compound 3-9-2: Chiral HPLC analysis: Retention time 2.968 minutes, chiral purity >99% (Column: ChiralPak IG, 250 × 30 mm ID, 10 μm, Mobile phase: A: CO2, B: Methanol (0.1% NH3H2O)) Racemic Set 3-9 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 5.97 (br, 1H), 4.66-4.57 (m, 2H), 4.40-4.34 (q, J = 7.2 Hz, 2H), 3.16-3.11 (t, J = 8.8 Hz, 2H), 2.18-2.13 (m, 1H), 1.38-1.35(t, J = 6.8 Hz, 3H), 1.31-1.25 (m, 1H). 0.61-0.51 (m, 1H), 0.42-0.39 (m, 1H).

[0143] Step 9 [ka] 0.25 mL of methanol and 0.25 mL of 1,4-dioxane were added to a reaction flask, 3-9-1 (54.8 mg, 0.200 mmol, 1.0 eq) was added, and 0.25 mL of 25% wt aqueous sodium hydroxide solution was added. The reaction was carried out overnight at 50°C. The mixture was concentrated under vacuum to remove methanol and 1,4-dioxane, and 1 mL of deionized water was added. The system was adjusted to pH=8 with 6 M hydrochloric acid and extracted with MTBE. The aqueous phase was further adjusted to pH=1-2 with 6 M hydrochloric acid. The aqueous phase was extracted with 5 mL of ethyl acetate to remove any product, and the organic phase was combined. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and concentrated under vacuum to obtain a total of 40.8 mg of free acid. The free acid was dissolved in 4 mL of acetonitrile, 2.0 eq of sodium hydroxide was accurately weighed, and 4 mL of aqueous solution was prepared. This was added to the above reaction system and stirred at room temperature for 30 min. The solution was concentrated under vacuum to remove acetonitrile, and the aqueous phase was directly freeze-dried to obtain a total of 39.5 mg of the 3-Na product. 1H NMR (400 MHz, CD3OD) δ 6.83 (s, 1H), 4.48-4.36 (t, J = 8.8 Hz, 2H), 3.02-2.98 (t, J = 8.8 Hz, 2H), 1.88 (br, 1H), 1.69-1.64 (m, 1H), 1.29 (br, 1H), 0.72-0.67 (m, 1H), 0.28-0.22 (m, 1H), 0.20-0.16 (m, 1H). Example 4

[0144] Step 1 Compound 1i was separated by reverse-phase preparative separation (column: Waters Atlantis T3 19×150 mm, 5 μm, mobile phase 1: 0.05% FA / H2O, mobile phase 2: ACN) to obtain isomer 1i-1 (17 mg, yield 14%) and isomer 1i-2 (52 mg, yield 42%). Compound 1i-1: MS (ESI) m / z 455.5 [M+H] + HPLC analysis: Retention time 4.16 minutes (Column: Waters Acquity BEH C18 2.1 × 50 mm, 1.8 μm, Mobile phase 1: 0.05% FA / H2O, Mobile phase 2: 0.05% FA / ACN). Compound 1i-2: MS (ESI) m / z 455.5 [M+H] + HPLC analysis: Retention time 4.22 minutes (Column: Waters Acquity BEH C18 2.1×50 mm, 1.8 μm, Mobile phase 1: 0.05% FA / H2O, Mobile phase 2: 0.05% FA / ACN).

[0145] Step 2 Compound 1-1 was prepared using compound 1i-2 as a reactant according to the method of step 9 of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 6.85 (s, 1H), 4.18 (tq, J = 6.2, 3.6 Hz, 4H), 4.12 (d, J = 9.5 Hz, 1H), 2.16 (td, J = 7.9, 4.0 Hz, 1H), 1.24 (ddd, J = 10.8, 7.9, 3.3 Hz, 1H), 0.44 (ddd, J = 10.5, 8.1, 6.0 Hz, 1H), 0.22 (dt, J = 6.4, 3.7 Hz, 1H); MS (ESI) m / z 263.3 [M+H] +

[0146] Step 3 [ka] Compound 1-1 was added to the reaction flask, 2.05 eq of an aqueous NaOH solution was added, and the mixture was stirred for 1 hour. The solution was then freeze-dried to obtain compound 1-1-Na. 1 H NMR (400 MHz, CD3OD) δ 6.51 (s, 1H), 4.18-4.09 (m, 4H), 1.67-1.62 (m, 1H), 1.30 (br, 1H), 0.77-0.72 (m, 1H), 0.33-0.30 (m, 1H), 0.26-0.20 (m, 1H). Biological evaluation

[0147] 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

[0148] 1. Objective of the experiment The minimum inhibitory concentrations (MICs) of compound / compound combinations against three strains of drug-resistant bacteria were tested.

[0149] 2. Materials for the experiment 1) The antibiotics were cefepime and biapenem (purchased from MCE), and the two antibiotics were diluted in the corresponding solvent to a 12.8 mg / mL solution. 2) QPX-7728 (synthesis details are in WO2018005662A1), VNRX-5133 (synthesis details are in WO2014089365A1), compound 1, and compound 2 were prepared in a 3.2 mg / mL DMSO solution. 3) Strains awaiting testing include Escherichia coli ARLG-2829 (Urine), which is applicable to testing its ability to enhance cefepime against type B and type D β-lactamases; Klebsiella pneumoniae ATCC BAA-1705, which is applicable to testing its ability to enhance cefepime and biapenem against type A β-lactamases; and Klebsiella pneumoniae ATCC BAA-2472, which is applicable to testing its ability to enhance cefepime and biapenem against type B β-lactamases.

[0150] 3. Experimental Procedure The biological safety cabinet was sterilized with ultraviolet light for 30 minutes. Glycerol tubes were removed from the -80°C refrigerator, and the contents of the glycerol tubes were gently stirred several times with an inoculation loop to inoculate the bacteria onto MHIIA solid plates. The plates were placed in a 37°C incubator and incubated overnight.

[0151] 30 μL of the compound mother liquor was taken and added to the first row of a 96-v well plate, and DMSO was added to rows 2 through 10. Then, 15 μL of the solution was taken from row 1 using a pipette gun and added to row 2, and gently mixed uniformly. Another 15 μL of the solution was taken from row 2 and added to row 3, and so on, with gradient dilution proceeding down to row 10. (Prepared as a 200 x β-lactamase inhibitor agonist). The two antibiotics were diluted to a 1.6 mg / mL solution with the corresponding solvent.

[0152] 1 μL of a 200x β-lactamase inhibitor solution and 1 μL of a 1.6 mg / mL antibiotic were each taken and placed in a new 96-well round-bottom plate. The plate cultured overnight was taken out of the incubator, and several single clones were selected with an inoculation loop and placed in physiological saline to adjust the bacterial liquid concentration to about 1.0×10 8 CFU / mL, diluted 200-fold with the medium, and 198 μL of the adjusted bacterial liquid was taken and placed in the test plate. The test plate was placed in an incubator at 37 °C and cultured for 18 h to 24 h. The 96-well plate cultured for 20 h was taken out of the incubator, and the concentration at which no visible bacterial growth was observed was defined as the minimum inhibitory concentration.

[0153] The minimum inhibitory concentrations of compound 1 and compound 2 against three different strains in the presence of cefepime and biapenem are shown in the following table.

[0154] [Table 1] Test Example 2

[0155] 1. Purpose of the experiment The minimum inhibitory concentration (MIC) of the combination of compound 1-1-Na and QPX-7728 with cefepime against drug-resistant bacteria was tested.

[0156] 2. Materials for the experiment 1) The antibiotic cefepime was diluted with the corresponding solvent to a 12.8 mg / mL solution. 2) QPX-7728 and compound 1-1-Na were prepared in a 3.2 mg / mL DMSO solution. 3) Strains awaiting testing include cefepime-resistant Acinetobacter baumannii (FDA-CDC AR-BANK#0033, FDA-CDC AR-BANK#0035, FDA-CDC AR-BANK#0078), cefepime-resistant Escherichia coli (FDA-CDC AR-BANK#0055, FDA-CDC AR-BANK#0114, FDA-CDC AR-BANK#0371, FDA-CDC AR-BANK#0370), cefepime-resistant Klebsiella pneumoniae (FDA-CDC AR-BANK#0003, FDA-CDC AR-BANK#0126, FDA-CDC AR-BANK#0080, FDA-CDC AR-BANK#0076, FDA-CDC AR-BANK#0158), and cefepime-resistant Pseudomonas erginosa (FDA-CDC AR-BANK#0439, FDA-CDC AR-BANK#0444, FDA-CDC AR-BANK#0246, and FDA-CDC AR-BANK#0441 were obtained from Eurofins.

[0157] 3. Experimental Procedure The biological safety cabinet was sterilized with ultraviolet light for 30 minutes. Glycerol tubes were removed from the -80°C refrigerator, and the contents of the glycerol tubes were gently stirred several times with an inoculation loop to inoculate the bacteria onto MHIIA solid plates. The plates were placed in a 37°C incubator and incubated overnight.

[0158] 30 μL of the compound mother liquor was taken and added to the first row of a 96-v well plate, and DMSO was added to rows 2 through 10. Then, 15 μL of the solution was taken from row 1 using a pipette gun and added to row 2, and gently mixed uniformly. Another 15 μL of the solution was taken from row 2 and added to row 3, and so on, with gradient dilution proceeding down to row 10. (Prepared as a 200 x β-lactamase inhibitor agonist). The antibiotic was diluted to a 1.6 mg / mL solution with the corresponding solvent.

[0159] The minimum inhibitory concentrations of QPX-7728 and compound 1-1-Na against three different bacterial strains in the presence of cefepime are shown in the table below.

[0160] [Table 2-1] [Table 2-2]

[0161] As a result, it was found that both compound 1-1-Na and QPX-7728 can clearly restore the antibacterial activity of cefepime against cefepime-resistant E. coli and Klebsiella pneumoniae. Test Example 3

[0162] 1. Objective of the experiment We compared the ability of compound 1-1-Na and QPX7728 to restore the bactericidal activity of CPM.

[0163] 2. Materials for the experiment 1) The antibiotic cefepime was diluted with the corresponding solvent to a 12.8 mg / mL solution. 2) QPX-7728 and compound 1-1-Na were prepared in a 3.2 mg / mL DMSO solution. 3) Cefepime-resistant Klebsiella pneumoniae strains expressing various β-lactamases and awaiting testing (ARLG-1127 (Urine), ARLG-1195, ARLG-1196, ATCC BAA-1705, ATCC BAA-1898, ATCC BAA-1899, ATCC BAA-2343, ATCC BAA-2470) were obtained from Eurofins.

[0164] 3. Experimental Procedure The biological safety cabinet was sterilized with ultraviolet light for 30 minutes. Glycerol tubes were removed from the -80°C refrigerator, and the contents of the glycerol tubes were gently stirred several times with an inoculation loop to inoculate the bacteria onto MHIIA solid plates. The plates were placed in a 37°C incubator and incubated overnight.

[0165] 30 μL of the compound stock solution was taken and added to the first column of a 96-well plate, and DMSO was added to the second to tenth columns. Then, 15 μL was taken from the first column using a pipette gun and added to the second column, and gently mixed uniformly. Further, 15 μL of the solution was taken from the second column and added to the third column, and serial dilutions were performed up to the tenth column in sequence. (Prepared into a 200x β-lactamase inhibitor working solution). The antibiotic was diluted to a 1.6 mg / mL solution with the corresponding solvent.

[0166] The minimum growth inhibitory concentrations of ceftazidime against three different strains in the presence of QPX-7728 and Compound 1-1-Na are shown in the following table.

[0167]

Table 3-1

Table 3-2

[0168] As a result, it was found that both Compound 1-1-Na and QPX-7728 can clearly restore the antibacterial activity of ceftazidime against ceftazidime-resistant Klebsiella pneumoniae. Test Example 4

[0169] 1. Purpose of the experiment The exposures of Compound 1-1-Na and QPX7728 disodium salt after single intravenous administration to ICR mice were compared.

[0170] 2. Materials for the experiment Compound QPX-7728 disodium salt (synthesized and obtained by referring to CN109415386) and Compound 1-1-Na (free drug theoretical amount = weighed amount × correction factor) were accurately weighed, first dissolved in sterile water for injection to 40 mg / mL, and then diluted to the administration concentration with physiological saline. Prepared on the day of administration and stored under the condition of 4°C.

[0171] 3. Experimental procedure ICR mice were administered a single intravenous injection according to the group classification described below. Approximately 0.1 mL of blood was collected from the saphenous vein or fundus venous plexus at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, and 12 h after administration. A bioanalysis method was established to measure blood drug concentrations at various time points, and parameters related to pharmacokinetics were calculated.

[0172] [Table 4-1] [Table 4-2]

[0173] The results are as shown in the table below. [Table 5]

[0174] As a result, the exposure level of compound 1-1-Na to mice after a single intravenous administration was nearly five times that of QPX7728 disodium salt, indicating that reducing the dosage when obtaining similar therapeutic effects is advantageous in reducing drug toxicity and side effects.

Claims

1. A compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterium compound thereof, 【Chemistry 1】 Of these, ring A is cyclopropyl, Y1 is -O-, R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl groups. R3 is -C(O)OR k, R k is hydrogen, R4 is a hydroxyl group, Ring B is, 【Chemistry 2】 And, Y is independently selected from CH2 and O. Ra is independently selected from C1-C6 alkyl groups, halogens, and C1-C6 alkoxy groups. n is selected from 1, 2, 3, and 4. m is selected from 0, 1, 2, 3 and 4. Y ２ ' is CR ５ And, R ５ It is hydrogen. Compounds represented by formula (I-1) or pharmaceutically acceptable salts thereof, or stereoisomers, rotational isomers, tautomers, or deuterium compounds thereof. 【Request Item 2】 【Chemistry 3】 Alternatively, a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or deuterium compound thereof, selected from among, Y is independently CH ２ n is chosen from and O, and n is independently chosen from 1, 2, 3 and 4, X １ These are independently selected from F, Cl and Br. The compound according to claim 1. 【Request Item 3】 【Chemistry 4】 Alternatively, a pharmaceutically acceptable salt thereof, or selected from its stereoisomers, tautomers, or deuterium compounds, The compound according to claim 1. [Request Item 4] [Chemistry 5] or selected from its pharmaceutically acceptable salt, or its tautomer or deuterium compound, The compound according to claim 1. [Request Item 5] [Transformation 6] or selected from its tautomers or deuterium compounds, The compound according to claim 1.

6. A compound comprising at least one of the compounds described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or stereoisomers, rotational isomers, tautomers or deuterium compounds thereof, and a pharmaceutically acceptable vector, diluent or excipient. Pharmaceutical composition.

7. A compound comprising at least one of the compounds described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or stereoisomers, rotational isomers, tautomers or deuterium compounds thereof, and a pharmaceutically acceptable vector, diluent or excipient. A pharmaceutical composition for treating bacterial infections.

8. The aforementioned infections include Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophylla, Francisella tularensis, Morganella morganii, Proteus mirabilis, and Proteus vulgaris. Vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella para pertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multicida), Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile difficult), Mycobacterium tubaculosistuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius This includes bacteria selected from Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus hae molyticus, Staphylococcus hominis, or Staphylococcus saccharolitisus. The pharmaceutical composition according to claim 7.

9. The aforementioned infections include Pseudomonas aeruginosa, Pseudomonas fluorescein, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, and Salmonella enteritidis. Enterobacter enteris, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter chalcoseticus calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticusHaemophilus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovatus, Bacteroides stethetaiotaomicron, Bacteroides uniformis Bacteria selected from Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus, The pharmaceutical composition according to claim 7.

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