Boric acid derivatives acts as β-lactamase inhibitor

Abstract

This disclosure relates to boric acid derivatives as inhibitors of β-lactamase. Specifically, this disclosure relates to compounds of formula I or pharmaceutically acceptable salts thereof, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds. These boric acid derivatives can be used to treat bacterial infections.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically concerning a boric acid derivative that acts as a β-lactamase inhibitor. Prior Technology

[0002] β-lactam antibiotics are the most widely used and most effective class of antibacterial drugs in clinical practice. Currently, the most important antibiotics available are several classes of compounds containing a β-lactam ring, including penicillins, penicillenes, carbapenems, cephalosporins, monocyclic lactams, and sulfactams. These β-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 both Gram-negative and Gram-positive bacteria.

[0003] Although β-lactam antibiotics remain very important worldwide, resistance to β-lactamase-based antibiotics has emerged in various infectious pathogens, reducing the effectiveness of treatment for bacterial infections. The most significant resistance mechanism is the production of type A, C, and D β-lactamases with serine residues at their active sites. These enzymes degrade β-lactam antibiotics, leading to inactivation of their antibacterial activity. Type A β-lactamases have primary receptor specificity against penicillin-based drugs, while type C β-lactamases have primary receptor specificity against cephalosporin-based drugs. Commercially available β-lactamase inhibitors include clavulanic acid, sulbactam, and tazobactam. These inhibitors are primarily effective against type A β-lactamase-producing bacteria and are used in combination with penicillin-based antibiotics. However, more than 250 types of β-lactamases have been reported to date. Among them, in addition to the spread of type C β-lactamases and extended-spectrum β-lactamases (ESBLs) belonging to types A and D, drug-resistant bacteria of type A, such as KPC-2, which even decompose carbapenems, the last barrier of β-lactam antibiotics, are also considered a problem.

[0004] In recent years, novel β-endorhynchase inhibitors have become a hot topic of development, such as QPX-7728 and VNRX-5133. WO2014107536, WO2014089365, WO2018005662, and WO2019226931 disclose a series of β-endorhynchase inhibitors, with the aim of improving resistance to β-endorhynchase inhibitors.

[0005] Summary of the Invention

[0006] The purpose of this disclosure is to provide a boric acid derivative as a β-lactamase inhibitor that can be used to treat bacterial infections.

[0007] This disclosure provides, on the one hand, compounds of Formula I or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0008] in,

[0009] Ring A is selected from the following ring systems that require substitution: carbocyclic, heterocyclic, aromatic, or heteroaromatic;

[0010] Y1 is selected from -O- or -S-;

[0011] Y2 is selected from CR5 or N, Y3 is selected from CR5' or N, and Y2 and Y3 are not both N at the same time;

[0012] R1 and R2 are each independently selected from hydrogen or, as desired, from the following groups: alkyl, alkenyl, alkynyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy, alkylthioether, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0013] R3 is independently selected from hydrogen or, as desired, from the following groups: alkyl, alkenyl, alkynyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy, alkyl thioether, and carboxylic acid isoforms;

[0014] R4 is independently selected from the following groups that require substitution: -NRiRj, hydroxyl, alkoxy, halogen;

[0015] R5 is selected from hydrogen or, as desired, the following groups: alkyl, alkenyl, alkynyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy, alkylthioether, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R5 and R6 together with their adjacent carbon atoms form, as desired, the following ring systems: carbocyclic, heterocyclic, aromatic, heteroaromatic, spirocarbon, spiroheterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic;

[0016] R5' is selected from hydrogen or, as desired, the following groups: alkyl, alkenyl, alkynyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy, alkyl thioether, cycloalkyl, heterocyclic, aryl, and heteroaryl; or R5' and R6 together with their adjacent carbon atoms form, as desired, the following ring systems: carbocyclic, heterocyclic, aromatic, heteroaromatic, spirocarbon, spiroheterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic;

[0017] The condition is that R6 forms a ring system with at least one of R5 and R5' and an adjacent carbon atom;

[0018] Ri and Rj are each independently selected from hydrogen atoms, hydroxyl groups, C1~C6 alkyl groups, and C1~C6 alkoxy groups;

[0019] Rk is independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, hydroxy, -NRiRj, wherein the alkyl, alkoxy, haloalkyl is substituted as needed by one or more substituents selected from alkyl, halogen, hydroxy, mercapto, -NRiRj, oxy, thio, carboxyl, nitro, cyano, alkoxy, alkylthioether, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0020] B represents boron atoms.

[0021] In some embodiments, Rk is independently selected from hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, -NRiRj, wherein the alkyl, alkoxy, haloalkyl is substituted as needed with one or more substituents selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NRiRj, oxy, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl.

[0022] In some embodiments, the compound represented by Formula I is the compound represented by Formula I-1 or I-2.

[0023]

[0024] Wherein, ring B and ring C are each independently selected from the following ring systems that need to be substituted: carbocyclic, heterocyclic, aromatic, heteroaromatic, spirocarbon, spiroheterocyclic, fused carbocyclic, fused heterocyclic, fused aromatic, fused heteroaromatic;

[0025] Y2' is selected from CR5 or N;

[0026] Y3' is selected from CR5' or N;

[0027] R5 and R5' are each independently selected from hydrogen or, as desired, the following groups: alkyl, alkenyl, alkynyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy, alkylthioether, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0028] In some embodiments, the ring system formed by R6 and at least one of R5 and R5', as well as adjacent carbon atoms, or rings B and C, are independently selected from the following ring systems:

[0029] in,

[0030] Y is independently selected from CH2, NH, O, and S;

[0031] Ra and Rb are each independently selected from the following groups as desired for substitution: C1-C6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NRiRj, oxy, thio, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclic, 7 to 10-membered fused cycloalkyl, 7 to 10-membered fused heterocyclic, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, 8 to 12-membered fused cycloaryl, 5 to 12-membered heteroaryl;

[0032] n is selected from 1, 2, 3, 4, 5, or 6;

[0033] m and p are each independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0034] In some embodiments, R1 and R2 are each independently selected from hydrogen or, as desired, the following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, deuterium, hydroxyl, -NRiRj, C1-C6 alkoxy.

[0035] In some embodiments, ring A is selected from 3 to 12 members, more preferably 3 to 6 members, of a carbon ring or heterocycle that needs to be replaced.

[0036] In some embodiments, R3 is independently selected from the desired-substitute -C(O)ORk and the desired-substitute carboxylic acid isosteres.

[0037] In some embodiments, the carboxylic acid isosteres may be selected from tetrazolium, -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, wherein R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, and 3 to 6-membered heterocyclic.

[0038] In some embodiments, the compound is selected from...

[0039]

[0040] Or its medicinal salts, or its stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0041] Wherein, Y is independently selected from CH2, NH, O, S; n is independently selected from 1, 2, 3, 4, 5 or 6; X1 is independently selected from F, Cl, Br.

[0042] In some embodiments, the compound is selected from...

[0043] , , Or its medicinal salt, or its stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0044] In some embodiments, the compound is selected from...

[0045] , Or its medicinal salt, or its stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0046] In some embodiments, the acceptable salt of the drug is selected from alkali metal salts or ammonium salts. In some embodiments, the acceptable salt of the drug is a sodium salt, including disodium salt.

[0047] In some embodiments, the compound is selected from... Or its stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0048] In some embodiments, the compound is selected from... ,

[0049] Or its stereoisomers, rotational isomers, tautomers, or deuterated compounds.

[0050] The "alkyl" as described in this disclosure is preferably a C1-C6 alkyl.

[0051] The "alkenyl" disclosed herein is preferably a C2-C6 alkenyl.

[0052] The "alkynyl" group described in this disclosure is preferably a C2-C6 alkynyl group.

[0053] The "alkylene group" described in this disclosure is preferably a C1-C6 alkylene group.

[0054] The "sub-alkenyl" disclosed herein is preferably a C2-C6 sub-alkenyl.

[0055] The "sub-chain alkynyl" disclosed herein is preferably a C2-C6 sub-chain alkynyl.

[0056] The "alkoxy group" described in this disclosure is preferably a C1-C6 alkoxy group.

[0057] The "alkyl thioether group" disclosed herein is preferably a C1-C6 alkyl thioether group.

[0058] The “cycloalkyl” as described in this disclosure is preferably 3 to 12 members, and more preferably 3 to 6 members.

[0059] The "fused cycloalkyl" as described in this disclosure is preferably 6 to 14 members, more preferably 7 to 10 members.

[0060] The "heterocyclic group" disclosed herein preferably has 3 to 12 members, and more preferably 3 to 6 members.

[0061] The "fused heterocyclic group" disclosed herein preferably has 6 to 14 members, and more preferably 7 to 10 members.

[0062] The "aryl" in this disclosure is preferably 6 to 14 aryl groups, and more preferably 6 to 10 aryl groups.

[0063] The "fused-ring aryl" group described in this disclosure preferably has 8 to 14 members, and more preferably 8 to 12 members.

[0064] The "heteroaryl" group described in this disclosure is preferably 5 to 12 members, and more preferably 5 to 10 members.

[0065] The "dense aryl" group described in this disclosure is preferably 5 to 14 members, and more preferably 5 to 12 members.

[0066] The "substitutable" group described in this disclosure may be selected as needed from alkyl (preferably C1-C6 alkyl), halogen, deuterium, hydroxyl, mercapto, -NRiRj, oxy, thio, -C(O)Rk, -C(O)ORk, -S(O)Rk, -S(O)ORk, -S(O)(O)Rk, -S(O)(O)ORk, -C(S)Rk, nitro, cyano, alkoxy (preferably C1-C6 alkoxy), alkyl thioether (preferably C1-C6 alkyl thioether), olefin... The substituent is selected from one or more of the following: alkenyl (preferably C2-C6 alkenyl), alkynyl (preferably C2-C6 alkynyl), cycloalkyl (preferably 3 to 6-membered cycloalkyl), heterocyclic (preferably 3 to 6-membered heterocyclic), fused cycloalkyl (preferably 7 to 10-membered fused cycloalkyl), fused heterocyclic (preferably 7 to 10-membered fused heterocyclic), aryl (preferably 6 to 10-membered aryl), heteroaryl (preferably 5 to 10-membered heteroaryl), fused cyclic aryl (preferably 8 to 12-membered fused cyclic aryl), and fused heteroaryl (preferably 5 to 12-membered fused heteroaryl). Ri, Rj, and Rk are as previously described. The group of optional substituents for each "substitutable as desired" group can be the same or different.

[0067] This disclosure also provides a pharmaceutical composition comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, or stereoisomers, rotational isomers, tautomers or deuterated compounds thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0068] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0069] 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.

[0070] 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.

[0071] This disclosure also provides the use of the compounds described herein, or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds, for the treatment of bacterial infections. 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. Proteus, Campylobacter, Citrobacter, Neisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella, and other organisms.

[0072] 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 typhi murium*, *Salmonella typhi*, *Salmonella paratyphi*, *Salmonella enteritidis*, and *Shigella dysenteriae*. The following bacteria are listed: *Shigella dysenteriae*, *Shigella flexneri*, *Shigella sornei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, *Francisella tularensis*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providencia alcalifaciens*, *Providencia rettgeri*, *Providencia stuartii*, and *Acinetobacter baumannii*. Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocoliticaYersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, BacteroidesBacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes The bacteria include *Staphylococcus pyogenes*, *Enterococcus faecalis*, *Enterococcus faecium*, *Staphylococcus aureus*, *Staphylococcus epidermidis*, *Staphylococcus saprophyticus*, *Staphylococcus intermedius*, *Staphylococcus hyicus subsp. hyicus*, *Staphylococcus haemolyticus*, *Staphylococcus hominis*, and *Staphylococcus saccharolyticus*.

[0073] The compounds disclosed herein, or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds, can 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.

[0074] This disclosure further provides a method for treating bacterial infections in mammals, which may be human or non-human mammals, for therapeutic purposes, including administering to the mammal the compounds described in this disclosure or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds, or pharmaceutical compositions thereof.

[0075] This disclosure further provides a kit comprising the compounds described herein or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, tautomers, or deuterated compounds, or pharmaceutical compositions.

[0076] Terminology Explanation:

[0077] Unless otherwise stated, the terms used in the specification and the scope of the patent application shall have the following meanings.

[0078] 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, tributyl, dibutyl, 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, the alkyl group contains 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, syloxy, carboxyl, or carboxylic acid ester group.

[0079] 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-epenylethyl (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-epenylpropyl (-CH2CH(CH3)-), 1,3-epenylpropyl (-CH2CH2CH2-), 1,4-epenylbutyl (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted, and when substituted, the substituent can be replaced at any usable connection point.

[0080] The term "alkenyl" refers to a linear alkenyl group containing 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.

[0081] The term "sub-chain ynyl" includes linear sub-chain 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, sub-ethynyl, sub-propynyl, sub-butynyl, sub-pentynyl, sub-hexynyl, etc.

[0082] 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. "Carbocyclic" refers to the ring system within the cycloalkyl group.

[0083] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 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 consists of 6 to 14 rings, more preferably 7 to 10 rings. Spirocycloalkyl groups are classified as 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, they are 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. "Spirocarbon ring" refers to the ring system within the spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0084]

[0085] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring shares an adjacent pair of carbon atoms with the 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 members, more preferably 7 to 10 members. 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. "Fused-carbon ring" refers to the ring system within a fused-ring alkyl group. Non-limiting examples of fused-ring alkyl groups include:

[0086]

[0087] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group with 5 to 20 members, 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 has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0088]

[0089] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group can be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, cycloalkylthio, syloxy, carboxyl, or carboxylic acid ester group.

[0090] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it comprises 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. "Heterocyclic" refers to the ring system within the heterocyclic group.

[0091] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it consists of 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. "Spiroheterocyclic" refers to the ring system within the spirocyclic group. Non-limiting examples of spirocyclic groups include:

[0092]

[0093] 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 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 heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. "Fused ring" refers to the ring system in the fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0094]

[0095] 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 heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0096]

[0097] The heterocyclic ring can 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:

[0098] and wait.

[0099] The heterocyclic group can be substituted or unsubstituted as needed. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, syloxy, carboxyl, or carboxylic acid ester group.

[0100] 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 the aryl ring. "Aromatic ring" refers to the ring system within the aryl group. Non-limiting examples of aryl groups include:

[0101]

[0102] 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, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group, preferably phenyl.

[0103] 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. "Fused aromatic ring" refers to the ring system within the fused-ring aryl group. Specific examples of fused-ring aryl groups include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl.

[0104] 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 members, such as imidazolyl, furanyl, thienyl, 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 attached to the parent structure is the heteroaryl ring. "Heteroaryl ring" refers to the ring system within the heteroaryl group. Non-limiting examples of heteroaryl groups include:

[0105]

[0106] The heteroaryl group may be substituted or unsubstituted as needed. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0107] 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. It may also include carbon, nitrogen, and sulfur atoms, preferably "5-12 member fused aryl", "7-12 member fused aryl", "9-12 member fused aryl", etc., such as benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindol, benzoxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridineyl, phenanthridineyl, benzopyridinyl, phthalazinyl, quinazolinyl, quinoxalinyl, quinoxalinyl, phenazinyl, pteridineyl, purine, naphthidyl, phenazine, phenothiazine, etc. "Dense aromatic rings" refers to the ring system in dense aromatic groups.

[0108] The fused heteroaryl group can be substituted or unsubstituted as needed. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0109] 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 may be substituted or unsubstituted as desired, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0110] 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, propanethio, butanethio, cyclopropanethio, cyclobutanethio, cyclopentanethio, and cyclohexanethio. Alkathio groups can be substituted or unsubstituted as desired. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkathio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkathio, and heterocycloalkathio.

[0111] The term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0112] The term "haloalkyl" refers to an alkyl group that has been substituted with a halogen, wherein the alkyl group is as defined above.

[0113] 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.

[0114] The term "hydroxyl group" refers to the -OH group.

[0115] The term "oxygen group" refers to the =O group. For example, a carbon atom and an oxygen atom are connected by a double bond, forming a ketone or aldehyde group.

[0116] The term "thio group" refers to the =S group. For example, a carbon atom and a sulfur atom are connected by a double bond to form a thiocarbonyl group -C(S)-.

[0117] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0118] The term "amine" refers to -NH2.

[0119] The term "cyano" refers to -CN.

[0120] The term "nitro" refers to -NO2.

[0121] The term "carboxyl group" refers to -C(O)OH.

[0122] The term "aldehyde group" refers to -CHO.

[0123] 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.

[0124] The term "halogen" refers to compounds containing a -C(O)-halogen group.

[0125] The term "sulfonyl" refers to -S(O)(O)-.

[0126] The term "sulfinyl" refers to -S(O)-.

[0127] The “electron isosteres” of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazolium is an electron isostere of carboxylic acids because it mimics the properties of carboxylic acids, even though the two have very different molecular formulas. Tetrazolium is one of many possible electron isostere substitutions for carboxylic acids. Other anticipated electron isosteres of carboxylic acids include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSO2R, and -CONRCN, where R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups as defined herein. Furthermore, electron isosteres of carboxylic acids may contain a 5- to 7-membered carbocyclic or heterocyclic ring, which contains any combination of CH2, O, S, or N in any chemically stable oxidation state, wherein any atom of the ring structure is substituted at one or more positions as desired. It is also expected that when chemical substituents are added to the carboxyl isostere, the compound retains the properties of the carboxyl isostere. It is anticipated that when the carboxyl isosteric group is substituted as required by one or more portions of R as defined above, the degree of substitution and substitution position will be chosen so as not to eliminate the carboxylic acid isosteric property of the compound. Similarly, it should also be anticipated that if one or more R substituents would disrupt the carboxylic acid isosteric property of the compound, such substituents will not be located on the carbocyclic or heterocyclic carboxylic acid isosteric group at one or more atoms that would preserve or complete the carboxylic acid isosteric property of the compound.

[0128] "As needed" or "as needed" means that the event or circumstance described below may but does not have to occur, and the description includes the possibility or absence of the event or circumstance. For example, "heterocyclic groups substituted with alkyl groups as needed" means that alkyl groups may but do not have to be present, and the description includes cases where heterocyclic groups are substituted with alkyl groups and cases where heterocyclic groups are not substituted with alkyl groups.

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

[0130] In the chemical structure of the compound disclosed herein, the bond " / " does not specify a configuration; that is, the bond " / " can be " "or" ", or both contain " "and" "Two configurations. In the chemical structure of the compound disclosed herein, the bond..." "No configuration is specified, which means it can be Z configuration or E configuration, or both configurations at the same time."

[0131] This disclosure also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, respectively.

[0132] The compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or C-14 (14C). As another example, deuterated drugs may be formed by replacing hydrogen with deuterium. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations in the compounds of this application, regardless of radioactivity, are included within the scope of this application.

[0133] Furthermore, substitution with a heavier isotope (such as deuterium (i.e., 2H)) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain cases, where the deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium. Implementation

[0134] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts disclosed herein, but these examples are not intended to limit the scope of this disclosure.

[0135] 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.

[0136] NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD), and deuterated acetonitrile (CD₃CN). The internal standard was tetramethylsilane (TMS).

[0137] MS measurements were performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0138] HPLC determinations were performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-performance liquid chromatographs (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).

[0139] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID,3um, Chiralcel OD-3 100×4.6mm ID,3μm, ChiralCel OJ-H 150×4.6mm ID,5um, Chiralcel OJ-3 150×4.6mm ID, 3um chromatographic column; thin layer chromatography silicone plates are Yantai Huanghai HSGF254 or Qingdao GF254 silicone plates. The silicone plates used for thin layer chromatography (TLC) are 0.15mm~0.2mm in size, and the silicone plates used for thin layer chromatography separation and purification are 0.4mm~0.5mm in size.

[0140] Column chromatography typically uses Yantai Huanghai silicone 100-200 mesh, 200-300 mesh, or 300-400 mesh silicone as a carrier.

[0141] Chiral preparation columns used were DAICL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).

[0142] The CombiFlash rapid preparation system uses a CombiFlash Rfl50 (TELEDYNE ISCO).

[0143] The average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0144] The known starting materials disclosed herein can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0145] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0146] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0147] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0148] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0149] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0150] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0151] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0152] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0153] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography system used for purifying the compounds, and the TLC developing solvent system 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 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.

[0154] The abbreviations used in the following experiments have the following meanings:

[0155] DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; CH3CN: acetonitrile; MeOH: methanol; THF: tetrahydrofuran; NaOH: sodium hydroxide; TsOH: p-toluenesulfonic acid.

[0156] [Example 1]

[0157]

[0158]

[0159] first step

[0160] Compound 1a (5 g, 32.86 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection and cooled to 0 °C. Sodium hydride (2.1 g, 52.50 mmol) was added in portions, and the mixture was stirred. Then, bromomethyl methyl ether (6.15 g, 49.22 mmol) was added dropwise to the reaction system. After the reaction was complete, water (100 mL) was added to quench the reaction. The mixture 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 = 2 / 1) and concentrated to give the title compound. [1b](4.39g, yield 68%).

[0161] Step 2

[0162] 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, and cooled to -78 °C. Butyllithium (15 mL, 37.5 mmol) was added dropwise to the reaction mixture and stirred. Crushed dry ice (11 g, 250 mmol) was added to the reaction mixture, and the mixture was stirred. The temperature was slowly raised to room temperature, and the reaction was quenched with 1 mol / L hydrochloric acid solution (100 mL). Trifluoroacetic acid (3 mL) was added and stirred at room temperature. The mixture was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) and concentrated to give the title compound. [1c](6.3g, 100% yield).

[0163] MS(ESI)m / z 195.2[MH]-

[0164] Step 3

[0165] Compound at room temperature [1c] (3.9 g, 19.88 mmol) was dissolved in 40 mL of N,N-dimethylformamide. N-bromobutyldiamide (3.18 g, 17.89 mmol) was added in portions to the reaction mixture, 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), and concentrated to give the title compound. [1d](3.9g, yield 71.3%).

[0166] MS(ESI) m / z 275.2,277.2[M+H]+

[0167] Step 4

[0168] compound [1d] (3.0 g, 10.90 mmol) and trifluoroacetic acid (8 mL) were added to a reaction flask and the mixture was heated to 70 °C. Acetone (3.8 g, 65.44 mmol) and trifluoroacetic anhydride (4.6 g, 21.71 mmol) were slowly added to the reaction mixture simultaneously using two syringe pumps. The mixture was stirred at 70 °C. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and 150 mL of saturated sodium bicarbonate solution 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 (n-hexane / ethyl acetate = 1 / 1) and concentrated to give the title compound. [1e](1.97g, yield 57.6%). MS(ESI) m / z 315.2, 317.2 [M+H]+

[0169] Step 5

[0170] 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 nitrogen purging, 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 concentrate was then used to obtain the title compound. [1f](1.4g, yield 73.1%). MS(ESI) m / z 307.4 [M+H]+

[0171] Step 6

[0172] Compound at room temperature [1f] (1.5 g, 4.90 mmol) was dissolved in 20 mL of chloroform, purged with nitrogen, and cooled to 0 °C. Liquid bromine (2.0 mL, 5.36 mmol) was added dropwise to the reaction mixture over 5 minutes at 0 °C, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure and 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 mixture over 2 minutes at 0 °C, the mixture was slowly heated to room temperature, and stirred for 12 hours. Water (50 mL) was added, and 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 give the title compound. [1g] (310mg, yield 18.6%). MS (ESI) m / z 340.9, 342.9 [M+H]+

[0173] Step 7

[0174] compound [1 g] (310 mg, 1.03 mmol), bis(+)-pinenediol diboryl ester (553 mg, 1.54 mmol), potassium acetate (202 mg, 2.06 mmol), 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (115 mg, 0.15 mmol) were dissolved in 1,4-dioxane (8 mL). After nitrogen purging, the mixture was reacted at 60 °C for 2 hours, cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (hexane / ethyl acetate = 1 / 1 extraction). The concentration yielded the title compound. [1h](210mg, yield 51%). MS (ESI) m / z 441.5 [M+H]+

[0175] Step 8

[0176] Add 3 mL of dichloromethane to a 25 mL reaction flask, purge with nitrogen, and cool to -78 °C. At -78 °C, add 2.2 mL of diethylzinc n-hexane solution (2.2 mmol) and 876 mg of diiodomethane (3.26 mmol) dropwise to the reaction flask, and stir at -78 °C for 20 minutes. [The compound is then...] [1i] (120 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL) and added dropwise to the reaction over 5 minutes. After the addition was complete, the mixture was stirred at -78 °C for 1 hour, then slowly brought to room temperature and stirred at room temperature for 18 hours. The reaction was quenched with saturated ammonium chloride solution (10 mL), and the mixture was 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 give the title compound. [1i] (52 mg, yield 42%). MS (ESI) m / z 455.5 [M+H]+

[0177] Step 9

[0178] Compound at room temperature [1i] (100 mg, 0.22 mmol) was dissolved in 0.5 mL of 1,4-dioxane, and sodium hydroxide solution (3 mol / L, 0.5 mL) was added. The mixture was stirred. The temperature was then lowered to 0 °C, and triethylsilane (30.4 mg, 0.26 mmol), isobutylboronic acid (33.7 mg, 0.33 mmol), and trifluoroacetic acid (0.8 mL) were added sequentially. The mixture was slowly heated to room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by C18 reverse-phase column chromatography [water (0.1% trifluoroacetic acid) / acetonitrile = 1 / 1], and after lyophilization, the title compound was obtained. [1] (12.3 mg, yield 21.3%), which is a pair of enantiomers.

[0179] 1H NMR(400MHz,DMSO-d 6)δ 6.85(s,1H),4.19(dq,J=8.9,3.1Hz,4H),4.12(d,J=9.7Hz,1H),2.16(td,J=7.9,4.0Hz,1H),1.24(ddd ,J=10.8,7.9,3.3Hz,1H),0.44(ddd,J=10.4,8.1,6.0Hz,1H),0.22(dt,J=6.5,3.7Hz,1H);MS(ESI)m / z 263.3[M+H]+

[0180] [Example 2]

[0181]

[0182]

[0183] first step

[0184] Compound 2a (5 g, 28.7 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection and cooled to 0 °C. Sodium hydride (1.7 g, 43.0 mmol) was added in portions, and the mixture was stirred at 0 °C. Then, bromomethyl methyl ether (2.8 mL, 34.5 mmol) was added dropwise to the reaction mixture to continue the reaction. After the reaction was complete, water (100 mL) was added to quench the reaction, and the mixture 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) and concentrated to give the title compound. [2b](4.5g, yield 72%). MS(ESI) m / z 219.3 [M+H]+

[0185] Step 2

[0186] 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, and cooled to -78 °C. Butyllithium (13.2 mL, 33.0 mmol) was added dropwise to the reaction mixture, and the mixture was stirred continuously. Crushed dry ice (11 g, 250 mmol) was added to the reaction mixture, and the mixture was stirred at -78 °C. The mixture was then slowly heated to room temperature, quenched with 1 mol / L hydrochloric acid solution (100 mL), and trifluoroacetic acid (3 mL) was added while stirring at room temperature. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane / methanol = 10 / 1) and concentrated to give the title compound. [2c](2.5g, yield 55%). MS (ESI) m / z 217.2 [MH]-

[0187] Step 3

[0188] Compound at room temperature [2c] (2.5 g, 11.5 mmol) was dissolved in 40 mL of DCM. N-bromosuccinimide (2.2 g, 12.6 mmol) was added in portions to the reaction mixture, and the mixture was stirred at room temperature. After the reaction was complete, water (50 mL) was added, and 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), and concentrated to give the title compound. [2d](2.8g, yield 82%).

[0189] MS(ESI) m / z 296.2,297.2[M+H]+

[0190] Step 4

[0191] intermediate [2d] (2.8 g, 9.4 mmol) was dissolved in 20 mL of THF. Sodium hydride (0.56 mL, 28.3 mmol) was added under ice-water bath, and the mixture was stirred. BnBr (3.4 mL, 28.3 mmol) was slowly added to the reaction mixture, and stirring continued. After the reaction was complete, a saturated ammonium chloride aqueous solution was added, followed by extraction with ethyl acetate, drying to anhydrous sodium sulfate, and removal of the solution under reduced pressure. The solution was then subjected to column chromatography (hexane / ethyl acetate = 7 / 1) to obtain the compound. [2e](2.0g, yield 44%). MS (ESI) m / z 477.2, 479.2 [M+H]+

[0192] Step 5

[0193] 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 nitrogen purging, 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 concentrate was then used to obtain the title compound. [2f](2.1g, yield 54%). MS(ESI) m / z 469.4 [M+H]+

[0194] Step 6

[0195] Compound at room temperature [2f] (1.1 g, 2.4 mmol) was dissolved in 20 mL of chloroform, purged with nitrogen, and cooled to 0 °C. Liquid bromine (1.0 mL, 2.6 mmol) was added dropwise to the reaction mixture at 0 °C with stirring. The reaction mixture was concentrated under reduced pressure and dissolved in N,N-dimethylformamide (20 mL), cooled to 0 °C, and triethylamine (0.6 mL, 4.3 mmol) was added dropwise to the reaction mixture. The mixture was slowly heated to room temperature with 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) and concentrated to give the title compound. [2g] (400mg, yield 32%). MS (ESI) m / z 503.2, 505.2 [M+H]+

[0196] Step 7

[0197] compound [2 g] (400 mg, 0.79 mmol), bis(+)-pinenediol diboryl ester (427 mg, 1.19 mmol), potassium acetate (156 mg, 1.59 mmol), and 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (117.9 mg, 0.16 mmol) were dissolved in 1,4-dioxane (8 mL), and the mixture was reacted at 60 °C after nitrogen purging. After the reaction was completed, the mixture was cooled to room temperature, filtered, concentrated, and the crude product was purified by column chromatography (n-hexane / ethyl acetate = 2 / 1). The concentration yielded the title compound. [2h](300mg, yield 62%). MS (ESI) m / z 603.4 [M+H]+

[0198] Step 8

[0199] Add 6 mL of dichloromethane to a 25 mL reaction flask, purge with nitrogen, and cool to -78 °C. At -78 °C, add 19.9 mL of diethylzinc n-hexane solution (19.9 mmol) and 2.68 mL of diiodomethane (33.2 mmol) dropwise to the reaction flask, and stir the reaction mixture at -78 °C. [The compound is then...] [2h] (400 mg, 0.66 mmol) was dissolved in dichloromethane (6 mL) and added dropwise to the reaction mixture. The mixture was stirred at -78 °C and then slowly brought to room temperature. 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) and concentrated to give the title mixture. [2i] (40 mg, yield 9.7%). MS (ESI) m / z 617.3 [M+H]+

[0200] Step 9

[0201] Compound at room temperature [2i] (10 mg, 0.016 mmol) was dissolved in 2 mL of dichloromethane, and a dichloromethane solution of boron tribromide (0.2 mL, 1 M) was added. The mixture was stirred at -78 °C. The temperature was then slowly 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 crude product was purified by C18 reverse-phase column chromatography (water (0.1% trifluoroacetic acid) / acetonitrile = 1 / 1). After lyophilization, the title compound was obtained. [2] (2 mg, yield 43%), which is a pair of enantiomers.

[0202] 1H NMR(400MHz, DMSO-d 6 )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]+

[0203] [Example 3]

[0204]

[0205] first step

[0206]

[0207] 250 mL of DMF was added to the reaction flask. Under N2 protection, NaH (15.6 g, 3900 mmol, 1.8 eq, 60% wt) was added dropwise in portions and slowly in an ice bath. [3-1] (29.5 g, 216.9 mmol, 1.0 eq) (Preparation reference J. Am. Chem. Soc. 1948, 70, 3619) DMF solution (50 mL) was added dropwise, and the mixture was kept in an ice bath and stirred for 10 min after the addition was complete. MOMBr (43.4 g, 347 mmol, 1.6 eq) was slowly added dropwise, and the mixture was allowed to warm to room temperature naturally and stirred until the reaction was complete. The reaction was quenched slowly with water, diluted with 250 mL of ethyl acetate and 250 mL of water, separated, and 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 then subjected to silica gel column chromatography to obtain... [3-2] Approximately 25.8g.

[0208] 1H NMR (400MHz, CDCl3)δ 7.07-7.05(d,J=8.4Hz,1H),6.53-6.51(m,2H),5.13(s,2H),4.59-4.55(t,J=8.8Hz,2H),3.47(s,3H),3.16-3.12(t,J=8.8Hz,2H).

[0209] Step 2

[0210]

[0211] Add to reaction flask [3-2] (25.8 g, 143 mmol, 1.0 eq), TMDPA (20.0 g, 172 mmol, 1.2 eq), nitrogen was purged, and anhydrous THF (258 mL, 10 V) was added. The system was cooled to below -65 °C. 1.6 M n-BuLi (143 mL, 229 mmol, 1.6 eq) was added dropwise under N2 protection, maintaining the temperature below -65 °C. After the addition was complete, the mixture was stirred at -65 °C for 1 h. Dry ice (20 eq) was washed with anhydrous THF and added in portions to the reaction solution, maintaining the reaction temperature below -30 °C. The reaction was quenched by adding 200 mL of saturated citric acid solution under ice bath conditions. The mixture was separated, and the aqueous phase was extracted with EA / THF (1:1) (150 mL × 3). The organic phases were 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 slurried with 400 mL of PE / EA (3:1) for 1 h, filtered, and the final product was obtained. [3-3] Approximately 24.4g, yield 76.0%.

[0212] 1H NMR(400MHz,DMSO-d6)δ 12.82(br,1H),7.19-7.16(d,J=8.4Hz,1 H),6.60-6.58(d,J=8.4Hz,1 H),5.14(s,2H),4.59-4.55(t,J=8.8Hz,2H),3.37(s,3H),3.14-3.09(t,J=8.8Hz,2H).

[0213] Step 3

[0214]

[0215] Weighing [3-3] (22.2 g, 98.8 mmol, 1.0 eq) was added to a reaction flask, followed by EtOH (330 mL, 15 V). TfOH (23.7 g, 158 mmol, 1.6 eq) was added under ice bath conditions, maintaining the ice bath and stirring for 20 min. The reaction mixture was diluted with 300 mL of ethyl acetate and 300 mL of saturated NaCl solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum until dry to obtain the final product. [3-4] Crude product.

[0216] 1H NMR(400MHz,DMSO-d6)δ 11.48(br,2H),7.28-7.26(d,J=8.0Hz,1 H),6.36-6.34(d,J=8.0Hz,1 H),4.63-4.58(t,J=8.8Hz,2H),3.09-3.05(t,J=8.8Hz,2H).

[0217] Step 4

[0218]

[0219] Weighing [3-4] (26.0 g, 144 mmol, 1.0 eq) was added to the reaction flask, followed by EtOH (260 mL, 10 V) and TfOH (26.0 g, 173 mmol, 1.2 eq). The mixture was refluxed overnight. Another 260 mL of EtOH was added, and the mixture was refluxed overnight. EtOAc (300 mL) and saturated NaCl solution (300 mL) were added to dilute the reaction mixture. The mixture was separated, and the aqueous phase was extracted with EtOAc (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography to obtain... [3-5] Approximately 13.2g, with a two-step yield of 64%.

[0220] 1H NMR(400MHz,DMSO-d6)δ 10.60(br,1H),7.25-7.23(d,J=8.0Hz,1 H),6.38-6.36(d,J=8.0Hz,1 H),4.63-4.59(t,J=8.8Hz,2H),4.34-4.29(q,J=7.2Hz,2H),3.10-3.05(t,J=8.8Hz,2H),1.31-1.27(t,J=7.2Hz,3H).

[0221] Step 5

[0222]

[0223] Weighing compounds [3-5] (13.2 g, 63.5 mmol, 1.0 eq) was added to a reaction flask, along with DMF (132 mL, 10 V) and t-BuOK (9.26 g, 82.5 mmol, 1.3 eq). 2-Bromo-1,1-diethoxyethane (15.0 g, 76.2 mmol, 1.2 eq) was added dropwise under ice bath conditions. After the addition was complete, the mixture was heated to 140 °C and stirred overnight. EtOAc (200 mL) and H2O (200 mL) were added to dilute the reaction solution. The mixture was separated, and the aqueous phase was extracted with EtOAc (100 mL × 2). The organic phases were combined and washed successively with H2O (200 mL × 2) and saturated NaCl solution (200 mL). The mixture was 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... [3-6] Approximately 9.00g, yield 43.8%.

[0224] 1H NMR (400MHz, CDCl3)δ 7.12-7.09(m,1H),6.39-6.37(d,J=8.4Hz,1H),4.81-4.78(t,J=5.2Hz,1H),4.67-4.62(t,J=8.8Hz,2H),4.39-4.33(q,J=7.2Hz,2H),4.00 -3.99(d,J=5.2Hz,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=14.0Hz,3H),1.25-1.21(t,J=6.8Hz,6H).

[0225] Step 6

[0226]

[0227] Add to reaction flask [3-6] (9.80 g, 30.2 mmol, 1.0 eq), 98 mL DCE (10 V) and 2.38 g of Amberlyst 15 (25% wt), refluxed until the reaction was complete. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silicone column chromatography to obtain... [3-7] Approximately 4.51 g of product was produced, with a yield of 64.3%.

[0228] 1H NMR (400MHz, CDCl3)δ 7.62-7.61(d,J=2.0Hz,1H),7.47-7.46(m,1H),6.67-6.66(d,J=2.4Hz,1H),4.80-4.76(t, J=8.4Hz,2H),4.50-4.51(q,J=6.8Hz,2H),3.30-3.25(m,2H),1.46-1.42(t,J=7.2Hz,3H).

[0229] Step 7

[0230]

[0231] Weigh nickel chloride (0.505 g, 3.88 mmol, 0.2 eq) into a reaction flask, add tetrahydrofuran (22.5 mL, 5V), then add tri-n-octylphosphine (3.20 g, 7.78 mmol, 0.4 eq), purge with nitrogen, reflux for 1 h, and then cool to room temperature. [3-7] (4.51 g, 19.4 mmol, 1.0 eq) was added to another reaction flask, followed by tetrahydrofuran (67.5 mL, 15 V), then pinacol diboronate (7.41 g, 29.2 mmol, 1.5 eq), potassium carbonate (7.24 g, 54.5 mmol, 2.7 eq), cesium carbonate (1.90 g, 5.83 mmol, 0.3 eq), and finally the catalyst system prepared in nickel chloride / tri-n-octylphosphine was added. Nitrogen gas was purged, and the reaction was refluxed for 2 h. The reaction system was cooled to 0-5 °C, and MTBE (199 mL, 15 V) and deionized water (199 mL, 15 V) were added. The pH was adjusted to 1 with 6N hydrochloric acid, and the mixture was stirred at 0-5 °C for 30 min. The layers were separated, and the aqueous phase was extracted once with MTBE (132 mL, 10 V). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified using a C18 reverse-phase preparative column. The positive fraction was collected, concentrated, and the pH was adjusted to 1-2 with 6N hydrochloric acid. Extraction was then performed with methyl tributyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.14 g of the product. [3-8], yield 82.1%.

[0232] 1H NMR(400MHz,DMSO-d6)δ 8.99(br,1H),7.78-7.75(d,J=12.0Hz,1 H),7.48(s,1H),6.00-5.97(d,J=12.0Hz,1 H),4.73-4.69(t,J=17.2Hz,2 H),4.39-4.33(q,J=7.2Hz,2 H),3.28-3.24(t,J=8.8Hz,2 H),1.37-1.33(t,J=7.2Hz,3 H).

[0233] Step 8

[0234]

[0235] The reaction flask was purged with argon gas, and 55.7 mL (4.0 eq) of a 1M diethylzinc solution in n-hexane was added. The reaction system was then cooled to -40°C. Diiodomethane (29.8 g, 111 mmol, 8.0 eq) was dissolved in 9 mL of dichloromethane, and the solution was slowly added dropwise using a syringe. The mixture was stirred at -40°C for 30 min. Trifluoroacetic acid (6.35 g, 55.7 mmol, 4.0 eq) was dissolved in 9 mL of dichloromethane, and the solution was slowly added dropwise using a syringe. The mixture was stirred at -40°C for 30 min. [3-8] (3.62 g, 13.9 mmol, 1.0 eq) was dissolved in 12.5 mL of dichloromethane and slowly added dropwise to the above system using a syringe. After the addition was complete, the temperature was slowly raised and the reaction continued for 3 h. The reaction was quenched with 1 M hydrochloric acid, and the system was diluted with 25 mL of dichloromethane. The organic phase was separated, and the aqueous phase was extracted again with 25 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under vacuum, and then analyzed by HPLC to obtain 1.42 g of [a specific compound]. [3-9], yield 37.3%. Racemic mixture [3-9] After chiral splitting, we obtain [3-9-1] Approximately 320 mg, [3-9-2] Approximately 300 mg.

[0236] Single-configuration compounds [3-9-1:]

[0237] Chiral HPLC analysis: retention time 2.832 min, chiral purity >99% (chromatographic column: ChiralPak IG, 250×30mm ID, 10μm; mobile phase: A: CO2; B: Methanol (0.1% NH3·H2O))

[0238] Single-configuration compounds [3-9-2:]

[0239] Chiral HPLC analysis: retention time 2.968 min, chiral purity >99% (chromatographic column: ChiralPak IG, 250×30mm ID, 10μm; mobile phase: A: CO2; B: Methanol (0.1% NH3·H2O))

[0240] racemic [3-9 ] 1H NMR(400MHz, CDCl3)δ 7.16(s,1H),5.97(br,1H),4.66-4.57(m,2H),4.40-4.34(q,J=7.2Hz,2H),3.16-3.11(t,J=8.8Hz,2H), 2.18-2.13(m,1H),1.38-1.35(t,J=6.8Hz,3H),1.31-1.25(m,1H).0.61-0.51(m,1H),0.42-0.39(m,1H).

[0241] Step 9

[0242]

[0243] Add 0.25 mL of methanol and 0.25 mL of 1,4-dioxane to the reaction flask, then add... [3-9-1] (54.8 mg, 0.200 mmol, 1.0 eq) was added to 0.25 mL of 25% wt sodium hydroxide aqueous solution and reacted 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 pH of the system was adjusted to 8 with 6 M hydrochloric acid, and the mixture was extracted with MTBE. The aqueous phase was then adjusted to pH 1-2 with 6 M hydrochloric acid. The aqueous phase was extracted with 5 mL of ethyl acetate until no product was found. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain free acid. [3] A total of 40.8 mg was obtained. The free acid was dissolved in 4 mL of acetonitrile, and 2.0 eq of sodium hydroxide was accurately weighed and dissolved to prepare 4 mL of aqueous solution. This solution was added to the above reaction system and stirred at room temperature for 30 min. The acetonitrile was removed by vacuum concentration, and the aqueous phase was directly freeze-dried to obtain the product. [3-Na] Total 39.5 mg.

[0244] 1H NMR(400MHz,CD3OD)δ 6.83(s,1H),4.48-4.36(t,J=8.8Hz,2H),3.02-2.98(t,J=8.8Hz,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).

[0245] [Example 4]

[0246] first step

[0247] compound [1i] Preparative separation was achieved by reversed-phase chromatography (column: Waters Atlantis T3 19*150 mm, 5 μm; mobile phase 1: 0.05% FA / H2O; mobile phase 2: ACN). [Isomer 1i-1] (17 mg, yield 14%) and [Isomer 1i-2] (52 mg, yield 42%).

[0248] compound [1i-1:]

[0249] MS(ESI)m / z 455.5[M+H]+

[0250] HPLC analysis: retention time 4.16 min (chromatographic 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).

[0251] compound [1i-2:]

[0252] MS(ESI)m / z 455.5[M+H]+

[0253] HPLC analysis: retention time 4.22 min (chromatographic 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).

[0254] Step 2

[0255] According to the method in step nine of Example 1, with compound [1i-2] was used as a reactant to prepare the compound. [1-1].

[0256] 1H NMR(400MHz,DMSO-d 6)δ 6.85(s,1H),4.18(tq,J=6.2,3.6Hz,4H),4.12(d,J=9.5Hz,1H),2.16(td,J=7.9,4.0Hz,1H),1.24(ddd ,J=10.8,7.9,3.3Hz,1H),0.44(ddd,J=10.5,8.1,6.0Hz,1H),0.22(dt,J=6.4,3.7Hz,1H);MS(ESI)m / z 263.3[M+H]+

[0257] Step 3

[0258]

[0259] compound [1-1] Add to a reaction flask, add 2.05 eq of NaOH aqueous solution, stir for 1 h, and then freeze-dry the solution directly to obtain the compound. [1-1-Na].

[0260] 1H NMR(400MHz,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).

[0261] [Biological Evaluation]

[0262] The following examples further illustrate and explain the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0263] [Test Example 1]

[0264] [1. Experimental Objective]

[0265] The minimum inhibitory concentration (MIC) of the tested compounds / compound combinations against three drug-resistant bacteria was determined.

[0266] [2. Experimental Materials]

[0267] 1) The antibiotics cefepime and biapenem (purchased from MCE) were diluted with the appropriate solvents to a solution of 12.8 mg / mL.

[0268] 2) QPX-7728 (synthesis reference WO2018005662A1), VNRX-5133 (synthesis reference WO2014089365A1), compound 1 and compound 2 were prepared into a 3.2 mg / mL DMSO solution.

[0269] 3) The test strains are Escherichia coli ARLG-2829 (Urine), which can be used to test the ability of β-endorhynchase inhibitors to enhance the ability of cefepime against class B and D β-endorhynchases; Klebsiella pneumoniae ATCC BAA-1705, which can be used to test the ability of β-endorhynchase inhibitors to enhance the ability of cefepime and biapenem against class A β-endorhynchases; and Klebsiella pneumoniae ATCC BAA-2472, which can be used to test the ability of β-endorhynchase inhibitors to enhance the ability of cefepime and biapenem against class B β-endorhynchases.

[0270] [3. Experimental Procedure]

[0271] Sterilize the biosafety cabinet with UV light for 30 minutes. Remove the glycerol tube from the -80°C freezer, gently swipe the tube several times with an inoculation loop, and inoculate the bacteria onto an MHIIA agar plate. Incubate the plate overnight at 37°C.

[0272] Add 30 μL of the compound stock solution to column 1 of a 96-V plate. Add DMSO to columns 2 through 10. Then, pipette 15 μL from column 1 and add it to column 2, mix gently, then add 15 μL from column 2 to column 3, and continue this serial dilution until column 10. (Prepare a 200x β-lactamase inhibitor working solution). Dilute both antibiotics to 1.6 mg / mL solutions with their respective solvents.

[0273] Take 1 μL of 200x β-lactamase inhibitor solution and 1 μL of 1.6 mg / mL antibiotic into a new 96-well round-bottom agar plate. Remove the plate from the incubator after overnight incubation, pick several isolated bacterial strains with an inoculation loop and place them in physiological saline to adjust the bacterial concentration to approximately 1.0 x 10⁸ CFU / mL. Dilute the solution 200 times with culture medium, and add 198 μL of the adjusted bacterial solution to the test plate. Incubate the test plate at 37°C for 18–24 hours. After 20 hours of incubation, remove the 96-well plate from the incubator; the concentration at which no visible bacterial growth is observed is defined as the minimum inhibitory concentration (MIC).

[0274] The minimum inhibitory concentrations of compounds 1 and 2 against three different strains in the presence of cefepime and biapenem are shown in the table below.

[0275]

[0276] [Test Example 2]

[0277] [1. Experimental Objective]

[0278] The minimum inhibitory concentration (MIC) of compound 1-1-Na and QPX-7728 in combination with cefepime was tested against resistant bacteria.

[0279] [2. Experimental Materials]

[0280] 1) Dilute the antibiotic cefepime with the appropriate solvent to a solution of 12.8 mg / mL.

[0281] 2) QPX-7728, compound 1-1-Na was prepared as a 3.2 mg / mL DMSO solution.

[0282] 3) Test strains: 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), Cefepime-resistant Pseudomonas aeruginosa (FDA-CDC AR-BANK#0439, FDA-CDC AR-BANK#0444, FDA-CDC AR-BANK#0246, FDA-CDC AR-BANK#0441), from Eurofins.

[0283] [3. Experimental Procedure]

[0284] Sterilize the biosafety cabinet with UV light for 30 minutes. Remove the glycerol tube from the -80°C freezer, gently swipe the tube several times with an inoculation loop, and inoculate the bacteria onto an MHIIA agar plate. Incubate the plate overnight at 37°C.

[0285] Add 30 μL of the stock solution of the compound to column 1 of a 96-V plate. Add DMSO to columns 2 through 10. Then, pipette 15 μL from column 1 and add it to column 2, mix gently, then add 15 μL from column 2 to column 3, and continue this serial dilution until column 10. (This prepares a 200x β-lactamase inhibitor working solution). Dilute the antibiotic with the appropriate solvent to a solution of 1.6 mg / mL.

[0286] The minimum inhibitory concentrations of QPX-7728 and compound 1-1-Na against three different strains in the presence of cefepime are shown in the table below.

[0287]

[0288] The results showed that both compound 1-1-Na and QPX-7728 could significantly restore the antibacterial activity of cefepime against cefepime-resistant Escherichia coli and Klebsiella pneumoniae.

[0289] [Test Example 3]

[0290] [1. Experimental Objective]

[0291] The ability of compound 1-1-Na and QPX7728 to restore the bactericidal activity of CPM was compared.

[0292] [2. Experimental Materials]

[0293] 1) Dilute the antibiotic cefepime with the appropriate solvent to a solution of 12.8 mg / mL.

[0294] 2) QPX-7728, compound 1-1-Na was prepared as a 3.2 mg / mL DMSO solution.

[0295] 3) The tested strains of cefepime-resistant Klebsiella pneumoniae (ARLG-1127(Urine), ARLG-1195, ARLG-1196, ATCC BAA-1705, ATCC BAA-1898, ATCC BAA-1899, ATCC BAA-2343, ATCC BAA-2470) expressed different types of β-lactamases and were obtained from Eurofins.

[0296] [3. Experimental Procedure]

[0297] Sterilize the biosafety cabinet with UV light for 30 minutes. Remove the glycerol tube from the -80°C freezer, gently swipe the tube several times with an inoculation loop, and inoculate the bacteria onto an MHIIA agar plate. Incubate the plate overnight at 37°C.

[0298] Add 30 μL of the stock solution of the compound to column 1 of a 96-V plate. Add DMSO to columns 2 through 10. Then, pipette 15 μL from column 1 and add it to column 2, mix gently, then add 15 μL from column 2 to column 3, and continue this serial dilution until column 10. (This prepares a 200x β-lactamase inhibitor working solution). Dilute the antibiotic with the appropriate solvent to a solution of 1.6 mg / mL.

[0299] The minimum inhibitory concentrations of QPX-7728 and compound 1-1-Na against three different strains in the presence of cefepime are shown in the table below.

[0300]

[0301] The results showed that both compound 1-1-Na and QPX-7728 could significantly restore the antibacterial activity of cefepime in cefepime-resistant Klebsiella pneumoniae.

[0302] [Test Example 4]

[0303] [1. Experimental Objective]

[0304] Compare the single intravenous exposure of compounds 1-1-Na and QPX7728 disodium salt in ICR mice.

[0305] [2. Experimental Materials]

[0306] Accurately weigh the disodium salt of compound QPX-7728 (synthesized according to CN109415386) and compound 1-1-Na (theoretical amount of free drug = weighed amount * correction factor), dissolve them first in sterile water for injection to 40 mg / mL, and then dilute with physiological saline to the dosing concentration. Prepare on the day of administration and store at 4℃.

[0307] [3. Experimental Procedure]

[0308] ICR mice were administered a single intravenous injection according to the following grouping method. At 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, and 12h after administration, approximately 0.1mL of blood was collected from the saphenous vein or fundus venous plexus at each time point. A bioanalytical method was established to determine the blood drug concentration at different time points and to calculate drug metabolism-related parameters.

[0309]

[0310] The results are shown in the table below.

[0311]

[0312] The results showed that the single intravenous exposure of compound 1-1-Na in mice was nearly 5 times that of QPX7728 disodium salt, which is beneficial for reducing the dosage and minimizing drug toxicity while achieving similar efficacy.

Claims

1. A compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof, wherein, Ring A is selected from a 3-membered carbon ring; Y1 is selected from -O-; R1 and R2 are each independently selected from hydrogen, C1-C6 alkyl, halogen, and C1-C6 alkoxy; R3 is independently selected from -C(O)ORk; Rk is independently selected from hydrogen atom and C1-C6 alkyl; R4 is independently selected from hydroxyl; Ring B is selected from; Y is independently selected from CH2 and O; Ra is each independently selected from C1-C6 alkyl, halogen, and C1-C6 alkoxy; n is selected from 1, 2, 3, or 4; m is selected from 0, 1, 2, 3, or 4; Y2' is selected from CR5; R5 is selected from hydrogen.

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof, selected from the pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof, wherein, Y is independently selected from CH2 and O; n is independently selected from 1, 2, 3 or 4; X1 is independently selected from F, Cl, and Br.

3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer or deuterated compound thereof, selected from the pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer or deuterated compound thereof.

4. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof, wherein the compound is selected from the pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof.

5. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof, wherein the compound is selected from [the group consisting of], or a stereoisomer, rotational isomer, tautomer, or deuterated compound thereof.

6. A pharmaceutical composition comprising at least one compound as described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer or deuterated compound thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

7. Use of any compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, tautomer or deuterated compound thereof, in the preparation of a medicament for treating bacterial infections.

8. The use as claimed in claim 7, wherein the infection comprises bacteria selected from the following: *Pseudomonas acidovorans*, *Pseudomonas alcaligenes*, *Pseudomonas putida*, *Burkholderia cepacia*, *Aeromonas hydrophilia*, *Francisella tularensis*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providencia alcalifaciens*, *Providencia rettgeri*, *Providencia stuartii*, *Acinetobacter baumannii*, and *Bordetella pertussis*. * *Bordetella parapertussis*, *Bordetella bronchiseptica*, *Haemophilus ducreyi*, *Pasteurella multocida*, *Pasteurella haemolytica*, *Branhamella catarrhalis*, *Borrelia burgdorferi*, *Kingella*, *Gardnerella vaginalis*, *Bacteroides distasonis*, *Bacteroides 3452A homology group*, *Clostridium difficile*, *Mycobacterium tuberculosis*, *Mycobacterium avium*, *Mycobacterium intracellulare* intracellulare, Mycobacterium leprae, Corynebacterium diphtheriaeThe following bacteria are listed: *Streptococcus diphtheriae*, *Corynebacterium ulcerans*, *Streptococcus pneumoniae*, *Streptococcus agalactiae*, *Streptococcus pyogenes*, *Enterococcus faecalis*, *Enterococcus faecium*, *Staphylococcus aureus*, *Staphylococcus epidermidis*, *Staphylococcus saprophyticus*, *Staphylococcus intermedius*, *Staphylococcus hyicus subsp. hyicus*, *Staphylococcus haemolyticus*, *Staphylococcus hominis*, or *Staphylococcus saccharolyticus*.

9. The use as claimed in claim 7, wherein the infection comprises bacteria selected from the following: *Pseudomonas aeruginosa*, *Pseudomonas fluorescens*, *Stenotrophomonas maltophilia*, *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhi*, *Salmonella paratyphi*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella flexneri*, *Shigella sonnei*, *Enterobacter cloacae*, and *Enterobacter aerogenes*. aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus Campylobacter jejuni, Campylobacter coli, and Vibrio cholerae.The bacteria include *Vibrio parahaemolyticus*, *Legionella pneumophila*, *Listeria monocytogenes*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Moraxella*, *Bacteroides fragilis*, *Bacteroides vulgatus*, *Bacteroides ovalus*, *Bacteroides thetaiotaomicron*, *Bacteroides uniformis*, *Bacteroides eggerthii*, and *Bacteroides splanchnicus*.

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