Azacyclo antifungal compound and application thereof

Abstract

The invention provides an azacyclo antifungal compound and application thereof, the structure of the azacyclo antifungal compound is shown as a formula I, # imgabs0, the compound provided by the invention has a very good inhibition effect on fungi, especially tritirachium album, aspergillus fumigatus and cryptococcus neoformans, and the azacyclo antifungal compound can be used for preventing or treating fungal infection.

Description

[0001] This application claims the priority of Chinese patent application with application number CN202311380804.4 filed on October 23, 2023, and invention name “A nitrogen heterocyclic antifungal compound and its use”, the entire contents of which are incorporated into this application by reference. Technical Field

[0002] The present application belongs to the field of medical technology, and specifically relates to a nitrogen heterocyclic antifungal compound and its use, and in particular to a nitrogen heterocyclic antifungal compound as a GPI-anchored protein inhibitor and its use in preventing or treating fungal infections. Background Art

[0003] Invasive fungal infections have become a serious problem for clinicians, with at least 1.35 million people dying from fungal infections worldwide each year. In the past few decades, hospital-acquired invasive fungal infections have increased significantly, mainly in intensive care units (ICUs), respiratory departments, hematology departments, and surgery-related departments. Despite the emergence of new diagnostic and treatment strategies, the mortality rate of invasive diseases caused by Candida and Aspergillus remains as high as 30% to 50%.

[0004] At present, the drugs used in clinical practice mainly include three structures: polyenes, azoles and echinocandins. These antifungal drugs still have many limitations, such as the high nephrotoxicity of amphotericin B, the narrow antibacterial spectrum of flucytosine drugs, and the drug resistance of azole drugs. Therefore, the development of antifungal drugs can no longer meet the needs of clinical treatment of fungal infections.

[0005] GPI-anchored proteins (Glycosylphosphatidylinositol-anchored proteins) are a class of proteins that are anchored to the surface of eukaryotic cell membranes through the glycosylated phosphatidylinositol structure at their carboxyl termini, and play an important role in immune recognition, complement regulation, and transmembrane signal transduction. Due to the presence of the GPI structure, fungi have a stronger ability to move on the cell membrane of the phospholipid bilayer. Adherence to host cells is very important for fungi to exert their pathogenicity, and the adhesion factors involved in fungal cell adhesion are transported to the surface of the cell wall after glycosylphosphatidylinositol (GPI) is anchored to the cell membrane. The Gwt1 protein is a key enzyme that catalyzes the acylation reaction of inositol in the early steps of fungal glycosylphosphatidylinositol (GPI) synthesis, and plays an important role in the synthesis of eukaryotic cell wall structures. Gwt1 has low homology with the orthologous gene PIG-W that has the same catalytic effect in humans, so it has become an important target for new antifungal drug research.

[0006] At present, existing literature also discloses some GPI-anchored protein inhibitory compounds and their deuterated compounds, which have a certain inhibitory effect on Candida, but a low inhibitory effect on Aspergillus and Cryptococcus, and the derivatives obtained after deuterated modification have not been able to improve the inhibitory effect on Aspergillus and Cryptococcus. Therefore, it is necessary to develop a new compound that has a high inhibitory effect on Candida, Aspergillus and / or Cryptococcus and has good pharmacokinetics. Summary of the invention

[0007] The present application provides a compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in,

[0010] W is selected from N and N + -CH2OPO3H - ;

[0011] R 1 , R 2 are independently selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4Alkylene-(6- to 10-membered aryl), -C 0～4 Alkylene-(5- to 10-membered heteroaryl), -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ;

[0012] R 1a , R 1b are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4 Alkylene-(6-10 membered aryl) and -C 0～4 Alkylene-(5- to 10-membered heteroaryl);

[0013] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are independently selected from N, O, S and CH;

[0014] R 3 Selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4 Alkylene-(6- to 10-membered aryl), -C 0～4 Alkylene-(5- to 10-membered heteroaryl), -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ;

[0015] R 4 , R 5 are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C0～4 Alkylene-NR 1a R 1b and -C 0～4 Alkylene-NR 1a C(O)R 1b ;

[0016] R 6 are independently selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ;

[0017] m and n are independently 0 to 2;

[0018] L is selected from a single bond, C 1～4 Alkylene, -O-, -S-, -NH-, -CH2O-, -CH2CH2O-, -CH2NH-, and -SCH2-;

[0019] R 7 Selected from -OH, -C 1～6 Alkyl, -C2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group; wherein R 7 Optionally one or more R 1c replace;

[0020] R 1c Selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, -C substituted by cyano 1～6 Alkyl, halo-C 1～6 Alkyl, halo-C 2～6 Alkenyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a or -C 0～4 Alkylene-OS(O)2R 1a , 6- to 10-membered aryl groups and 5- to 10-membered heteroaryl groups.

[0021] In some embodiments, the compound as described above in Formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein X 1 and X 2 One of them is O and the other is N.

[0022] In a further preferred embodiment, X1 is O and X2 is N.

[0023] In a further preferred embodiment, X1 is N and X2 is O.

[0024] In some embodiments, the compound as described above in Formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein X 3 , X 4 , X 5 , X 6 , X 7 are independently selected from N and CH.

[0025] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 4 , R 5 are each independently selected from hydrogen and deuterium.

[0026] In a further preferred embodiment, R 4 , R 5 All are deuterium.

[0027] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 1 Selected from hydrogen, -NR 1a R 1b and-NR 1a C(O)R 1b ; Among them, R 1a , R 1b are independently selected from hydrogen and -C 1～4 alkyl.

[0028] In a further preferred embodiment, R 1 is -NH2.

[0029] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 2 Selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C1～4 Alkoxy, halo-C 1～4 Alkoxy, -NR 1a R 1b and-NR 1a C(O)R 1b ; Among them, R 1a , R 1b are independently selected from hydrogen and -C 1～4 alkyl.

[0030] In a further preferred embodiment, R 2 For hydrogen.

[0031] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 3 Selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C 1～4 Alkoxy and halo-C 1～4 Alkoxy.

[0032] In a further preferred embodiment, R 3 For hydrogen.

[0033] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 6 Selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C 1～4 Alkoxy and halo-C 1～4 Alkoxy.

[0034] In a further preferred embodiment, R 6 is selected from hydrogen and halogen.

[0035] In some embodiments, the compound of formula I as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein m and n are independently 0, 1 or 2.

[0036] In some embodiments, the compound of formula I as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein L is selected from -CH2-, -O-, -NH-, -CH2O-, -CH2NH- and -CH2CH2O-.

[0037] In a further preferred embodiment, L is selected from -O-, -CH2O- and -NH-.

[0038] In a further preferred embodiment, L is selected from -O- and -CH2O-.

[0039] In a further preferred embodiment, L is -O-.

[0040] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 7 Selected from -OH, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, 3- to 6-membered cycloalkyl, -C1 alkylene-(3- to 6-membered cycloalkyl), 3- to 10-membered heterocyclic group, -C1 alkylene-(3- to 10-membered heterocyclic group), 6-membered aryl and 5- to 10-membered heteroaryl.

[0041] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 7 Selected from -OH, isobutyl, neopentyl, allyl, propenyl, propargyl, propynyl, prop-2-yn-1-yl, cyclopropyl, cyclopropylmethyl, oxirane, oxiranemethyl, oxetanyl, oxetanyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptyl, pyridyl, phenyl, pyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrimidinyl, triazolyl, thiazolyl and benzo-1,3-dioxazolyl.

[0042] In some embodiments, R 7 Selected from allyl, propargyl, cyclopropylmethyl, pyridyl and phenyl.

[0043] In a further preferred embodiment, R 7 Selected from

[0044]

[0045] In some embodiments, the compound of formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 7 Optionally one or two R 1c replace.

[0046] In some embodiments, the compound of formula I as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 1c Selected from hydrogen, halogen, cyano, -C 1～4Alkyl, -C substituted by cyano 1～4 Alkyl and halo-C 1～4 alkyl.

[0047] In some embodiments, R 1c is selected from the group consisting of hydrogen, F, Cl, Br, cyano, methyl, cyanomethyl and trifluoromethyl.

[0048] In some embodiments, R 1c is selected from the group consisting of hydrogen, methyl, F, Cl and Br.

[0049] In some embodiments, the compound as described above as shown in Formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein Formula I is the structure shown in Formula II;

[0050]

[0051] In some embodiments, the compound represented by Formula II, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein X 4 is N or CH, X 3 , X 6 , X 7 are each independently selected from CH.

[0052] In some embodiments, in the compound represented by formula II as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein L is O.

[0053] In some embodiments, the compound represented by Formula II, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 7 It is phenyl or pyridyl.

[0054] In some embodiments, the compound represented by Formula II, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, R 7 Optionally one or more R 1c Replacement, where R 1c is selected from hydrogen, F and Cl.

[0055] In a further preferred embodiment, R 7 Selected from

[0056] In some embodiments, the compound as described above in Formula I, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein Formula I is a structure as shown in Formula III;

[0057]

[0058] In some embodiments, the compound represented by the aforementioned formula III, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein X 3 , X 4 , X 5 , X 7 All are CH.

[0059] In some embodiments, in the compound represented by Formula III as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein L is -O-.

[0060] In some embodiments, the compound represented by formula III as described above, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, wherein R 7 Selected from phenyl, pyridyl, propargyl, allyl and cyclopropylmethyl.

[0061] In a further preferred embodiment, R 7 Selected from propargyl and allyl.

[0062] In some embodiments, the compound represented by Formula III, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, R 7 Optionally one or more R 1c Replacement, where R 1c is selected from the group consisting of hydrogen, methyl, F, Cl and Br.

[0063] In a further preferred embodiment, R 1c is selected from hydrogen, methyl and Br.

[0064] In a further preferred embodiment, R 7 Selected from

[0065] In a further preferred embodiment, R 7 Selected from

[0066] In some specific embodiments of the present application, the compound described in Formula I is selected from the following structures:

[0067]

[0068]

[0069]

[0070] On the other hand, the present application also provides a pharmaceutical composition, comprising any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients. The carriers, diluents or excipients are all known common excipients, and the pharmaceutical composition can be prepared into various dosage forms such as tablets, granules, ointments, etc., and different excipients can be selected according to needs.

[0071] On the other hand, the present application also provides the use of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof in the preparation of drugs for preventing or treating fungal infections.

[0072] In some embodiments, the fungal infection is caused by Candida albicans, Aspergillus fumigatus, or Cryptococcus neoformans.

[0073] The compounds and derivatives provided in this application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0074] Explanation of terms

[0075] Unless otherwise stated, the initial definitions provided for groups or terms in this application apply to the groups or terms throughout the specification; for terms that are not specifically defined in this application, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0076] The term "hydrogen" refers to -H.

[0077] The term "deuterium" refers to -D.

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

[0079] The term "halogen" refers to F, Cl, Br or I.

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

[0081] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (i.e., C 1～20 The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1～6 alkyl), more preferably an alkyl group having 1 to 4 carbon atoms (i.e., C 1～4Alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, and the like.

[0082] The term "-C substituted by cyano 1～6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms substituted by one or more cyano groups, and the alkyl group is as defined above. 1～6 Non-limiting examples of alkyl include -CH2CN or -CHCNCH3 and the like.

[0083] The term "halogenated-C 1～6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms substituted by one or more halogens, and the alkyl group is as defined above. 1～6 Non-limiting examples of alkyl groups include trifluoromethyl, difluoromethyl, trifluoroethyl and the like.

[0084] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 carbon atoms (i.e., C 2～12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2～6 -C 2～6 Non-limiting examples of alkenyl groups include ethenyl, propenyl, allyl, 2-methyl-propenyl, 2-methylallyl, isopropenyl, butenyl, or 3-methylallyl, and the like.

[0085] The term "halogenated-C 2～6 "Alkenyl" refers to an alkenyl group having 1 to 6 carbon atoms substituted by one or more halogens, and alkenyl is as defined above. 2～6 Non-limiting examples of alkenyl groups include 2-bromoallyl, 2-chloroallyl, 2-fluoroallyl, 1,1-dichloroallyl, 1,2-dichloroallyl, 1,1,1-trifluoro-2-allylbutyl, 1-chloro-2-fluoroallyl, or 1-chloroallyl, and the like.

[0086] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 carbon atoms (i.e., C 2～12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2～6 -C 2～6 Non-limiting examples of alkynyl groups include ethynyl, propynyl, propargyl, 2-methylpropargyl or butynyl and the like.

[0087] The term "halogenated-C 2～6 "Alkynyl" refers to an alkynyl group having 1 to 6 carbon atoms substituted by one or more halogens, and the alkynyl group is as defined above.2～6 Non-limiting examples of alkynyl groups include 2-bromopropargyl, 2-chloropropargyl, 2-fluoropropargyl, 1,1-dichloropropargyl, 1,2-dichloropropargyl, 1,1,1-trifluoro-2-ynbutyl, 1-chloro-2-fluoropropargyl, or 1-chloropropargyl, and the like.

[0088] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having 1 to 20 carbon atoms (i.e., C 1～20 The alkylene group is preferably an alkylene group having 1 to 4 carbon atoms (i.e., C 1～4 When the alkylene group is absent, it is represented by C0. 1～4 Non-limiting examples of alkylene include -CH2-, -CH2CH2-, -C(CH3)2-, -CH2CH(CH3)-, -CH(CH3)-, -CH(CH2CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-, and the like.

[0089] The term "-C 0～4 Alkylene-OR 1a " means -OR 1a , or by -OR 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-OR 1a Non-limiting examples include: -OH, -CH2OH, -OCH3, -OCF3 or -OCH2CH3 and the like.

[0090] The term "-OC(O)R 1a " means

[0091] The term "-C 0～4 Alkylene-OC(O)R 1a ” refers to -OC(O)R 1a , or -OC(O)R 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-OC(O)R 1a Non-limiting examples include: -OC(O)H, -OC(O)CH3, -CH2OC(O)CH3, -OC(O)CF3 or -OC(O)CH2CH3 and the like.

[0092] The term "-C 0～4 Alkylene-SR 1a ” refers to SR 1a , or by -SR 1aSubstituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-SR 1a Non-limiting examples include: -SH, -CH2SH, -SCH3, -SCF3 or -SCH2CH3 and the like.

[0093] The term "-C(O)R 1a " means

[0094] The term "-C 0～4 Alkylene-C(O)R 1a ” refers to -C(O)R 1a , or -C(O)R 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-C(O)R 1a Non-limiting examples include: -C(O)H, -C(O)CH3, -CH2C(O)CH3, -C(O)CF3 or -C(O)CH2CH3 and the like.

[0095] The term "-C(O)OR 1a " means

[0096] The term "-C 0～4 Alkylene-C(O)OR 1a " means -C(O)OR 1a , or -C(O)OR 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-C(O)OR 1a Non-limiting examples include: -C(O)OH, -C(O)OCH3, -CH2C(O)OCH3, -C(O)OCF3 or -C(O)OCH2CH3 and the like.

[0097] The term "-C(O)NR 1a R 1b " means

[0098] The term "-C 0～4 Alkylene-C(O)NR 1a R 1b ” refers to -C(O)NR 1a R 1b , or -C(O)NR 1a R 1b Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-C(O)NR1a R 1b Non-limiting examples include: -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -CH2C(O)N(CH3)2, -C(O)N(CH3)CF3 or -C(O)NHCH2CH3 and the like.

[0099] The term "-C 0～4 Alkylene-NR 1a R 1b ” means -NR 1a R 1b , or by -NR 1a R 1b Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-NR 1a R 1b Non-limiting examples include: -NH2, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -N(CH3)CF3 or -NHCH2CH3 and the like.

[0100] The term "-NR 1a C(O)R 1b " means

[0101] The term "-C 0～4 Alkylene-NR 1a C(O)R 1b ” means -NR 1a C(O)R 1b , or by -NR 1a C(O)R 1b Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-NR 1a C(O)R 1b Non-limiting examples include: -NHC(O)H, -NHC(O)CH3, -N(CH3)C(O)CH3, -CH2N(CH3)C(O)CH3, -N(CH3)C(O)CF3 or -NHC(O)CH2CH3 and the like.

[0102] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 ring atoms (i.e., 3-20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 10 ring atoms (i.e., 3-12-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3-6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl; non-limiting examples of polycyclic cycloalkyls include: bicyclohexyl, bicyclopentyl,

[0103] The term "-C 0～4 The term "alkylene-(3- to 10-membered cycloalkyl)" refers to a 3- to 10-membered cycloalkyl or a methylene group containing 1 to 4 carbon atoms substituted by a 3- to 10-membered cycloalkyl group, wherein the 3- to 10-membered cycloalkyl group and the methylene group are as defined above.

[0104] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclic group) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclic group), which contains at least one heteroatom selected from nitrogen, oxygen and sulfur in the ring and has 3 to 20 ring atoms (i.e., a 3-20-membered heterocyclic group). The heterocyclic group is preferably a heterocyclic group having 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclic group); more preferably, a heterocyclic group having 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclic group). Non-limiting examples of monocyclic heterocyclic groups include: oxacyclopropyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl or morpholinyl; non-limiting examples of polycyclic heterocyclic groups include: 2-oxa-6-azaspiro[3.3]heptyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl or 9-aza-bicyclo[3.3.1]nonyl.

[0105] The term "-C 0～4 The term "alkylene-(3- to 10-membered heterocyclic group)" refers to a 3- to 10-membered heterocyclic group or a methylene group containing 1 to 4 carbon atoms substituted by a 3- to 10-membered heterocyclic group, wherein the heterocyclic group and the methylene group are as defined above.

[0106] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 ring atoms (i.e., 6-14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., 6-10-membered aromatic group). Non-limiting examples of the aryl group include phenyl, naphthyl, anthracenyl, phenanthrenyl, wait.

[0107] The term "-C 0～4 The term "alkylene-(6- to 10-membered aryl)" refers to a 6- to 10-membered aryl group or a methylene group having 1 to 4 carbon atoms substituted by a 6- to 10-membered aryl group, wherein the aryl group and the methylene group are as defined above.

[0108] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, wherein the ring contains at least one heteroatom selected from nitrogen, oxygen and sulfur, and has 5 to 14 ring atoms (i.e., a 5-14-membered heteroaryl). The heteroaryl preferably has a heteroaromatic group having 5 to 10 ring atoms (i.e., a 5-10-membered heteroaryl). Non-limiting examples of monocyclic heteroaryls include furanyl, oxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyridonyl, pyrazinyl or pyridazinyl, etc. Non-limiting examples of polycyclic heteroaryl groups include indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, wait.

[0109] The term "-C 0～4 The term "alkylene-(5- to 10-membered heteroaryl)" refers to a 5- to 10-membered heteroaryl group or a methylene group having 1 to 4 carbon atoms substituted by a 5- to 10-membered heteroaryl group, wherein the heteroaryl group and the methylene group are as defined above.

[0110] The term "-S(O)2R 1a " means

[0111] The term "-C 0～4 Alkylene-S(O)2R 1a ” refers to -S(O)2R 1a , or -S(O)2R 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-S(O)2R 1a Non-limiting examples include: -S(O)2H, -S(O)2CH3, -CH2S(O)2CH3, -S(O)2CF3 or -S(O)2CH2CH3 and the like.

[0112] The term "-S(O)R 1a " means

[0113] The term "-C 0～4 Alkylene-S(O)R 1a ” refers to -S(O)R 1a , or -S(O)R 1aSubstituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-S(O)R 1a Non-limiting examples include: -S(O)H, -S(O)CH3, -CH2S(O)CH3, -S(O)CF3 or -S(O)CH2CH3 and the like.

[0114] The term "-S(O)2NR 1a R 1b " means

[0115] The term "-C 0～4 Alkylene-S(O)2NR 1a R 1b ” refers to -S(O)2NR 1a R 1b , or -S(O)2NR 1a R 1b Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-S(O)2NR 1a R 1b Non-limiting examples include: -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, -CH2S(O)2N(CH3)2, -S(O)2N(CH3)CF3 or -S(O)2NHCH2CH3, etc.

[0116] The term "-S(O)NR 1a R 1b " means

[0117] The term "-C 0～4 Alkylene-S(O)NR 1a R 1b ” refers to -S(O)NR 1a R 1b , or -S(O)NR 1a R 1b Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-S(O)NR 1a R 1b Non-limiting examples include: -S(O)NH2, -S(O)NHCH3, -S(O)N(CH3)2, -CH2S(O)N(CH3)2, -S(O)N(CH3)CF3 or -S(O)NHCH2CH3 and the like.

[0118] The term "-OS(O)2R 1a " means

[0119] The term "-C 0～4 Alkylene-OS(O)2R 1a ” refers to -OS(O)2R 1a , or -OS(O)2R 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-OS(O)2R 1a Non-limiting examples include: -OS(O)2CH3, -CH2OS(O)2CH3, -OS(O)2CF3 or -OS(O)2CH2CH3 and the like.

[0120] The term "-S(O)2OR 1a " means

[0121] The term "-C 0～4 Alkylene-S(O)2OR 1a ” refers to -S(O)2OR 1a , or -S(O)2OR 1a Substituted methylene containing 1 to 4 carbon atoms, wherein the methylene group is as defined above. 0～4 Alkylene-S(O)2OR 1a Non-limiting examples include: -S(O)2OH, -S(O)2OCH3, -CH2S(O)2OCH3, -S(O)2OCF3 or -S(O)2OCH2CH3 and the like.

[0122] The term "deuterated compound" refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0123] "Substitution" means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0124] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0125] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent). These salts may form a precipitate in the solution and be collected by filtering, or be recovered after solvent evaporation, or be obtained by freeze drying after reaction in an aqueous medium. The salt described in the present application can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0126] In certain embodiments, one or more compounds of the present application can be used in combination with each other. It is also possible to select the compounds of the present application to be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds can be administered to the subject simultaneously, separately or in order.

[0127] Obviously, based on the above content of this application, in accordance with common technical knowledge and customary means in this field, without departing from the above basic technical ideas of this application, other various forms of modifications, replacements or changes can be made.

[0128] The above contents of the present application are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples. All technologies implemented based on the above contents of the present application belong to the scope of the present application. DETAILED DESCRIPTION

[0129] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR measurements were performed using a Bruker Avance III HD 400 and Bruker Avance NEO 400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0130] LC-MS determination was performed using a Shimadzu LC-MS2020 (ESI) instrument. HPLC determination was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A, LC-20AD, LC-2030C). The thin layer chromatography silica gel plate used was a Shandong Rushan SGF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product was 0.4 mm to 0.5 mm. Column chromatography used 200 to 300 mesh silica gel (reagent grade) from Yucheng Chemical (Shanghai) Co., Ltd. as the carrier.

[0131] The known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from companies such as Anage Chemical, Inochem, MacLean, Shaoyuan Chemical Technology, Bidex, Yaoshi Technology, and Bailingwei Technology.

[0132] Unless otherwise specified in the examples, solution refers to aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Unless otherwise specified in the examples, M is mole per liter. The percentage content involved in this article, unless otherwise specified, refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0133] Synthesis of intermediate MA

[0134]

[0135] Step 1: Synthesis of compound MA-2

[0136] Under ice bath, compound MA-1 (20g, 146.90mmol) was dissolved in toluene (250mL), pivaloyl chloride (26.57g, 220.34mmol, 27.11mL) and triethylamine (23.78g, 235.03mmol, 32.78mL) were added, and the reaction was carried out at room temperature for 3h. The reaction solution was poured into water, the pH was adjusted to 8 with 5N sodium hydroxide aqueous solution, and then extracted with ethyl acetate (200mL×3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the residue was separated by CombiFlash column (120g, 0-50% ethyl acetate / petroleum ether) to obtain compound MA-2 (29g, 131.66mmol, yield: 89.63%), a light brown oil. LCMS: ESI[M+H] + =221.

[0137] Step 2: Synthesis of compound MA-3

[0138] Under ice bath, compound MA-2 (80g, 363.20mmol) and diethyl oxalate (106.16g, 726.39mmol, 98.66mL) were dissolved in ethanol (800mL) to obtain solution 1. Potassium tert-butoxide (81.36g, 726.39mmol) was dissolved in ethanol (300mL) and added to solution 1. Stir at 0℃ for 1h and monitor the disappearance of the raw material. Add hydrochloric acid (6M, 121.07mL, purity 37%) and hydroxylamine hydrochloride (50.48g, 726.39mmol). Stir at room temperature for 1h and monitor the disappearance of the raw material by LCMS. Adjust the pH of the reaction solution to 7 with 5N sodium hydroxide. Extract with water and ethyl acetate (800mL×3). Dry over anhydrous sodium sulfate, filter and spin dry. The residue was dissolved in ethanol, triethylamine (73.50 g, 726.39 mmol, 101.31 mL) was added, and the temperature was raised to 80°C for overnight reaction. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by CombiFlash column (120 g × 3, 0-60% ethyl acetate / petroleum ether) to obtain the product, and then slurried with petroleum ether / ethyl acetate = 20:1 to obtain compound MA-3 (50 g, 157.56 mmol, yield: 43.38%), an off-white solid. LCMS: ESI [M+H] + =318.1.

[0139] Step 3: Synthesis of compound MA-4

[0140] Compound MA-3 (6 g, 18.91 mmol) was dissolved in deuterated methanol (40 mL), and sodium deuterated borohydride (3.18 g, 75.63 mmol) was slowly added at 0°C. Stir at room temperature for 3 h. The reaction was quenched with acetone, and the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (40 g, 0-10% methanol / dichloromethane) to obtain compound MA-4 (4 g, 14.42 mmol, yield: 76.29%), a light yellow solid. LCMS: ESI [M+H] + =278.1.

[0141] Step 4: Synthesis of compound MA-5

[0142] Compound MA-4 (4 g, 14.42 mmol) was dissolved in hydrochloric acid (6 M, 40 mL), heated to 90 ° C and stirred overnight. The solvent was removed by concentration under reduced pressure, then dissolved in ethyl acetate, pH adjusted to 7 with saturated sodium bicarbonate aqueous solution, extracted three times with ethyl acetate, and the aqueous phase was extracted three times with dichloromethane and methanol 10:1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound MA-5 (2.79 g, 14.44 mmol, yield: 100.00%) as a yellow solid. The next step was directly carried out without purification. LCMS: ESI [M + H]+ =194.1.

[0143] Step 5: Synthesis of intermediate MA

[0144] Compound MA-5 (2.79 g, 14.44 mmol) was dissolved in dichloromethane (30 mL), thionyl chloride (13.74 g, 115.53 mmol, 8.39 mL) was added, and the temperature was raised to 40 ° C and stirred overnight. The solvent was removed by concentration under reduced pressure, water and ethyl acetate were added, and the pH value was adjusted to greater than 7 with saturated sodium bicarbonate aqueous solution. Then ethyl acetate was extracted three times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then slurried with petroleum ether: ethyl acetate = 50:1, filtered to obtain a filter cake, and the filter cake was dried to obtain the intermediate MA (2.8 g, 13.23 mmol, yield: 91.61%), a light yellow solid. LCMS: ESI [M + H] + =212.1.

[0145] 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=4.8,2.0Hz,1H),7.91(dd,J=7.6,2.0Hz,1H),7.04(s,1H),6.71(dd,J=7.6,4.8Hz,1H),6.32(s,2H).

[0146] Synthesis of intermediate MB

[0147]

[0148] Step 1: Synthesis of compound MB-2

[0149] Compound MB-1 (20 g, 163.77 mmol) was dissolved in tetrahydrofuran (200 mL), di-tert-butyl dicarbonate (125.10 g, 573.19 mmol, 131.68 mL), triethylamine (99.43 g, 982.60 mmol, 137.05 mL) and 4-dimethylaminopyridine (4.00 g, 32.75 mmol) were added, and the mixture was heated to 60 °C for 20 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and then extracted with ethyl acetate (400 mL × 3), the organic layers were combined, washed with saturated brine, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain compound MB-2 (22 g, 68.25 mmol, yield: 41.67%), a light yellow solid. LCMS: ESI [M + H-156] + =167.1.

[0150] Step 2: Synthesis of compound MB-3

[0151] Compound MB-2 (22 g, 68.25 mmol) and potassium acetate (10.05 g, 102.37 mmol) were dissolved in water (50 mL) and ethanol (240 mL), and hydroxylamine hydrochloride (7.11 g, 102.37 mmol, hydrochloric acid) was added, and heated to 60 ° C and stirred for 1 hour. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound MB-3 (22 g, 65.21 mmol, yield: 95.55%), a white solid. The next step reaction was carried out without purification. LCMS: ESI [M + H-156] + =182.1.

[0152] Step 3: Synthesis of compound MB-4

[0153] Compound MB-3 (22 g, 65.21 mmol) was dissolved in water (30 mL) and methanol (200 mL), and (bis(trifluoroacetoxy)iodo)benzene (46.95 g, 97.82 mmol) and methyl propiolate (10.96 g, 130.42 mmol, 11.60 mL) were added to react at room temperature overnight. After the reaction solution was concentrated, water was added, and it was extracted with ethyl acetate (200 mL×2). The organic layers were combined, washed with saturated brine, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain compound MB-4 (17 g, 40.53 mmol, yield: 62.15%), a yellow oil. LCMS: ESI [M+H-156] + =264.1.

[0154] Step 4: Synthesis of compound MB-5

[0155] Compound MB-4 (17 g, 40.53 mmol) was dissolved in deuterated methanol (150 mL), sodium deuterated borohydride (5.96 g, 141.86 mmol) was added under ice bath, and the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched with acetone, and the solvent was removed by concentration under reduced pressure to obtain compound MB-5 (15.5 g, 39.40 mmol, yield: 97.20%), a yellow solid, which was directly used for the next step without purification. LCMS: ESI [M+H-156] + =238.1.

[0156] Step 5: Synthesis of intermediate MB

[0157] Compound MB-5 (15.5 g, 39.40 mmol) was dissolved in dichloromethane (200 mL), thionyl chloride (46.87 g, 393.97 mmol, 28.61 mL) was added dropwise at 0 °C, and then the temperature was raised to 40 °C for overnight reaction. The reaction solution was spin-dried, and then ethyl acetate and water were added. The pH value was adjusted to greater than 8 with saturated sodium bicarbonate, and ethyl acetate was extracted three times, and the organic phases were combined to obtain a crude product. The crude product was slurried with petroleum ether: ethyl acetate = 20:1, filtered to obtain a solid, and dried to obtain the intermediate MB (4.9 g, 23.15 mmol, yield: 58.77%), a light yellow solid. LCMS: ESI [M + H] + =212.1.

[0158] 1 H NMR (400MHz, DMSO-d6) δ8.09(dd,J=4.8,2.0Hz,1H),8.00(dd,J=7.6,2.0Hz,1H),7.25(s,1H),6.88(s,2H),6.69(dd,J=7.6,4.8Hz,1H).

[0159] Example 1: Synthesis of Compound H-1

[0160]

[0161] Step 1: Synthesis of compound H-1-b

[0162] Compound H-1-a (1g, 9.08mmol) and 2,6-difluoropyridine (1.05g, 9.08mmol) were dissolved in a mixed solvent of dimethyl sulfoxide: water = 5:1 (12mL), cooled to 0°C, sodium hydride (1.09g, 27.25mmol, purity 60%) was added in batches, and the reaction solution was stirred at 50°C for 1 hour. The reaction solution was slowly dripped into ice water and ethyl acetate, extracted with ethyl acetate three times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-1-b (1.35g, yield: 72.45%), a pink solid. LCMS: ESI [M+H] + =206.1.

[0163] Step 2: Synthesis of compound H-1

[0164] Compound H-1-b (38.7 mg, 189.00 μmol) and MA (59.8 mg, 283.49 μmol) were dissolved in N,N-dimethylformamide (3 mL), cesium carbonate (184.74 mg, 566.99 μmol) and sodium iodide (56.66 mg, 377.99 μmol) were added, and the temperature was raised to 45°C for 16 hours. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a concentrate. The concentrate was purified by column chromatography (petroleum ether: ethyl acetate = 50%: 50%) to obtain a crude product, which was then purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-1 (55.82 mg, 146.75 μmol, yield: 77.65%, purity: 100%). LCMS: ESI [M+H] + =381.1.

[0165] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=4.4,1.6Hz,1H),7.97(dd,J=16.4,8.0Hz,1H),7.92(dd,J=7.6,1. 6Hz,1H),7.15-7.09(m,4H),7.07(s,1H),6.87-6.81(m,2H),6.71(dd,J=7.6,4.8Hz,1H),6.34(s,2H).

[0166] Example 2: Synthesis of Compound H-2

[0167]

[0168] Step 1: Synthesis of compound H-2-c

[0169] Compounds H-2-a (0.5 g, 4.54 mmol) and H-2-b (522.57 mg, 4.54 mmol) were dissolved in dimethyl sulfoxide (8 mL) and water (3 mL), and sodium hydroxide (363.25 mg, 9.08 mmol) was added. The mixture was heated to 80 °C and stirred for 3 hours. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-10% ethyl acetate / petroleum ether) to obtain compound H-2-c (500 mg, yield: 53.66%), a colorless oil. LCMS: ESI [M+H] + =206.1.

[0170] Step 2: Synthesis of compound H-2

[0171] Compound MA (50 mg, 236.25 μmol) and H-2-c (63 mg, 307.12 μmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (153.95 mg, 472.49 μmol) and sodium iodide (70.82 mg, 472.49 μmol) were added. The mixture was heated to 45 °C and stirred overnight. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-2 (33.25 mg, yield: 36.63%, purity: 99.00%), a light yellow solid. LCMS:ESI[M+H] + =381.2.

[0172] 1 H NMR (400MHz, DMSO-d6) δ8.10(dd,J=4.8,2.0Hz,1H),8.00(q,J=8.0Hz,1H),7.91(dd,J=7.6,2.0Hz,1H),7.36(t,J=8.0H z,1H),7.05(s,1H),6.98-6.94(m,1H),6.93-6.85(m,3H),6.80-6.75(m,1H),6.70(dd,J=7.6,4.8Hz,1H),6.32(s,2H).

[0173] Example 3: Synthesis of Compound H-3

[0174]

[0175] Compound H-1-b (70 mg, 0.341 mmol), MB (100 mg, 0.472 mmol), cesium carbonate (222.31 mg, 0.682 mmol) and sodium iodide (68.18 mg, 0.454 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-3 (37.22 mg, yield: 42.24%, purity: 98.17%), a white solid. LCMS: ESI [M+H] + =381.1.

[0176] 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=4.0Hz,1H),8.06-7.97(m,2H),7.33(s,1H),7.19-7.11(m,4H),6.96-6.82(m,4H),6.72(m,1H).

[0177] Example 4: Synthesis of Compound H-4

[0178]

[0179] Step 1: Synthesis of compound H-4-b

[0180] Compounds H-1-a (2g, 18.16mmol) and H-4-a (2.29g, 23.61mmol) were dissolved in a mixed solvent of water (2mL) and dimethyl sulfoxide (10mL), and sodium hydroxide (2.18g, 54.49mmol) was added. The reaction solution was stirred at 50°C for 16 hours. The reaction solution was slowly dripped into ice water and ethyl acetate, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-4-b (380mg, yield: 11.18%), a light yellow solid. LCMS: ESI [M+H] + =188.1.

[0181] Step 2: Synthesis of compound H-4

[0182] Compound H-4-b (53.07 mg, 0.283 mmol), MB (40 mg, 0.189 mmol), cesium carbonate (184.74 mg, 0.566 mmol) and sodium iodide (56.66 mg, 0.377 mmol) were dissolved in N,N-dimethylformamide (3 mL). The reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-4 (49.09 mg, yield: 70.42%, purity: 98.24%), a white solid. LCMS: ESI [M+H] + =363.1.

[0183] 1 H NMR(400MHz,DMSO-d6)δ8.16-8.09(m,2H),8.05(dd,J=7.2,2.0Hz,1H),7.83(m,1H),7.33(s,1H) ,7.11(s,4H),7.10-7.07(m,1H),6.98(d,J=8.4Hz,1H),6.93(s,2H),6.72(dd,J=7.6,4.8Hz,1H).

[0184] Example 5: Synthesis of Compound H-5

[0185]

[0186] Compound H-2-c (58.17 mg, 0.283 mmol), MB (40.00 mg, 0.189 mmol), cesium carbonate (184.74 mg, 0.566 mmol) and sodium iodide (56.66 mg, 0.377 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-5 (10.81 mg, yield: 15.04%, purity: 100%), a white solid. LCMS: ESI [M+H] + =381.1.

[0187] 1 H NMR(400MHz, DMSO-d6)δ8.11(dd,J=4.0,2.0Hz,1H),8.05-7.98(m,2H),7.39(t,J=12.0Hz,1H),7.3 1(s,1H),6.99(dd,J=8.0,2.0Hz,1H),6.96-6.86(m,5H),6.81(dd,J=7.6,2.0Hz,1H),6.71(m,1H).

[0188] Example 6: Synthesis of Compound H-6

[0189]

[0190] Step 1: Synthesis of compound H-6-b

[0191] Compound H-2-a (200 mg, 1.82 mmol) and potassium carbonate (251.03 mg, 1.82 mmol) were dissolved in N, N-dimethylformamide (3 mL), and compound H-6-a (49.04 mg, 0.363 mmol) was slowly added, and the reaction solution was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-20% ethyl acetate / petroleum ether) to obtain compound H-6-b (71 mg, yield: 23.81%), a colorless liquid. LCMS: ESI [M+H] + =165.0.

[0192] Step 2: Synthesis of compound H-6

[0193] Compound H-6-b (46.55 mg, 0.283 mmol), MA (40.00 mg, 0.189 mmol), cesium carbonate (184.74 mg, 0.566 mmol) and sodium iodide (56.66 mg, 0.377 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-6 (52.52 mg, yield: 81.88%, purity: 100%) as a white solid. LCMS: ESI [M+H] + =340.2.

[0194] 1 H NMR (400MHz, DMSO-d6) δ8.12(dd,J=8.0,4.0Hz,1H),7.94(dd,J=8.0,4.0Hz,1H),7.20(m,1H),7.07(s,1H),6.73 (m,1H),6.68-6.62(m,2H),6.61-6.54(m,1H),6.36(s,2H),5.04(s,1H),4.94(s,1H),4.46(s,2H),1.76(s,3H).

[0195] Example 7: Synthesis of Compound H-7

[0196]

[0197] Step 1: Synthesis of compound H-7-b

[0198] Compound H-2-a (314.60 mg, 2.86 mmol), H-7-a (500.00 mg, 2.86 mmol), cuprous iodide (16.32 mg, 0.085 mmol), ferric triacetylacetonate (60.55 mg, 0.171 mmol) and potassium carbonate (789.75 mg, 5.71 mmol) were dissolved in N-methylpyrrolidone (8 mL), and the reaction solution was stirred in a microwave at 150 ° C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-20% ethyl acetate / petroleum ether) to obtain compound H-7-b (75 mg, yield: 12.86%), a blue liquid. LCMS: ESI [M + H] + =205.2.

[0199] Step 2: Synthesis of compound H-7

[0200] Compound H-7-b (72.36 mg, 0.354 mmol), MB (50.00 mg, 0.236 mmol), cesium carbonate (230.92 mg, 0.708 mmol) and sodium iodide (70.82 mg, 0.472 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-7 (7.99 mg, yield: 8.91%, purity: 100%), a white solid. LCMS: ESI [M+H] + =380.1.

[0201] 1 H NMR (400 MHz, DMSO-d6) δ8.11 (m, 1H), 8.02 (dd, J = 8.0, 2.0 Hz, 1H), 7.45-7.33 (m, 2H), 7.29 (s, 1H), 6.98 (m, 1H), 6.94-6.90 (m, 3H), 6.89-6.79 (m, 3H), 6.74-6.65 (m, 2H). Example 8: Synthesis of Compound H-8

[0202]

[0203] Step 1: Synthesis of compound H-8-a

[0204] Compound MB-4 (1.2 g, 2.86 mmol) was dissolved in methanol (15 mL), and sodium borohydride (324.72 mg, 8.58 mmol) was added at 0°C. Stir at room temperature for 3 hours. Acetone was added to quench the reaction, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 90%: 10%) to obtain compound H-8-a (1 g, yield: 89.30%), a light yellow oil. LCMS: ESI [M+H] + =236.1.

[0205] Step 2: Synthesis of compound H-8-b

[0206] Compound H-8-a (1g, 2.55mmol) was dissolved in dichloromethane (15mL), thionyl chloride (1.52g, 12.77mmol, 927.80μL) was added, the temperature was raised to 40°C and stirred overnight, then the solvent was removed by concentration under reduced pressure, then dissolved in dichloromethane (10mL), trifluoroacetic acid (3mL) was added, and stirred at room temperature for 3 hours. The reaction solution was dried by rotation, the residue was dissolved in water, extracted once with dichloromethane, the pH was adjusted to 8 with saturated sodium bicarbonate, and extracted three times with dichloromethane. Wash with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry to obtain compound H-8-b (0.38g, yield: 70.95%), a yellow solid. The next step reaction was carried out without purification. LCMS: ESI [M + H] + =210.1.

[0207] Step 3: Synthesis of compound H-8

[0208] Compound H-8-b (60 mg, 286.22 μmol) and H-1-b (70.47 mg, 343.46 μmol) were dissolved in cesium carbonate (186.51 mg, 572.43 μmol) and sodium iodide (85.80 mg, 572.43 μmol). The mixture was heated to 40°C and stirred overnight. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 20%: 80%) to obtain a crude product, which was purified by preparative liquid chromatography (preparative column: 21.2×250mm C18 column; system: 10mM NH4HCO3-H2O; wavelength: 254 / 214nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-8 (24.56mg, yield: 22.04%, purity: 97.19%), a white solid. LCMS: ESI [M+H] + =379.1.

[0209] 1 H NMR(400MHz, DMSO-d6)δ8.09(dd,J=4.8,2.0Hz,1H),8.06-7.94(m,2H),7.31(s,1H),7.13( d,J=1.6Hz,4H),6.91(s,2H),6.88-6.81(m,2H),6.70(dd,J=7.6,4.8Hz,1H),5.36(s,2H).

[0210] Example 9: Synthesis of Compound H-9

[0211]

[0212] Step 1: Synthesis of compound H-9-c

[0213] Dissolve compound H-9-a (1.1 g, 5.49 mmol) in N,N-dimethylformamide (15 mL), add compound H-9-b (632.21 mg, 5.49 mmol) and cesium carbonate (3.58 g, 10.99 mmol). Stir at 85 °C for 16 h. LCMS monitors the completion of the reaction. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated by CombiFlash column (20 g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-9-c (1.2 g, yield: 73.97%), a light yellow solid. LCMS: ESI [M+H] + =296.2.

[0214] Step 2: Synthesis of compound H-9-d

[0215] Dissolve compound H-9-c (450 mg, 1.52 mmol) in methanol (10 mL), add palladium carbon (55.52 mg, 457.15 μmol), replace hydrogen 3 times, and react under a hydrogen balloon for 2 h. LCMS monitors the completion of the reaction. The reaction solution is filtered and the filter cake is washed once with methanol. The filtrate is dried to obtain compound H-9-d (250 mg, yield: 79.9%) as a light yellow solid. LCMS: ESI [M+H] + =206.1.

[0216] Step 3: Synthesis of compound H-9

[0217] Compound H-9-d (50 mg, 243.68 μmol) was dissolved in N,N-dimethylformamide (4 mL), sodium iodide (18.26 mg, 121.84 μmol) and MB (61.89 mg, 292.42 μmol) were added, and the mixture was reacted at 40°C for 16 hours. The reaction was completed by LCMS monitoring. Water was added, and the mixture was extracted once with ethyl acetate. The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-9 (10.79 mg, yield: 11.64%, purity: 100%) as a white solid. LCMS: ESI[M+H] + =383.1.

[0218] 1H NMR(400MHz,DMSO-d6)δ8.12-8.08(m,2H),8.02(dd,J=7.6,1.6Hz,1H),7.31(s,1H),7.24-7 .14(m,4H),6.90(s,2H),6.83-6.81(m,1H),6.70(dd,J=7.6,4.8Hz,1H),6.58(d,J=2Hz,1H).

[0219] Example 10: Synthesis of Compound H-10

[0220]

[0221] Step 1: Synthesis of compound H-10-c

[0222] Compounds H-10-a (1g, 5.68mmol) and H-10-b (700.69mg, 6.25mmol) were dissolved in N,N-dimethylformamide (10mL), potassium carbonate (1.57g, 11.36mmol) was added, and the temperature was raised to 80°C and stirred for 16h. Water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column separation (12g, 0-4% ethyl acetate / petroleum ether) to obtain compound H-10-c (1.1g, yield: 72.21%), a colorless oil. LCMS: ESI [M+H] + =268.0.

[0223] Step 2: Synthesis of compound H-10-d

[0224] Compound H-10-c (1.1 g, 4.10 mmol) and biboronic acid pinacol ester (1.56 g, 6.15 mmol) were dissolved in dioxane (20 mL), potassium acetate (805.38 mg, 8.21 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (297.75 mg, 410.32 μmol) were added under argon protection, and the mixture was heated to 90 ° C and stirred overnight. The solid was filtered off, and the mother liquor was concentrated under reduced pressure to obtain compound H-10-d (1.2 g, yield: 92.80%), a black oil. The crude product was directly subjected to the next step without purification.

[0225] Step 3: Synthesis of compound H-10-e

[0226] Compound H-10-d (1.2 g, 3.81 mmol) was dissolved in acetonitrile (15 mL), and hydrogen peroxide (4.32 g, 38.08 mmol, 4 mL, purity: 30%) was added, and stirred at room temperature for 1 hour. Sodium sulfite aqueous solution was added to quench the reaction, and ethyl acetate was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-15% ethyl acetate / petroleum ether) to obtain compound H-10-e (0.7 g, yield: 89.60%), a light yellow solid. LCMS: ESI [M+H] + =206.1.

[0227] Step 4: Synthesis of compound H-10

[0228] Compound H-10-e (69.80 mg, 340.19 μmol) and MB (60.00 mg, 283.49 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then cesium carbonate (184.74 mg, 566.99 μmol) and sodium iodide (84.99 mg, 566.99 μmol) were added. The temperature was raised to 40 °C and stirred overnight. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 30%: 70%) to obtain a crude product, which was purified by preparative liquid chromatography (preparative column: 21.2×250mm C18 column; system: 10mM NH4HCO3-H2O; wavelength: 254 / 214nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-10 (35.58mg, yield: 33.00%, purity: 100%) as a white solid. LCMS: ESI [M+H] + =363.1.

[0229] 1 H NMR (400MHz, DMSO-d6) δ8.09 (dd, J=4.8, 2.0Hz, 1H), 8.06-7.99 (m, 2H), 7.67 (dd, J=8.8, 3.2Hz, 1H), 7.40 (td, J=8.0 ,6.8Hz,1H),7.31(s,1H),7.09(d,J=8.8Hz,1H),7.04-6.95(m,2H),6.93-6.85(m,3H),6.69(dd,J=7.6,4.8Hz,1H).

[0230] Example 11: Synthesis of Compound H-11

[0231]

[0232] Step 1: Synthesis of compound H-11-b

[0233] Compound H-2-b (723.03 mg, 6.28 mmol) and H-11-a (1 g, 5.24 mmol) were dissolved in N, N-dimethylformamide (15 mL), potassium carbonate (1.45 g, 10.47 mmol) was added, and the temperature was raised to 75 ° C and stirred for 16 h. Water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash column separation (12 g, 0-2% ethyl acetate / petroleum ether) to obtain compound H-11-b (1.2 g, 4.19 mmol, yield: 80.12%), a colorless oil. LCMS: ESI [M+H] + =286.0.

[0234] Step 2: Synthesis of compound H-11-c

[0235] Compound H-11-b (1.2 g, 4.19 mmol) and biboronic acid pinacol ester (1.60 g, 6.29 mmol) were dissolved in dioxane (20 mL), potassium acetate (823.35 mg, 8.39 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (304.39 mg, 419.47 μmol) were added under argon protection, and the mixture was heated to 90 ° C and stirred overnight. The solid was filtered off, and the mother liquor was concentrated under reduced pressure to obtain compound H-11-c (1.3 g, yield: 93.03%), a black oil. The crude product was directly subjected to the next step without purification. LCMS: ESI [M + H] + =334.1.

[0236] Step 3: Synthesis of compound H-11-d

[0237] Compound H-11-c (1.3 g, 3.90 mmol) was dissolved in acetonitrile (15 mL), and hydrogen peroxide (4.42 g, 39.02 mmol, 4 mL, purity: 30%) was added and stirred at room temperature for 1 hour. Sodium sulfite aqueous solution was added to quench the reaction, and ethyl acetate was extracted three times. The organic phases were combined and dried over anhydrous sodium sulfate to obtain a crude product. The crude product was purified by CombiFlash column separation (12 g, 0-15% ethyl acetate / petroleum ether) to obtain compound H-11-d (0.7 g, yield: 80.38%), a colorless oil. LCMS: ESI [M+H] + =224.1.

[0238] Step 4: Synthesis of compound H-11

[0239] Compound H-11-d (75.92 mg, 340.19 μmol) and MB (60.00 mg, 283.49 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then cesium carbonate (184.74 mg, 566.99 μmol) and sodium iodide (84.99 mg, 566.99 μmol) were added. The mixture was heated to 40 °C and stirred overnight. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50%: 50%) to obtain a crude product, which was purified by preparative liquid chromatography (preparative column: 21.2×250mm C18 column; system: 10mM NH4HCO3-H2O; wavelength: 254 / 214nm; gradient: 5%-95% acetonitrile change) to obtain compound H-11 (56.59mg, yield: 50.03%, purity: 99.85%), a white solid. LCMS: ESI [M+H] + =399.1.

[0240] 1 H NMR(400MHz, DMSO-d6)δ8.09(dd,J=4.8,2.0Hz,1H),8.06-7.98(m,2H),7.29(s,1H),6.97(dd,J=8.0,1.6H z,1H),6.93(q,J=2.4Hz,1H),6.90(dd,J=4.0,2.0Hz,3H),6.81-6.74(m,2H),6.69(dd,J=7.6,4.8Hz,1H).

[0241] Example 12: Synthesis of Compound H-12

[0242]

[0243] Step 1: Synthesis of compound H-12-b

[0244] Compound H-12-a (200 mg, 1.74 mmol), H-2-a (172.23 mg, 1.56 mmol) and potassium carbonate (720.57 mg, 5.21 mmol) were dissolved in N, N-dimethylformamide (10 mL) and heated at 80 ° C for 16 hours. After adding water to the reaction solution, it was extracted with ethyl acetate (10 mL × 2), the organic layers were combined, washed with water and saturated brine in turn, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain compound H-12-b (70 mg, 341.16 μmol, yield: 19.63%), a white solid. LCMS: ESI [M + H] + =206.1.

[0245] Step 2: Synthesis of compound H-12

[0246] Compound MB (40.00 mg, 189.00 μmol) and H-12-b (42.66 mg, 207.90 μmol) were dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (123.16 mg, 377.99 μmol) and sodium iodide (56.66 mg, 377.99 μmol) were added, and the mixture was heated to 45 °C and stirred for 16 hours. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50%: 50%) to obtain the target compound H-12 (39.05 mg, yield: 54.32%, purity: 100%), as a white solid. LCMS: ESI [M+H] + =381.1.

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.09(dd,J=4.8,1.6Hz,1H),8.00(dd,J=8.0,1.6Hz,1H),7.94-7.91(m,1H),7.89-7.82(m,1H),7.35( t,J=8.0Hz,1H),7.28(s,1H),7.21-7.17(m,1H),6.96-6.86(m,4H),6.78(dd,J=7.6,1.6Hz,1H),6.69(dd,J=7.6,4.8Hz,1H).

[0248] Example 13: Synthesis of Compound H-13

[0249]

[0250] Step 1: Synthesis of compound H-13-c

[0251] Compounds H-13-a (2.4 g, 19.35 mmol, 1.2 eq) and H-13-b (2 g, 16.1 mmol, 1.0 eq) were placed in a 100 mL clean single-necked flask, N, N-dimethylformamide (25 mL) was added to dissolve, and then potassium carbonate (6 g, 48.37 mmol, 3.0 eq) and tetrabutylammonium bromide (484 mg, 1.6 mmol, 0.1 eq) were added, the gas was replaced 3 times, and the reaction was carried out at 65 ° C for 16 h. The reaction solution was slowly added to ice water, and ethyl acetate (50 mL × 3) was added to extract three times, the organic phase was washed with a saturated sodium chloride solution, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and purified to obtain compound H-13-c (2.9 g, yield: 81%). LCMS: ESI [M + H] + =238.

[0252] Step 2: Synthesis of compound H-13-d

[0253] At zero degrees, compound H-13-c (1.5 g, 6.3 mmol, 1 eq) was added to a dichloromethane (20 mL) solution of boron tribromide (4.7 g, 18.9 mmol, 3.0 eq), then returned to room temperature and stirred for 4 h, and the reaction solution was slowly poured into a cold saturated sodium bicarbonate aqueous solution. Ethyl acetate was extracted three times (200 mL × 3), and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified to obtain compound H-13-d (600 mg, yield: 42.5%). LCMS: ESI [MH] - =222.

[0254] Step 3: Synthesis of compound H-13

[0255] Compound H-13-d (100 mg, 0.448 mmol, 1.5 eq), potassium carbonate (123 mg, 0.896 mmol, 3.0 eq) and MB (75 mg, 0.298 mmol, 1.0 eq) were added to anhydrous N,N-dimethylformamide (5 mL), and the reaction system was kept at 60 ° C overnight. 50 mL of water was added to the reaction solution, and ethyl acetate (50 mL × 3) was used for extraction three times. A saturated sodium chloride solution was added to the organic phase for washing, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by preparative thin layer chromatography to obtain the target compound H-13 (52 mg, yield: 38.5%). LCMS: ESI [M + H] + =399.

[0256] 1H NMR(400MHz, DMSO-d6)δ8.11(dd,J=4.7,1.6Hz,1H),8.09-8.01(m,1H),7.99(t,J=2.4Hz,1H),7.5 5(td,J=8.3,2.6Hz,1H),7.31(s,1H),7.19-7.13(m,4H),6.92(s,2H),6.72(dd,J=7.6,4.8Hz,1H).

[0257] Example 14: Synthesis of Compound H-14

[0258]

[0259] Step 1: Synthesis of compound H-14-b

[0260] Dissolve compound H-2-a (1.15 g, 10.46 mmol) in acetone (15 mL), add potassium carbonate (2.17 g, 15.70 mmol) and H-14-b (1 g, 5.23 mmol). Heat to 60 °C and stir overnight. Filter out the solid and concentrate under reduced pressure to obtain a crude product. The crude product is separated by CombiFlash column (12 g, 0-10% ethyl acetate / petroleum ether) to obtain compound H-14-b (0.5 g, yield: 64.51%), a light yellow oil. LCMS: ESI [M+H] + =149.1.

[0261] Step 2: Synthesis of compound H-14

[0262] Compound H-14-b (50.40 mg, 340.19 μmol) and MB (60 mg, 283.49 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then cesium carbonate (184.74 mg, 566.99 μmol) and sodium iodide (84.99 mg, 566.99 μmol) were added. The mixture was heated to 40 °C and stirred for 2 h. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50%: 50%) to obtain a crude product, which was purified by preparative liquid chromatography (preparative column: 21.2×250mm C18 column; system: 10mM NH4HCO3-H2O; wavelength: 254 / 214nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-14 (50.92mg, 157.48μmol, yield: 55.55%, purity: 100%), a white solid. LCMS: ESI [M+H] + =324.2.

[0263] 1H NMR (400MHz, DMSO-d6) δ8.09 (dd, J=4.8, 2.0Hz, 1H), 8.01 (dd, J=7.6, 2.0Hz, 1H), 7.28 (s, 1H), 7.27-7.19 (m,1H),6.89(s,2H),6.72-6.67(m,3H),6.64-6.60(m,1H),4.77(d,J=2.4Hz,2H),3.54(t,J=2.4Hz,1H).

[0264] Example 15: Synthesis of Compound H-15

[0265]

[0266] Step 1: Synthesis of compound H-15-b

[0267] Compound H-15-a (1 g, 7.78 mmol), H-10-a (1.37 g, 7.78 mmol) and potassium carbonate (2.15 g, 15.56 mmol) were dissolved in N, N-dimethylformamide (6 mL), and the reaction solution was stirred at 80 ° C for 12 hours. The reaction was quenched with cold water, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20 g, 0-20% ethyl acetate / petroleum ether) to obtain compound H-15-b (2.05 g, yield: 92.62%), a white solid. LCMS: ESI [M+H] + =284.0.

[0268] Step 2: Synthesis of compound H-15-c

[0269] Compound H-15-b (2.05 g, 7.20 mmol), biboronic acid pinacol ester (2.74 g, 10.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.05 g, 1.44 mmol) and potassium acetate (1.41 g, 14.41 mmol) were dissolved in 1,4-dioxane (12 mL). The temperature was raised to 90 ° C under argon protection and stirred for 12 hours. Filter, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound H-15-c (2.3 g, yield: 86.64%), a black oil. LCMS: ESI [M + H] + =332.1.

[0270] Step 3: Synthesis of compound H-15-d

[0271] Compound H-15-c (2.3 g, 6.94 mmol) was dissolved in acetonitrile (10 mL), and hydrogen peroxide (2.36 g, 69.36 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. Sodium sulfite aqueous solution was added to quench the reaction, and then extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by CombiFlash column (12 g, 0-15% ethyl acetate / petroleum ether) to obtain compound H-15-d (1.4 g, yield: 83.78%), a white solid. LCMS: ESI [M+H] + =222.1.

[0272] Step 4: Synthesis of compound H-15

[0273] Compound H-15-d (78.54 mg, 0.354 mmol), MB (50 mg, 0.236 mmol), cesium carbonate (230.92 mg, 0.708 mmol) and sodium iodide (70.82 mg, 0.472 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-15 (53.86 mg, yield: 57.45%, purity: 100%) as a white solid. LCMS: ESI [M+H] + =397.1.

[0274] 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=4.8,2.0Hz,1H),8.03(dd,J=8.0,2.4Hz,2H),7.69(dd,J=8.8,3.2Hz,1H),7.42(t,J=8.0Hz,1H),7.33(s ,1H),7.27-7.22(m,1H),7.19(t,J=2.0Hz,1H),7.11(d,J=8.8Hz,1H),7.06(dd,J=8.0,2.0Hz,1H),6.90(s,2H),6.71(dd,J=7.6,4.8Hz,1H).

[0275] Example 16: Synthesis of Compound H-16

[0276]

[0277] Step 1: Synthesis of compound H-16-b

[0278] At room temperature, compound H-2-a (1g, 9.08mmol), H-16-a (735.64mg, 5.45mmol), potassium carbonate (1.51g, 10.90mmol) and N,N-dimethylformamide (10mL) were mixed and reacted at room temperature for 16 hours. The reaction solution was filtered and added with water, extracted with ethyl acetate (10mL×2), the organic layers were combined, washed with water and saturated brine in turn, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 70%: 30%) to obtain compound H-16-b (370mg, 2.25mmol, yield: 24.81%), a colorless liquid. LCMS: ESI[M+H] + =165.1.

[0279] Step 2: Synthesis of compound H-16

[0280] Compound MB (40.00 mg, 189.00 μmol) and H-16-b (34.14 mg, 207.90 μmol) were dissolved in N,N-dimethylformamide (5 mL), cesium carbonate (123.16 mg, 377.99 μmol) and sodium iodide (56.66 mg, 377.99 μmol) were added, and the mixture was heated to 45°C and stirred for 2 hours. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-16 (17.68 mg, yield: 27.31%, purity: 99.07%), a white solid. LCMS: ESI [M+H] + =340.2.

[0281] 1 H-NMR (400MHz, DMSO-d6) δ8.09(dd,J=4.8,2.0Hz,1H),8.01(dd,J=8.0,2.0Hz,1H),7.27(s,1H),7.20-7.15(m,1H),6.89(s,2H),6.69(dd,J=7.6, 4.8Hz,1H),6.63-6.59(m,2H),6.54(ddd,J=8.0,2.0,0.8Hz,1H),3.78(d ,J=7.2Hz,2H),1.23-1.15(m,1H),0.57-0.52(m,2H),0.31-0.27(m,2H).

[0282] Example 17: Synthesis of Compound H-17

[0283]

[0284] Step 1: Synthesis of compound H-17-b

[0285] Compound H-17-a (2g, 22.7mmol, 1eq) was dissolved in N,N-dimethylformamide (50mL), compound H-2-a (5g, 45.4mmol, 2eq) was added, and potassium carbonate (9.4g, 68.1mmol, 3eq) was finally added, and the mixture was reacted at 70°C for 16h, and the reaction was monitored by LCMS to complete. After the reaction, the reaction solution was added to water, and the reaction solution was extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound H-17-b (2g, yield: 56%), a yellow oil. LCMS: ESI [M + H] + =165.1.

[0286] Step 2: Synthesis of compound H-17

[0287] Compound MB (0.05 g, 0.24 mmol, 1.0 eq) was dissolved in ultra-dry N,N-dimethylformamide (7 mL), H-17-b (0.078 g, 0.48 mmol, 2.0 eq) was added, and potassium carbonate (0.1 g, 0.72 mmol, 3.0 eq) was finally added. The nitrogen was replaced three times, and the reaction was carried out at 60°C for 16 hours. The raw material disappeared after monitoring by LCMS, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine three times, dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target compound H-17 (16 mg, yield: 6%) as a white solid. LCMS: ESI [M+H] + =381.0.

[0288] 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=4.8,1.8Hz,1H),8.03(dd,J=7.7,1.8Hz,1H),7.29(s,1H),7.21(t,J=8.5Hz,1H),6.92(s ,2H),6.72(dd,J=7.6,4.8Hz,1H),6.68-6.62(m,2H),6.63-6.54(m,1H),5.04(s,1H),4.94(s,1H),4.46(s,2H),1.76(s,3H).

[0289] Example 18: Synthesis of Compound H-18

[0290]

[0291] Step 1: Synthesis of compound H-18-b

[0292] Compound H-2-a (200 mg, 1.82 mmol), compound H-18-a (72.61 mg, 0.363 mmol) and potassium carbonate (251.03 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at room temperature for 18 hours. Water was added to the reaction solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-20% ethyl acetate / petroleum ether) to obtain compound H-18-b (131 mg, yield: 31.48%), a colorless liquid. LCMS: ESI [M+H] + =229.1.

[0293] Step 2: Synthesis of compound H-18

[0294] Compound H-18-b (32.47 mg, 0.141 mmol), MB (20.00 mg, 0.094 mmol), cesium carbonate (92.37 mg, 0.283 mmol) and sodium iodide (28.33 mg, 0.189 mmol) were dissolved in N, N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain compound H-18 (26.60 mg, yield: 69.44%, purity: 99.72%) as a white solid. LCMS:ESI[M+H] + =404.1.

[0295] 1H NMR (400MHz, DMSO-d6) δ8.11 (dd, J=8.0, 2.0Hz, 1H), 8.02 (dd, J=8.0, 2.0Hz, 1H), 7.30-7.19 (m, 2H), 6. 90(s,2H),6.75-6.67(m,3H),6.65-6.59(m,1H),6.17-6.09(m,1H),5.74(d,J=2.0Hz,1H),4.76(s,2H).

[0296] Example 19: Synthesis of Compound H-19

[0297]

[0298] Step 1: Synthesis of compound H-19-b

[0299] Dissolve compound H-19-a (2g, 19.22mmol) in tetrahydrofuran (20mL), cool to 0℃ in an ice bath, slowly add borane tetrahydrofuran complex (BH3·THF, 1M, 23.06mmol, 23.06mL), stir at low temperature for 20 minutes, then add borane tetrahydrofuran complex (BH3·THF, 1M, 9.61mmol, 9.61mL). Slowly return to room temperature and stir for 2.5 hours. Slowly drop the reaction solution into ice water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound H-19-b (1.5g, yield: 86.64%), a colorless liquid. LCMS: ESI[M+H] + =91.1.

[0300] Step 2: Synthesis of compound H-19-c

[0301] Compound H-19-b (1.5 g, 16.65 mmol) and triethylamine (3.37 g, 33.30 mmol, 4.64 mL) were dissolved in dry dichloromethane (20 mL), and p-toluenesulfonyl chloride (3.49 g, 18.31 mmol) was added under argon protection. The reaction solution was stirred at room temperature for 16 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (40 g, 0-10% ethyl acetate / petroleum ether) to obtain compound H-19-c (3 g, 12.28 mmol, yield: 73.76%), a colorless liquid. LCMS: ESI [M+H] + =245.1.

[0302] Step 3: Synthesis of compound H-19-d

[0303] Compound H-19-c (332.78 g, 1.36 mmol), H-2-a (500 mg, 4.54 mmol) and potassium carbonate (753.09 mg, 5.45 mmol) were dissolved in N,N-dimethylformamide (6 mL), and the reaction solution was stirred at 80 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20 g, 0-5% ethyl acetate / petroleum ether) to obtain compound H-19-d (150 mg, yield: 18.13%), a colorless liquid. LCMS: ESI [M+H] + =183.1.

[0304] Step 4: Synthesis of compound H-19

[0305] Compound H-19-d (64.56 mg, 0.354 mmol), MB (50 mg, 0.236 mmol), cesium carbonate (230.92 mg, 0.708 mmol) and sodium iodide (70.82 mg, 0.472 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-19 (47.79 mg, yield: 56.43%, purity: 99.69%) as a white solid. LCMS:ESI[M+H] + =358.1.

[0306] 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=8.0,2.0Hz,1H),8.03(dd,J=7.6,2.0Hz,1H),7.29(s,1H),7.23(t,J=8.0 Hz,1H),6.90(s,2H),6.75-6.65(m,3H),6.64-6.60(m,1H),4.27(d,J=20.0Hz,2H),1.12(m,2H),0.85(m,2H).

[0307] Example 20: Synthesis of Compound H-20

[0308]

[0309] Step 1: Synthesis of compound H-20-b

[0310] Compound H-2-a (500 mg, 4.54 mmol) was dissolved in N, N-dimethylformamide (5 mL), and sodium hydride (181.62 mg, 4.54 mmol, 60% purity) was added to the mixture in an ice bath at 0°C. After stirring for 10 minutes, H-20-a (201.56 mg, 1.81 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. Water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (12 g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-20-b (310 mg, yield: 36.98%), a colorless liquid. LCMS: ESI [M+H] + =185.1.

[0311] Step 2: Synthesis of compound H-20

[0312] Compound H-20-b (39.25 mg, 0.212 mmol), MB (30.00 mg, 0.141 mmol), cesium carbonate (138.55 mg, 0.425 mmol) and sodium iodide (42.49 mg, 0.283 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction solution was stirred at 45 ° C for 12 hours. Water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-20 (29.99 mg, yield: 57.97%, purity: 98.59%), a white solid. LCMS:ESI[M+H] + =360.1.

[0313] 1 H NMR (400MHz, DMSO-d6) δ8.11(dd,J=4.8,2.0Hz,1H),8.03(dd,J=8.0,2.0Hz,1H),7.29(d,J=1.2Hz,1H),7.27-7. 18(m,1H),6.91(s,2H),6.75-6.53(m,4H),6.20(m,1H),4.73(dd,J=6.0,2.0Hz,1H),4.58(dd,J=6.4,1.2Hz,1H).

[0314] Example 21: Synthesis of Compound H-21

[0315]

[0316] Step 1: Synthesis of compound H-21-b

[0317] Compound H-21-a (5 g, 55.52 mmol) was dissolved in N, N-dimethylformamide (40 mL), potassium carbonate (15.35 g, 111.05 mmol) and benzyl bromide (9.50 g, 55.52 mmol, 6.59 mL) were added, and stirred at room temperature overnight. Water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (120 g, 0-10% ethyl acetate / petroleum ether) to obtain compound H-21-b (9 g, 49.95 mmol, yield: 89.97%), a light yellow oil. LCMS: ESI [M+H] + =181.1.

[0318] Step 2: Synthesis of compound H-21-c

[0319] Dissolve lithium aluminum tetrahydride (2.84 g, 74.93 mmol) in ether (50 mL), add compound H-21-b (9 g, 49.95 mmol) and ether (50 mL) dropwise under ice bath, slowly return to room temperature and stir overnight. Quench the reaction with 2N dilute hydrochloric acid, filter out the solid, extract three times with methyl tert-butyl ether, combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure at low temperature to obtain compound H-21-c (3.5 g, yield: 92.11%), a light yellow oil. Proceed to the next step without purification. LCMS: ESI [M + H] + =77.0.

[0320] Step 3: Synthesis of compound H-21-d

[0321] Compound H-21-c (1g, 13.15mmol) and triethylamine (3.99g, 39.44mmol, 5.50mL) were dissolved in dichloromethane (15mL), and methanesulfonyl chloride (3.01g, 26.29mmol, 2.03mL) was slowly added dropwise at 0°C, and stirred at room temperature for 4 hours. Water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound H-21-d (2g, 12.97mmol, yield: 98.69%), a light yellow oil, which was directly used for the next step without purification. LCMS: ESI [M + H] + =155.1.

[0322] Step 4: Synthesis of compound H-21-e

[0323] Compound H-2-a (2.14 g, 19.46 mmol) and potassium carbonate (2.69 g, 19.46 mmol) were dissolved in acetone (20 mL), H-21-d (2 g, 12.97 mmol) was added, and the temperature was raised to 60 ° C and stirred overnight. Water was added, and ethyl acetate was extracted three times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20 g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-21-e (0.3 g, yield: 13.75%), a light yellow oil. LCMS: ESI [M+H] + =169.1.

[0324] Step 5: Synthesis of compound H-21

[0325] Compound H-21-e (95.35 mg, 566.99 μmol) and MB (60 mg, 283.49 μmol) were dissolved in N, N-dimethylformamide (2 mL), and then cesium carbonate (184.74 mg, 566.99 μmol) and sodium iodide (84.99 mg, 566.99 μmol) were added. The mixture was heated to 40 °C and stirred for 2 h. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-21 (29.08 mg, yield: 29.36%, purity: 98.26%) as a white solid. LCMS:ESI[M+H] + =344.1.

[0326] 1 H NMR(400MHz, DMSO-d6)δ8.09(dd,J=4.8,2.0Hz,1H),8.01(dd,J=7.6,2.0Hz,1H),7.27(s,1H),7.22(t,J= 8.0Hz,1H),6.88(s,2H),6.73-6.66(m,3H),6.65-6.61(m,1H),4.95-4.79(m,2H),4.65(d,J=14.8Hz,2H).

[0327] Example 22: Synthesis of Compound H-22

[0328]

[0329] Step 1: Synthesis of compound H-22-b

[0330] Sodium iodide (1.18 g, 7.89 mmol), copper powder (16.71 mg, 262.90 μmol) and tetrahydrofuran (15 mL) were mixed and compound H-22-a (1.90 g, 7.36 mmol) was added, and the mixture was reacted at room temperature for 5 hours. Compound H-5 (1 g, 2.63 mmol) and toluene (15 mL) were added to the above solution, followed by 5N sodium hydroxide aqueous solution (15 mL), and the mixture was reacted at room temperature for 24 hours. Sodium iodide (1.18 g, 7.89 mmol), copper powder (16.71 mg, 262.90 μmol, 22.52 μL), compound H-22-a (1.90 g, 7.36 mmol) and tetrahydrofuran (15 mL) were added, and the mixture was reacted at room temperature for 24 hours. The upper organic layer of the reaction solution was separated, and the lower aqueous phase was extracted with tetrahydrofuran:toluene = 1:1 (20 mL×2). All organic layers were combined and concentrated to obtain a tetrahydrofuran / toluene solution of the crude product to obtain compound H-22-b (1.3 g, 2.15 mmol, yield 81.92%), and the crude product was directly subjected to the next step reaction.

[0331] Step 2: Synthesis of compound H-22

[0332] Trifluoroacetic acid (8 mL) was added to the crude solution of compound H-22-b at 0°C, and the mixture was reacted at room temperature for 4 hours. After the reaction solution was concentrated, the pH was adjusted to >10 with 5N sodium hydroxide solution at 0°C, and solids precipitated. The filtrate was collected and washed with ethyl acetate (15 mL × 3). The aqueous phase was stirred in an ice bath for 0.5 hours, and some solids precipitated again. The filtrate was collected by filtration. The filtrate was purified by preparative liquid chromatography (preparative column: 21.2 × 250 mm C18 column; system: 10 mM NH4HCO3-H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target compound H-22 (116.72 mg, 235.33 μmol, yield: 10.93%), a white solid. LCMS: ESI [M+H] + =491.1.

[0333] 1 H NMR (400MHz, DMSO-d6) δ8.57(dd,J=7.6,1.4Hz,1H),8.40(dd,J=6.8,1.2Hz,1H),7.98(q,J=8.0Hz,1H),7.44(s,1H), 7.17-7.11(m,4H),7.08-7.03(m,1H),6.86(dd,J=8.0,1.6Hz,1H),6.83(dd,J=8.0,2.4Hz,1H),5.77(d,J=9.6Hz,2H).

[0334] Example 23: Synthesis of Compound H-23

[0335]

[0336] Step 1: Synthesis of compound H-23-b

[0337] Compound H-16 (230 mg, 0.6784 mmol) was added to a single-mouth bottle, dissolved with dichloromethane (11.5 mL), and then a tetrahydrofuran solution of compound H-23-a (4 eq., 11.5 mL) and sodium hydroxide (5N, 11.5 mL) were added. The reaction solution was stirred at 25°C for 7 days. After the reaction was completed, the mixture was extracted with ethyl acetate, the organic layer was dried and filtered, and the filtrate was concentrated under reduced pressure at low temperature to obtain 150 mg of a yellow oily liquid. The compound H-23-b (100 mg, yield: 26.2%) was purified by reverse preparative column (0.1% TFA) to obtain a white solid. LCMS: ESI [M+H] + =506.

[0338] Step 2: Synthesis of compound H-23

[0339] Compound H-23-b (90 mg, 0.16 mmol) was added to a single-mouth bottle, acetonitrile (2 mL) was added to dissolve, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure and purified by reverse preparative column (0.1% trifluoroacetic acid) to obtain the target compound H-23 (35.6 mg, yield 49.5%) as a white solid. LCMS: ESI [M+H] + =450.1.

[0340] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=6.4Hz,1H),8.42(d,J=6.6Hz,1H),7.43(s,1H),7.20(dd,J=11.4,5.6Hz,1H),7.12(t,J=7.1Hz,1H),6.71-6.59( m,2H),6.59-6.49(m,1H),5.84(d,J=10.2Hz,2H),3.80(d,J=7.0Hz,2H), 1.20(ddd,J=12.7,7.5,4.8Hz,1H),0.60-0.47(m,2H),0.38-0.21(m,2H).

[0341] Example 24: Synthesis of Compound H-24

[0342]

[0343] Step 1: Synthesis of compound H-24-b

[0344] Compound H-24-a (2g, 28.53mmol) was dissolved in dichloromethane (30mL), and p-toluenesulfonyl chloride (5.98g, 31.39mmol) and triethylamine (5.77g, 57.07mmol, 7.96mL) were added to react at room temperature for 16h. The reaction was completed by LCMS monitoring. Water was added to the reaction solution, extracted with dichloromethane twice, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to obtain a crude product. The crude product was separated by CombiFlash column (20g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-24-b (4g, yield: 62.5%), a white solid. LCMS: ESI[M+H] + =224.1.

[0345] Step 2: Synthesis of compound H-24-c

[0346] Compound H-24-b (1 g, 4.46 mmol) was dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (2.91 g, 8.92 mmol) and compound H-2-a (981.92 mg, 8.92 mmol) were added, and the mixture was reacted at 80°C overnight. The reaction was completed by LCMS monitoring. Water and ethyl acetate were added, and the mixture was extracted once with ethyl acetate. The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by CombiFlash column (20 g, 0-30% ethyl acetate / petroleum ether) to obtain compound H-24-c (500 mg, yield: 69.14%), a white solid. LCMS: ESI [M+H] + =163.1.

[0347] Step 3: Synthesis of compound H-24

[0348] Compound H-24-c (100 mg, 616.58 μmol) was dissolved in N,N-dimethylformamide (5 mL), and compound MB (156.59 mg, 739.90 μmol), cesium carbonate (401.79 mg, 1.23 mmol) and sodium iodide (18.48 mg, 123.32 μmol) were added, and the mixture was reacted at 45°C for 16 h. The reaction was completed by LCMS monitoring. Water and ethyl acetate were added, and the mixture was extracted once with ethyl acetate. The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography (preparative column: 21.2×250 mm C18 column; system: 10 mM NH4HCO3 H2O; wavelength: 254 / 214 nm; gradient: 5%-95% acetonitrile change) to obtain the target product H-24 (88.66 mg, yield: 42.62%, purity: 100%) as a white solid. LCMS: ESI [M+H] + =338.1.

[0349] 1 H NMR (400MHz, DMSO-d6) δ8.09(dd,J=4.8,2Hz,1H),8.01(dd,J=7.6,2Hz,1H),7.27(s,1H),6.88( s,2H),6.71-6.65(m,3H),6.64-6.61(m,1H),5.09(qd,J=6.4,2.0Hz,1H),1.52(d,J=6.4Hz,3H).

[0350] Example 25: Synthesis of Compound H-25

[0351]

[0352] Step 1: Synthesis of compound H-25-c

[0353] Compound H-25-a (300 mg, 2.34 mmol) was added to a single-mouth bottle, dimethyl sulfoxide (10 mL) and water (2 mL) were added to dissolve, sodium hydroxide (281 mg, 7.02 mmol) and compound H-25-b (348 mg, 2.58 mmol) were added, and the mixture was stirred at 70°C for 1 h. TLC (petroleum ether / ethyl acetate = 10:1) was used for monitoring. After the reaction was completed, water (20 mL) was added to the reaction solution to quench, and ethyl acetate (20 mL × 2) was used for extraction. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain compound H-25-c (208 mg, yield 48.8%), a yellow oil. LCMS: m / z = 183.1 [M+H] + .

[0354] Step 2: Synthesis of compound H-25

[0355] Compound MB (58 mg, 0.275 mmol) was added to a single-mouth bottle, N,N-dimethylformamide (2 mL) was added to dissolve, compound H-25-c (50 mg, 0.275 mmol) and cesium carbonate (224 mg, 0.687 mmol) were added, and the mixture was stirred at 70°C for 2 h. After the reaction was completed, water (40 mL) was added to quench, and ethyl acetate (40 mL×2) was used for extraction. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. The crude product was purified by reverse phase preparation (NH4HCO3) to obtain the target compound H-25 (63.82 mg, yield 65.1%), a white solid. LCMS: m / z=358[M+H] + .

[0356] 1 H NMR(400MHz, CDCl3)δ8.07(d,J=4.8Hz,1H),7.85(dd,J=7.6,1.5Hz,1H),7.17-6.89(m,3H),6.82-6.75(m, 2H),6.72-6.59(m,2H),3.88(d,J=7.0Hz,2H),1.39-1.24(m,1H),0.71-0.62(m,2H),0.36(q,J=4.8Hz,2H).

[0357] Test Example 1: Antibacterial Concentration Test

[0358] Purpose

[0359] The minimum inhibitory concentration (MIC) and minimum effective concentration (MEC) of the test drugs against fungi.

[0360] Experimental strains and test media

[0361] Experimental strains: Candida albicans ATCC 90028, Aspergillus fumigatus ATCC MYA-4609, Cryptococcus neoformans ATCC 208821.

[0362] Culture medium: RPMI 1640 (containing 0.165 mol / L MOPS buffer, pH 7.0).

[0363] Experimental procedures

[0364] 1) Preparation of compound masterbatch

[0365] Dissolve the compound in the bottle in DMSO to prepare a solution with a concentration of 4 mg / mL. Then dilute 10 times with DMSO to 0.4 mg / mL for later use. Use DMSO to perform a 2-fold gradient dilution of the compound solution 0.4 mg / mL on a 96-well plate to obtain 400μg / mL, 200μg / mL, 100μg / mL, 50μg / mL, 25μg / mL, 13μg / mL, 6μg / mL, 3μg / mL, 1.6μg / mL, 0.78μg / mL, 0.39μg / mL. 100% DMSO was used as a control.

[0366] 2) Preparation of inoculum

[0367] The -80°C frozen bacteria Candida albicans ATCC 90028 were streaked onto SDA plates and placed in a 33±2°C incubator for aerobic culture for 24 h.

[0368] The -80°C frozen bacteria Cryptococcus neoformans ATCC 208821 were streaked onto SDA plates and placed in a 35±2°C incubator for aerobic culture for 48 hours.

[0369] The -80°C frozen bacteria Aspergillus fumigatus ATCC MYA-4609 were streaked onto SDA plates and cultured in an anaerobic incubator at 30±2°C for 6 days.

[0370] For strains Candida albicans ATCC 90028 and Cryptococcus neoformans ATCC208821, the plates were removed, pure cultures on the plates were picked, suspended in physiological saline, and then the turbidity of the bacterial suspension was adjusted to OD using a turbidity meter. 600 =0.2, the concentration of this bacterial suspension is about 3.0×10 6 CFU / mL. Dilute the bacterial suspension with the test medium to a concentration of about 3.0×10 3 CFU / mL, this is the inoculum.

[0371] For strain Aspergillus fumigatus ATCC MYA-4609, after removing the plate, add 3 mL of 0.9% saline containing 0.1% Tween 20 to the plate and gently collect the spores. Count them with a hemocytometer and adjust the spore suspension to approximately 5 × 10 6 Spores / mL. Dilute the spore suspension to 0.8-1×10 5 Spores / mL.

[0372] 3) MIC and MEC detection

[0373] Transfer 2 μL of working solution from the compound master plate to a 96-well plate containing 98 μL of test medium, and then add 100 μL of bacterial inoculum to each well to obtain a MIC test plate.

[0374] For strain Candida albicans ATCC 90028, all test plates were placed in an incubator at 33±2°C for aerobic culture.

[0375] For the mold strain Aspergillus fumigatus ATCC MYA-4609, all test plates were placed in an incubator at 35±2°C for 48 h under aerobic conditions.

[0376] For Cryptococcus neoformans ATCC 208821, all test plates were placed in an incubator at 35±2°C for 72 hours under aerobic conditions.

[0377] 4) Read MIC and MEC

[0378] For Candida albicans ATCC 90028, the MIC was read from the wells with 100% growth inhibition (compared to the wells with normal growth) by visual observation.

[0379] For Cryptococcus neoformans ATCC 208821, the MIC was read from the wells with 100% growth inhibition (compared to the wells with normal growth) by visual observation.

[0380] For Aspergillus fumigatus ATCC MYA-4609, MEC was read from wells with changed hyphal morphology (small, rounded, compact hyhaphal forms compared to normal growth wells) under microscope observation.

[0381] Experimental Results

[0382] The antifungal activity of the compounds provided in the present application was determined using the above method, and the results are shown in Table 1.

[0383] Table 1 Antifungal activity results of the compounds provided in this application

[0384]

[0385]

[0386] NT: Not tested.

[0387] It can be concluded from the table that the compounds provided in the present application have very good inhibitory effects on Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans.

Claims

1. A compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: in, W is selected from N and N + -CH2OPO3H - ; R 1 , R 2 are independently selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4 Alkylene-(6- to 10-membered aryl), -C 0～4 Alkylene-(5- to 10-membered heteroaryl), -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ; R 1a , R 1b are independently selected from hydrogen, deuterium, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4 Alkylene-(6-10 membered aryl) and -C 0～4 Alkylene-(5- to 10-membered heteroaryl); X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are independently selected from N, O, S and CH; R 3 Selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 2～6 Alkenyl, halo-C 2～6 Alkenyl, -C 2～6 Alkynyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), -C 0～4 Alkylene-(6- to 10-membered aryl), -C 0～4 Alkylene-(5- to 10-membered heteroaryl), -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ; R 4 , R 5 are independently selected from hydrogen, deuterium, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b and -C 0～4 Alkylene-NR 1a C(O)R 1b ; R 6 are independently selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, halo-C 1～6 Alkyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a and -C 0～4 Alkylene-OS(O)2R 1a ; m and n are independently 0 to 2; L is selected from a single bond, C 1～4 Alkylene, -O-, -S-, -NH-, -CH2O-, -CH2CH2O-, -CH2NH-, and -SCH2-; R 7 Selected from -OH, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, -C 0～4 Alkylene-(3- to 10-membered cycloalkyl), -C 0～4 Alkylene-(3- to 10-membered heterocyclic group), 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group; wherein R 7 Optionally one or more R 1c replace; R 1c Selected from hydrogen, deuterium, nitro, halogen, cyano, -C 1～6 Alkyl, -C substituted by cyano 1～6 Alkyl, halo-C 1～6 Alkyl, halo-C 2～6 Alkenyl, halo-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 1a , -C 0～4 Alkylene-OC(O)R 1a , -C 0～4 Alkylene-SR 1a , -C 0～4 Alkylene-C(O)R 1a , -C 0～4 Alkylene-C(O)OR 1a , -C 0～4 Alkylene-C(O)NR 1a R 1b , -C 0～4 Alkylene-NR 1a R 1b , -C 0～4 Alkylene-NR 1a C(O)R 1b , -C 0～4 Alkylene-S(O)2R 1a , -C 0～4 Alkylene-S(O)R 1a , -C 0～4 Alkylene-S(O)2NR 1a R 1b , -C 0～4 Alkylene-S(O)NR 1a R 1b , -C 0～4 Alkylene-S(O)2OR 1a , -C 0～4 Alkylene-OS(O)2R 1a , 6- to 10-membered aryl groups and 5- to 10-membered heteroaryl groups.

2. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: X 1 and X 2 One of them is O and the other is N; Preferably, X1 is N, and X2 is O; Preferably, X 3 , X 4 , X 5 , X 6 , X 7 are independently selected from N and CH.

3. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R 4 , R 5 are independently selected from hydrogen or deuterium; Preferably, R 4 , R 5 All are deuterium.

4. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from hydrogen, -NR 1a R 1b or -NR 1a C(O)R 1b ; Among them, R 1a , R 1b are independently selected from hydrogen and -C 1～4 alkyl; Preferably, R 1 is -NH2; Preferably, R 2 Selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C 1～4 Alkoxy, halo-C 1～4 Alkoxy, -NR 1a R 1b or -NR 1a C(O)R 1b ; Among them, R 1a , R 1b are independently selected from hydrogen and -C 1～4 alkyl; Preferably, R 2 is hydrogen; Preferably, R 3 Selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C 1～4 Alkoxy and halo-C 1～4 Alkoxy; Preferably, R 3 is hydrogen; Preferably, R 6 is selected from hydrogen, halogen, -C 1～4 Alkyl, halo-C 1～4 Alkyl, -C 1～4 Alkoxy and halo-C 1～4 Alkoxy; Preferably, R 6 Selected from hydrogen and halogen.

5. The compound according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from -CH2-, -O-, -NH-, -CH2O-, -CH2NH- and -CH2CH2O-; Preferably, L is selected from -O-, -CH2O- and -NH-; Preferably, L is selected from -O- and -CH2O-; Preferably, L is -O-; Preferably, R 7 is selected from the group consisting of -OH, isobutyl, neopentyl, allyl, propenyl, propargyl, propynyl, prop-2-yn-1-yl, cyclopropyl, cyclopropylmethyl, oxirane, oxiranemethyl, oxetanyl, oxetanylmethyl, pyrrolidinyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyridyl, phenyl, pyrazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrimidinyl, triazolyl, thiazolyl and benzo-1,3-dioxazolyl; Preferably, R 7 is selected from allyl, propargyl, cyclopropylmethyl, pyridyl and phenyl; preferably, R 7 Optionally one or two R 1c replace; Preferably, R 1c Selected from hydrogen, halogen, cyano, -C 1～4 Alkyl, -C substituted by cyano 1～4 Alkyl and halo-C 1～4 alkyl; Preferably, R 1c is selected from the group consisting of hydrogen, F, Cl, Br, cyano, methyl, cyanomethyl and trifluoromethyl; Preferably, R 1c is selected from the group consisting of hydrogen, methyl, F, Cl and Br.

6. The compound or deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Formula I is the structure shown in Formula II; Preferably, X 4 Selected from N and CH, X 3 , X 6 , X 7 are independently CH; Preferably, L is O; Preferably, R 7 is selected from phenyl and pyridyl; Preferably, R 7 Optionally one or more R 1c Replacement, where R 1c is selected from hydrogen, F and Cl.

7. The compound or deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Formula I is the structure shown in Formula III; Preferably, X 3 , X 4 , X 5 , X 7 All are CH; Preferably, L is -O-; Preferably, R 7 is selected from phenyl, pyridyl, propargyl, allyl and cyclopropylmethyl; Preferably, R 7 is selected from propargyl and allyl; Preferably, R 7 Optionally one or more R 1c Replacement, where R 1c is selected from the group consisting of hydrogen, methyl, F, Cl and Br; Preferably, R 1c is selected from hydrogen, methyl and Br.

8. The compound or deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The compound is specifically:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

10. Use of the compound according to any one of claims 1 to 8, or its deuterated compound, or its stereoisomer, or its prodrug, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing or treating fungal infection; preferably, the medicament for preventing or treating fungal infection is a medicament for preventing or treating Candida albicans, Aspergillus fumigatus or Cryptococcus neoformans infection.

Images