3C-like protease inhibitors

Abstract

The invention provides a 3C-like protease inhibitor as shown in a formula (I), or pharmaceutically acceptable salts, isotope variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates of the 3C-like protease inhibitor. The invention also provides a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in treating or preventing diseases caused by virus infection. # imgabs0 #

Description

3C-like protease inhibitors

[0001] This application claims priority to Chinese application No. 202210600337.0 filed on May 27, 2022, and Chinese application No. 202310077572.9 filed on January 20, 2023, which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to a novel class of 3C-like protease inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates, or solvates thereof. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in treating or preventing diseases caused by viral infections. Background Art

[0003] The novel coronavirus discovered in December 2019 was initially named 2019-nCoV. The World Health Organization (WHO) renamed it COVID-19, and the International Committee on Taxonomy of Viruses later officially named it SARS-CoV-2 based on systematics, taxonomy, and convention. SARS-CoV-2 can cause severe acute respiratory syndrome (SARI) symptoms, including fever, dyspnea, fatigue, and pneumonia.

[0004] Among all known RNA viruses, the largest genome length of coronavirus is between about 26 and 32 kb. In addition to encoding structural proteins, most of the coronavirus genome is also transcribed and translated into polypeptides, which encode proteins necessary for viral replication and gene expression. The main protease (Mpro) of approximately 306 aa is a key enzyme for coronavirus replication. It is also encoded by this polypeptide and is responsible for processing the polypeptide into functional proteins. Mpro has a cleavage site specificity similar to that of the picornavirus 3C protease (3Cpro), and is therefore also called 3C-like protease (3CLpro). Studies have shown that 3CLpro of different coronaviruses is highly conserved in both sequence and 3D structure. These characteristics and their functional importance make 3CLpro a target for the design of anti-coronavirus drugs.

[0005] The role of 3CLpro is to hydrolyze and cleave the expressed peptide chain at the appropriate site, preparing the peptide chain to form a three-dimensional or four-dimensional structure, thereby forming the enzyme required for viral proliferation. During the catalytic process, the enzyme does not change, but the activation energy of the hydrolysis reaction is reduced, thereby accelerating the rate of the hydrolysis reaction. Among them, the sulfhydryl group on the cysteine ​​plays a key role in the entire catalytic hydrolysis process. See Thanigaimalai et al., An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy, Journal of Medicinal Chemistry, 59(14): 6595-6628.

[0006] There are public documents on 3CLpro inhibitors in the prior art. For example, WO2021 / 250648A1 discloses a compound currently known as Nirmatrelvir (PF-07321332), which is one of the active ingredients of Paxlovid and, when used in combination with ritonavir, can reduce the risk of death and hospitalization caused by the new coronavirus SARS-CoV-2.

[0007] In addition, WO2021 / 205290A1 also discloses compounds of similar structures, which treat diseases caused by SARS-CoV-2 through pathways mediated by 3C-like protease inhibitors.

[0008] However, the compounds in the prior art all have disadvantages. For example, parovide also inhibits the CYP3A4 enzyme, which may interfere with the metabolism of other drugs by the enzyme, change the half-life and clearance rate, reduce the efficacy or produce adverse reactions. For example, when a patient takes parovide and terfenadine at the same time, parovide inhibits the oxidative metabolism of terfenadine by CYP3A4, causing the concentration of the latter in the patient's body to increase abnormally, causing QT wave prolongation and arrhythmia in the heart. The compounds disclosed in WO2021 / 205290A1 also face the problem of ineffectiveness when administered orally. Therefore, the need to develop new 3C-like protease inhibitors is becoming increasingly urgent.

[0009] Summary of the Invention

[0010] The present invention uses 3C-like proteases as targets and develops a new class of small molecule inhibitors that can be used to treat or prevent viral infections.

[0011] The compound of the present invention targets 3C-like proteases, has excellent inhibitory activity against 3C-like proteases with P132H mutations, and can significantly inhibit the proliferation of SARS-CoV-2.

[0012] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0013] in:

[0014] in,

[0015] Y is N or CR7;

[0016] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0017] L1 is selected from chemical bonds, C 1-6 Alkylene, -NH-, -O-, or -S-;

[0018] R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl;

[0019] R 1s Selected from H, deuterium, CN, NO2, NH2, OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;

[0020] Alternatively, two R on the same carbon atom 1s Together they form oxo or thio;

[0021] L2 is selected from a chemical bond or C 1-6 alkylene;

[0022] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace;

[0023] R 2s Selected from H, D, halogen, CN, -L 2a -R' or

[0024] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a for -S-;

[0025] R# is selected from H, halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0026] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0027] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1- 10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S;

[0028] m is selected from 0, 1, 2, 3, 4 or 5;

[0029] R' is selected from H, NH2, CN, C 0-6 Alkylene-C(O)R a 、C 0-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-OC(O)-R a 、C 0-6 Alkylene-NHC(O)R a 、C 0-6 Alkylene-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylene-OR a 、C 2-6 Alkenyl or C 2- 6-alkynyl;

[0030] L3 is -NR b -or-CR a R b -;

[0031] R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0032] R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1- 6-alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0033] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0034] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0035] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0036] in:

[0037] Y is N or CR7;

[0038] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0039] L1 is selected from a chemical bond or C 1-6 Alkylene, -NH-, -O- or -S-;

[0040] R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl;

[0041] R 1s Selected from H, deuterium, CN, NO2, NH2, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;

[0042] L2 is selected from a chemical bond or C 1-6 alkylene;

[0043] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace;

[0044] R 2s Selected from H, D, halogen, CN, -L 2a -R' or

[0045] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-;

[0046] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0047] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0048] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C1-10 Halogenated alkyl, C 1-10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S;

[0049] m is selected from 0, 1, 2, 3, 4 or 5;

[0050] R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0051] L3 is -NR b -or-CR a R b -;

[0052] R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0053] R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1- 6-alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0054] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0055] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0056] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0057] In another aspect, the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, which further contains other therapeutic agents, for example, selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir (Lopinavir), Molnupiravir (Molnupiravir), Ritonavir (Ritonavir), Chloroquine (Chloroquine or Sigma-C6628), Hydroxychloroquine or α-interferon.

[0058] In another aspect, the present invention provides use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing diseases caused by viral infection.

[0059] In another aspect, the present invention provides a method for treating and / or preventing a disease caused by a viral infection in a subject, comprising administering to the subject a compound or pharmaceutical composition of the present invention.

[0060] In another aspect, the present invention provides the compound or pharmaceutical composition of the present invention for use in treating and / or preventing diseases caused by viral infection.

[0061] In a specific embodiment, the compounds or pharmaceutical compositions of the present invention are used to inhibit viral proliferation;

[0062] In another embodiment, the compound or pharmaceutical composition of the present invention inhibits the activity of viral 3CL protease.

[0063] In another specific embodiment, the 3CL protease has a P132H mutation.

[0064] In another specific embodiment, the virus is a coronavirus, preferably an alphacoronavirus and / or a betacoronavirus, more preferably SARS-CoV-2.

[0065] In another specific embodiment, the present invention is used to treat and / or prevent the following diseases caused by viral infection: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder, taste disorder and its complications, or a combination thereof.

[0066] definition

[0067] Chemical definition

[0068] Definitions of specific functional groups and chemical terms are described in more detail below.

[0069] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0070] “C 1-10 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. 1-6Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0071] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0072] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-"Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0073] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0074] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0075] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0076] “C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 Alkylene", "C 0-3 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-3 "Alkylene".

[0077] “C 1-10 "Alkoxy" refers to OC 1-10 In some embodiments, C 1-6 Alkyl is preferred. In other embodiments, C 1-4 Alkoxy groups are preferred, for example, methoxy, ethoxy and the like.

[0078] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0079] Therefore, “C 1-10 "Haloalkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-6 Halogenated alkyl is preferred, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-3Halogenated alkyl, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0080] “C 1-6 "Haloalkoxy" refers to OC 1-6 In some embodiments, C 1-4 A haloalkoxy group is preferred, for example, a halomethoxy group, a haloethoxy group and the like.

[0081] “C 3-10 Cycloalkyl" and "C 3-10 "Cycloalkenyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, C 5-10 Cycloalkyl, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-7 Cycloalkyl and C 5-6 Cycloalkyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Cycloalkyl also includes cycloalkyl rings in which the substituents on any non-adjacent carbon atoms are linked to form a bridged ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes cycloalkyl rings in which the substituents on the same carbon atom are linked to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. A cycloalkyl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0082] “C 3-10 "Cycloalkylene" refers to the removal of C 3-10 In some embodiments, C 5-10Cycloalkylene, C 5-7 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, and cyclopropylene is especially preferred.

[0083] "3-14 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 7 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, a 3-10 membered heterocyclyl is preferably a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 5-10 membered heterocyclyl is preferably a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5-7 membered heterocyclyl is preferably a 5-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-6 membered heterocyclyl is preferably a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; and a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. More preferably, a 5-membered heterocyclyl is a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes the above-mentioned heterocyclyl ring, wherein the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes the above-mentioned heterocyclyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiol. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include those in which the aforementioned heterocyclyl groups share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spirocyclic ring. The shared atoms may be carbon or nitrogen atoms as long as valence permits. Heterocyclyl groups also include those in which the aforementioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0084] “C 6-20 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-20 ring carbon atoms and zero heteroatoms. In some embodiments, C 6-10 Aryl is preferred. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0085] "3-20 membered heteroaryl" refers to a group of a 3-20 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-8 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-14 membered heteroaryl groups are particularly preferred, which are 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-6 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are particularly preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-3 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl or pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepantatrienyl, and thiepantatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzopyrazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0086] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0087] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0088] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NRbb SO2R aa 、-SO2N(R bb )2, -SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0089] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb)2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0090] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0091] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0092] R ccEach of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0093] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0094] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0095] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0096] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3+ X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1- 6 alkyl) 2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0097] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、- C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom ccThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0098] Other definitions

[0099] The term "coronavirus" includes, but is not limited to, the following viruses: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and / or SARSCoV-2.

[0100] In one embodiment, the term "coronavirus" is an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus.

[0101] In one embodiment, the alphacoronavirus is selected from HCoV-229E and HCoV-NL63, preferably HCoV-229E.

[0102] In one embodiment, the beta coronavirus is selected from HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, more preferably SARS-CoV-2.

[0103] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0104] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0105] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0106] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention, the salts are equivalent to their respective free acids.

[0107] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0108] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0109] "Disease," "disorder," and "condition" are used interchangeably herein.

[0110] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0111] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0112] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0113] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0114] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0115] As used herein, the term "compound of the present invention" refers to a compound of the following formula (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII), (VIII'), (IX), (IX'), (X), (X'), (XI), (XI'), (XII) or (XII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0116] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0117] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0118] in,

[0119] Y is N or CR7;

[0120] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0121] L1 is selected from chemical bonds, C 1-6 Alkylene, -NH-, -O-, or -S-;

[0122] R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl;

[0123] R 1s Selected from H, deuterium, CN, NO2, NH2, OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;

[0124] Alternatively, two R on the same carbon atom 1s Together they form oxo or thio;

[0125] L2 is selected from a chemical bond or C 1-6 alkylene;

[0126] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace;

[0127] R 2s Selected from H, D, halogen, CN, -L 2a -R' or

[0128] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a for -S-;

[0129] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0130] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0131] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S;

[0132] m is selected from 0, 1, 2, 3, 4 or 5;

[0133] R' is selected from H, NH2, CN, C 0-6 Alkylene-C(O)R a 、C 0-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-OC(O)-R a 、C 0-6 Alkylene-NHC(O)R a 、C 0-6 Alkylene-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylene-OR a 、C 2-6 Alkenyl or C 2- 6-alkynyl;

[0134] L3 is -NR b -or-CR a R b -;

[0135] R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0136] R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1- 6-alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0137] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0138] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0139] In another embodiment, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0140] in:

[0141] Y is N or CR7;

[0142] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0143] L1 is selected from a chemical bond or C 1-6 Alkylene, -NH-, -O- or -S-;

[0144] R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl;

[0145] R 1s Selected from H, deuterium, CN, NO2, NH2, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C6-10 Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;

[0146] L2 is selected from a chemical bond or C 1-6 alkylene;

[0147] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace;

[0148] R 2s Selected from H, D, halogen, CN, -L 2a -R' or

[0149] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2aPreferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-;

[0150] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0151] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0152] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S;

[0153] m is selected from 0, 1, 2, 3, 4 or 5;

[0154] R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0155] L3 is -NR b -or-CR a R b -;

[0156] R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0157] R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1- 6-alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0158] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0159] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0160] Y

[0161] Y is N or CR7 or CR7R8;

[0162] In one embodiment, Y is CR7, such as CH; in another embodiment, Y is CR7R8, such as CH2; in another embodiment, Y is N.

[0163] The Y may be optionally substituted with D up to full deuteration.

[0164] R7 and R8

[0165] In one embodiment, R7 is H; in another embodiment, R7 is C 1-6 Alkyl; in another embodiment, R7 is C 1-6 Halogenated alkyl.

[0166] In one embodiment, R8 is H; in another embodiment, R8 is C 1-6 Alkyl; in another embodiment, R8 is C 1-6 Halogenated alkyl.

[0167] The R7 and R8 may be optionally substituted with D up to full deuteration.

[0168] L1

[0169] In one embodiment, L1 is a chemical bond; in another embodiment, L1 is C 1-6 Alkylene; in another embodiment, L1 is -NH-; in another embodiment, L1 is -O-; in another embodiment, L1 is -S-.

[0170] The L1 may be optionally substituted with D up to full deuteration.

[0171] R1

[0172] In one embodiment, R1 is C 1-6 Alkyl; in another embodiment, R1 is C 1-6 In another embodiment, R1 is C 1-6 Alkoxy, such as C 1-4 Alkoxy; in another embodiment, R1 is C 1-6 Haloalkoxy, such as C 1-4 In another embodiment, R1 is C 3-10 In another embodiment, R1 is a 3-10 membered heterocyclic group; In another embodiment, R1 is C 6-20 Aryl, such as C 6-10 Aryl; in another embodiment, R1 is a 5-20 membered heteroaryl, such as a 5-10 membered heteroaryl, and also such as a 5-6 membered heteroaryl.

[0173] In one embodiment, R1 is OCH3; in another embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is

[0174] In one embodiment, R1 is unsubstituted; in another embodiment, R1 is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 1s replace.

[0175] The R1 may be optionally substituted with D up to full deuteration.

[0176] R 1s

[0177] In one embodiment, R 1s is H; in another embodiment, R 1s is deuterium; in another embodiment, R 1s is CN; in another embodiment, R 1s is NO2; in another embodiment, R 1s is NH2; in another embodiment, R 1s is OH; in another embodiment, R 1s is halogen, such as F; in another embodiment, R 1s C 1-6 Alkyl groups, such as C 1-4 Alkyl; in another embodiment, R 1s C 1-6 Halogenated alkyl, preferably C 1-4 Haloalkyl, such as CH3; in another embodiment, R 1s C 1-6 Alkoxy, preferably C 1-4 Alkoxy, such as OCH3; in another embodiment, R 1s C 1-6 Halogenated alkoxy, preferably C 1-4 Haloalkoxy; in another embodiment, R 1s C 2-6 alkenyl; in another embodiment, R 1s Halogenated C2-6 alkenyl; in another embodiment, R 1s C 2-6 Alkynyl; in another embodiment, R 1s Halogenated C 2-6 Alkynyl; in another embodiment, R 1s C 6-10 Aryl; In another embodiment, R 1s is a 3- to 8-membered heterocyclic group; in another embodiment, R 1s is a 3- to 8-membered heteroaryl group; in another embodiment, R 1s -NH(C 1-6 alkyl); in another embodiment, R 1s -N(C 1-6 alkyl) 2; In another embodiment, R 1s -NH-C 3-8 Cycloalkyl; in another embodiment, R 1s -NH-C 6- 10 Aryl; In another embodiment, R 1s is -NH-3-8 membered heterocyclyl; in another embodiment, R 1s is -NH-3-8 membered heteroaryl; in another embodiment, R 1s For-OC 1-6 Alkyl; in another embodiment, R 1s For-OC 2-6 alkenyl; in another embodiment, R 1s For-OC 2-6 Alkynyl; in another embodiment, R 1s For-OC 3-8 Cycloalkyl; in another embodiment, R 1s For-OC 6-10 Aryl; In another embodiment, R 1s is -O-3-8 membered heterocyclyl; in another embodiment, R 1s It is -O-3-8 membered heteroaryl.

[0178] In one embodiment, two R on the same carbon atom 1s Together they form oxo or thio.

[0179] The R 1s may be optionally substituted with D up to full deuteration.

[0180] L2

[0181] In one embodiment, L2 is a chemical bond; in another embodiment, L2 is C1-6 Alkylene, preferably C 1-4 Alkylene, such as -CH2-;

[0182] The L2 may be optionally substituted with D up to full deuteration.

[0183] R2

[0184] In one embodiment, R2 is C 3-10 In another embodiment, R2 is a 3-10 membered heterocyclyl; in another embodiment, R2 is C 6-10 Aryl, preferably C 6-10 Aryl, more preferably phenyl; in another embodiment, R2 is a 5-10 membered heteroaryl.

[0185] In one embodiment, R2 is unsubstituted; in another embodiment, R2 is optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s replace.

[0186] The R2 may be optionally substituted with D up to full deuteration.

[0187] R 2s

[0188] In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s is CN; in another embodiment, R 2s -L 2a -R'; In another embodiment, R 2s for

[0189] The R 2s may be optionally substituted with D up to full deuteration.

[0190] R 2a and R 2b

[0191] In one embodiment, R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a for In another embodiment, R 2a -L 2a -R'.

[0192] In one embodiment, R 2bis H; in another embodiment, R 2b is D; in another embodiment, R 2b for In another embodiment, R 2b -L 2a -R'.

[0193] The R 2a and R 2b may be optionally substituted with D up to full deuteration.

[0194] L 2a

[0195] In one embodiment, L 2a is a chemical bond; in another embodiment, L 2a -C 1-6 Alkylene; in another embodiment, L 2a -C 0-6 Alkylene-OC 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-SC 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-NH-C 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-; In another embodiment, L 2a -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-.

[0196] In a specific embodiment, L 2a is a chemical bond; in another specific embodiment, L 2a is -O-; in another specific embodiment, L 2a is -S-; in another specific embodiment, L 2a -C 1-6 Alkylene-; In another specific embodiment, L2a -C 1-6 Alkylene-O-; In another specific embodiment, L 2a For-OC 1-6 Alkylene-; In another specific embodiment, L 2a is -C(O)-; in another specific embodiment, L 2a is -C(O)O-; in another specific embodiment, L 2a is -NH-; in another specific embodiment, L 2a is -C(O)NH-; in another specific embodiment, L 2a is -NHC(O)-; in another specific embodiment, L 2a C 2-6 Alkenylene.

[0197] In a more specific embodiment, L 2a is a chemical bond; in another more specific embodiment, L 2a is -O-; in another more specific embodiment, L 2a is -S-; in another more specific embodiment, L 2a is -CH2-; in another more specific embodiment, L 2a is -CH2-O-; in another more specific embodiment, L 2a is -CH2-CH2-O-; in another more specific embodiment, L 2a is -O-CH2-; in another more specific embodiment, L 2a is -C(O)-; in another more specific embodiment, L 2a is -C(O)O-; in another more specific embodiment, L 2a is -NH-; in another more specific embodiment, L 2a is -C(O)NH-; in another more specific embodiment, L 2a is -NH-C(O)- or -CH=CH-; in another more specific embodiment, the above L 2a Optionally substituted with CH3.

[0198] In one embodiment, the L 2a is unsubstituted; in another embodiment, said L 2a Optionally substituted with 1, 2, 3, 4, or 5 independently selected R#.

[0199] The L 2a may be optionally substituted with D up to full deuteration.

[0200] R#

[0201] In one embodiment, R# is H; in another embodiment, R# is halogen; in another embodiment, R# is C 1- 6 alkyl, such as C 1-4 Alkyl; in another embodiment, R# is C 1-6 Haloalkyl, such as C 1-4 In another embodiment, R# is C 1-6 Alkoxy, such as C 1-4 Alkoxy; In another embodiment, R# is C 1-6 Haloalkoxy, such as C 1-4 In another embodiment, R# is C 2-6 In another embodiment, R# is C 2-6 Alkynyl.

[0202] The R# may be optionally substituted with D up to full deuteration.

[0203] Ring A, R and m

[0204] In one embodiment, Ring A is C 3-10 Cycloalkyl; In another embodiment, Ring A is C 5-10 Cycloalkyl; In another embodiment, Ring A is C 5-8 Cycloalkyl; In another embodiment, Ring A is C 3-8 Cycloalkyl; In another embodiment, Ring A is C 3-6 Cycloalkyl; In another embodiment, Ring A is C 5-6 In another embodiment, ring A is a 3-10 membered heterocyclyl; In another embodiment, ring A is a 4-10 membered heterocyclyl, such as a 3-8 membered heterocyclyl, such as a 4-7 membered heterocyclyl; In another embodiment, ring A is a 5-6 membered heterocyclyl; In another embodiment, ring A is C 6-10 In another embodiment, ring A is phenyl; in another embodiment, ring A is a 5-10 membered heteroaryl; in another embodiment, ring A is a 5-6 membered heteroaryl, for example, the 5-6 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N; in another embodiment, ring A is a 5-6 membered heteroaryl, for example, the 5-6 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N; in another embodiment, ring A is a 5-membered heteroaryl, for example, the 5-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from N, O or S.

[0205] In a specific embodiment, Ring A is Wherein, Q1 is CH or N.

[0206] In a specific embodiment, Ring A is wherein Q2 is selected from S or NH, and Q3 is selected from CH or N.

[0207] In a specific embodiment, Ring A is Among them, one of Q4, Q5 and Q6 is N, and the other two are CH.

[0208] In a specific embodiment, Ring A is In another specific embodiment, ring A is a 5-membered heteroaryl group, such as a heteroaryl group containing 1-2 heteroatoms selected from S or N.

[0209] In one embodiment, X 2a is CR; in another embodiment, X 2a is N.

[0210] In one embodiment, X 2b is CR; in another embodiment, X 2b is N.

[0211] In one embodiment, R is H; in another embodiment, R is halogen; in another embodiment, R is CN; in another embodiment, R is OR a In another embodiment, R is NR b R c In another embodiment, R is C 1- 10 Alkyl; in another embodiment, R is C 1-6 Alkyl; in another embodiment, R is C 1-10 Alkoxy; in another embodiment, R is C 1-6 Alkoxy; in another embodiment, R is C 1-10 In another embodiment, R is C 1-6 In another embodiment, R is C 1-10 In another embodiment, R is C 1-6 Haloalkoxy; in another embodiment, R is C(O)R a In another embodiment, R is C(O)OR a In another embodiment, R is NHC(O)R a In another embodiment, R is C(O)NH-R a In another embodiment, R is Boc; In another embodiment, R is C 2-6In another embodiment, R is C 2-6 Alkynyl; in another embodiment, two R on the same carbon atom are taken together to form C=O or C=S.

[0212] In one embodiment, R is independently selected from H; in another specific embodiment, R is halogen, such as F or Cl; in another embodiment, R is CN; in another embodiment, R is OH; in another embodiment, R is NH2; in another embodiment, R is C 1-6 Halogenated alkyl, preferably C 1-4 Haloalkyl, such as CF3; in another embodiment, R is C 1-6 Alkoxy; in another embodiment, R is C 1-6 Halogenated alkoxy, preferably C 1-4 Haloalkoxy, such as OCF3; in another embodiment, R is Boc.

[0213] In one embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3; in another embodiment, m is 4; in another embodiment, m is 5.

[0214] In a specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for

[0215] In a specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for

[0216] In another specific embodiment, Selected from

[0217] The above rings A, R, and m etc. may be optionally substituted by D until fully deuterated.

[0218] R'

[0219] In one embodiment, R' is H; in another embodiment, R' is NH2; in another embodiment, R' is CN; in another embodiment, R' is C(O)R a In another embodiment, R' is C(O)OR a In another embodiment, R' is NHC(O)R a , preferably NHC(O)-C 1-6 Haloalkyl, such as NHC(O)-CF3; in another embodiment, R' is C(O)NH-R a , preferably C(O)NH-C 1-6 Haloalkyl, such as C(O)NH-CF3; in another embodiment, R' is C 0-6 Alkylene-C(O)R a In another embodiment, R' is C 0-6 Alkylene-C(O)OR a In another embodiment, R' is C 1-6 Alkylene-OC(O)-R a In another embodiment, R' is C 0-6 Alkylene-NHC(O)R a In another embodiment, R' is C 0-6 Alkylene-C(O)NR b R c In another embodiment, R' is C 1-6 Alkyl; in another embodiment, R' is C 1-6 Halogenated alkyl, preferably C 1-4 Haloalkyl, such as CHF2 or CF3; in another embodiment, R' is C 1-6 Alkoxy; in another embodiment, R' is C 1-6 In another embodiment, R' is C 2-6 In another embodiment, R' is C 2-6 Alkynyl.

[0220] In one embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is

[0221] The R' may be optionally substituted with D up to full deuteration.

[0222] R 2c and R 2d

[0223] In one embodiment, R 2c is halogen, preferably F.

[0224] In one embodiment, R 2d is halogen, preferably Cl; in another embodiment, R 2d For CN.

[0225] R”

[0226] In one embodiment, R" is H; in another embodiment, R" is halogen, such as F or Cl; in another embodiment, R" is C 1-6 In another embodiment, R" is C 1-6 Halogenated alkoxy, preferably C 1-4 Haloalkoxy, such as OCF3.

[0227] The R" may be optionally substituted with D, up to full deuteration.

[0228] L3 and L3'

[0229] In one embodiment, L3 is -NR b -, such as -NH-; in another embodiment, L3 is -CR a R b -, for example -CH2-.

[0230] In one embodiment, L3' is -N=; in another embodiment, L3' is -CR a =, for example -CH=.

[0231] The L3 and L3' may be optionally substituted with D up to full deuteration.

[0232] R3

[0233] In one embodiment, R3 is C 6-14 Aryl, preferably C 6-10 Aryl; in another embodiment, R3 is 5-14 heteroaryl, for example 5-10 heteroaryl; in another embodiment, R3 is C 3-8 In another embodiment, R3 is a 3-14 membered heterocyclyl.

[0234] In a specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is

[0235] In one embodiment, the R3 is unsubstituted; in another embodiment, the R3 is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 3s replace.

[0236] The R3 may be optionally substituted with D up to full deuteration.

[0237] R 3s

[0238] In one embodiment, R 3s is H; in another embodiment, R 3s is deuterium; in another embodiment, R 3s is halogen; in another embodiment, R 3s is CN; in another embodiment, R 3s is NO2; in another embodiment, R 3s is NH2; in another embodiment, R 3s C 1-6 Alkyl, preferably C 1-4 Alkyl; in another embodiment, R 3s C 1-6 Alkoxy, preferably C 1-4 Alkoxy; in another embodiment, R 3s C 2-6 alkenyl; in another embodiment, R 3s C 2-6 Alkynyl; in another embodiment, R 3s Halogenated C 1-6 Alkyl; in another embodiment, R 3s Halogenated C 1-6 Alkoxy; in another embodiment, R 3s Halogenated C 2-6 alkenyl; in another embodiment, R 3s Halogenated C 2-6 Alkynyl; in another embodiment, R 3s C 6-10 Aryl; In another embodiment, R 3s is a 3-8 membered heterocyclic group; in another embodiment, R 3s is a 3-8 membered heteroaryl; in another embodiment, R 3s -NH(C 1-6 alkyl); in another embodiment, R3s -N(C 1-6 alkyl) 2; In another embodiment, R 3s -NH-C 3-8 Cycloalkyl; in another embodiment, R 3s -NH-C 6-10 Aryl; In another embodiment, R 3s is -NH-3-8 membered heterocyclyl; in another embodiment, R 3s is -NH-3-8 membered heteroaryl; in another embodiment, R 3s For-OC 1-6 Alkyl; in another embodiment, R 3s For-OC 2-6 alkenyl; in another embodiment, R 3s For-OC 2-6 Alkynyl; in another embodiment, R 3s For-OC 3-8 Cycloalkyl; in another embodiment, R 3s For-OC 6-10 Aryl; In another embodiment, R 3s is -O-3-8 membered heterocyclyl; in another embodiment, R 3s is -O-3-8 membered heteroaryl; in another embodiment, two R on the same carbon atom 3s Together form C=O; in another embodiment, two R 3s Together they form C=S.

[0239] The R 3s may be optionally substituted with D up to full deuteration.

[0240] R 3a and R 3f

[0241] In one embodiment, R 3a is halogen, preferably Cl.

[0242] In one embodiment, R 3f C 1-6 Alkyl, preferably C 1-4 Alkyl, such as CH3.

[0243] The R 3s may be optionally substituted with D up to full deuteration.

[0244] R a 、R b and R c

[0245] In one embodiment, R a is H; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 haloalkyl; in another embodiment, R a C 2-6 alkenyl; in another embodiment, R a C 2-6 Alkynyl.

[0246] In one embodiment, R b is H; in another embodiment, R b C 1-6 Alkyl; in another embodiment, R b C 1-6 haloalkyl; in another embodiment, R b C 2-6 alkenyl; in another embodiment, R b C 2-6 Alkynyl.

[0247] In one embodiment, R c is H; in another embodiment, R c C 1-6 Alkyl; in another embodiment, R c C 1-6 haloalkyl; in another embodiment, R c C 2-6 alkenyl; in another embodiment, R c C 2-6 Alkynyl.

[0248] The R a 、R b and R c may be optionally substituted with D up to full deuteration.

[0249] Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in any other specific embodiments. For example, any technical solution or any combination thereof of R1 may be combined with any technical solution or any combination thereof of Y, L1, L2, R2, L3, and R3, etc. The present invention is intended to include all combinations of these technical solutions, which are not listed one by one due to space limitations.

[0250] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0251] in:

[0252] Y is N or CR7;

[0253] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0254] L1 is selected from a chemical bond or C 1-6 Alkylene, -NH-, -O- or -S-;

[0255] R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl;

[0256] R 1s Selected from H, deuterium, CN, NO2, NH2, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;

[0257] L2 is selected from a chemical bond or C 1-6 alkylene;

[0258] R2 is selected from C3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace;

[0259] R 2s Selected from H, D, halogen, CN, -L 2a -R' or

[0260] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-;

[0261] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0262] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0263] Each R is independently selected from H, halogen, CN, OR a NRb R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S;

[0264] m is selected from 0, 1, 2, 3, 4 or 5;

[0265] R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0266] L3 is -NR b -or-CR a R b -;

[0267] R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0268] R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1- 6-alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0269] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0270] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0271] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (I'):

[0272] in:

[0273] Y' is NR7 or CR7R8;

[0274] R7 and R8 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0275] L3' is -N= or -CR a =;

[0276] The other groups are as defined above.

[0277] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII) or (VIII'):

[0278] in,

[0279] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0280] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-;

[0281] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0282] Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0283] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S;

[0284] R" is selected from H, halogen, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0285] R 2c is halogen, preferably F;

[0286] R 2d is halogen or CN, preferably Cl;

[0287] m is selected from 0, 1, 2, 3, 4 or 5;

[0288] R 3a is a halogen, preferably Cl;

[0289] R 3f C 1-6 Alkyl, preferably CH3;

[0290] The other groups are as defined above.

[0291] In a more specific embodiment, the present invention provides a compound of formula (II) or (II'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0292] in:

[0293] L1 is selected from a chemical bond or C 1-6 alkylene;

[0294] R1 is selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s replace;

[0295] R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0296] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0297] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#;

[0298] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0299] Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0300] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S;

[0301] m is selected from 0, 1, 2, 3, 4 or 5;

[0302] R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0303] R 2c is halogen, preferably F;

[0304] R 2d is halogen or CN, preferably Cl;

[0305] L3 is -NR b -or-CR a R b -;

[0306] L3' is -N= or -CR a =;

[0307] R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0308] R 3s Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0309] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0310] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0311] In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0312] L1 is selected from a chemical bond or C 1-6 alkylene;

[0313] R1 is selected from C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s replace;

[0314] R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0315] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0316] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#;

[0317] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0318] Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0319] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S;

[0320] m is selected from 0, 1, 2, 3, 4 or 5;

[0321] R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0322] R 2c is halogen, preferably F;

[0323] R 2d is halogen or CN, preferably Cl;

[0324] L3 is -NR b -or-CR a R b -;

[0325] L3' is -N= or -CR a =;

[0326] R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace;

[0327] R 3s Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0328] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0329] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0330] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (III) or (III'):

[0331] in:

[0332] R 2a Selected from or -L 2a -R';

[0333] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or C 2-6 Alkenylene, L 2a Optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups;

[0334] Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0335] Each R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C1-6 Haloalkyl or C(O)NH-C 1-6 Haloalkyl, or two R on the same carbon atom together form C=O or C=S;

[0336] m is 0, 1, 2, 3, 4 or 5;

[0337] R' is selected from NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide;

[0338] R 2c selected from halogen;

[0339] R 2d Selected from halogen or CN;

[0340] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0341] In a more specific embodiment, the present invention provides a compound of formula (III) or (III') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0342] R 2a Selected from or -L 2a -R';

[0343] L 2a Selected from chemical bonds, -O-, -S-, -C 1-6 Alkylene-, -C 1-6 Alkylene-O-, -OC 1-6 Alkylene-, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)- or C 2-6 Alkenylene, L 2a Optionally substituted by 1, 2 or 3 independently selected from halogen or C 1-6 Substitution of alkyl groups;

[0344] Ring A is selected from C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0345] Each R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or NHC(O)-C 1-6 Haloalkyl, or two R on the same carbon atom together form C=O;

[0346] m is 0, 1, 2, 3 or 4;

[0347] R' is selected from NH2, CN, C 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide;

[0348] R 2c selected from halogen;

[0349] R 2d Selected from halogen or CN;

[0350] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0351] In a more specific embodiment, the present invention provides a compound of formula (III) or (III') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0352] R 2a Selected from or -L 2a -R';

[0353] L 2a is selected from a chemical bond, -O-, -S-, -CH2-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NH-C(O)- or -CH=CH-, wherein L 2a Optionally substituted with CH3;

[0354] Selected from

[0355] R' is selected from CN, NHC(O)-CF3 or CF3;

[0356] R 2c Selected from F or Cl, preferably F;

[0357] R 2d is selected from F, Cl or CN, preferably Cl.

[0358] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0359] in:

[0360] L 2a Selected from -O-, -S- or -C 2-6 alkenylene-;

[0361] Ring A is selected from C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0362] Each R is independently selected from H, halogen, CN, OH, NH2, -C(O)-C 1-6 Haloalkyl, -C(O)OC 1-6 Haloalkyl, -NHC(O)-C 1-6 Haloalkyl, -C(O)NH-C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or, two R on the same carbon atom together form C=O or C=S;

[0363] m is selected from 0, 1, 2, 3, 4 or 5;

[0364] R 2c is halogen, preferably F;

[0365] R 2d is selected from halogen or CN, preferably Cl.

[0366] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0367] L 2a Selected from -O- or -C 2-6 alkenylene-;

[0368] Ring A is selected from C 5-8 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0369] Each R is independently selected from H, halogen, CN, OH, NH2, -NHC(O)-C 1-6 Haloalkyl, -C(O)NH-C 1-6 Halogenated alkoxy, C1-6 Alkoxy or C 1-6 Haloalkoxy; or, two R on the same carbon atom together form C=O;

[0370] m is selected from 0, 1, 2, 3, 4 or 5;

[0371] R 2c is halogen, preferably F;

[0372] R 2d is selected from halogen or CN, preferably Cl.

[0373] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0374] L 2a Selected from -O- or -C 2-4 alkenylene-;

[0375] Ring A is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;

[0376] Each R is independently selected from H, halogen, CN, -NHC(O)-C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy, preferably H, F, Cl, CN, OCH3, OCF3 or -NHC(O)-CF3; or, two R on the same carbon atom together form C=O;

[0377] m is selected from 0, 1, 2 or 3;

[0378] R 2c is halogen, preferably F;

[0379] R 2d is selected from halogen or CN, preferably Cl.

[0380] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0381] L 2a Selected from -O-, -CH=CH-;

[0382] Selected from

[0383] R 2c Selected from F or Cl, preferably F;

[0384] R 2d is selected from F, Cl or CN, preferably Cl.

[0385] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0386] in:

[0387] L 2a C 2-6 alkenylene;

[0388] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0389] R is selected from H, halogen or C 1-6 alkyl halide;

[0390] m is selected from 0, 1, 2, 3, 4 or 5;

[0391] R 2c is halogen, preferably F;

[0392] R 2d is a halogen, preferably Cl;

[0393] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0394] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0395] L 2a C 2-4 Alkenylene, preferably -CH=CH-;

[0396] Ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the 5 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N;

[0397] R is selected from H or halogen, preferably H or F;

[0398] m is selected from 0, 1, 2 or 3;

[0399] R 2c is halogen, preferably F;

[0400] R 2d is halogen, preferably Cl.

[0401] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0402] L 2a C 2-4 Alkenyl, preferably -CH=CH-;

[0403] Selected from

[0404] R 2c is F;

[0405] R 2d is Cl or F, preferably Cl.

[0406] In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0407] in:

[0408] L 2a is -O- or -S-;

[0409] Ring A is selected from or a 5-membered heteroaryl group;

[0410] X 2a and X 2b independently selected from CR or N;

[0411] Each R is independently selected from H, halogen, CN, OH, NH2, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably H, F, Cl, CN, OCF3;

[0412] m is selected from 0, 1, 2, 3, 4 or 5;

[0413] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0414] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0415] L2a is -O-;

[0416] Ring A is selected from or a 5-membered heteroaryl group;

[0417] X 2a and X 2b independently selected from CR or N;

[0418] Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy;

[0419] m is selected from 0, 1, 2, 3, 4 or 5;

[0420] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0421] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0422] L 2a is -O-;

[0423] Ring A is selected from or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;

[0424] X 2a and X 2b independently selected from CR or N;

[0425] Each R is independently selected from H, halogen, CN or C 1-4 Haloalkoxy, preferably H, F, Cl, CN or OCF3;

[0426] m is selected from 0, 1, 2 or 3;

[0427] Preferably,

[0428] Selected from

[0429] In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0430] in,

[0431] R 2b for or -L2a -R';

[0432] L 2a -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-;

[0433] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0434] Each R is independently selected from H, halogen, NH2, OH, CN, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0435] R' is selected from C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide;

[0436] R 2c is a halogen;

[0437] R 2d Selected from halogen or CN;

[0438] m is 0, 1, 2, 3, 4 or 5;

[0439] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0440] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0441] R 2b for or -L 2a -R';

[0442] L 2a Selected from -O-, -S-, -C 1-4 Alkylene-, -C 1-4 Alkylene-O-, -OC 1-4 Alkylene-, -C 1-4 Alkylene-S- or -SC 1-4 Alkylene-;

[0443] Ring A is phenyl or a 5-6 membered heteroaryl group, wherein the 5 membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;

[0444] Each R is independently selected from H, halogen, CN, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably H, F, Cl, CN, CF3 or OCF3;

[0445] R' is selected from NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 Haloalkyl, preferably NHC(O)CF3;

[0446] R 2c is a halogen;

[0447] R 2d Selected from halogen or CN;

[0448] m is 0, 1, 2, or 3;

[0449] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0450] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0451] R 2b for or -L 2a -R';

[0452] L 2a is -O-, -S-, -CH2-, -CH2-O-, -CH2-CH2-O- or -O-CH2-;

[0453] Selected from

[0454] R' is NHC(O)CF3;

[0455] R 2c is F;

[0456] R 2d Selected from F, Cl or CN, preferably Cl.

[0457] In a more specific embodiment, the present invention provides a compound of formula (VI) or (VI'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0458] in,

[0459] L 2a is -O- or -S-;

[0460] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0461] Each R is independently selected from H, halogen, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0462] m is 0, 1, 2, 3, 4 or 5;

[0463] R 2c is a halogen;

[0464] R 2d Selected from halogen or CN;

[0465] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0466] In a more specific embodiment, the present invention provides a compound of formula (VI) or (VI') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0467] L 2a is -O-;

[0468] Ring A is phenyl;

[0469] Each R is independently selected from H, halogen, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably H, F, Cl, CF3 or OCF3;

[0470] m is 0, 1, 2, or 3;

[0471] Preferably, Selected from

[0472] R 2c is halogen, preferably F;

[0473] R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;

[0474] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0475] In a more specific embodiment, the present invention provides a compound of formula (VII) or (VII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0476] in,

[0477] L 2a O or S;

[0478] R is selected from H or halogen;

[0479] R" is selected from H, halogen, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0480] In a more specific embodiment, the present invention provides a compound of formula (VII) or (VII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0481] L 2a Selected from -O-;

[0482] R is selected from H or halogen, preferably H, F or Cl;

[0483] R" is selected from H, halogen or C 1-4 The haloalkoxy group is preferably H, F, Cl or OCF3.

[0484] In a more specific embodiment, the present invention provides a compound of formula (II) or (II'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0485] in,

[0486] L1 is selected from a chemical bond or C 1-6 alkylene;

[0487] R1 is selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, wherein R1 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 1s replace;

[0488] R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6haloalkoxy;

[0489] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0490] L 2a Selected from chemical bonds, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#;

[0491] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0492] Ring A is selected from C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0493] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or Boc, preferably H, F, Cl, CN, CF3, OCF3 or Boc;

[0494] m is selected from 0, 1, 2, 3, 4 or 5;

[0495] R' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6haloalkoxy;

[0496] R 2c is halogen, preferably F;

[0497] R 2d is a halogen, preferably Cl;

[0498] L3 is -NR b -or-CR a R b -;

[0499] R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 3s replace;

[0500] R 3s Selected from H, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S;

[0501] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0502] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0503] In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0504] L1 is selected from a chemical bond or C 1-4 alkylene;

[0505] R1 is selected from C 1-4 Alkoxy or 5-6 membered heteroaryl, wherein R1 is optionally replaced by 1, 2 or 3 independently selected R 1s replace;

[0506] R 1s Selected from H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably F, CH3 or OCH3;

[0507] R 2a and R 2b One of them is or -L2a -R', the other is H or D;

[0508] L 2a Selected from chemical bonds, -O-, -S-, -C 1-4 Alkylene-O-, -OC 1-4 Alkylene-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or C 2-4 Alkenylene, the L 2a Optionally substituted with 1, 2 or 3 independently selected R#;

[0509] R# is selected from H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0510] Ring A is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0511] Each R is independently selected from H, halogen, CN, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy or Boc, preferably H, F, Cl, CN, CF3, OCF3 or Boc;

[0512] m is selected from 0, 1, 2 or 3;

[0513] R' is selected from C 1-4 Alkyl or C 1-4 alkyl halide;

[0514] R 2c is halogen, preferably F;

[0515] R 2d is a halogen, preferably Cl;

[0516] L3 is -NH-;

[0517] R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2 or 3 independently selected R 3s replace;

[0518] R 3s Selected from H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, or two R on the same carbon atom 3s Together they form C=O;

[0519] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0520] In a more specific embodiment, the present invention provides a compound of formula (II) or (II') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0521] L1 is selected from a chemical bond or -CH2-;

[0522] R1 is selected from OCH3,

[0523] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0524] L 2a is selected from a chemical bond, -O-, -S-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, wherein L 2a Optionally substituted with CH3;

[0525] Selected from

[0526] R' is selected from CHF2 or CF3;

[0527] R 2c Selected from F;

[0528] R 2d selected from F or Cl;

[0529] L3 is -NH-;

[0530] R3 is selected from

[0531] L1 is selected from a chemical bond or -CH2-;

[0532] R1 is selected from OCH3,

[0533] R 2a and R 2b One of them is or -L 2a -R', the other is H or D;

[0534] L 2ais selected from a chemical bond, -O-, -S-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, wherein L 2a Optionally substituted with CH3;

[0535] Selected from

[0536] R' is selected from CHF2 or CF3;

[0537] R 2c Selected from F;

[0538] R 2d selected from F or Cl;

[0539] L3 is -NH-;

[0540] R3 is selected from

[0541] In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0542] in:

[0543] L 2a O or S;

[0544] R 1s Selected from halogen or C 1-6 haloalkoxy;

[0545] R is selected from halogen, CN, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0546] R 3a is a halogen, preferably Cl;

[0547] R 3f C 1-6 Alkyl, preferably CH3.

[0548] In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0549] L 2a is O;

[0550] R 1s Selected from halogen or C 1-4 Haloalkoxy, preferably F or OCH3;

[0551] R is selected from halogen, CN, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably F, CN, CF3 or OCF3;

[0552] R 3a is a halogen, preferably Cl;

[0553] R 3f C 1-4 Alkyl, preferably CH3.

[0554] In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0555] in:

[0556] L 2a O or S;

[0557] R 1s Selected from halogen or C 1-6 haloalkoxy;

[0558] R is selected from halogen or CN;

[0559] R 3a is a halogen, preferably Cl;

[0560] R 3f C 1-6 Alkyl, preferably CH3;

[0561] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0562] In a more specific embodiment, the present invention provides a compound of formula (VIII) or (VIII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0563] L 2a is O;

[0564] R 1s Selected from halogen or C 1-4 Haloalkoxy, preferably F or OCH3;

[0565] R is selected from halogen or CN, preferably F or CN;

[0566] R 3a is a halogen, preferably Cl;

[0567] R 3f C 1-4 Alkyl, preferably CH3.

[0568] In a more specific embodiment, the present invention provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (IV), (IV'), (V), (V'), (IX), (IX'), (X), (X'), (XI), (XI'), (XII) or (XII'):

[0569] R 2a and R 2b One of or -L 2a -R', the other is H or D;

[0570] L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-;

[0571] R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy or C 1-6 haloalkoxy;

[0572] Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0573] Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S;

[0574] R 2c is halogen, preferably F;

[0575] R 2d is halogen or CN, preferably Cl;

[0576] m is selected from 0, 1, 2, 3, 4 or 5;

[0577] R 3a is a halogen, preferably Cl;

[0578] R 3f C 1-6 Alkyl, preferably CH3;

[0579] The other groups are as defined above.

[0580] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0581] in,

[0582] L 2a Selected from -S- or -O-;

[0583] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0584] R is selected from H, halogen, CN, OR a NRb R c 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0585] m is selected from 0, 1, 2, 3, 4 or 5;

[0586] R 2d selected from halogen;

[0587] R 2c selected from halogen;

[0588] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0589] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0590] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0591] L 2a Selected from -S- or -O-;

[0592] Ring A is selected from phenyl or 5-6 membered heteroaryl;

[0593] R is selected from H, halogen, CN, OH, NH2, C(O)NH2 or C 1-4 Haloalkyl, preferably H, F, Cl, CN, OH, NH2, C(O)NH2 or CF3;

[0594] m is selected from 1, 2 or 3;

[0595] R 2d is selected from halogen, preferably Cl or F;

[0596] R 2c is selected from halogen, preferably F.

[0597] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0598] L 2a is -S- or -O-;

[0599] Selected from

[0600] R 2d is selected from halogen, preferably Cl or F;

[0601] R 2c is selected from halogen, preferably F.

[0602] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0603] L 2a Selected from -S- or -O-;

[0604] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0605] R is selected from H, halogen, CN, NH2, C 1-6 Alkyl or C 1-6 alkyl halide;

[0606] m is selected from 0, 1, 2, 3, 4 or 5;

[0607] R 2d is selected from halogen, preferably Cl;

[0608] R 2c is selected from halogen, preferably F;

[0609] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0610] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0611] L 2a Selected from -S- or -O-;

[0612] Ring A is selected from phenyl or 5-6 membered heteroaryl;

[0613] R is selected from H, halogen, CN, NH2 or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2 or CF3;

[0614] m is selected from 1, 2 or 3;

[0615] R 2dis selected from halogen, preferably Cl;

[0616] R 2c is selected from halogen, preferably F.

[0617] In a more specific embodiment, the present invention provides a compound of formula (IV) or (IV') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0618] L 2a is -S- or -O-, preferably -S-;

[0619] Selected from

[0620] R 2d is selected from halogen, preferably Cl;

[0621] R 2c is selected from halogen, preferably F.

[0622] In a more specific embodiment, the present invention provides a compound of formula (V) or (V'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0623] in,

[0624] R 2b Selected from or -L 2a -R';

[0625] L 2a Selected from -S- or -O-;

[0626] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 6-10 membered heteroaryl;

[0627] R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0628] m is selected from 0, 1, 2, 3, 4 or 5;

[0629] R' is selected from C 0-6 Alkylene-OC1-6 Alkyl or C 0-6 Alkylene-OC 1-6 alkyl halide;

[0630] R 2d selected from halogen;

[0631] R 2c selected from halogen;

[0632] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0633] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0634] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0635] R 2b Selected from or -L 2a -R';

[0636] L 2a Selected from -S- or -O-;

[0637] Ring A is selected from a 4-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group;

[0638] R is selected from H, halogen, NH2, CN, OH or C 1-4 Haloalkyl, preferably H, F, NH2, CN, OH or CF3;

[0639] m is selected from 1, 2 or 3;

[0640] R' is C 1-4 Alkylene-OC 1-4 alkyl;

[0641] R 2d is selected from halogen, preferably Cl;

[0642] R 2c is selected from halogen, preferably F.

[0643] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0644] R 2b Selected from or -L 2a -R';

[0645] L 2a Selected from -S- or -O-;

[0646] Selected from

[0647] R' is

[0648] R 2d is selected from halogen, preferably Cl;

[0649] R 2c is selected from halogen, preferably F.

[0650] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0651] R 2b Selected from or -L 2a -R';

[0652] L 2a Selected from -S- or -O-;

[0653] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 6-10 membered heteroaryl;

[0654] R is selected from H, halogen, C 0-6 Alkylene-NH2, C 0-6 Alkylene -CN or C 0-6 Alkylene-OH;

[0655] m is selected from 0, 1, 2, 3, 4 or 5;

[0656] R' is selected from C 0-6 Alkylene-OC 1-6 Alkyl or C 0-6 Alkylene-OC 1-6 alkyl halide;

[0657] R 2d selected from halogen;

[0658] R 2c selected from halogen;

[0659] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0660] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0661] R 2b Selected from or -L 2a -R';

[0662] L 2a Selected from -S- or -O-;

[0663] Ring A is selected from a 4-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group;

[0664] R is selected from H, halogen, NH2, CN or OH, preferably H, F, NH2, CN or OH;

[0665] m is selected from 1, 2 or 3;

[0666] R' is C 1-4 Alkylene-OC 1-4 alkyl;

[0667] R 2d is selected from halogen, preferably Cl;

[0668] R 2c is selected from halogen, preferably F.

[0669] In a more specific embodiment, the present invention provides a compound of formula (V) or (V') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0670] R 2b Selected from or -L 2a -R';

[0671] L 2a Selected from -S- or -O-;

[0672] Selected from

[0673] R' is

[0674] R 2d is selected from halogen, preferably Cl;

[0675] R 2cis selected from halogen, preferably F.

[0676] In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0677] in,

[0678] R 1S Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0679] L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-;

[0680] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0681] R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy C 2- 6 alkenyl or C 2-6 Alkynyl;

[0682] m is selected from 0, 1, 2, 3, 4 or 5;

[0683] R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;

[0684] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0685] R 3a is a halogen, preferably Cl;

[0686] R 3f C 1-6 Alkyl, preferably CH3;

[0687] R a 、R b and R cIndependently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0688] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0689] In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0690] R 1S Selected from H, halogen, C 1-4 Alkyl or C 1-4 alkoxy;

[0691] L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-;

[0692] Ring A is selected from phenyl or 5-6 membered heteroaryl;

[0693] R is selected from H, halogen, CN, NH2, OH, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2, OH, CH3 or CF3;

[0694] m is selected from 1, 2 or 3;

[0695] R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;

[0696] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0697] R 3a is a halogen, preferably Cl;

[0698] R 3f C 1-4 Alkyl, preferably CH3.

[0699] In a more specific embodiment, the present invention provides a compound of formula (IX) or (IX') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0700] R 1S Selected from H, F, CH3 or OCH3;

[0701] L 2ais -S- or -S-CH2-;

[0702] Selected from

[0703] R 2d Selected from Cl or CN;

[0704] R 2c Selected from H or F;

[0705] R 3a is Cl;

[0706] R 3f For CH3.

[0707] In a more specific embodiment, the present invention provides a compound of formula (X) or (X'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0708] in,

[0709] R 1S Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0710] L 2a is -S- or -O-;

[0711] Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;

[0712] R is selected from H, halogen, CN, NR b R c , OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0713] m is selected from 0, 1, 2, 3, 4 or 5;

[0714] R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;

[0715] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0716] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0717] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0718] In a more specific embodiment, the present invention provides a compound of formula (X) or (X') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0719] R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy;

[0720] L 2a is -S- or -O-;

[0721] Ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;

[0722] R is selected from H, halogen, CN, NH2, OH, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2, OH, CH3 or CF3;

[0723] m is selected from 1, 2 or 3;

[0724] R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;

[0725] R 2c is selected from H or halogen, preferably H or F, more preferably F.

[0726] In a more specific embodiment, the present invention provides a compound of formula (X) or (X') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0727] R 1S Selected from CH3 or OCH3;

[0728] L 2a is -S- or -O-, preferably -S-;

[0729] Selected from

[0730] R 2d Selected from Cl or CN;

[0731] R 2c Selected from H or F.

[0732] In a more specific embodiment, the present invention provides a compound of formula (XI) or (XI'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0733] in,

[0734] R 1S Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0735] R 2b Selected from or -L 2a -R';

[0736] L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-;

[0737] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0738] R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0739] m is selected from 0, 1, 2, 3, 4 or 5;

[0740] R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NR b R c or C 1-6 Alkylene-OR a ;

[0741] R 2d Selected from halogen or CN;

[0742] R 2c is selected from H or halogen;

[0743] R 3a is a halogen;

[0744] R 3f C 1-6 alkyl;

[0745] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0746] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0747] In a more specific embodiment, the present invention provides a compound of formula (XI) or (XI') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0748] R 1S is CH3;

[0749] R 2b Selected from or -L 2a -R';

[0750] L 2a for -S-;

[0751] Selected from

[0752] R' is selected from

[0753] R 2d Selected from F, Cl or CN;

[0754] R 2c Selected from H or F;

[0755] R 3a is Cl;

[0756] R 3f For CH3.

[0757] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:

[0758] in,

[0759] R 1S Selected from C 1-6 Alkyl or C 1-6 alkoxy;

[0760] R 2b Selected from or -L 2a -R';

[0761] L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-;

[0762] Ring A is selected from 3-8 membered heterocyclic groups, or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S;

[0763] Q1 is CH or N;

[0764] R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0765] m is selected from 0, 1, 2, 3, 4 or 5;

[0766] R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NRb R c or C 1-6 Alkylene-OR a ;

[0767] R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;

[0768] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0769] R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0770] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0771] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0772] R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy;

[0773] R 2b Selected from or -L 2a -R';

[0774] L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-;

[0775] Ring A is selected from 3-6 membered heterocyclic groups,

[0776] Q1 is CN or N;

[0777] Q2 is selected from S or NH;

[0778] Q3 is selected from CH or N;

[0779] One of Q4, Q5 and Q6 is N, and the other two are CH;

[0780] R is selected from H, halogen, OH, CN, NR b R c 、C 1-4 Alkyl or C 1-4Haloalkyl, preferably H, F, OH, CN, NH2, NHCH3, CF3 or CH3;

[0781] m is selected from 1, 2 or 3;

[0782] R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)NR b R c or C 1-6 Alkylene-OR a ;

[0783] R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;

[0784] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0785] R a 、R b and R c Independently selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0786] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0787] R 1S is CH3;

[0788] R 2b Selected from or -L 2a -R';

[0789] L 2a for -S-;

[0790] Selected from

[0791] R' is selected from

[0792] R 2d Selected from F, Cl or CN;

[0793] R 2c Selected from H or F.

[0794] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0795] R 1S Selected from C 1-6 Alkyl or C 1-6 alkoxy;

[0796] R 2b Selected from or -L 2a -R';

[0797] L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-;

[0798] Ring A is selected from phenyl, thienyl, pyrazolyl or thiazolyl;

[0799] R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0800] m is selected from 0, 1, 2, 3, 4 or 5;

[0801] R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NH2 or C 1-6 Alkylene-OR a ;

[0802] R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;

[0803] R 2c is selected from H or halogen, preferably H or F, more preferably F;

[0804] Ra 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0805] Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

[0806] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0807] R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy;

[0808] R 2b Selected from or -L 2a -R';

[0809] L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-;

[0810] Ring A is selected from phenyl, thienyl,

[0811] R is selected from H, halogen, CN, NR b R c 、C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, CN, NH2, NHCH3, CF3 or CH3;

[0812] R b and R c Independently selected from H, C 1-4 Alkyl or C 1-4 alkyl halide;

[0813] m is selected from 1, 2 or 3;

[0814] R' is selected from C 1-4 Alkylene-NHC(O)-C 1-4 Halogenated alkyl, C 1-4 Alkylene-C(O)NH2 or C 1-4 Alkylene-OC 1-4 alkyl;

[0815] R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;

[0816] R 2c is selected from H or halogen, preferably H or F, more preferably F.

[0817] In a more specific embodiment, the present invention provides a compound of formula (XII) or (XII') above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:

[0818] R 1S is CH3;

[0819] R 2b Selected from or -L 2a -R';

[0820] L 2a for -S-;

[0821] Selected from

[0822] R' is selected from

[0823] R 2d Selected from F, Cl or CN;

[0824] R 2c Selected from H or F.

[0825] In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

[0826] In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:

[0827] Specifically, the present invention also relates to the following technical solutions:

[0828] 1. A compound of formula (PI) or a physiologically / pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopically labeled substance, a prodrug or a metabolite thereof:

[0829] in,

[0830] Ring A represents a 5- to 20-membered heteroaryl group or C 6-20 Aryl,

[0831] R 1 Each independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, nitro, amino, halo C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3 to 8-membered heterocyclic group, -NH-3 to 8-membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3 to 8-membered heterocyclic group, -O-3 to 8-membered heteroaryl,

[0832] L 1 represents a single bond, -CH2-, -NH-, -O- or -S-,

[0833] n is an integer from 0 to 10,

[0834] R 2 Indicates H, C 1-6 Alkyl, halogen or deuterated C 1-6 alkyl,

[0835] R 3 Each independently selected from H, C 1-6 alkyl, halogen, cyano, nitro or amino,

[0836] m is an integer from 0 to 3.

[0837] 2. The compound of formula (PI) according to technical solution 1, which has the structure of the following formula (P-IA):

[0838] Among them, ring A, R 1 、R 2 、R 3 , n and m are as defined in formula (PI).

[0839] 3. The compound of formula (PI) according to technical solution 1, which has the structure of the following formula (P-IB):

[0840] Among them, ring A, R 1 and n are as defined in formula (PI).

[0841] 4. A compound of formula (PI) according to any one of technical solutions 1 to 3, wherein ring A represents a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group, a 9- or 10-membered fused heteroaryl group, such as a thiazolyl group, a pyrazolyl group, a pyridyl group, an isoquinolyl group, a pyrazolopyridyl group, or a pyrrolopyridyl group.

[0842] 5. A compound of formula (PI) according to any one of technical solutions 1 to 4, wherein represents the following groups:

[0843] 6. The compound of formula (PI) according to any one of technical solutions 1 to 6, wherein the compound of formula (PI) has the structure of the following formula (P-IC), (P-ID) or (P-IE):

[0844] Among them, R 1 、R 2 、R 3 , n and m are as defined in formula (PI).

[0845] 7. A compound of formula (P-II) or a physiologically / pharmaceutically acceptable salt or ester thereof, a stereoisomer or tautomer, a racemate, a nitrogen oxide, a solvate, an isotopically labeled substance, a prodrug or a metabolite thereof:

[0846] in,

[0847] Ring B represents a 5- to 20-membered heteroaryl group or C 6-20 Aryl,

[0848] L 2represents a single bond, -CH2-, -NH-, -O- or -S-,

[0849] R 4 Each independently selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, nitro, amino, halo C 1- 6-alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1- 6 alkyl) 2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3 to 8-membered heterocyclic group, -NH-3 to 8-membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3 to 8-membered heterocyclic group, -O-3 to 8-membered heteroaryl,

[0850] L 3 Represents -(CH2) p -O-, -O-(CH2) q -、-(CH2) r -NH-, -NH-(CH2) s -、-(CH2) t -S- or -S-(CH2) t -,

[0851] o, p, q, r, s, t and u are each independently an integer from 0 to 3,

[0852] E represents unsubstituted or optionally substituted with one, two or more R 5 Substituted with the following groups: C 1-6 Alkylcarbonyl, 5 to 20 membered heteroaryl or C 6-20 Aryl,

[0853] R 5 Each independently represents H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, cyano, nitro, amino, halo C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10Aryl, 3 to 8 membered heterocyclic group, 3 to 8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3 to 8-membered heterocyclic group, -NH-3 to 8-membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3 to 8-membered heterocyclyl, -O-3 to 8-membered heteroaryl.

[0854] R 6 Indicates H, C 1-6 Alkyl, halogen or deuterated C 1-6 alkyl.

[0855] 8. The compound of formula (P-II) according to technical solution 7, which has the structure of the following formula (P-IIA):

[0856] Wherein, ring B is a 5-membered or 6-membered heteroaryl group, R 4 、R 6 、o、L 3 and E are as defined in formula (P-II).

[0857] 9. A compound of formula (P-II) according to technical solution 7 or 8, wherein ring B is pyridyl or triazolyl, more preferably pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl or 1H-1,2,4-triazol-5-yl.

[0858] 10. The compound of formula (P-II) according to any one of technical solutions 7 to 9, which has the structure of the following formula (P-IIB) or (P-IIC):

[0859] 11. A compound of formula (P-II) according to any one of technical solutions 7 to 10, wherein L 3 It represents -(CH2)-O-, -O-(CH2)-, -(CH2)-NH-, -NH-(CH2)-, -(CH2)-S- or -S-(CH2)-.

[0860] 12. A compound of formula (P-II) according to any one of technical solutions 7 to 11, wherein E represents an unsubstituted or optionally substituted one, two or more R 4 Substituted with the following groups: C 1-6Alkylcarbonyl, 5- to 10-membered heteroaryl or C 6-12 Aryl, preferably C 1-3 alkylcarbonyl, 5- to 10-membered heteroaryl or phenyl, wherein R 4 Each independently represents halogen, cyano, halo 1-6 Alkyl or -N(C 1-6 Alkyl)2.

[0861] 13. A compound of formula (P-II) according to any one of technical solutions 7 to 12, wherein EL 3 - represents a benzyloxy group, a 2-chlorobenzyloxy group, a 3-chlorobenzyloxy group, a 4-chlorobenzyloxy group, a 3-cyanobenzyloxy group, a 2-fluorobenzyloxy group, a 3-fluorobenzyloxy group, a 4-fluorobenzyloxy group, a 3,4-fluorobenzyloxy group, a 3-chloro-4-fluorobenzyloxy group, a 2-fluoro-3-chlorobenzyloxy group, a 3-cyanobenzyloxy group, a thiazol-5-ylmethoxy group, a 4-trifluoromethylthiazol-5-ylmethoxy group, a 5-cyanothiazol-2-ylmethoxy group, a 5-dimethylaminothiazol-2-ylmethoxy group, a trifluoroacetylaminomethyl group, a pyridin-2-ylmethoxy group, a pyridin-3-ylmethoxy group, a 1,2,4-triazolo[1,5-a]pyridin-7-ylmethoxy group, a 1H-benzo[d]imidazol-6-ylmethoxy group, a phenoxymethyl group, or a phenoxy group.

[0862] 14. The compound of formula (PI) or formula (P-II) according to any one of technical solutions 1 to 13, which has the following structure:

[0863] 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (PI) or a compound of formula (P-II) according to any one of technical solutions 1 to 14, or a salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites, and optionally at least one physiologically / pharmaceutically acceptable excipient.

[0864] 16. The pharmaceutical composition according to technical solution 15, which optionally contains additional active ingredients; preferably, the additional active ingredients include remdesivir, lopinavir, monouprivir, ritonavir, chloroquine, hydroxychloroquine and / or α-interferon.

[0865] 17. Use of a compound of formula (PI) or formula (P-II) or a salt or ester thereof according to any one of technical solutions 1 to 14, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites in the preparation of a medicament; preferably, the medicament is an RNA-dependent RNA polymerase inhibitor, a 3CLpro protease inhibitor, a CYP3A4 inhibitor or a host-targeted antiviral drug; more preferably, the medicament optionally contains additional active ingredients, wherein the additional active ingredients include remdesivir, lopinavir, monoupivir, ritonavir, chloroquine, hydroxychloroquine and / or α-interferon; more preferably, the medicament is used to prevent or treat a disease, condition, syndrome and / or disorder selected from the following group, or to alleviate the symptoms of a disease, condition, syndrome and / or disorder selected from the following group: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory and taste disorders and complications thereof, or a combination thereof caused by SARS-CoV-2 coronavirus infection.

[0866] 18. A method for treating or preventing diseases, conditions, syndromes and / or disorders caused by SARS-CoV-2 coronavirus infection, comprising administering to an individual in need thereof a compound of formula (PI) or a compound of formula (P-II) according to any one of technical solutions 1 to 14, or a salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites, or a pharmaceutical composition according to technical solution 15 or 16.

[0867] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0868] The compounds of the present invention may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are the enol and keto tautomers.

[0869] For example, in the formula (I) of the present invention, the compounds represented when Y is N and X is NH, and the compounds represented by formulas (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII) and (VIII') include the following tautomers:

[0870] For example, in formula (I) of the present invention, when Y is CH and X is NH, the compound includes the following tautomers:

[0871] For example, the compound of Example 1 of the present invention includes the following tautomers:

[0872] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0873] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0874] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by the general formula R·x H2O, for example, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R·0.5H2O) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O).

[0875] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can cause one crystalline form to dominate. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0876] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I) but for which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0877] In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form that has a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

[0878] A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such a prodrug is administered to a patient. Prodrugs are typically prepared by modifying functional groups in such a way that the modification can be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, can be cleaved to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide, and benzoate / amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of compounds of formula (I). Additionally, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, and the like can be used. Esters themselves can be active and / or can be hydrolyzed under human in vivo conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily decompose in the human body to release the parent acid or its salt.

[0879] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0880] Pharmaceutical compositions and kits

[0881] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0882] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0883] Suitable formulations for administering the compounds of the present invention will be readily apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (particularly solutions for injection (subcutaneous, intravenous, intramuscular) and infusion (injection)), elixirs, syrups, cachets, emulsions, inhalants, or dispersible powders. The content of the one or more pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the composition as a whole, i.e., an amount sufficient to achieve the dosage range specified below. If necessary, the specified dosage may be administered several times a day.

[0884] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0885] Drug administration

[0886] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0887] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0888] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0889] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0890] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0891] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0892] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0893] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0894] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0895] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0896] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0897] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0898] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0899] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0900] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0901] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0902] Indications

[0903] For diseases caused by viral infection, the development of 3C-like protease inhibitors can provide therapeutic benefits for a large number of tumor patients. The compounds of the present invention exert their therapeutic effects by negatively regulating the activity of 3C-like proteases in viruses, especially viruses with 3C-like proteases with the P132H mutation.

[0904] In some embodiments, the 3C-like protease inhibitors of the present invention can be used to treat various diseases caused by viral infection and their complications.

[0905] More specifically, these compounds can be used to treat the following diseases caused by viral infection: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder, taste disorder and their complications.

[0906] More specifically, these compounds can be used for the above-mentioned diseases or symptoms caused by SARS-CoV-2 infection.

[0907] Combination therapy

[0908] The 3C-like protease inhibitors described in the present invention can be combined with other drugs to treat cancer, including at least one target drug / viral activity modulator, including Remdesivir (Remdesivir or GS-5734), Lopinavir (Lopinavir), Molnupiravir (Molnupiravir), Ritonavir (Ritonavir), Chloroquine (Chloroquine or Sigma-C6628), Hydroxychloroquine and / or α-interferon, etc.

[0909] Example

[0910] The compounds and preparation methods disclosed herein will be described in further detail below with reference to specific examples. It should be understood that the following examples are intended only to illustrate and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the contents of the present invention are encompassed within the scope of protection intended by the present invention.

[0911] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples are all available from commercial channels.

[0912] Synthesis of Example 1

[0913] 1. Synthesis of Intermediate 1-2

[0914] 1-1 (1 g, 5.32 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and m-chlorobenzyl bromide (1.02 g, 5.94 mmol) and potassium carbonate (2.05 g, 14.85 mmol) were added. The mixture was stirred at 70°C for 16 hours. After completion of the reaction, water (100 mL) and ethyl acetate (300 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (3 x 100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to afford 1-2 as a pale yellow oil (1.1 g, yield: 66.1%).

[0915] LCMS (ESI) m / z: 313.1 [M+H] + .

[0916] 2. Synthesis of Intermediates 1-3

[0917] To a solution of 1-2 (1.1 g, 3.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.59 g, 7.54 mmol) under ice-cooling. The mixture was stirred under ice-water bath for 2 hours, and then 15% sodium hydroxide solution was added under ice-water bath to produce solid particles. The solid particles were filtered and the filtrate was dried to give 1-3 (0.80 g, yield: 79.9%) as a white solid.

[0918] LCMS (ESI) m / z: 285.1 [M+H] + .

[0919] 3. Synthesis of Intermediates 1-4

[0920] To a solution of 1-3 (0.8 g, 2.82 mmol) in dichloromethane (10 mL) was added triphenylphosphine (1.26 g, 4.80 mmol) and N-bromosuccinimide (0.85 g, 4.80 mmol) under ice-cooling. The mixture was stirred at 0°C for 30 minutes. After completion of the reaction, water (50 mL) and dichloromethane (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to afford 1-4 as a yellow solid (0.8 g, yield: 82.1%).

[0921] LCMS (ESI) m / z: 346.9 [M+H] + .

[0922] 4. Synthesis of Intermediates 1-6

[0923] To a solution of 1-4 (300 mg, 0.87 mmol) in acetonitrile (10 mL) were added potassium carbonate (379 mg, 2.88 mmol) and compound 1-5 (241.8 mg, 1.06 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. Water (10 mL) and dichloromethane (150 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 3:1) to afford 1-6 as a light yellow oil (396 mg, yield: 91.9%).

[0924] LCMS (ESI) m / z: 496.1 [M+H] + .

[0925] 5. Synthesis of Intermediates 1-7

[0926] 1-6 (400 mg, 0.81 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid solution (6 mL) at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 with sodium carbonate solution in an ice bath. Dichloromethane (100 mL) was added to the mixed solution for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain 1-7 as a light yellow oil (301 mg, yield: 84.4%).

[0927] LCMS (ESI) m / z: 440.1 [M+H] + .

[0928] 6. Synthesis of Intermediates 1-9

[0929] To a solution of 1-7 (300 mg, 0.68 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (295 mg, 2.13 mmol) and 1-8 (139.5 mg, 1.07 mmol) at room temperature, and the mixture was stirred at 70°C for 2 hours. After completion of the reaction, water (100 mL) and ethyl acetate (300 mL) were added for extraction. The organic phase was washed with saturated sodium chloride solution (3 x 100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 10:1) to afford 1-9 (250 mg, 68.8% yield) as a white solid.

[0930] LCMS (ESI) m / z: 535.1 [M+H] + .

[0931] 7. Synthesis of Compound 1

[0932] To a solution of 1-9 (200 mg, 0.37 mmol) in tetrahydrofuran (7 mL) was added 1-10 (111 mg, 0.62 mmol) under ice-bath, followed by lithium bis(trimethylsilyl)amide (1.2 mL), and the mixture was stirred at -15°C for 2 hours. Water (50 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure preparative chromatography to give Compound 1 (7.2 mg, 2.97% yield) as a white solid.

[0933] LCMS (ESI) m / z: 654.1 [M+H] + .

[0934] 1 HNMR(400MHz,DMSO-d6)δ8.28(s,1H),8.16(s,1H),7.68–7.60(m,1H),7.45–7.30(m,4H ),7.24–7.18(m,2H),5.28(s,2H),5.09(s,2H),5.04(s,2H),4.17(s,3H),3.84(s,3H).

[0935] The compounds shown in Table A below were synthesized in the same manner as above.

[0936] Table A

[0937] Example 86 Synthesis of Compound 86

[0938] Synthesis of intermediate 86-2

[0939] To a solution of 1-1 (2.00 g, 10.6 mmol) in dichloromethane (20 mL) were added 4-dimethylaminopyridine (2.60 g, 21.3 mmol), 86-1 (4.46 g, 31.9 mmol), and copper acetate (3.86 g, 21.3 mmol) at room temperature. The mixed solution was stirred at 25°C under an oxygen flow for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 30:1) to obtain compound 86-2 (401 mg, yield: 15.8%) as a yellow oil.

[0940] LCMS (ESI) m / z: 283.1 [M+H] + .

[0941] Synthesis of intermediate 86-3

[0942] To a solution of 86-2 (626 mg, 2.22 mmol) in tetrahydrofuran (7 mL) was added lithium aluminum tetrahydride (210 mg, 5.55 mmol) under ice-cooling. The mixed solution was stirred at 0°C for 1 hour under nitrogen protection. After the reaction was completed, water (0.21 mL), 15% aqueous sodium hydroxide solution (0.21 mL), and water (0.63 mL) were added sequentially at 0°C to quench the reaction. The mixed solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 86-3 (390 mg, yield: 58.8%) as a light yellow oil.

[0943] GCMS (ESI) m / z: 254.1 [M] + .

[0944] Synthesis of intermediate 86-4

[0945] To a solution of 86-3 (390 mg, 1.53 mmol) in dichloromethane (4 mL) was added triphenylphosphine (604 mg, 2.30 mmol) and carbon tetrabromide (763 mg, 2.30 mmol) under an ice bath. The mixture was stirred at 0°C for 1 hour under nitrogen. After the reaction was complete, the mixture was extracted with water (40 mL) and dichloromethane (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1) to afford compound 86-4 (324 mg, yield: 63.3%) as a pale yellow oil.

[0946] GCMS (ESI) m / z: 316.0 [M] + .

[0947] Synthesis of intermediate 86-5

[0948] To a solution of 86-4 (180 mg, 0.785 mmol) in acetonitrile (2 mL) were added potassium carbonate (217 mg, 1.57 mmol) and 2-5 (324 mg, 1.02 mmol) at room temperature, and the mixed solution was stirred at 80°C for 4 hours. After the reaction was complete, ethyl acetate (100 mL) was added to the mixed solution, which was washed sequentially with water (40 mL) and saturated sodium chloride solution (40 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain compound 86-5 (400 mg, yield: 93.0%) as a light yellow oil.

[0949] LCMS (ESI) m / z: 466.1 [M+H] + .

[0950] Synthesis of intermediate 86-6

[0951] 86-5 (400 mg, 0.860 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid solution (8 mL) at room temperature, and the mixture was stirred at 30°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a white solid 86-6 (346 mg, yield: 93.4%).

[0952] LCMS (ESI) m / z: 410.1 [M+H] + .

[0953] Synthesis of intermediate 86-7

[0954] To a solution of 86-6 (346 mg, 0.845 mmol) in N,N-dimethylformamide (4 mL) were added 1-8 (170 mg, 1.01 mmol) and potassium carbonate (350 mg, 2.54 mmol) at room temperature. The mixture was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 30:1) to afford compound 86-7 (259 mg, 57.9% yield) as a pale yellow oil.

[0955] LCMS (ESI) m / z: 505.1 [M+H] + .

[0956] Synthesis of compound 86

[0957] To a solution of 86-7 (260 mg, 0.515 mmol) in tetrahydrofuran (2.5 mL) was added 1-10 (112 mg, 0.618 mmol) under ice-cooling. The mixed solution was then added lithium bis(trimethylsilyl)amide (1.5 mL) under nitrogen. The mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixed solution was quenched by addition of water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 40-60) to afford compound 86 (44.8 mg, 13.2% yield) as a white solid.

[0958] LCMS (ESI) m / z: 624.1 [M+H] + .

[0959] 1 H NMR (400MHz, CD3OD) δ8.40–8.30(m,1H),8.26–8.04(s,1H),7.84–7.66(m,1H),7.62–7.50(m,1 H),7.45–7.09(m,2H),7.02–6.72(m,4H),5.30(s,2H),5.05(s,2H),4.20(s,3H),3.90(s,3H).

[0960] The compounds shown in Table B below were synthesized using the same method as above.

[0961] Table B

[0962] Example 115 Synthesis of Compound 115

[0963] Synthesis of Intermediate 115-3

[0964] BINAP (0.99 g, 1.59 mol), cesium carbonate (7.8 g, 23.9 mol), and palladium acetate (0.36 g, 1.59 mol) were added to a toluene solution of 115-1 (2.0 g, 7.97 mol) and 115-2 (1.13 g, 15.9 mol) at room temperature. The reaction solution was heated to 100 degrees and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered, and dried. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to give a light yellow oil 115-3 (398 mg, yield: 20.8%).

[0965] LCMS (ESI) m / z: 241.9 [M+H] + .

[0966] Synthesis of Intermediate 115-4

[0967] To a solution of 115-3 (0.40 g, 1.66 mol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.13 g, 3.31 mol) under ice-water bath. The mixture was stirred under ice-water bath for 2 hours, and then 15% sodium hydroxide solution was added under ice-water bath to produce solid particles. The solid particles were filtered and the filtrate was dried to give a light yellow oil 115-4 (303 mg, yield: 84.9%).

[0968] LCMS (ESI) m / z: 213.9 [M+H] + .

[0969] Synthesis of Intermediate 115-5

[0970] Thionyl chloride (452 ​​mg, 3.8 mmol) was added to a solution of 115-4 (270 mg, 1.3 mmol) in dichloromethane (6 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was dried to give a light yellow oil 115-5 (291 mg, yield: 98.9%).

[0971] Synthesis of Intermediate 115-6

[0972] To a solution of 1-5 (290 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (519 mg, 1.95 mmol) and compound 115-5 (344 mg, 1.5 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. Water (50 mL) and ethyl acetate (150 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to afford 115-6 as a pale yellow oil (248 mg, yield: 47.0%).

[0973] LCMS (ESI) m / z: 424.8 [M+H] + .

[0974] Synthesis of Intermediate 115-7

[0975] 115-6 (250 mg, 0.59 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid solution (10 mL) at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 7 with sodium carbonate solution under an ice bath. Dichloromethane (100 mL) was added to the mixed solution for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain 115-7 (171 mg, crude product) as a pale yellow solid.

[0976] LCMS (ESI) m / z: 368.8 [M+H] + .

[0977] Synthesis of Intermediate 115-8

[0978] To a solution of 115-7 (80 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (90 mg, 0.65 mmol) and 3-9 (42 mg, 0.32 mmol) at room temperature, and the mixture was stirred at 60°C for 16 hours. Water (10 mL) and dichloromethane (10 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to afford 115-8 as a brown oil (20 mg, yield: 19.8%).

[0979] LCMS (ESI) m / z: 464 [M+H] + .

[0980] Synthesis of compound 115

[0981] To a solution of 115-8 (20 mg, 0.04 mmol) in N,N-dimethylformamide (5 mL) was added 1-10 (11 mg, 0.06 mmol) under ice-cooling, followed by the addition of lithium bis(trimethylsilyl)amide (0.1 mL). The mixture was stirred at 0°C for 2 hours. Water (10 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by preparative high-pressure chromatography to afford compound 115 as a white solid (1.1 mg, 4.41% yield).

[0982] LCMS (ESI) m / z: 582.7 [M+H] + .

[0983] 1H NMR (400MHz, CD3OD) δ8.28(s,1H),8.16(s,1H),7.64(d,J=17.0Hz,2H),7.60–7.48(m,1H),7.26(dd ,J=12.2,7.4Hz,1H),5.20(s,2H),5.03(s,2H),4.12(s,3H),3.78(s,3H),3.07(m,4H)1.71(m,4H).

[0984] The compounds shown in Table C below were synthesized in the same manner as above.

[0985] Table C

[0986] Example 125 Synthesis of Compound 125

[0987] Synthesis of Intermediate 125-2

[0988] 125-1 (3.0 g, 0.01 mol) was dissolved in anhydrous toluene (100 mL) at -78°C. A solution of diisobutylaluminum hydride in n-hexane (13 mL, 0.013 mol) was added and stirred for 30 minutes. The mixed solution was stirred at 25°C for 16 hours. After completion of the reaction, saturated ammonium chloride solution (100 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (500 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to obtain 125-2 as a light yellow oil (2.7 g, yield: 98.3%).

[0989] LCMS (ESI) m / z: 269.0 [MH] + .

[0990] Synthesis of Intermediate 125-3

[0991] To a solution of 125-2 (2.7 g, 0.01 mol) in dichloromethane (100 mL) was added triphenylphosphine (4.0 g, 0.015 mol) and carbon tetrabromide (4.0 g, 0.012 mol) under ice-cooling. The mixture was stirred at 0°C for 30 minutes. After completion of the reaction, the reaction solution was directly concentrated under pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to afford 125-3 (3.0 g, yield: 89%) as a pale yellow oil.

[0992] 1H NMR (400MHz, CDCl3) δ7.65 (dd, J=9.3, 7.7Hz, 1H), 7.33 (dd, J=10.6, 7.9Hz, 1H), 4.51 (s, 2H).

[0993] Synthesis of Intermediate 125-4

[0994] To a solution of 125-3 (3.0 g, 0.009 mol) in acetonitrile (100 mL) were added potassium carbonate (3.74 g, 0.027 mol) and compound 1-5 (2.1 g, 0.009 mol) at room temperature. The mixed solution was stirred at 80°C for 16 hours. Water (10 mL) and dichloromethane (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to afford 125-4 (3.8 g, 87% yield) as a pale yellow oily solid.

[0995] LCMS (ESI) m / z: 504.0 [M+Na] + .

[0996] Synthesis of Intermediate 125-5

[0997] To a solution of 125-4 (3.8 g, 0.008 mol) in tetrahydrofuran (150 mL) was added compound 1-10 (1.44 g, 0.008 mol) under ice-salt bath, followed by lithium bis(trimethylsilyl)amide (16 mL). The mixed solution was stirred under ice-salt bath for 2 hours. After completion of the reaction, saturated ammonium chloride solution (50 mL) was added to the reaction solution for quenching, followed by extraction with ethyl acetate (400 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain 125-5 (4.3 g, yield: 90%) as a white solid.

[0998] LCMS (ESI) m / z: 601.0 [M+H] + .

[0999] Synthesis of Intermediate 125-7

[1000] At room temperature, compound 125-5 (1.0 g, 1.66 mmol) was added to a solution of N,N-dimethylformamide (20 mL). Compound 125-6 (867 mg, 8.3 mmol), triethylamine (505 mg, 5.0 mmol), palladium acetate (37 mg, 0.16 mmol), and tri(o-methylphenyl)phosphine (51 mg, 0.16 mmol) were added sequentially. After the addition was complete, the mixture was protected with nitrogen. The mixed solution was stirred at 80°C for 12 hours. Water (60 mL) and ethyl acetate (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain 125-7 (590 mg, yield: 55%) as a brown oil.

[1001] LCMS (ESI) m / z: 577.2 [M+H] + .

[1002] Synthesis of Intermediate 125-8

[1003] 125-7 (590 mg, 1.0 mmol) was added to a dichloromethane / trifluoroacetic acid solution (6 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a light yellow solid 125-8 (241 mg, crude product).

[1004] LCMS (ESI) m / z: 521.2 [M+H] + .

[1005] Synthesis of compound 125

[1006] To a solution of 125-8 (240 mg, 0.46 mmol) in N,N-dimethylformamide (10 mL) was added compound 1-8 (116 mg, 0.69 mmol) at room temperature, followed by cesium carbonate (450 mg, 1.38 mmol) and sodium iodide (138 mg, 0.92 mmol). The mixture was stirred at 80°C for 3 hours. Water (10 mL) and ethyl acetate (500 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to afford compound 125 (73 mg, 25% yield) as a white solid.

[1007] LCMS (ESI) m / z: 616.2 [M+Na] + .

[1008] 1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.10(s,1H),7.66(s,1H),7.58–7.35(m,5H),7.33– 7.13(m,4H),7.01(d,J=14.4Hz,1H),5.40(s,2H),5.04(s,2H),4.14(s,3H),3.80(s,3H).

[1009] The compounds shown in Table D below were synthesized in the same manner as above.

[1010] Table D

[1011] Example 141 Synthesis of Compound 141

[1012] Refer to Example 1 to synthesize intermediate 141-1.

[1013] Synthesis of Intermediate 141-3

[1014] To a solution of 141-1 (150 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) were added triethylamine (173 mg, 1.71 mmol), 141-2 (209 mg, 1.71 mmol), copper acetate (124 mg, 0.682 mmol), and molecular sieves (380 mg) at room temperature. The mixed solution was stirred at 60°C under an oxygen flow for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 30:1) to obtain compound 141-3 (141 mg, yield: 75.5%) as a yellow oil.

[1015] LCMS (ESI) m / z: 517.1 [M+H] + .

[1016] Synthesis of compound 141

[1017] To a solution of 141-3 (140 mg, 0.271 mmol) in tetrahydrofuran (2 mL) was added 1-10 (59.0 mg, 0.325 mmol) under ice-cooling. The mixed solution was then added lithium bis(trimethylsilyl)amide (0.5 mL) under nitrogen protection. The mixture was stirred at 0°C for 2 hours. After completion of the reaction, the mixed solution was quenched by addition of water (10 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 40-60) to afford compound 141 (36.2 mg, 20.2% yield) as a white solid.

[1018] LCMS (ESI) m / z: 636.1 [M+H] + .

[1019] 1 H NMR (400MHz, CD3OD) δ8.73–8.65(m,2H),8.20(s,1H),8.18–8.14(m,1H),7.81–7.75(m,1H),7.67(s, 1H),7.54–7.46(m,3H),7.35–7.31(m,1H),7.23–7.10(m,3H),5.32(s,2H),5.23(s,2H),4.18(s,3H).

[1020] The compounds shown in Table E below were synthesized in the same manner as above.

[1021] Table E

[1022] Example 168 Synthesis of Compound 168

[1023] Refer to Example 1 to synthesize intermediate 168-1.

[1024] Synthesis of intermediate 168-2

[1025] To a solution of 168-1 (20 mg, 0.044 mmol) and 1-10 (12 mg, 0.066 mmol) in N,N-dimethylformamide (3 mL) was added lithium bis(trimethylsilyl)amide (0.08 mL, 0.088 mmol) under ice-cold conditions. Stir at -20°C for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (50 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by thin-layer chromatography to afford 168-2 (28 mg, 100% yield) as a brown solid.

[1026] LCMS (ESI) m / z: 574.0 [M+H] + .

[1027] Synthesis of intermediate 168-3

[1028] 168-2 (28 mg, 0.048 mmol) was added to a dichloromethane / trifluoroacetic acid solution (1 / 1) (4 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give a light yellow solid 168-3 (30 mg, crude product).

[1029] LCMS (ESI) m / z: 518.0 [M+H] + .

[1030] Synthesis of compound 168

[1031] To a solution of 168-3 (140 mg, 0.27 mmol) and 141-2 (49 mg, 0.405 mmol) in N,N-dimethylformamide (10 mL) were added copper acetate (97 mg, 0.54 mmol), triethylamine (136 mg, 1.351 mmol), and 4A molecular sieves (140 mg) at room temperature. The mixture was stirred at 60°C for 16 hours. Water (20 mL) and ethyl acetate (50 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by preparative high pressure chromatography to afford compound 168 (3 mg, 1.8% yield) as a white solid.

[1032] LCMS (ESI) m / z: 595.0 [M+H] + .

[1033] 1H NMR (400MHz, CD3OD) δ8.71(d,J=17.0Hz,2H),8.19-8.16(m,2H),7.78-7.75(m,2H),7.53-7.48(m,2H),6.72(dd,J=12.6,7.7H z,1H),5.20(s,2H),4.18(s,3H),3.85–3.75(m,2H),3.41(td,J=11.6,2.1Hz,3H),1.85(d,J=11.7Hz,2H),1.42–1.22(m,2H).

[1034] The compounds shown in Table F below were synthesized in the same manner as above.

[1035] Table F

[1036] Example 176 Synthesis of Compound 176

[1037] Refer to Example 1 to synthesize intermediate 176-1.

[1038] Synthesis of intermediate 176-3

[1039] To a solution of 176-1 (200 mg, 0.47 mmol) in N,N-dimethylformamide (6 mL) were added copper acetate (170 mg, 0.94 mmol), 176-2 (359 mg, 2.35 mmol), triethylamine (238 mg, 2.35 mmol), and 4A molecular sieves (600 mg) at room temperature. The mixture was stirred at 60°C for 16 hours. Saturated sodium chloride solution (50 mL) and ethyl acetate (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 20:1) to afford 176-3 (151 mg, 30.0% yield) as a brown oil.

[1040] LCMS (ESI) m / z: 533.0 [M+H] + .

[1041] Synthesis of compound 176

[1042] To a solution of 176-3 (150 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added 1-10 (71 mg, 0.39 mmol) under ice-cooling, followed by potassium tert-butoxide (0.5 mL). The mixture was stirred at -78°C for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high pressure preparative chromatography to afford compound 176 (14.7 mg, 7.9% yield) as a light brown solid.

[1043] LCMS (ESI) m / z: 652.0 [M+H] + .

[1044] 1 H NMR(400MHz,CD3OD)δ8.40(s,1H),8.23(d,J=6.4Hz,2H),7.83–7.72(m,2H),7.68(s,1H),7.53 (s,1H),7.15(d,J=6.2Hz,4H),6.69(d,J=10.2Hz,1H),5.45(s,2H),4.22(s,3H),3.95(s,3H).

[1045] The compounds shown in Table G below were synthesized in the same manner as above.

[1046] Table G

[1047] Example 201 Synthesis of Compound 201

[1048] Refer to Example 125 to synthesize intermediate 201-1

[1049] Synthesis of compound 201-3

[1050] Compound 201-1 (88.0 mg, 0.20 mmol), copper acetate (108.6 mg, 0.60 mmol), triethylamine (201.7, 1.99 mmol), DMF (5 mL), and compound 201-2 (98.3 mg, 0.70 mmol) were mixed at room temperature and stirred at 60°C under an oxygen atmosphere for 16 hours. Water (10 mL) and ethyl acetate (10 mL x 5) were added for extraction. The combined organic phases were washed with saturated brine (10 mL x 3). The organic phase was separated, and the crude product was purified by column chromatography (silica gel, ethyl acetate) to afford compound 201-3 (202 mg, crude) as a pale yellow oil.

[1051] LCMS (ESI) m / z: 537.0 / 539.0 [M+H] + .

[1052] Synthesis of Intermediate 201-4

[1053] Compound 201-3 (300 mg, 0.56 mmol) and compound 1-10 (112 mg, 0.61 mmol) were added to a tetrahydrofuran (15 mL) solution at room temperature. The mixture was cooled to -60°C under nitrogen, followed by the addition of potassium tert-butoxide (0.16 mL, 1.12 mmol), and stirred at -60°C for 1 hour. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (10 mL x 5), and the organic phases were combined, washed with saturated brine (10 mL x 3), separated, and concentrated under reduced pressure. The resulting product was purified by column chromatography (silica gel, dichloromethane:methanol = 20:1) to afford compound 201-4 (229 mg, a yellow oil that solidified upon standing at room temperature, yield: 62.1%).

[1054] LCMS (ESI) m / z: 656.0 / 658.0 [M+H] + .

[1055] Synthesis of Intermediate 201-5

[1056] Under ice-water bath, 201-4 (600 mg, 0.92 mmol) was added to dichloromethane (20 mL), followed by DIPEA (238 mg, 1.84 mmol). MOMBr (138 mg, 1.1 mmol) was slowly added under nitrogen protection. After the addition, the mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the resulting product was purified by column chromatography (dichloromethane: methanol = 20:1) to give 201-5 (340 mg, yellow oil, which became solid after standing at room temperature, yield: 26.5%).

[1057] LCMS (ESI) m / z: 696.0 / 698.0 [M+H] + .

[1058] Synthesis of compound 201

[1059] A mixed solution of 201-5 (50 mg, 0.072 mmol), ethanol / water (3 mL / 2 mL), CuI (6.84 mg, 0.04 mmol), L-proline (8.27 g, 0.07 mmol), and K 3 PO 4 (30.5 mg, 0.14 mmol) was stirred at 80° C. under nitrogen for 16 hours. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was purified by high pressure preparative chromatography to afford Compound 201 (2 mg, 3.9% yield) as a pale yellow solid.

[1060] LCMS (ESI) m / z: 652.1 / 654.1 [M+H] + .

[1061] 1H NMR(400MHz,MeOD)δ8.61(d,J=18.7Hz,2H),8.19(d,J=23.2Hz,4H),7.84(d,J=8.4Hz,2H) ,7.73(s,1H),7.68(d,J=7.3Hz,2H),7.53(s,1H),5.24(s,2H),4.20(s,3H),2.51(s,3H).

[1062] The compounds shown in Table H below were synthesized using the same method as above.

[1063] Table H

[1064] Example 239 Synthesis of Compound 239

[1065] Synthesis of intermediate 239-3

[1066] To a solution of 239-1 (750 mg, 4.67 mmol) in 1,4-dioxane (8 mL) were added 239-2 (1.19 g, 5.14 mmol), N,N-dimethylglycine (241 mg, 2.34 mmol), cuprous iodide (445 mg, 2.34 mmol), and cesium carbonate (3.04 g, 9.34 mmol) at room temperature. Under nitrogen, the mixture was stirred at 110°C for 48 hours. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 50:1) to afford compound 239-3 (420 mg, 29.1% yield) as a yellow oil.

[1067] GCMS (ESI) m / z: 310.0 [M] + .

[1068] Synthesis of Intermediate 239-4

[1069] To a solution of 239-3 (410 mg, 1.32 mmol) in carbon tetrachloride (5 mL) was added azobisisobutyronitrile (21.6 mg, 0.132 mmol) and N-bromosuccinimide (235 mg, 1.32 mmol) under ice. The mixture was stirred at 80°C for 16 hours. Water (40 mL) and dichloromethane (40 mL x 3) were added to the mixture, and the mixture was extracted. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to afford compound 239-4 (450 mg, yield: 87.7%) as a yellow oil.

[1070] LCMS (ESI) m / z: 388.9 [M+H] + .

[1071] Synthesis of Intermediate 239-6

[1072] To a solution of 239-4 (230 mg, 0.591 mmol) in acetonitrile (3 mL) were added potassium carbonate (245 mg, 1.77 mmol) and 239-5 (120 mg, 0.591 mmol) at room temperature. The mixed solution was stirred at 80°C for 4 hours. Ethyl acetate (50 mL) was added to the mixed solution, which was washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to afford compound 239-6 (97.0 mg, 32.0% yield) as a yellow oil.

[1073] LCMS (ESI) m / z: 512.0 [M+H] + .

[1074] Synthesis of compound 239

[1075] To a solution of 239-6 (97.0 mg, 0.189 mmol) in tetrahydrofuran (3 mL) at -40°C was added 1-10 (34.3 mg, 0.189 mmol). Potassium tert-butoxide (0.57 mL) was added to the mixed solution under nitrogen. The mixture was stirred at -40°C for 2 hours. The mixed solution was quenched by addition of water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 40-70) to afford compound 240 (14.2 mg, 11.9% yield) as a white solid.

[1076] LCMS (ESI) m / z: 631.0 [M+H] + .

[1077] 1 H NMR (400MHz, CD3OD) δ8.44(s,1H),8.07(s,1H),7.96(s,1H),7.52(d,J=8.0Hz,1H),7.42(s,1H),7 .21(d,J=4.0Hz,1H),6.86(d,J=12.0Hz,1H),4.65(s,1H),4.47(s,1H),4.28(s,3H),3.95(s,3H).

[1078] Table H

[1079] Biological Examples

[1080] 1. Enzyme Activity Assay

[1081] Assay system (120uL): Protease (108uL): (150nM) WT or P132H

[1082] Substrate (10uL final concentration: 20uM)

[1083] Small molecules (2uL; 3-fold serial dilution)

[1084] Substrate: fluorescent substrate MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2; main protease universal primer reaction buffer: 50mM Tris pH 7.4, 1mM EDTA, 0.01% tritonX-100, incubate for 30min, and then detect with a microplate reader;

[1085] ELISA detection: excitation 320nm; emission 405nm;

[1086] The inhibition rate of the representative compound on the main protease was determined by the ratio of the initial reaction rate of the enzyme at different drug concentrations to the initial reaction rate of the control group, and then the IC was calculated using the nonlinear fitting curve of GraphPad Prism. 50 value.

[1087] Formula 1: Inhibition rate (%) = (RFU 100% enzyme activity control - RFU sample) / (RFU 100% enzyme activity control - RFU blank control) × 100%

[1088] Formula 2: Inhibition rate (%) = (NC initial velocity V0 - sample initial velocity V0) / NC initial velocity × 100;

[1089] NC is the DMSO-added control, and the enzyme activity is set as 100%

[1090] Initial velocity calculation = Slope (RFU within 200s: time s)

[1091] Formula 2 optimization: Inhibition rate (%) = (NC initial velocity V0 - (sample initial velocity V0 - protein-free small molecule control V0) / NC initial velocity V0 × 100 is used to eliminate the problem of negative V0 (slope).

[1092] 2. Anti-SARS-CoV-2

[1093] (1) Experimental materials

[1094] Cell lines: African green monkey kidney cells Vero E6 (ATCC, CRL-1586), human colorectal adenocarcinoma cells Caco-2 (ATCC, HTB-37), and human lung adenocarcinoma cells Calu-3 (ATCC, HTB-55).

[1095] Virus strain: 2019-nCoV-WIV04 (IVCAS 6.7512)

[1096] Infectious dose: MOI = 0.01

[1097] (2) Experimental methods

[1098] 1) 100 μL containing 2×10 4 The cells were seeded into 96-well plates and placed in a 37°C constant temperature and humidity incubator for overnight culture;

[1099] 2) After cells have adhered for 20 hours, the culture medium was aspirated and 100 μL of culture medium containing the indicated concentration of test compound plus CP-100356 was added to each well. Eight dilutions of each test compound were prepared, with 3-4 replicates per dilution. A DMSO-treated group and a normal cell group were also established. Except for the normal cell group, all other wells were treated with complete culture medium containing 0.01 MOI of virus and incubated at 37°C in a constant temperature and humidity incubator for 72 hours.

[1100] 3) 72 hours after infection, the cytopathic rate was recorded using a full-field cell scanner. Inhibition rate = (1 - cytopathic rate of the test compound group) × 100%.

[1101] 4) Calculate EC using four-parameter fitting based on the inhibition rate results 50 .

[1102] The test results of the representative compounds of the present invention are shown in Table 1.

[1103] Table 1

[1104] Example A1

[1105] Synthesis of 6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(pyridin-3-yl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione)

[1106] Synthesis of intermediate 1-2

[1107] Under ice-cooling, an aqueous solution (10 mL) of sodium nitrite (4.44 g, 0.06 mol) was added to a solution of intermediate 1-1 (10 g, 0.05 mol) in glacial acetic acid (100 mL) and mixed. The mixture was stirred at room temperature for 6 hours, then the reaction mixture was concentrated and diluted with ethyl acetate (200 mL). The mixture was washed with saturated sodium bicarbonate solution (100 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 1-2 (10 g) as a brown solid, which was used directly in the next reaction.

[1108] LCMS (ESI) m / z: 198.0 [M+H] + .

[1109] Synthesis of intermediates 1-3

[1110] To a solution of Intermediate 1-2 (10 g, 0.05 mol) in ethyl acetate (200 mL) was added trimethyloxonium tetrafluoroborate (11.34 g, 0.08 mol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was washed with water (200 mL) and saturated sodium chloride solution (200 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 4:1) to afford Intermediate 1-3 as a yellow solid (4.93 g, 46.1% yield).

[1111] LCMS (ESI) m / z: 212.0 [M+H] + .

[1112] Synthesis of intermediates 1-4

[1113] Saturated ammonium chloride solution (100 mL) and reduced iron powder (3.91 g, 0.07 mol) were added to a solution of intermediate 1-3 (4.93 g, 0.02 mol) in anhydrous ethanol (100 mL) at room temperature. Stir at 80°C overnight. After cooling, the mixture was filtered, the filtrate was concentrated under reduced pressure, and diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 1:1) to afford intermediate 1-4 as a brown solid (3.4 g, 80.9% yield).

[1114] LCMS (ESI) m / z: 182.2 [M+H] + .

[1115] Synthesis of intermediates 1-6

[1116] To a solution of Intermediate 1-5 (10.0 g, 0.054 mol) in N,N-dimethylformamide (60 mL) at 0°C were added 2-isocyanato-2-methylpropane (5.62 g, 0.057 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52 g, 0.069 mol). The mixture was stirred at room temperature for 5 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52 g, 0.069 mol) and N,N-carbonyldiimidazole (10.51 g, 0.065 mol) were then added at 0°C. The mixture was stirred at room temperature for 24 hours. The pH was adjusted to 3-4 with 1N HCl and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane:ethyl acetate = 5:1) to give intermediate 1-6 (5.23 g, 45.1% yield) as a white solid.

[1117] LCMS (ESI) m / z: 252.0 [M+Na] + .

[1118] Synthesis of intermediates 1-7

[1119] 1-(Bromomethyl)-2,4,5-trifluorotoluene (8.46 g, 37.6 mmol) was added to a mixture of 1-6 (5.75 g, 25.0 mmol), potassium carbonate (6.93 g, 50.0 mmol), and acetonitrile (30 mL) and stirred at 85°C for 16 hours. After cooling, water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 2:1) to afford Intermediate 1-7 as a white solid (8.6 g, yield: 89%).

[1120] LCMS (ESI) m / z: 318.0 [M+H-56] + .

[1121] Synthesis of intermediates 1-8

[1122] Intermediate 1-7 (6.7 g, 17.9 mmol) was dissolved in dichloromethane and trifluoroacetic acid (30 / 30 mL) and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure to obtain a white solid 1-8 (7.8 g), which was used directly in the next reaction.

[1123] LCMS (ESI) m / z: 318.0 [M+H] + .

[1124] Synthesis of intermediates 1-9

[1125] A mixture of Intermediate 1-8 (160 mg, 0.5 mmol), pyridin-3-ylboranediol (93 mg, 0.75 mmol), copper acetate (92 mg, 0.5 mmol), 4-dimethylaminopyridine (247 mg, 2.0 mmol), pyridine (100 mg, 1.2 mmol), and dioxane (10 mL) was stirred at 100°C under a balloon of oxygen for 16 hours. After cooling, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, dichloromethane:methanol = 20:1) to afford Intermediate 1-9 as a white solid (120 mg, 40% yield).

[1126] LCMS (ESI) m / z: 395.0 [M+H] + .

[1127] Synthesis of Compound 1 (6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(pyridin-3-yl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione)

[1128] To a solution of Intermediate 1-9 (120 mg, 0.3 mmol) in tetrahydrofuran (20 mL) at 0°C were added lithium hexamethyldisilazide (0.6 mmol, 0.6 mL, 1.0 M in THF) and Intermediate 1-4 (67 mg, 0.37 mmol) in sequence. The mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high pressure chromatography (Gemini-C18 150 x 21.2 mm, 5 μm, acetonitrile-water (0.1% formic acid), gradient: 30%-60%) to afford 1 as a white solid (14.5 mg, 9% yield).

[1129] LCMS (ESI) m / z: 513.9 [M+H] + .

[1130] 1H NMR(400MHz,DMSO-d6,DCl in D2O)δ9.17(d,J=2.0Hz,1H),9.05(d,J=5.5Hz,1H),8.77–8.74(m,1H),8.54(s,1H), 8.32-8.27(m,1H),7.88-7.82(m,2H),7.64-7.56(m,2H),5.34(s,2H),4.21(s,3H).

[1131] The compounds shown in Table A1 below were synthesized by referring to the method of Example A1 above.

[1132] Table A1

[1133] Example A2

[1134] Synthesis of (E)-1-(2-(Benzyloxy)-4,5-difluorobenzyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1,3,5-triazine-2,4-dione

[1135] Synthesis of intermediate 2-2

[1136] To a solution of intermediate 2-1 (10.0 g, 0.054 mol) in N,N-dimethylformamide (60 mL) at 0°C, 2-isocyanato-2-methylpropane (5.62 g, 0.057 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52 g, 0.069 mol) were added at room temperature. The mixture was stirred for 5 hours. 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52 g, 0.069 mol) and N,N-carbonyldiimidazole (10.51 g, 0.065 mol) were then added at 0°C. The mixture was stirred for 24 hours at room temperature. The pH was adjusted to 3-4 with 1N HCl, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane:ethyl acetate=5:1) to give intermediate 2-2 as a white solid (5.23 g, yield 45.1%).

[1137] LCMS (ESI) m / z: 252.0 [M+Na] + .

[1138] Synthesis of intermediate 2-4

[1139] To a solution of intermediate 2-3 (10 g, 0.0884 mol) in dichloromethane (100 mL) was added dropwise thionyl chloride (15.8 g, 0.133 mol) at 0°C. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure to afford intermediate 2-4 (14 g) as a white solid. This was used directly in the next reaction.

[1140] LCMS (ESI) m / z: 131.9 [M+H] + .

[1141] Synthesis of intermediate 2-6

[1142] Sodium hydroxide (34 g, 0.85 mol) was added to a solution of intermediate 2-5 (30 g, 0.17 mol) in 1,3-dimethyl-2-imidazolidinone (500 mL) under ice-cooling. The mixture was stirred at 120°C for 16 hours. After cooling to room temperature, the semisolid was dissolved in water and the pH was adjusted to 2 with hydrochloric acid under ice-cooling. The mixture was filtered to afford intermediate 2-6 (32 g, 97.0% yield) as a white solid.

[1143] LCMS (ESI) m / z: 173.1 [MH] - .

[1144] Synthesis of intermediate 2-7

[1145] Concentrated sulfuric acid (50 mL) was added to a solution of Intermediate 2-6 (32 g, 0.18 mol) in methanol (300 mL) under ice. The mixture was refluxed at 70°C for 16 hours, concentrated under reduced pressure, and water (100 mL) was added and filtered. The filter cake was dried to afford Intermediate 2-7 (18 g, 49.4% yield) as a white solid.

[1146] 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.79-7.66(m,1H),7.15-7.03(m,1H),3.89(s,3H).

[1147] Synthesis of intermediate 2-8

[1148] To a solution of intermediate 2-7 (2 g, 0.01 mol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (4.4 g, 0.03 mol) and benzyl bromide (2.18 g, 0.013 mol) at room temperature. The mixture was stirred at 70°C for 16 hours and then cooled to room temperature. The reaction mixture was washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-8 (2.4 g) as a white solid, which was used directly in the next reaction.

[1149] 1 H NMR (400MHz, DMSO-d6) δ7.73 (dd, J = 10.8, 9.4 Hz, 1H), 7.62-7.23 (m, 6H), 5.17 (s, 2H), 3.77 (dd, J = 6.4, 1.0 Hz, 3H).

[1150] Synthesis of intermediate 2-9

[1151] To a solution of Intermediate 2-8 (2.4 g, 8.6 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum tetrahydride (820 mg, 21.5 mmol) under ice. The mixture was slowly warmed to room temperature and stirred for 16 hours. The mixed solution was quenched with water (30 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was separated and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain Intermediate 2-9 (1.8 g) as a white solid, which was used directly in the next reaction.

[1152] LCMS (ESI) m / z: 273.0 [M+Na] + .

[1153] Synthesis of intermediate 2-10

[1154] To a solution of Intermediate 2-9 (500 mg, 2 mmol) in dichloromethane (10 mL) was added triphenylphosphine (786 mg, 3 mmol) and N-bromosuccinimide (534 mg, 3 mmol) under ice. The mixture was stirred at 0°C for 30 minutes. Water (10 mL) was added to the mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 20:1) to afford Intermediate 2-14 as a white solid (600 mg, yield: 96.1%).

[1155] 1 H NMR (400MHz, DMSO-d6) δ7.56 (dd, J = 10.9, 9.4Hz, 1H), 7.52-7.43 (m, 2H), 7.43-7.21 (m, 4H), 5.17 (s, 2H), 4.60 (s, 2H).

[1156] Synthesis of intermediate 2-11

[1157] To a solution of intermediate 2-2 (528 mg, 2.31 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (796 mg, 5.76 mmol) and intermediate 2-10 (600 mg, 1.92 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 2-11 (700 mg) as a white solid, which was used directly in the next reaction.

[1158] LCMS (ESI) m / z: 461.8 [M+H] + .

[1159] Synthesis of intermediate 2-12

[1160] Intermediate 2-11 (600 mg, 1.3 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid (6 mL) solution at room temperature, and the mixture was stirred for 16 hours. The reaction mixture was adjusted to pH 7 with sodium carbonate solution under an ice bath. Extraction was performed with dichloromethane (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 2-12 (500 mg) as a white solid, which was used directly in the next reaction.

[1161] LCMS (ESI) m / z: 406.0 [M+H] + .

[1162] Synthesis of intermediate 2-13

[1163] To a solution of intermediate 2-12 (250 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (426 mg, 3.08 mmol) and 2-4 (97 mg, 0.74 mmol) at room temperature. The mixture was stirred at 50°C for 16 hours. After cooling to room temperature, ethyl acetate (50 mL) was added to the mixture, which was then washed sequentially with water (10 mL) and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 2:1) to afford 2-13 (100 mg, 32.5% yield) as a white solid.

[1164] LCMS (ESI) m / z: 501.2 [M+H] + .

[1165] Synthesis of compound A21

[1166] To a solution of intermediate 2-13 (100 mg, 0.2 mmol) and 1-4 (45 mg, 0.24 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice-cooling. The mixture was stirred at 0°C for 2 hours. The mixture was quenched by addition of water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), gradient: 40-55) to afford compound 21 as a white solid (19.3 mg, yield: 14.9%).

[1167] LCMS (ESI) m / z: 620.0 [M+H] + .

[1168] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),8.24(s,1H),7.66(s,1H),7.54-7.16(m,8H),5.26-5.11(m,4H),4.88(s,2H),4.13(s,3H),3.78(s,3H).

[1169] Example A3

[1170] Synthesis of 6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-1-(3-((3-chlorobenzyl)oxy)-4,5-difluorobenzyl)-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1171] Synthesis of intermediate 3-2

[1172] To a solution of intermediate 3-1 (600 mg, 2.97 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.2 g, 8.91 mol) and 3-chlorobenzyl bromide (727 mg, 3.56 mol) at room temperature. The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the mixture was washed sequentially with water (20 mL) and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3-2 (700 mg) as a white solid, which was used directly in the next reaction.

[1173] Synthesis of intermediate 3-3

[1174] To a solution of 3-2 (500 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum tetrahydride (174 mg, 4.6 mmol) under ice. The mixed solution was slowly warmed to room temperature and stirred for 16 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3-3 (400 mg) as a white solid, which was used directly in the next reaction.

[1175] Synthesis of intermediate 3-4

[1176] To a solution of 3-3 (200 mg, 0.7 mmol) in dichloromethane (6 mL) was added triphenylphosphine (276 mg, 1.05 mmol) and N-bromosuccinimide (188 mg, 1.05 mmol) under ice-cooling. The mixture was stirred at 0°C for 30 minutes. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 3-4 (220 mg) as a white solid.

[1177] 1 H NMR (400MHz, DMSO-d6) δ7.56 (s, 1H), 7.55-7.26 (m, 4H), 7.26-7.12 (m, 1H), 5.24 (d, J = 12.2Hz, 2H), 4.66 (s, 2H).

[1178] Synthesis of intermediate 3-5

[1179] To a solution of 2-2 (182 mg, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (263 mg, 1.91 mmol) and intermediate 3-4 (220 mg, 0.63 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3-5 (230 mg) as a white solid, which was used directly in the next reaction.

[1180] LCMS (ESI) m / z: 496.1 [M+H] + .

[1181] Synthesis of intermediate 3-6

[1182] 3-5 (230 mg, 0.46 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid (6 mL) solution at room temperature and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 7 with sodium carbonate solution under ice-cooling. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 3-6 (180 mg) as a white solid, which was used directly in the next reaction.

[1183] LCMS (ESI) m / z: 440.0 [M+H] + .

[1184] Synthesis of intermediate 3-7

[1185] To a solution of 3-6 (180 mg, 0.41 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (283 mg, 2.05 mmol) and intermediate 2-4 (70 mg, 0.54 mmol) under ice-cooling. The mixture was stirred at 50°C for 16 hours. Ethyl acetate (50 mL) was added to the mixture, which was washed sequentially with water (10 mL) and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 2:1) to afford intermediate 3-7 as a white solid (130 mg, 53.4% ​​yield).

[1186] LCMS (ESI) m / z: 535.0 [M+H] + .

[1187] Synthesis of compound A22

[1188] To a solution of Intermediate 3-7 (100 mg, 0.18 mmol) and Intermediate 1-4 (41 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice-cooling. The mixture was stirred at 0°C for 2 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 55-65) to afford Compound 22 (16 mg, 13% yield) as a white solid.

[1189] LCMS (ESI) m / z: 653.9 [M+H] + .

[1190] 1H NMR (400MHz, DMSO-d6) δ8.33–8.19(m,3H),7.70(s,1H),7.41(s,1H),7.17(d,J=6 .8Hz,1H),7.11–7.06(m,1H),5.21(s,4H),4.91(s,2H),4.14(s,3H),3.78(s,3H).

[1191] The compounds shown in Table B below were synthesized by referring to the methods of Examples A2 and A3 above.

[1192] Table A2

[1193] Example A4 Synthesis of Compound 61 ((E)-1-(2-(Benzyloxy)-4,5-difluorobenzyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino)-3-(pyridin-2-yl)-1,3,5-triazine-2,4-dione)

[1194] Synthesis of intermediate 4-1

[1195] A mixture of Intermediate 2-12 (380 mg, 0.93 mmol), pyridin-3-ylboranediol (230 mg, 1.87 mmol), copper acetate (560 mg, 2.8 mmol), 4-dimethylaminopyridine (11.4 mg, 0.09 mmol), pyridine (370 mg, 4.68 mmol), molecular sieves (380 mg), and dioxane (10 mL) was stirred at 100°C under a balloon of oxygen for 16 hours. After cooling, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether:ethyl acetate = 1:1) to afford Intermediate 4-1 as a white solid (200 mg, yield: 44.2%).

[1196] LCMS (ESI) m / z: 483.1 [M+H] + .

[1197] Synthesis of compound A61

[1198] To a solution of Intermediate 4-1 (200 mg, 0.36 mmol) and Intermediate 1-4 (90 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice-cooling. The mixture was stirred at 0°C for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 40-55) to afford Compound 61 as a pink solid (38.8 mg, yield: 14.9%).

[1199] LCMS (ESI) m / z: 602.1 [M+H] + .

[1200] 1 H NMR(400MHz,DMSO-d6)δ8.59(s,2H),8.32(s,1H),7.90(d,J=8.0Hz,1H),7.61–7 .54(m,4H),7.43(d,J=7.2Hz,2H),7.35–7.23(m,4H),5.15(s,4H),4.12(s,3H).

[1201] Biological Example A

[1202] Safety assessment of hERG potassium channel

[1203] HEK293 cells stably expressing hERG ion channels were purchased from Invitrogen. The cells were cultured, digested, and seeded on glass slides for subsequent manual patch clamp experiments.

[1204] The test compound was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM. The stock solution was diluted with DMSO as the solvent at a ratio of 1:3 to form three other intermediate concentration solutions, with concentrations of (mM): 3.33, 1.11 and 0.37. Before the experiment began, the intermediate gradient solution of the test compound was diluted again at a ratio of 1:1000 with extracellular fluid to form a series of working solutions with final concentrations of (M): 10, 3.33, 1.11 and 0.37, and the 30M working solution was prepared by diluting the 10 mM stock solution 333.33 times. The content of DMSO in the working solution was 0.1-0.3% (volume ratio). Five working solutions with different concentration gradients of 30, 10, 3.33, 1.11 and 0.37 M were used to determine the potential inhibitory effect of the compound on the hERG channel and to fit the dose-effect curve and calculate the IC 50 .

[1205] Place a small glass slide containing HEK293 cells in a culture dish into the perfusion chamber on the microscope stage. Under an Olympus IX51, IX71, or IX73 inverted microscope, center the field of view with an appropriate cell. Using a ×10x objective, locate the tip of the glass electrode and position it in the center of the field of view. Then, use the micromanipulator to lower the electrode while adjusting the coarse focus knob to slowly approach the cell. Once close to the cell, switch to a ×40x objective for observation and, using the micromanipulator, fine-tune the electrode to gradually approach the cell surface. Apply negative pressure until a seal with a resistance greater than 1G is formed between the electrode tip and the cell membrane. Compensate for the transient capacitive current, Cfast, in voltage-clamp mode. Repeated brief negative pressure bursts are then applied to rupture the membrane, ultimately establishing whole-cell recording mode. With the membrane potential clamped at -60 mV, compensate for the slow capacitive current, Cslow, the cell membrane capacitance (Cm), and the input membrane resistance (Ra). After the cells stabilized, the clamping voltage was changed to -90 mV, the sampling frequency was set to 20 kHz, and the filtering frequency was set to 10 kHz. Leakage current was detected with the clamping voltage changed to -80 mV and a time duration of 500 ms.

[1206] The hERG current measurement method is as follows: a 4.8-second depolarization command voltage is applied to depolarize the membrane potential from -80 mV to +30 mV. Then, a 5.2-second repolarization voltage is applied to reduce the membrane potential to -50 mV to eliminate channel inactivation, allowing the observation of the hERG tail current. The peak value of the tail current is the magnitude of the hERG current.

[1207] The hERG currents used to detect test compounds were recorded for 120 seconds before administration to assess the stability of hERG currents generated by the test cells. Only cells that were stable within the acceptable range of the evaluation criteria were allowed to proceed to subsequent compound testing.

[1208] Test of the inhibitory effect of the test compound on hERG current: First, the hERG current measured in the extracellular fluid containing 0.1% DMSO is used as the detection baseline. After the hERG current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells in sequence from low concentration to high concentration. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cells and record the hERG current synchronously. After the recorded current tends to stabilize, record the last 5 hERG current values, and take the average as the final current value at a specific concentration. After testing the compound, add 150nM dofetilide to the same cell to completely inhibit its current as a positive control for the cell. At the same time, the positive compound dofetilide is synchronously detected using the same patch clamp system before and after the end of the test drug experiment to ensure the reliability and sensitivity of the entire detection system.

[1209] After perfusing blank solvent or compound gradient solution, the average value of the 5 consecutive current values ​​obtained was calculated and used as the "tail current size" 空白 ” and “tail current size 化合物 ”.

[1210] The current suppression percentage is calculated using the following formula.

[1211] The dose-effect curve was fitted and the IC was calculated using Graphpad Prism 8.0 software. 50 value.

[1212] Table A3

[1213] Pharmacokinetics in male CD1 mice after oral administration

[1214] Male CD1 mice were fasted overnight prior to dosing, with free access to water. Four hours after dosing, chow was given. The dose was 10 mg / kg in a 10 mL / kg volume, administered orally. The sample was prepared in 5% DMSO / 95% 10% HP-β-CD in water.

[1215] Blood was collected from the dorsal foot vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours. 30 μL of blood was collected at each time and placed in an anticoagulant tube containing EDTA-K2 and mixed thoroughly by inversion several times. Whole blood samples were centrifuged at 4000 g for 5 minutes at 4°C to separate plasma. Plasma samples were aliquoted into clean polyethylene microcentrifuge tubes and stored at -75 ± 15°C until analysis.

[1216] The LC-MS / MS method is used to detect the plasma results, and the pharmacokinetic parameters are calculated using WinNonlin 8.3 (Phoenix™) or other similar software.

[1217] Table A4 Oral (10 mg / kg) Pharmacokinetic Parameters of Representative Compounds of the Disclosure

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in, Y is N or CR7; R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; L1 is selected from chemical bonds, C 1-6 Alkylene, -NH-, -O-, or -S-; R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl; R 1s Selected from H, deuterium, CN, NO2, NH2, OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl; Alternatively, two R on the same carbon atom 1s Together they form oxo or thio; L2 is selected from a chemical bond or C 1-6 alkylene; R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace; R 2s Selected from H, D, halogen, CN, -L 2a -R' or L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a for -S-; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1- 10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from H, NH2, CN, C 0-6 Alkylene-C(O)R a 、C 0-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-OC(O)-R a 、C 0-6 Alkylene-NHC(O)R a 、C 0-6 Alkylene-C(O)NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkylene-OR a 、C 2-6 Alkenyl or C 2-6 Alkynyl; L3 is -NR b -or-CR a R b -; R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally substituted by 1, 2 , 3, 4 or 5 R 3s replace; R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1- 6-alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof: in: Y is N or CR7; R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; L1 is selected from chemical bonds, C 1-6 Alkylene, -NH-, -O-, or -S-; R1 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s Substituted; the R1 is preferably C 6-10 Aryl or 5-10 membered heteroaryl; R 1s Selected from H, deuterium, CN, NO2, NH2, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, halogenated C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1- 6 alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -O- C 1-6 Alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl; L2 is selected from a chemical bond or C 1-6 alkylene; R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 6-10 Aryl, more preferably phenyl, said R2 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s replace; R 2s Selected from H, D, halogen, CN, -L 2a -R' or L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a for -S-; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、Boc、C 2-6 Alkenyl or C 2-6 Alkynyl, or two R on the same carbon atom together form C=O or C=S; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl or C 2-6 Alkynyl; L3 is -NR b -or-CR a R b -; R3 is selected from C 6-14 Aryl or 5-14 heteroaryl, C 3-8 Cycloalkyl, 3 to 14 membered heterocyclic group, wherein R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace; R 3s Selected from H, deuterium, halogen, CN, NO2, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 2-6 Alkenyl, halogenated C 2-6 Alkynyl, C 6-10 Aryl, 3-8 membered heterocyclic group, 3-8 membered heteroaryl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, -NH-C 6-10 Aryl, -NH-3-8 membered heterocyclic group, -NH-3-8 membered heteroaryl, -OC 1- 6-alkyl, -OC 2-6 Alkenyl, -OC 2-6 Alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 Aryl, -O-3-8 membered heterocyclic group, -O-3-8 membered heteroaryl, or two R on the same carbon atom 3s Together they form C=O or C=S; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (I'): in: Y' is NR7 or CR7R8; R7 and R8 are independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; L3' is -N= or -CR a =; The other groups are as defined in claim 1.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of Formula (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII) or (VIII'): in, R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S; R" is selected from H, halogen, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R 2c is halogen, preferably F; R 2d is halogen or CN, preferably Cl; m is selected from 0, 1, 2, 3, 4 or 5; R 3a is a halogen, preferably Cl; R 3f C 1-6 Alkyl, preferably CH3; The other groups are as defined in any one of claims 1 to 3.

5. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (II) or (II'): in: L1 is selected from a chemical bond or C 1-6 alkylene; R1 is selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s replace; R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2c is halogen, preferably F; R 2d is halogen or CN, preferably Cl; L3 is -NR b -or-CR a R b -; L3' is -N= or -CR a =; R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace; R 3s Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

6. The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L1 is selected from a chemical bond or C 1-6 alkylene; R1 is selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, said R1 is optionally replaced by 1, 2, 3, 4 or 5 R 1s replace; R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from H, NH2, CN, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2c is halogen, preferably F; R 2d is halogen or CN, preferably Cl; L3 is -NR b -or-CR a R b -; L3' is -N= or -CR a =; R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 R 3s replace; R 3s Selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

7. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (III) or (III'): in: R 2a Selected from or -L 2a -R'; L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or C 2-6 Alkenylene, L 2a Optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, C 1-6 Alkyl or C 1-6 Substitution of haloalkyl groups; Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 Haloalkyl, or two R on the same carbon atom together form C=O or C=S; m is 0, 1, 2, 3, 4 or 5; R' is selected from NH2, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide; R 2c selected from halogen; R 2d Selected from halogen or CN; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

8. The compound of claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2a Selected from or -L 2a -R'; L 2a Selected from chemical bonds, -O-, -S-, -C 1-6 Alkylene-, -C 1-6 Alkylene-O-, -OC 1-6 Alkylene-, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)- or C 2-6 Alkenylene, L 2a Optionally substituted by 1, 2 or 3 independently selected from halogen or C 1-6 Substitution of alkyl groups; Ring A is selected from C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or NHC(O)-C 1-6 Haloalkyl, or two R on the same carbon atom together form C=O; m is 0, 1, 2, 3 or 4; R' is selected from NH2, CN, C 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide; R 2c selected from halogen; R 2d Selected from halogen or CN; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

9. The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2a Selected from or -L 2a -R'; L 2a is selected from a chemical bond, -O-, -S-, -CH2-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NH-C(O)- or -CH=CH-, wherein L 2a Optionally substituted with CH3; Selected from R' is selected from CN, NHC(O)-CF3 or CF3; R 2c Selected from F or Cl, preferably F; R 2d Selected from F, Cl or CN, preferably Cl.

10. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (IV) or (IV'): in: L 2a Selected from -O-, -S- or -C 2-6 alkenylene-; Ring A is selected from C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OH, NH2, -C(O)-C 1-6 Haloalkyl, -C(O)OC 1-6 Haloalkyl, -NHC(O)-C 1-6 Haloalkyl, -C(O)NH-C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or, two R on the same carbon atom together form C=O or C=S; m is selected from 0, 1, 2, 3, 4 or 5; R 2c is halogen, preferably F; R 2d is selected from halogen or CN, preferably Cl.

11. The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -O- or -C 2-6 alkenylene-; Ring A is selected from C 5-8 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OH, NH2, -NHC(O)-C 1-6 Haloalkyl, -C(O)NH-C 1-6 Halogenated alkoxy, C 1-6 Alkoxy or C 1-6 Haloalkoxy; or, two R on the same carbon atom together form C=O; m is selected from 0, 1, 2, 3, 4 or 5; R 2c is halogen, preferably F; R 2d is selected from halogen or CN, preferably Cl.

12. The compound of claim 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -O- or -C 2-4 alkenylene-; Ring A is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, -NHC(O)-C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy, preferably H, F, Cl, CN, OCH3, OCF3 or -NHC(O)-CF3; or, two R on the same carbon atom together form C=O; m is selected from 0, 1, 2 or 3; R 2c is halogen, preferably F; R 2d is selected from halogen or CN, preferably Cl.

13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -O-, -CH=CH-; Selected from R 2c Selected from F or Cl, preferably F; R 2d Selected from F, Cl or CN, preferably Cl.

14. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (IV) or (IV'): in: L 2a C 2-6 alkenylene; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R is selected from H, halogen or C 1-6 alkyl halide; m is selected from 0, 1, 2, 3, 4 or 5; R 2c is halogen, preferably F; R 2d is a halogen, preferably Cl; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

15. The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a C 2-4 Alkenylene, preferably -CH=CH-; Ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the 5 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N; R is selected from H or halogen, preferably H or F; m is selected from 0, 1, 2 or 3; R 2c is halogen, preferably F; R 2d is halogen, preferably Cl.

16. The compound of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a C 2-4 Alkenyl, preferably -CH=CH-; Selected from Preferably, Selected from R 2c is F; R 2d is Cl or F, preferably Cl.

17. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (V) or (V'): in: L 2a is -O- or -S-; Ring A is selected from or a 5-membered heteroaryl group; X 2a and X 2b independently selected from CR or N; Each R is independently selected from H, halogen, CN, OH, NH2, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably H, halogen, CN, OH or NH2, more preferably H, F, Cl or CN; m is selected from 0, 1, 2, 3, 4 or 5; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

18. The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is -O-; Ring A is selected from or a 5-membered heteroaryl group; X 2a and X 2b independently selected from CR or N; Each R is independently selected from H, halogen, CN or C 1-6 Haloalkoxy, preferably H, halogen or CN; m is selected from 0, 1, 2, 3, 4 or 5; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

19. The compound of claim 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is -O-; Ring A is selected from or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N; X 2a and X 2b independently selected from CR or N; Each R is independently selected from H, halogen, CN or C 1-4 Haloalkoxy, preferably H, halogen or CN, more preferably H, F, Cl or CN; m is selected from 0, 1, 2 or 3; Preferably, Selected from Preferably 20. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (V) or (V'): in, R 2b for or -L 2a -R'; L 2a -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-; Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, NH2, OH, CN, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R' is selected from C(O)-C 1-6 Haloalkyl, C(O)OC 1-6 Haloalkyl, NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 alkyl halide; R 2c is a halogen; R 2d Selected from halogen or CN; m is 0, 1, 2, 3, 4 or 5; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

21. The compound of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b for or -L 2a -R'; L 2a Selected from -O-, -S-, -C 1-4 Alkylene-, -C 1-4 Alkylene-O-, -OC 1-4 Alkylene-, -C 1-4 Alkylene-S- or -SC 1-4 Alkylene-; Ring A is phenyl or a 5-6 membered heteroaryl group, wherein the 5 membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N; Each R is independently selected from H, halogen, CN, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably H, F, Cl, CN, CF3 or OCF3; R' is selected from NHC(O)-C 1-6 Haloalkyl or C(O)NH-C 1-6 Haloalkyl, preferably NHC(O)CF3; R 2c is a halogen; R 2d Selected from halogen or CN; m is 0, 1, 2, or 3; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

22. The compound of claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b for or -L 2a -R'; L 2a is -O-, -S-, -CH2-, -CH2-O-, -CH2-CH2-O- or -O-CH2-; Selected from R' is NHC(O)CF3; R 2c is F; R 2d Selected from F, Cl or CN, preferably Cl.

23. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (VI) or (VI'): in, L 2a is -O- or -S-; Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, C 1-6 Haloalkyl or C 1-6 haloalkoxy; m is 0, 1, 2, 3, 4 or 5; R 2c is a halogen; R 2d Selected from halogen or CN; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

24. The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is -O-; Ring A is phenyl; Each R is independently selected from H, halogen, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably H, F, Cl, CF3 or OCF3; m is 0, 1, 2, or 3; Preferably, Selected from R 2c is halogen, preferably F; R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

25. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (VII) or (VII'): in, L 2a O or S; R is selected from H or halogen; R" is selected from H, halogen, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

26. The compound of claim 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -O-; R is selected from H or halogen, preferably H, F or Cl; R" is selected from H, halogen or C 1-4 The haloalkoxy group is preferably H, F, Cl or OCF3.

27. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (II) or (II'): in, L1 is selected from a chemical bond or C 1-6 alkylene; R1 is selected from C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, wherein R1 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 1s replace; R 1s Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0- 6-alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is selected from C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or Boc, preferably H, F, Cl, CN, CF3, OCF3 or Boc; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2c is halogen, preferably F; R 2d is a halogen, preferably Cl; L3 is -NR b -or-CR a R b -; R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2, 3, 4 or 5 independently selected R 3s replace; R 3s Selected from H, halogen, C 1-6 Alkyl or C 1-6 Alkoxy, or two R on the same carbon atom 3s Together they form C=O or C=S; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

28. The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L1 is selected from a chemical bond or C 1-4 alkylene; R1 is selected from C 1-4 Alkoxy or 5-6 membered heteroaryl, wherein R1 is optionally replaced by 1, 2 or 3 independently selected R 1s replace; R 1s Selected from H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, preferably F, CH3 or OCH3; R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -O-, -S-, -C 1-4 Alkylene-O-, -OC 1-4 Alkylene-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or C 2-4 Alkenylene, the L 2a Optionally substituted with 1, 2 or 3 independently selected R#; R# is selected from H, C 1-4 Alkyl or C 1-4 alkyl halide; Ring A is selected from C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy or Boc, preferably H, F, Cl, CN, CF3, OCF3 or Boc; m is selected from 0, 1, 2 or 3; R' is selected from C 1-4 Alkyl or C 1-4 alkyl halide; R 2c is halogen, preferably F; R 2d is a halogen, preferably Cl; L3 is -NH-; R3 is selected from C 6-10 Aryl or 5-10 heteroaryl, said R3 is optionally replaced by 1, 2 or 3 independently selected R 3s replace; R 3s Selected from H, halogen, C 1-4 Alkyl or C 1-4 Alkoxy, or two R on the same carbon atom 3s Together they form C=O; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

29. The compound of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L1 is selected from a chemical bond or -CH2-; R1 is selected from OCH3, R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a is selected from a chemical bond, -O-, -S-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, wherein L 2a Optionally substituted with CH3; Selected from R' is selected from CHF2 or CF3; R 2c Selected from F; R 2d selected from F or Cl; L3 is -NH-; R3 is selected from L1 is selected from a chemical bond or -CH2-; R1 is selected from OCH3, R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -O-, -S-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, the L 2a Optionally substituted with CH3; Selected from R' is selected from CHF2 or CF3; R 2c Selected from F; R 2d selected from F or Cl; L3 is -NH-; R3 is selected from 30. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of Formula (VIII) or (VIII'): in: L 2a O or S; R 1s Selected from halogen or C 1-6 haloalkoxy; R is selected from halogen, CN, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R 3a is a halogen, preferably Cl; R 3f C 1-6 Alkyl, preferably CH3.

31. The compound of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is O; R 1s Selected from halogen or C 1-4 Haloalkoxy, preferably F or OCH3; R is selected from halogen, CN, C 1-4 Haloalkyl or C 1-4 Haloalkoxy, preferably F, CN, CF3 or OCF3; R 3a is a halogen, preferably Cl; R 3f C 1-4 Alkyl, preferably CH3.

32. The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of Formula (VIII) or (VIII'): in: L 2a O or S; R 1s Selected from halogen or C 1-6 haloalkoxy; R is selected from halogen or CN; R 3a is a halogen, preferably Cl; R 3f C 1-6 Alkyl, preferably CH3; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

33. The compound of claim 32, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is O; R 1s Selected from halogen or C 1-4 Haloalkoxy, preferably F or OCH3; R is selected from halogen or CN, preferably F or CN; R 3a is a halogen, preferably Cl; R 3f C 1-4 Alkyl, preferably CH3.

34. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of Formula (IV), (IV'), (V), (V'), (IX), (IX'), (X), (X'), (XI), (XI'), (XII) or (XII'): R 2a and R 2b One of them is or -L 2a -R', the other is H or D; L 2a Selected from chemical bonds, -C 1-6 Alkylene, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-C(O)-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)OC 0-6 Alkylene-, -C 0-6 Alkylene-NH-C 0-6 Alkylene-, -C 0-6 Alkylene-C(O)NH-C 0-6 Alkylene-, -C 0-6 Alkylene-NHC(O)-C 0-6 Alkylene- or -C 2-6 Alkenylene-, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#; said L 2a Preferably, -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a Preferred -S-; R# is selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; Ring A is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Each R is independently selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, C(O)R a 、C(O)OR a 、NHC(O)R a 、C(O)NH-R a or Boc, or, two R on the same carbon atom together form C=O or C=S; R 2c is halogen, preferably F; R 2d is halogen or CN, preferably Cl; m is selected from 0, 1, 2, 3, 4 or 5; R 3a is a halogen, preferably Cl; R 3f C 1-6 Alkyl, preferably CH3; The other groups are as defined in any one of claims 1 to 3.

35. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (IV) or (IV'): in, L 2a Selected from -S- or -O-; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R is selected from H, halogen, CN, OR a NR b R c 、C(O)NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; m is selected from 0, 1, 2, 3, 4 or 5; R 2d selected from halogen; R 2c selected from halogen; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

36. The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -S- or -O-; Ring A is selected from phenyl or 5-6 membered heteroaryl; R is selected from H, halogen, CN, OH, NH2, C(O)NH2 or C 1-4 Haloalkyl, preferably H, F, Cl, CN, OH, NH2, C(O)NH2 or CF3; m is selected from 1, 2 or 3; R 2d is selected from halogen, preferably Cl or F; R 2c is selected from halogen, preferably F.

37. The compound of claim 35 or 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is -S- or -O-; Selected from R 2d is selected from halogen, preferably Cl or F; R 2c is selected from halogen, preferably F.

38. The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -S- or -O-; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R is selected from H, halogen, CN, NH2, C 1-6 Alkyl or C 1-6 alkyl halide; m is selected from 0, 1, 2, 3, 4 or 5; R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

39. The compound of claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a Selected from -S- or -O-; Ring A is selected from phenyl or 5-6 membered heteroaryl; R is selected from H, halogen, CN, NH2 or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2 or CF3; m is selected from 1, 2 or 3; R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

40. The compound of claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 2a is -S- or -O-, preferably -S-; Selected from R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

41. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (V) or (V'): in, R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 6-10 membered heteroaryl; R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 0-6 Alkylene-OC 1-6 Alkyl or C 0-6 Alkylene-OC 1-6 alkyl halide; R 2d selected from halogen; R 2c selected from halogen; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

42. The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Ring A is selected from a 4-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; R is selected from H, halogen, NH2, CN, OH or C 1-4 Haloalkyl, preferably H, F, NH2, CN, OH or CF3; m is selected from 1, 2 or 3; R' is C 1-4 Alkylene-OC 1-4 alkyl; R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Selected from R' is R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

44. The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 6-10 membered heteroaryl; R is selected from H, halogen, C 0-6 Alkylene-NH2, C 0-6 Alkylene -CN or C 0-6 Alkylene-OH; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 0-6 Alkylene-OC 1-6 Alkyl or C 0-6 Alkylene-OC 1-6 alkyl halide; R 2d selected from halogen; R 2c selected from halogen; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

45. The compound of claim 46, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Ring A is selected from a 4-7 membered heterocyclyl, a phenyl group or a 5-6 membered heteroaryl group; R is selected from H, halogen, NH2, CN or OH, preferably H, F, NH2, CN or OH; m is selected from 1, 2 or 3; R' is C 1-4 Alkylene-OC 1-4 alkyl; R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

46. ​​The compound of claim 44 or 45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2b Selected from or -L 2a -R'; L 2a Selected from -S- or -O-; Selected from R' is R 2d is selected from halogen, preferably Cl; R 2c is selected from halogen, preferably F.

47. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of Formula (IX) or (IX'): in, R 1S Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl; R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy C 2- 6 alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R 3a is a halogen, preferably Cl; R 3f C 1-6 Alkyl, preferably CH3; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

48. The compound of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from H, halogen, C 1-4 Alkyl or C 1-4 alkoxy; L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-; Ring A is selected from phenyl or 5-6 membered heteroaryl; R is selected from H, halogen, CN, NH2, OH, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2, OH, CH3 or CF3; m is selected from 1, 2 or 3; R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R 3a is a halogen, preferably Cl; R 3f C 1-4 Alkyl, preferably CH3.

49. The compound of claim 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from H, F, CH3 or OCH3; L 2a is -S- or -S-CH2-; Selected from R 2d Selected from Cl or CN; R 2c Selected from H or F; R 3a is Cl; R 3f For CH3.

50. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has a structure of formula (X) or (X'): in, R 1S Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; L 2a is -S- or -O-; Ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N; R is selected from H, halogen, CN, NR b R c , OR a 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

51. The compound of claim 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy; L 2a is -S- or -O-; Ring A is selected from phenyl or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N; R is selected from H, halogen, CN, NH2, OH, C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, Cl, CN, NH2, OH, CH3 or CF3; m is selected from 1, 2 or 3; R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F.

52. The compound of claim 50 or 51, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from CH3 or OCH3; L 2a is -S- or -O-, preferably -S-; Selected from R 2d Selected from Cl or CN; R 2c Selected from H or F.

53. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (XI) or (XI'): in, R 1S Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2b Selected from or -L 2a -R'; L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NR b R c or C 1-6 Alkylene-OR a ; R 2d Selected from halogen or CN; R 2c Selected from H or halogen; R 3a is a halogen; R 3f C 1-6 alkyl; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

54. The compound of claim 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S is CH3; R 2b Selected from or -L 2a -R'; L 2a for -S-; Selected from R' is selected from R 2d Selected from F, Cl or CN; R 2c Selected from H or F; R 3a is Cl; R 3f For CH3.

55. The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which has the structure of formula (XII) or (XII'): in, R 1S Selected from C 1-6 Alkyl or C 1-6 alkoxy; R 2b Selected from or -L 2a -R'; L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-; Ring A is selected from 3-8 membered heterocyclic groups, or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S; Q1 is CH or N; R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NR b R c or C 1-6 Alkylene-OR a ; R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

56. The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy; R 2b Selected from or -L 2a -R'; L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-; Ring A is selected from 3-6 membered heterocyclic groups, Q1 is CH or N; Q2 is selected from S or NH; Q3 is selected from CH or N; One of Q4, Q5 and Q6 is N, and the other two are CH; R is selected from H, halogen, OH, CN, NR b R c 、C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, OH, CN, NH2, NHCH3, CF3 or CH3; m is selected from 1, 2 or 3; R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)NR b R c or C 1-6 Alkylene-OR a ; R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R a 、R b and R c Independently selected from H, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

57. The compound of claim 55 or 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S is CH3; R 2b Selected from or -L 2a -R'; L 2a for -S-; Selected from R' is selected from R 2d Selected from F, Cl or CN; R 2c Selected from H or F.

58. The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from C 1-6 Alkyl or C 1-6 alkoxy; R 2b Selected from or -L 2a -R'; L 2a -C 0-6 Alkylene-OC 0-6 Alkylene- or -C 0-6 Alkylene-SC 0-6 Alkylene-; Ring A is selected from phenyl, thienyl, pyrazolyl or thiazolyl; R is selected from H, halogen, CN, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; m is selected from 0, 1, 2, 3, 4 or 5; R' is selected from C 1-6 Alkylene-NHC(O)-R a 、C 1-6 Alkylene-C(O)-R a 、C 1-6 Alkylene-OC(O)-R a 、C 1-6 Alkylene-C(O)OR a 、C 1-6 Alkylene-C(O)NH2 or C 1-6 Alkylene-OR a ; R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F; R a 、R b and R c Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Each of the radicals defined herein may be optionally substituted by D up to full deuteration.

59. The compound of claim 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S Selected from C 1-4 Alkyl or C 1-4 alkoxy; R 2b Selected from or -L 2a -R'; L 2a For-OC 0-4 Alkylene- or -SC 0-4 Alkylene-; Ring A is selected from phenyl, thienyl, R is selected from H, halogen, CN, NR b R c 、C 1-4 Alkyl or C 1-4 Haloalkyl, preferably H, F, CN, NH2, NHCH3, CF3 or CH3; R b and R c Independently selected from H, C 1-4 Alkyl or C 1-4 alkyl halide; m is selected from 1, 2 or 3; R' is selected from C 1-4 Alkylene-NHC(O)-C 1-4 Halogenated alkyl, C 1-4 Alkylene-C(O)NH2 or C 1-4 Alkylene-OC 1-4 alkyl; R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl; R 2c is selected from H or halogen, preferably H or F, more preferably F.

60. The compound of claim 58 or 59, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1S is CH3; R 2b Selected from or -L 2a -R'; L 2a for -S-; Selected from R' is selected from R 2d Selected from F, Cl or CN; R 2c Selected from H or F.

61. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein The compound is selected from the following:

62. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein The compound is selected from the following:

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally with another therapeutic agent; Preferably, the other therapeutic agent is selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, Chloroquine (Chloroquine or Sigma-C6628), Hydroxychloroquine or α-interferon.

64. Use of a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition according to claim 63 in the preparation of a medicament for treating or preventing a disease caused by a viral infection.

65. A method for treating or preventing a disease caused by a viral infection in a subject, comprising administering to the subject a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition of claim 63.

66. A compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 63, for use in treating or preventing a disease caused by a viral infection.

67. The use of claim 64 or the method of claim 65 or the use of the compound or pharmaceutical composition of claim 66, wherein The compound or pharmaceutical composition inhibits viral proliferation; Preferably, the compound or pharmaceutical composition inhibits the activity of viral 3CL protease; Preferably, the 3CL protease has a P132H mutation; Preferably, the virus is a coronavirus, preferably an alpha coronavirus and / or a beta coronavirus, more preferably SARS-CoV-2.

68. The use of claim 64 or the method of claim 65 or the use of the compound or pharmaceutical composition of claim 66, wherein The disease caused by the viral infection is selected from the group consisting of: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder, taste disorder and complications thereof, or a combination thereof.

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