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. 202310082317.3 filed on January 19, 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] Y is N or CR7;

[0015] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0016] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0017] R 1s for -C(O)NR 1b R 1c or

[0018] L 1a Selected from chemical bonds, O, S or NR 5a ;

[0019] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0020] R 1a 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 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0021] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b Rc 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0022] n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0023] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0024] R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0025] R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0026] R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0027] n3 is 0, 1, 2, or 3;

[0028] L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ;

[0029] R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0030] m1 is 0, 1, or 2;

[0031] R 4c Selected from H, C 1-6 Alkyl or C 1-6alkyl halide;

[0032] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace;

[0033] R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0034] L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ;

[0035] R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0036] R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0037] R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace;

[0038] R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SR a 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10Cycloalkyl or 3-10 membered heterocyclic group;

[0039] Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0040] R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl;

[0041] L 1c 、L 1d 、L 2a 、L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0042] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl;

[0043] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0044] Provided that, when ring A is pyridyl, L 1aFor NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In a specific embodiment, the compounds or pharmaceutical compositions of the present invention are used to inhibit viral proliferation;

[0051] In another embodiment, the compound or pharmaceutical composition of the present invention inhibits the activity of viral 3CL protease.

[0052] In another specific embodiment, the 3CL protease has a P132H mutation.

[0053] In another specific embodiment, the virus is a coronavirus, preferably an alphacoronavirus and / or a betacoronavirus, more preferably SARS-CoV-2.

[0054] 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.

[0055] definition

[0056] Chemical definition

[0057] Definitions of specific functional groups and chemical terms are described in more detail below.

[0058] 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.

[0059] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl, C 1-3 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples 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).

[0060] “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.

[0061] “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 2-6 "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). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0062] “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 1-3Alkylene 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.

[0063] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkenylene 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.

[0064] “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.

[0065] “C0-6 "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".

[0066] “C 1-6 "Alkoxy" refers to -OC 1-6 In some embodiments, C 1-4 Alkyl is preferred. In other embodiments, C 1-3 Alkoxy groups are preferred, for example, methoxy, ethoxy and the like.

[0067] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0068] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-3 Halogenated 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.

[0069] “C 1-6 "Haloalkoxy" refers to OC 1-6 In some embodiments, C 1-4 Haloalkoxy is preferred, for example, halomethoxy (eg, OCH2F, OCHF2 or OCF3), haloethoxy and the like.

[0070] “C 3-10 "Cycloalkyl" 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 5-6Cycloalkyl. 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.

[0071] “C 3-10 "Cycloalkylene" refers to the removal of C 3-10 In some embodiments, C 5-10 Cycloalkylene, 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.

[0072] "3-10 membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 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 5-10 membered heterocyclyl is preferred, which is 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 preferred, which is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 5-7 membered heterocyclyl is preferred, which is a 5-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-6 membered heterocyclyl is preferred, which is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferred, which is 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 preferred, which is 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 heterocyclic groups 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 thienyl. 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, dihydrobenzothiophenyl, benzoxazolinone, 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.

[0073] “C 6-10 "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 6-10 ring carbon atoms and zero heteroatoms. 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.

[0074] "5-10 membered heteroaryl" refers to a group of a 5-10 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 1-4 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, 5-6 membered heteroaryl is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups 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, indanyl, 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, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0075] 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".

[0076] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0077] 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 、-NR bb 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;

[0078] 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;

[0079] 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;

[0080] 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;

[0081] R cc Each 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 Rdd group substitution;

[0082] 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;

[0083] 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;

[0084] 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;

[0085] 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 1-6Alkyl, -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 1-6 alkyl), 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 1-6alkyl), -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.

[0086] 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 cc 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 dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0087] Other definitions

[0088] 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.

[0089] In one embodiment, the term "coronavirus" is an alphacoronavirus and / or a betacoronavirus, more preferably a betacoronavirus.

[0090] In one embodiment, the alphacoronavirus is selected from HCoV-229E and HCoV-NL63, preferably HCoV-229E.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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).

[0097] "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), cattle, 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.

[0098] "Disease," "disorder," and "condition" are used interchangeably herein.

[0099] 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").

[0100] 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.

[0101] 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.

[0102] 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.

[0103] "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. DETAILED DESCRIPTION

[0104] Herein, "compounds of the present invention" refers to compounds of the following formula (I), formula (II), formula (III-1), formula (III-2) and formula (III-3), and pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0105] 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.

[0106] 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:

[0107] in,

[0108] Y is N or CR7;

[0109] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0110] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0111] R 1s for -C(O)NR 1b R 1c or

[0112] L 1a Selected from chemical bonds, O, S or NR 5a ;

[0113] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0114] R 1a 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 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0115] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b R c 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0116] n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0117] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0118] R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0119] R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0120] R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0121] n3 is 0, 1, 2, or 3;

[0122] L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ;

[0123] R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0124] m1 is 0, 1, or 2;

[0125] R 4c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0126] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace;

[0127] R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0128] L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ;

[0129] R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0130] R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0131] R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace;

[0132] R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SRa 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0133] Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0134] R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl;

[0135] L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0136] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R cand the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl;

[0137] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0138] Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

[0139] Y

[0140] In one embodiment, Y is CR7, such as CH; in another embodiment, Y is N.

[0141] R7

[0142] 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.

[0143] Ring A

[0144] In one embodiment, Ring A is C 3-10 Cycloalkyl; in another embodiment, ring A is a 3-10 membered heterocyclyl; in another embodiment, ring A is C 6-10 Aryl, such as phenyl; In another embodiment, ring A is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl, such as pyridyl, such as thiazolyl, such as For example

[0145] In one embodiment, Ring A is C 6-10 In another more specific embodiment, ring A is phenyl or 5-6 membered heteroaryl; In another more specific embodiment, ring A is 5-6 membered heteroaryl; In another more specific embodiment, ring A is pyridyl or thiazolyl; In another more specific embodiment, ring A is pyridyl; In another more specific embodiment, ring A is In a more specific embodiment, Ring A is

[0146] In one embodiment, Ring A and R 1s composition In another specific embodiment, Ring A and R 1s composition

[0147] R 1s

[0148] In one embodiment, R 1s for For example For example More specifically, for example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R 1s C(O)NR 1b R 1c , such as C(O)NHCH3; in another embodiment, R 1s for For example

[0149] In a more specific embodiment, R 1s Selected from In another more specific embodiment, R1s Selected from In another more specific embodiment, R 1s Selected from In another more specific embodiment, R 1s Selected from In another more specific embodiment, R 1s Selected from In another more specific embodiment, R 1s Selected from In another more specific embodiment, R 1s Not for

[0150] In a more specific embodiment, R 1s Selected from Preferably Preferably

[0151] In a more specific embodiment, R 1s Selected from: Preferably selected from: Preferably, for Preferably, for Preferably, for

[0152] In a more specific embodiment, R 1s Selected from: Preferably: Preferably Preferably, for

[0153] In a more specific embodiment, R 1s Selected from: Preferably Preferably Preferably Preferably, for

[0154] L 1a

[0155] In one embodiment, L 1a is O; in another embodiment, L 1a is S; in another embodiment, L 1a NR 5a , such as NH, such as NMe; in another embodiment, L 1a For chemical bonds.

[0156] In a more specific embodiment, L 1a is selected from O, S, NH or NMe; in another more specific embodiment, L 1a is selected from O, S or NH; in another more specific embodiment, L 1a is O or NH; in another more specific embodiment, L 1a Is O or S; in another more specific embodiment, L 1a Selected from O, S, NR 5a .

[0157] L 1b

[0158] In one embodiment, L 1b is a chemical bond; in another embodiment, L 1b is O; in another embodiment, L 1b is S; in another embodiment, L 1b NR 5b , such as NH, such as NMe.

[0159] In a more specific embodiment, L 1b Selected from O, S or NR 5b In another more specific embodiment, L 1b Selected from O or NR 5b In another more specific embodiment, L 1b is selected from O, S or NMe; in another more specific embodiment, L 1b is selected from O or S; in another more specific embodiment, L 1b is selected from O or NMe; in another more specific embodiment, L 1b Selected from O, S or NR 5b .

[0160] R 1a

[0161] In one embodiment, R 1a C 1-6 Alkyl, such as Me; in another embodiment, R 1a C 1-6 haloalkyl; in another embodiment, R 1a C 3-10 Cycloalkyl, such as C 3-7 Cycloalkyl, such as C 3-5 Cycloalkyl, such as cyclopropyl; in another embodiment, R 1a is a 3-10 membered heterocyclic group, such as a 3-7 membered heterocyclic group, such as a 3-5 membered heterocyclic group, such as a 4-6 membered heterocyclic group, such as a 4-5 membered heterocyclic group, such as For example For example For example, a 5-membered heterocyclic group, such as For example For example In another embodiment, R 1a C 6-10 Aryl, such as phenyl; in another embodiment, R 1a is a 5-10 membered heteroaryl group, for example a 5-6 membered heteroaryl group, for example For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R 1a C 1-6 Alkoxy, such as OMe; in another embodiment, R 1a C 1-6 Haloalkoxy, for example OCHF2, for example OCF3.

[0162] In one embodiment, R 1a is unsubstituted; in another embodiment, R 1a By 1 R 1as In another embodiment, R 1a By 2 R 1as In another embodiment, R 1a By 3 R1as replace.

[0163] In a more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 3-7 Cycloalkyl or 3-7 membered heterocyclic group.

[0164] In a more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-5 Cycloalkyl; in another more specific embodiment, R 1a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; in another more specific embodiment, R 1a Selected from Me, OMe, cyclopropyl or In another more specific embodiment, R 1a is selected from Me, OMe or cyclopropyl; in another more specific embodiment, R 1a is Me or cyclopropyl; in another more specific embodiment, R 1a Selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from In another more specific embodiment, R 1a Selected from: In another more specific embodiment, R 1a Selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl.

[0165] In a more specific embodiment, Selected from: Preferably: Preferably Preferably, for In a more specific embodiment, Selected from: Preferably

[0166] In a more specific embodiment, Selected from: Preferably Preferably Preferably Preferably, for

[0167] R 1as

[0168] In one embodiment, R 1as is H; in another embodiment, R 1as is D; in another embodiment, R 1as is halogen, such as F; in another embodiment, R 1as is cyano; in another embodiment, R 1as C 1-6 Alkyl, such as Me; in another embodiment, R 1as C 1-6 haloalkyl; in another embodiment, R 1as -L 1c -OR a , preferably OR a In another embodiment, R 1as -L 1c -SR a , preferably SR a In another embodiment, R 1as -L 1c -NR b R c , preferably NR b R c , such as NH2, such as -NHCH3, such as -NH(CH3)2; in another embodiment, R 1as C 3-10 Cycloalkyl, such as C 3-7 Cycloalkyl; in another embodiment, R 1as is a 3-10 membered heterocyclic group, such as a 3-7 membered heterocyclic group; in another embodiment, R 1as C6-10 Aryl; In another embodiment, R 1as It is a 5-10 membered heteroaryl group.

[0169] In a more specific embodiment, R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a SR a NR b R c 、C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1as Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0170] In a more specific embodiment, R 1as Independently selected from H, D, halogen, cyano, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1as Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1as is independently selected from H, F, Me, NH2, -NHCH3 or -NH(CH3)2; in another more specific embodiment, R 1as are independently selected from H, F, Me, NH2 or -NHCH3; in another more specific embodiment, R 1as Independently selected from H, D or NR b R c ; preferably selected from H, NH2 or -N(CH3)2; in another more specific embodiment, R 1as are independently selected from H or NH2; in another more specific embodiment, R 1as are independently selected from H, F, Me, NH2 or NHCH3; in another more specific embodiment, R 1as are independently H, F or Me.

[0171] n1 and n2

[0172] In one embodiment, n1 is 0; in another embodiment, n1 is 1; in another embodiment, n1 is 2; in another embodiment, n1 is 3; in another embodiment, n1 is 4; in another embodiment, n1 is 5; in another embodiment, n1 is 6.

[0173] In one embodiment, n2 is 0; in another embodiment, n2 is 1; in another embodiment, n2 is 2; in another embodiment, n2 is 3; in another embodiment, n2 is 4; in another embodiment, n2 is 5; in another embodiment, n2 is 6.

[0174] In a more specific embodiment, n1 is selected from 0, 1, 2 or 3; in another more specific embodiment, n1 is selected from 0, 1 or 2; in another more specific embodiment, n1 is selected from 1, 2 or 3.

[0175] In a more specific embodiment, n2 is selected from 0, 1, 2 or 3; in another more specific embodiment, n2 is selected from 0 or 1; in another more specific embodiment, n2 is 0, 1 or 2.

[0176] R 5a and R 5b

[0177] In one embodiment, R 5a is H; in another embodiment, R 5a C 1-6 Alkyl groups, such as C 1-3 Alkyl, such as Me; in another embodiment, R 5a C 1-6 Haloalkyl, such as C 1-3 Halogenated alkyl.

[0178] In one embodiment, R 5b is H; in another embodiment, R 5b C 1-6 Alkyl groups, such as C 1-3 Alkyl, such as Me; in another embodiment, R 5b C 1-6 Haloalkyl, such as C 1-3 Halogenated alkyl.

[0179] In a more specific embodiment, R 5a It is H or Me.

[0180] In a more specific embodiment, R 5b Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0181] R 1b and R 1c

[0182] In one embodiment, R 1b is H; in another embodiment, R 1b C 1-6 Alkyl, such as Me; in another embodiment, R 1b C 1-6 Halogenated alkyl.

[0183] In one embodiment, R 1c is H; in another embodiment, R 1c C 1-6 Alkyl, such as Me; in another embodiment, R 1cC 1-6 haloalkyl; in another embodiment, R 1c C 3-10 Cycloalkyl; in another embodiment, R 1c is a 3-10 membered heterocyclic group; in another embodiment, R 1c C 6-10 Aryl; In another embodiment, R 1c It is a 5-10 membered heteroaryl group.

[0184] In a more specific embodiment, R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1c Selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 1c Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0185] R' 1s

[0186] In one embodiment, R' 1s is H; in another embodiment, R' 1s is D; in another embodiment, R' 1s is halogen; in another embodiment, R' 1s is cyano; in another embodiment, R' 1s -L 1d -OR a , preferably OR a In another embodiment, R' 1s -L 1d -SR a , preferably SR a In another embodiment, R' 1s -L 1d -NR b R c , preferably NR b R c In another embodiment, R' 1s C 1-6 Alkyl; in another embodiment, R' 1s C 1-6 Haloalkyl; in another embodiment, R' 1s C 3-10Cycloalkyl; in another embodiment, R' 1s It is a 3-10 membered heterocyclic group.

[0187] In a more specific embodiment, R' 1s Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R' 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0188] n3

[0189] In one embodiment, n3 is 0; in another embodiment, n3 is 1; in another embodiment, n3 is 2; in another embodiment, n3 is 3.

[0190] In a more specific embodiment, n3 is 0 or 1; in another more specific embodiment, n3 is 0.

[0191] L2

[0192] In one embodiment, L2 is -(CR 4a R 4b ) m1 -, such as CR 4a R 4b , such as methylene; in another embodiment, L2 is O; in another embodiment, L2 is S; in another embodiment, L2 is NR 4c .

[0193] R 4a and R 4b

[0194] In one embodiment, R 4a is H; in another embodiment, R 4a is D; in another embodiment, R 4a C 1-6 Alkyl; in another embodiment, R 4a C 1-6 Halogenated alkyl.

[0195] In one embodiment, R 4b is H; in another embodiment, R 4b is D; in another embodiment, R 4b C1-6 Alkyl; in another embodiment, R 4b C 1-6 Halogenated alkyl.

[0196] m1

[0197] In one embodiment, m1 is 0; in another embodiment, m1 is 1; in another embodiment, m1 is 2.

[0198] R 4c

[0199] In one embodiment, R 4c is H; in another embodiment, R 4c C 1-6 Alkyl; in another embodiment, R 4c C 1-6 Halogenated alkyl.

[0200] R2

[0201] 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 In another embodiment, R2 is a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl.

[0202] In one embodiment, R2 is unsubstituted; in another embodiment, R2 is replaced by 1 R 2s In another embodiment, R2 is replaced by 2 R 2s In another embodiment, R2 is replaced by 3 R 2s In another embodiment, R2 is replaced by 4 R 2s In another embodiment, R2 is replaced by 5 R 2s Substituted; in another embodiment, R2 is For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example

[0203] In a more specific embodiment, R2 is selected from C 6-10 Aryl or 5-10 membered heteroaryl; In another more specific embodiment, R2 is phenyl or 5-6 membered heteroaryl; In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from In another more specific embodiment, R2 is selected from

[0204] In a more specific embodiment, R2 is optionally replaced by 1, 2, 3 or 4 R 2s In another more specific embodiment, R2 is optionally replaced by 2 or 3 R 2s replace.

[0205] R 2s

[0206] In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen, such as F, such as Cl; in another embodiment, R 2s is cyano; in another embodiment, R 2s -L 2a -OR a , preferably OR a In another embodiment, R 2s -L 2a -SR a , preferably SR a In another embodiment, R 2s -L 2a -NR b R c , preferably NR b R c In another embodiment, R 2s C 1-6 Alkyl, such as Me; in another embodiment, R 2s C 1-6 haloalkyl; in another embodiment, R 2s C3-10 Cycloalkyl; in another embodiment, R 2s is a 3-10 membered heterocyclic group; in another embodiment, R 2s C 1-6 Alkoxy, such as OMe; in another embodiment, R 2s C 1-6 Haloalkoxy, such as OCHF2, such as OCF3; in another embodiment, R 2s for

[0207] In a more specific embodiment, R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2s are independently selected from H, D, halogen, cyano or C 1-6 Alkyl; in another more specific embodiment, R 2s is independently selected from H, F, Cl, CN, Me, CHF2 or CF3; in another more specific embodiment, R 2s Independently selected from H, F, Cl, CN or Me.

[0208] In a more specific embodiment, R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or In another more specific embodiment, R 2s Independently selected from H, D, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy.

[0209] In a more specific embodiment, R 2s Independently R 2a 、R 2b 、R 2c or R 2d .

[0210] In a more specific embodiment, R2a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in another more specific embodiment, R 2a Selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy; in another more specific embodiment, R 2a Selected from halogen, C 1-4 Alkyl or C 1-4 Alkoxy; in another more specific embodiment, R 2a is selected from H, F, Me, CF3, OMe or OCHF2; in another more specific embodiment, R 2a is selected from F, Me or OMe; in another more specific embodiment, R 2a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 In another more specific embodiment, R 2a is selected from H, F, Cl or Me; in another more specific embodiment, R 2a is selected from H, Cl or Me; preferably selected from H, D or halogen; in another more specific embodiment, R 2a is selected from H or F; in another more specific embodiment, R 2a Selected from H, F or Me.

[0211] In a more specific embodiment, R 2b Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2b is selected from H, D or halogen; in another more specific embodiment, R 2b is selected from H or F; in another more specific embodiment, R 2b Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 In another more specific embodiment, R 2b is selected from H, F or Me; in another more specific embodiment, R 2b is selected from H or D; preferably in another more specific embodiment, R2b is H; in another more specific embodiment, R 2b Selected from H, D, C 1-4 Alkyl or C 1-4 In another more specific embodiment, R 2b Selected from H or Me.

[0212] In a more specific embodiment, R 2c Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2c is selected from H, D or halogen; in another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment, R 2c is selected from H or F; in another more specific embodiment, R 2c Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 In another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment, R 2c Selected from halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 2c is halogen; in another more specific embodiment, R 2c For F.

[0213] In a more specific embodiment, R 2d is selected from H, D, halogen or cyano; in another more specific embodiment, R 2d is halogen or cyano; in another more specific embodiment, R 2d is F, Cl or CN; in another more specific embodiment, R 2d is Cl or CN; in another more specific embodiment, R 2d is F or CN.

[0214] L3

[0215] In one embodiment, L3 is a chemical bond; in another embodiment, L3 is CR 6a R 6b ; In another embodiment, L3 is O; In another embodiment, L3 is S; In another embodiment, L3 is NR 6c , such as NH.

[0216] R 6a and R6b

[0217] In one embodiment, R 6a is H; in another embodiment, R 6a is D; in another embodiment, R 6a C 1-6 Alkyl; in another embodiment, R 6a C 1-6 Halogenated alkyl.

[0218] In one embodiment, R 6b is H; in another embodiment, R 6b is D; in another embodiment, R 6b C 1-6 Alkyl; in another embodiment, R 6b C 1-6 Halogenated alkyl.

[0219] R 6c

[0220] In one embodiment, R 6c is H; in another embodiment, R 6c C 1-6 Alkyl; in another embodiment, R 6c C 1-6 Halogenated alkyl.

[0221] R3

[0222] In one embodiment, R3 is C 3-10 In another embodiment, R3 is a 3-10 membered heterocyclyl; In another embodiment, R3 is C 6-10 Aryl, such as phenyl, for example For example In another embodiment, R3 is a 5-10 membered heteroaryl group, for example For example

[0223] In one embodiment, R3 is unsubstituted; in another embodiment, R3 is replaced by 1 R 3s In another embodiment, R3 is replaced by 2 R 3s In another embodiment, R3 is replaced by 3 R 3s In another embodiment, R3 is replaced by 4 R 3s In another embodiment, R3 is replaced by 5 R 3s replace.

[0224] In a more specific embodiment, R3 is selected from C6-10 Aryl or 5-10 membered heteroaryl; In another more specific embodiment, R3 is selected from

[0225] R 3s

[0226] In one embodiment, R 3s is H; in another embodiment, R 3s is D; in another embodiment, R 3s is halogen, such as Cl; in another embodiment, R 3s is cyano; in another embodiment, R 3s -L 3a -OR a , preferably OR a , such as OMe; in another embodiment, R 3s -L 3a -SR a , preferably SR a In another embodiment, R 3s -L 3a -NR b R c , preferably NR b R c In another embodiment, R 3s C 1-6 Alkyl; in another embodiment, R 3s C 1-6 haloalkyl; in another embodiment, R 3s C 3-10 Cycloalkyl; in another embodiment, R 3s is a 3-10 membered heterocyclic group; in another embodiment, two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, such as C 5-7 Cycloalkyl; In another embodiment, two adjacent R 3s and the atoms to which they are attached together form a 5-10 membered heterocyclic group, such as a 5-7 membered heterocyclic group, such as dihydrofuranyl For example; in another embodiment, two adjacent R 3s and the atoms they connect to form C 6-10 Aryl, such as phenyl; in another embodiment, two adjacent R 3s and the atoms to which they are attached together form a 5-10 membered heteroaryl, such as a 5-6 membered heteroaryl, such as a pyrazolyl, such as

[0227] In one embodiment, two adjacent R 3s and the atoms to which they are attached together to form a cyclic group are unsubstituted; in another embodiment, two adjacent R 3s and the atoms they connect together form a ring group that is formed by 1 R 3ss In another embodiment, two adjacent R 3s and the atoms they connect together form a ring group that is formed by two R 3ss In another embodiment, two adjacent R 3s The ring group formed by the atoms they connect is composed of 3 R 3ss replace.

[0228] In a more specific embodiment, R 3s Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3s Selected from H, D, halogen, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 3s Selected from H, D, halogen, OR a 、C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 3s is selected from H, D, Cl, OMe or Me; in another more specific embodiment, R 3s It is Cl or Me.

[0229] In a more specific embodiment, two adjacent R 3s and the atoms they connect to form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; In another more specific embodiment, two adjacent R 3s and the atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl; in another more specific embodiment, two adjacent R 3s and the atoms to which they are attached together form a pyrazolyl or dihydrofuranyl group; in another more specific embodiment, two adjacent R 3sand the atoms they connect to form

[0230] R 3ss

[0231] In one embodiment, R 3ss is H; in another embodiment, R 3ss is D; in another embodiment, R 3ss is halogen; in another embodiment, R 3ss is cyano; in another embodiment, R 3ss -L 3b -OR a , preferably OR a In another embodiment, R 3ss -L 3b -SR a , preferably SR a In another embodiment, R 3ss -L 3b -NR b R c NR is preferred b R c In another embodiment, R 3ss C 1-6 Alkyl, such as Me; in another embodiment, R 3ss C 1-6 haloalkyl; in another embodiment, R 3ss C 3-10 Cycloalkyl; in another embodiment, R 3ss is a 3-10 membered heterocyclic group; in another embodiment, R 3ss C 3-10 Aryl; In another embodiment, R 3ss is a 3-10 membered heteroaryl group;

[0232] In a more specific embodiment, R 3ss Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss Independently selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R 3ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0233] L 1c , L 1d , L 2a , L 3a and L 3b

[0234] In one embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently chemical bonds; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently C 1-6 Alkylene, such as C 1-3 Alkylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently C 2-6 Alkenylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently C 2-6 Alkyne; In another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently unsubstituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b is independently substituted by one selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, L1c , L 1d , L 2a , L 3a and L 3b Independently substituted by 2 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently substituted by 3 selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 In another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b is independently substituted by one selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently substituted by 2 selected from H, D, halogen, C 1-6 Alkyl or C 1-6 In another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Independently substituted by 3 selected from H, D, halogen, C 1-6 Alkyl or C 1-6 The haloalkyl group is substituted.

[0235] In a more specific embodiment, L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 The haloalkyl group is substituted.

[0236] R a 、Rb and R c

[0237] In one embodiment, R a 、R b and R c are independently H; in another embodiment, R a 、R b and R c Independently C 1-6 Alkyl, such as Me; in another embodiment, R a 、R b and R c Independently C 1-6 haloalkyl; in another embodiment, R a 、R b and R c Independently C 3-10 Cycloalkyl, such as C 3-7 Cycloalkyl; in another embodiment, R a 、R b and R c is independently a 3-10 membered heterocyclyl, such as a 3-7 membered heterocyclyl; in another embodiment, R a 、R b and R c Independently C 6-10 Aryl; In another embodiment, R a 、R b and R c are independently 5-10 membered heteroaryl; in another embodiment, R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group, for example a 3-7 membered heterocyclic group.

[0238] In a more specific embodiment, R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R a 、R b and R cEach independently selected from H, C 1-6 Alkyl or C 1-6 In another more specific embodiment, R b 、R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group.

[0239] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of Ring A can be combined with Y, R7, R 1s , L 1a , L 1b 、R 1a 、R 1as 、n1、n2、R 5a 、R 5b 、R 1b 、R 1c , R' 1s 、n3、L2、R 4a 、R 4b 、m1、R 4c , R2, R 2s , L3, R 6a 、R 6b 、R 6c , R3, R 3s 、R 3ss , L 1c , L 1d , L 2a , L 3a , L 3b 、R a 、R b and R c The present invention is intended to include all of these technical solutions, which are not listed one by one due to space limitations.

[0240] 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:

[0241] in,

[0242] Y is N or CR7;

[0243] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0244] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl or 5-10 membered heteroaryl;

[0245] R 1s for -C(O)NR 1b R 1c or

[0246] L 1a Selected from chemical bonds, O, S or NR 5a ;

[0247] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0248] R 1a 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 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0249] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b R c 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0250] n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0251] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0252] R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0253] R 1c Selected from H, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0254] R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0255] n3 is 0, 1, 2, or 3;

[0256] L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ;

[0257] R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0258] m1 is 0, 1, or 2;

[0259] R 4c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0260] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace;

[0261] R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0262] L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ;

[0263] R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0264] R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0265] R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace;

[0266] R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SR a 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0267] Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0268] R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl;

[0269] L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0270] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl;

[0271] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0272] Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

[0273] 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:

[0274] in,

[0275] Y is N or CR7;

[0276] R7 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0277] Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0278] R 1s for or -C(O)NR 1b R 1c ;

[0279] L 1a Selected from O, S or NR 5a ;

[0280] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0281] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0282] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b R c 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0283] n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0284] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0285] R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0286] R 1c Selected from H, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0287] R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0288] n3 is 0, 1, 2, or 3;

[0289] L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ;

[0290] R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0291] m1 is 0, 1, or 2;

[0292] R 4c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0293] R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace;

[0294] R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0295] L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ;

[0296] R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0297] R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0298] R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace;

[0299] R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SR a 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0300] Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0301] R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl;

[0302] L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups;

[0303] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl;

[0304] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0305] Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

[0306] 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, wherein Y is N.

[0307] 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, wherein Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably 5-6 membered heteroaryl, preferably pyridyl or thiazolyl; preferably pyridyl; preferably More preferably

[0308] 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, wherein R 1s Selected from Preferably selected from Preferably selected from Preferably selected from More preferably not

[0309] 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, wherein L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH; preferably O or NH; preferably O or S; preferably O; preferably S.

[0310] 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, wherein L 1b For chemical bonds.

[0311] Preferably, L 1b Selected from O, S or NR 5b ; preferably selected from O or NR 5b ; preferably selected from O, S or NMe; preferably selected from O or S; preferably selected from O or NMe; preferably O.

[0312] 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, wherein R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; preferably selected from C1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; preferably selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from Me, Preferably selected from Me, Preferably it is Me.

[0313] Preferably, R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably 3-7 membered heterocyclic group; preferably 4-5 membered heterocyclic group; preferably 5 membered heterocyclic group; preferably selected from Preferably

[0314] 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, wherein R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a SR a NR b R c 、C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

[0315] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n1 is selected from 0, 1, 2 or 3; preferably selected from 0, 1 or 2; preferably selected from 1, 2 or 3; preferably 0; preferably 1; preferably 2.

[0316] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n2 is selected from 0, 1, 2 or 3; preferably selected from 0 or 1; preferably 0.

[0317] 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, wherein R 5a is H or Me; preferably H.

[0318] 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, wherein R 5b Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

[0319] 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, wherein R 1b is H;

[0320] Preferably, R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

[0321] 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, wherein R' 1s Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0322] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n3 is 0 or 1; preferably 0.

[0323] In a more specific embodiment, the present invention provides a compound of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n3 is 1, 2 or 3; preferably 0 or 1; preferably 0.

[0324] 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, wherein L2 is -(CR 4a R 4b ) m1 -; preferably methylene.

[0325] Preferably, m1 is 1.

[0326] Preferably, R 4a and R 4b For H.

[0327] 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, wherein R2 is selected from C 6-10 Aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably phenyl.

[0328] Preferably, R2 is optionally replaced by 1, 2, 3 or 4 R 2s replace.

[0329] Preferably, R2 is optionally replaced by 2 or 3 R 2s replace.

[0330] Preferably, R2 is selected from Preferably selected from Preferably selected from

[0331] 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, wherein R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, cyano or C 1-6 Alkyl; preferably selected from H, F, Cl, CN, Me, CHF2 or CF3; preferably selected from H, F, Cl, CN or Me.

[0332] 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, wherein L3 is NR 6c ; preferably NH.

[0333] Preferably, R 6a and R 6b For H.

[0334] 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, wherein R3 is selected from C 6-10 Aryl or 5-10 membered heteroaryl; preferably

[0335] 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, wherein R 3s Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, ORa 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, Cl, OMe or Me; preferably Cl or Me.

[0336] 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, wherein two adjacent R 3s and the atoms they connect to form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably forming a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl; preferably forming a pyrazolyl or dihydrofuranyl; preferably forming Preferred Formation

[0337] 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, wherein R 3ss Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

[0338] 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, wherein L 1c 、L 1d 、L 2a 、L 3a and L 3b Each independently selected from a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6The group of haloalkyl is substituted; preferably selected from chemical bonds or C 1-3 Alkylene.

[0339] 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, wherein R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 alkyl halide;

[0340] or R b 、R c Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group; preferably a 3-7 membered heterocyclic group.

[0341] 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 the following structural formula:

[0342] in,

[0343] m2 is 1, 2, 3 or 4;

[0344] X1 for CR 3b or N, X2 is CR 3c or N;

[0345] Or X1 is C(O), X2 is NH;

[0346] R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0347] R 3b Selected from H, D, halogen, cyano, OR a SR aNR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0348] R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0349] or R 3b With R 3c and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0350] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0351] R 2d is selected from H, D, halogen or cyano;

[0352] R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0353] The remaining groups are as defined in the present invention.

[0354] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0355] in,

[0356] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0357] R 1s for or -C(O)NR 1b R 1c ;

[0358] L 1a Selected from O, S or NR 5a ;

[0359] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0360] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0361] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a SR a NR b R c 、C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0362] n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0363] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0364] R 1b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0365] R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0366] R' 1s Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0367] n3 is 0, 1, 2, or 3;

[0368] R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0369] m2 is 1, 2, 3 or 4;

[0370] X1 for CR 3b or N, X2 is CR 3c or N;

[0371] Or X1 is C(O), X2 is NH;

[0372] R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0373] R 3b Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0374] R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0375] or R 3b With R 3c and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0376] R 3ss Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0377] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group;

[0378] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0379] Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A halogenated alkyl group, and the compound is not of the following structure:

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

[0381] Ring A is phenyl or a 5-6 membered heteroaryl group;

[0382] R 1s for or -C(O)NHR 1c ; preferably

[0383] L 1a Selected from O, S or NR 5a ;

[0384] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0385] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0386] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0387] n1 and n2 are independently selected from 0, 1, 2 or 3;

[0388] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H;

[0389] R 1c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0390] R' 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0391] n3 is 0 or 1;

[0392] R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 alkyl halide;

[0393] m2 is 1, 2, 3 or 4;

[0394] X1 for CR 3b , X2 is CR 3c ;

[0395] Or X1 is C(O), X2 is NH;

[0396] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0397] R 3b Selected from OR a SR a or NR b R c ; preferably OR a or SR a ;

[0398] R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0399] or R 3b With R 3c and the atoms they connect to form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0400] R 3ss Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0401] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group.

[0402] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0403] Ring A is a 5-6 membered heteroaryl group, preferably a pyridyl group or a thiazolyl group;

[0404] R 1s for or -C(O)NHR 1c ; preferably

[0405] L 1a Selected from O, S, NR 5a ;

[0406] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0407] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0408] R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0409] n1 is selected from 0, 1 or 2;

[0410] n2 is selected from 0 or 1;

[0411] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; preferably R 5b C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me;

[0412] R 1c Selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0413] n3 is 0;

[0414] R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl;

[0415] m2 is 2 or 3;

[0416] X1 for CR 3b , X2 is CR 3c ;

[0417] Or X1 is C(O), X2 is NH;

[0418] R 3a is a halogen;

[0419] R 3b OR a ;

[0420] R 3c 、R 3d and R 3e independently H or D;

[0421] or R 3b With R 3c and the atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a pyrazolyl or dihydrofuranyl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0422] R 3ss Independently selected from H, D, C 1-6 Alkyl or C 1-6alkyl halide;

[0423] R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0424] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0425] Ring A is

[0426] R 1s for Or C(O)NHCH3; preferably

[0427] L 1a Selected from O, S, NH or NMe; preferably selected from O, S or NH;

[0428] L 1b Selected from O, S or NMe;

[0429] R 1a Selected from Me,

[0430] n1 is selected from 0, 1 or 2;

[0431] n2 is selected from 0 or 1;

[0432] n3 is 0;

[0433] R 2s Independently selected from H, F, Cl, CN, Me, CHF2 or CF3, preferably selected from H, F, Cl, CN or Me;

[0434] m2 is 2 or 3;

[0435] X1 for CR 3b , X2 is CR 3c ;

[0436] Or X1 is C(O), X2 is NH;

[0437] R 3a is Cl;

[0438] R 3b OMe

[0439] R 3c 、R 3d and R3e is H;

[0440] or R 3b With R 3c and the atoms they connect to form

[0441] Preferably, R 1s Selected from

[0442] Preferably, ring A and the substituents thereon together form:

[0443] Preferably, Selected from

[0444] Preferably, Selected from

[0445] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0446] in,

[0447] L 1a Selected from O, S or NR 5a ;

[0448] L 1b Selected from O, S or NR 5b ;

[0449] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0450] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0451] n1 is selected from 1, 2, 3, 4, 5 or 6;

[0452] n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0453] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0454] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0455] R 2d is selected from H, D, halogen or cyano;

[0456] R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0457] R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0458] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0459] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0460] L 1a Selected from O or S; preferably O; preferably S;

[0461] L 1b Selected from O, S or NR 5b ; preferably O or NR 5b ;

[0462] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0463] R 1as Independently selected from H, D, halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0464] n1 is selected from 1, 2 or 3; preferably 2;

[0465] n2 is selected from 0, 1, 2 or 3; preferably 0 or 1;

[0466] R 5b Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-3 Alkyl or C 1-3 alkyl halide;

[0467] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0468] R 2d is selected from halogen or cyano;

[0469] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0470] R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0471] Preferably,

[0472] R 2a Selected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0473] R 2b is H;

[0474] R 2c is selected from H, D or halogen;

[0475] R 2d is selected from halogen or cyano;

[0476] R 3a is a halogen;

[0477] R 3f C 1-6 Alkyl or C1-6 Halogenated alkyl.

[0478] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0479] L 1a Selected from O or S;

[0480] L 1b Selected from O or S;

[0481] R 1a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0482] n1 is 2;

[0483] n2 is 0 or 1;

[0484] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0485] R 2d is selected from halogen or cyano;

[0486] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0487] R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0488] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0489] L 1a Selected from O or S; preferably O;

[0490] L 1b is O;

[0491] R 1a Selected from C 1-6 Alkyl or C 1-6 alkyl halide;

[0492] n1 is 2;

[0493] n2 is 0;

[0494] R 2a 、R 2c and R 2d are independently halogen;

[0495] R 2b H or D;

[0496] R 3a is a halogen;

[0497] R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0498] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0499] L 1a Selected from O or S; preferably O;

[0500] L 1b Selected from O or NMe; preferably O;

[0501] R 1a Selected from Me, Preferably Me;

[0502] n1 is 2;

[0503] n2 is 0 or 1; preferably 0;

[0504] R 2a Selected from F or Me; preferably F;

[0505] R 2b is H;

[0506] R 2c Selected from H or F; more preferably F;

[0507] R 2d Selected from F, Cl or CN; preferably F or Cl;

[0508] R 3a is Cl;

[0509] R 3f For Me.

[0510] Preferably, Selected from: Preferably

[0511] Preferably, Selected from: Preferably

[0512] In a more specific embodiment, the present invention provides a compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0513] in,

[0514] L 1a Selected from O, S or NR 5a ;

[0515] R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0516] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0517] n1 is selected from 1, 2, 3, 4, 5 or 6;

[0518] R 5a Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0519] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0520] R 2d is selected from H, D, halogen or cyano;

[0521] R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0522] R 3f Selected from H, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0523] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0524] In a more specific embodiment, the present invention provides a compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0525] L 1a Selected from O or S; preferably O; preferably S;

[0526] R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0527] R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0528] n1 is selected from 1, 2 or 3;

[0529] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0530] R 2d is selected from halogen or cyano;

[0531] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0532] R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0533] In a more specific embodiment, the present invention provides a compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0534] L 1a Selected from O or S; preferably O;

[0535] R 1ais a 3-7 membered heterocyclic group, preferably a 4-5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0536] R 1as Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me;

[0537] n1 is 1;

[0538] R 2a 、R 2c and R 2d are independently halogen;

[0539] R 2b H or D;

[0540] R 3a is a halogen;

[0541] R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0542] In a more specific embodiment, the present invention provides a compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0543] L 1a Selected from O or S; preferably O;

[0544] R 1a Selected from

[0545] n1 is 1;

[0546] for

[0547] R 3a is Cl;

[0548] R 3f For Me.

[0549] Preferably, Selected from:

[0550] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0551] in,

[0552] L 1a Selected from O, S or NR 5a ;

[0553] R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0554] R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group;

[0555] R 5a Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0556] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0557] R 2d is selected from H, D, halogen or cyano;

[0558] R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0559] R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0560] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0561] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0562] L 1a Selected from O, S or NH; preferably O or NH; preferably S;

[0563] R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0564] R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0565] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0566] R 2d is selected from halogen or cyano;

[0567] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0568] R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0569] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0570] L 1a Selected from O, S or NH; preferably O or NH;

[0571] R 1a is a 4-6 membered heterocyclic group, preferably a 5 membered heterocyclic group, preferably a tetrahydrofuranyl group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0572] R 1as Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0573] R 2a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0574] R 2b is selected from H, D or halogen;

[0575] R 2c is a halogen;

[0576] R 2d is selected from halogen or cyano;

[0577] R 3a is a halogen;

[0578] R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0579] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein when R 1a With L 1a When the connecting atom of is a chiral carbon atom, for

[0580] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0581] L 1a Selected from O, S or NH; preferably O or NH;

[0582] R 1a Selected from Preferably More preferably

[0583] R 2a is H, F, Cl or Me;

[0584] R 2b H or F;

[0585] R 2c is F or Cl; preferably F;

[0586] R 2d is F, Cl or CN;

[0587] R 3a is Cl;

[0588] R 3f For Me.

[0589] Preferably, Selected from: Preferably not More preferably

[0590] Preferably, Selected from: Preferably selected from

[0591] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0592] in,

[0593] Ring A is phenyl or a 5-6 membered heteroaryl group;

[0594] R 1s for -C(O)NHR 1c or

[0595] L 1a Selected from chemical bonds, O, S or NR 5a ;

[0596] L 1b Selected from chemical bonds, O, S or NR 5b ;

[0597] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0598] R 1as Independently selected from H, D, halogen, cyano, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group;

[0599] n1 and n2 are independently selected from 0, 1, 2 or 3;

[0600] R 5a and R 5bIndependently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H;

[0601] R 1c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0602] R' 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0603] n3 is 0 or 1;

[0604] R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or

[0605] m2 is 1, 2, 3 or 4;

[0606] X1 for CR 3b , X2 is CR 3c ;

[0607] Or X1 is C(O), X2 is NH;

[0608] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0609] R 3b Selected from OR a SR a or NR b R c ; preferably OR a or SR a ;

[0610] R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0611] or R 3b With R 3c and the atoms they connect to form C 5-7Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace;

[0612] R 3ss Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0613] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0614] wherein each of the above groups is optionally deuterated, up to fully deuterated;

[0615] Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A halogenated alkyl group, and the compound is not of the following structure:

[0616] In a more specific embodiment, the present invention provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0617] Ring A is a 5-6 membered heteroaryl group, preferably a pyridyl group or a thiazolyl group, preferably a pyridyl group, preferably

[0618] R 1s for Preferably

[0619] L 1a Selected from O, S, NR 5a ;

[0620] L 1b Selected from chemical bonds, O or NR 5b ;

[0621] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R1as replace;

[0622] R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0623] n1 is selected from 0, 1 or 2;

[0624] n2 is selected from 0, 1 or 2;

[0625] R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; preferably R 5b C 1-3 Alkyl or C 1-3 alkyl halide;

[0626] n3 is 0;

[0627] R 2s Independently selected from H, D, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy;

[0628] m2 is 2 or 3;

[0629] X1 for CR 3b , X2 is CR 3c ;

[0630] Or X1 is C(O), X2 is NH;

[0631] R 3a is a halogen;

[0632] R 3b OR a ; preferably OMe;

[0633] R 3c 、R 3d and R 3e independently H or D;

[0634] or R 3b With R 3c and the atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss Substitution; preferably forming

[0635] R 3ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide;

[0636] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0637] In a more specific embodiment, Selected from Preferred Preferred

[0638] In a more specific embodiment, when L 1b When it is a chemical bond, R 1a C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

[0639] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0640] in,

[0641] L 1a Selected from O or S;

[0642] L 1b Selected from O, S or NR 5b ;

[0643] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0644] R 1as Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6alkyl halide;

[0645] n1 is selected from 1, 2 or 3;

[0646] n2 is selected from 0, 1, 2 or 3;

[0647] R 5b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0648] R 2a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0649] R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0650] R 2d is selected from H, D, halogen or cyano; preferably halogen or cyano;

[0651] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0652] R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0653] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0654] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0655] L 1a Selected from O or S;

[0656] L 1b O or NR 5b ; preferably O;

[0657] R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C3-5 Cycloalkyl or 3-5 membered heterocyclic group; preferably C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-5 Cycloalkyl; preferably C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl;

[0658] n1 is 2;

[0659] n2 is 0, 1, or 2;

[0660] R 5b C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me;

[0661] R 2a Selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy; preferably halogen, C 1-4 Alkyl or C 1-4 alkoxy;

[0662] R 2b is H, D or halogen;

[0663] R 2c is selected from H, D or halogen;

[0664] R 2d is halogen or CN;

[0665] R 3a is a halogen;

[0666] R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0667] In a more specific embodiment, the present invention provides a compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0668] L 1a Selected from O or S; preferably O;

[0669] L 1b Selected from O or NMe; preferably O;

[0670] R 1aSelected from Me, OMe, cyclopropyl or Preferably Me, OMe or cyclopropyl; Preferably Me or cyclopropyl;

[0671] n1 is 2;

[0672] n2 is 0, 1 or 2; preferably 0 or 1;

[0673] R 2a Selected from H, F, Me, CF3, OMe or OCHF2; preferably F, Me or OMe;

[0674] R 2b H or F;

[0675] R 2c Selected from H, F or Cl; more preferably H or F;

[0676] R 2d Selected from F, Cl or CN; preferably Cl or CN;

[0677] R 3a is Cl;

[0678] R 3f For Me.

[0679] In a more specific embodiment, Selected from: Preferably Preferably

[0680] In a more specific embodiment, Selected from: Preferably

[0681] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0682] in,

[0683] L 1a Selected from O, S or NR 5a ;

[0684] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1asreplace;

[0685] R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0686] R 5a Selected from H, C 1-3 Alkyl or C 1-3 Haloalkyl; preferably R 5a is H;

[0687] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0688] R 2d is selected from halogen or cyano;

[0689] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0690] R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0691] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0692] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0693] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0694] L 1a Selected from O, S or NH;

[0695] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0696] R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, F, Me, NH2, -NHCH3 or -NH(CH3)2; preferably selected from H, F, Me, NH2 or -NHCH3;

[0697] R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0698] R 2b Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0699] R 2c is H, D or halogen;

[0700] R 2d is halogen or cyano;

[0701] R 3a is a halogen;

[0702] R 3f C 1-6 Alkyl or C 1-6 alkyl halide;

[0703] R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0704] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein when R 1a With L 1a When the connecting atom of is a chiral carbon atom, for

[0705] In a more specific embodiment, the present invention provides a compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0706] L 1a Selected from O, S or NH;

[0707] R 1a Selected from Preferably selected from: Preferably, for

[0708] R 2a is H, F, Cl or Me;

[0709] R 2b is H, F or Me;

[0710] R 2c is H, F or Cl;

[0711] R 2d is F, Cl or CN;

[0712] R 3a is Cl;

[0713] R 3f For Me.

[0714] In a more specific embodiment, Selected from: Preferably selected from:

[0715] In a more specific embodiment, for

[0716] In a more specific embodiment, for

[0717] In a more specific embodiment, for

[0718] In a more specific embodiment, Selected from:

[0719] In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0720] in,

[0721] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0722] R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0723] R 2a and R 2b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0724] R 2c Selected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0725] R 2d is selected from halogen or cyano;

[0726] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0727] R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0728] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0729] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0730] In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0731] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R1as replace;

[0732] R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably selected from H, D or NR b R c ; preferably selected from H, NH2 or -N(CH3)2; preferably selected from H or NH2;

[0733] R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0734] R 2b is selected from H, D or halogen;

[0735] R 2c is a halogen;

[0736] R 2d is selected from halogen or cyano;

[0737] R 3a is a halogen;

[0738] R 3f C 1-6 Alkyl or C 1-6 alkyl halide;

[0739] R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H.

[0740] In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein when R 1a When the atom connected to O is a chiral carbon atom, for

[0741] In a more specific embodiment, the present invention provides a compound of formula (IV-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0742] L 1a Selected from O, S or NH; preferably O or NH;

[0743] Selected from: Preferably: Preferably Preferably, for

[0744] R 2a is H, F, Cl or Me; preferably H, Cl or Me;

[0745] R 2b is H or F; preferably H;

[0746] R 2c is F;

[0747] R 2d is F, Cl or CN; preferably Cl or CN;

[0748] R 3a is Cl;

[0749] R 3f For Me.

[0750] In a more specific embodiment, Selected from: Preferably selected from Preferably selected from

[0751] In a more specific embodiment, the present invention provides a compound of formula (IV-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0752] in,

[0753] R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0754] R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0755] R 2a and R 2b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0756] R 2cSelected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0757] R 2d is selected from halogen or cyano;

[0758] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0759] R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0760] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0761] In a more specific embodiment, the present invention provides a compound of formula (IV-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0762] R 1a is a 4-6 membered heterocyclic group, preferably a 5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0763] R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0764] R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; preferably selected from H, D or halogen;

[0765] R 2b Selected from H or D;

[0766] R 2c is a halogen;

[0767] R 2d is selected from halogen or cyano;

[0768] R 3a is a halogen;

[0769] R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0770] In a more specific embodiment, the present invention provides a compound of formula (IV-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein when R 1a When the connecting atom to NH is a chiral carbon atom, for

[0771] In a more specific embodiment, the present invention provides a compound of formula (IV-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0772] Selected from: Preferably

[0773] R 2a is H, F, Cl or Me; preferably H or F;

[0774] R 2b is H;

[0775] R 2c is F;

[0776] R 2d is F, Cl or CN; preferably F or CN;

[0777] R 3a is Cl;

[0778] R 3f For Me.

[0779] In a more specific embodiment, Selected from: Preferably selected from Preferably

[0780] In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,

[0781] in,

[0782] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0783] R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide;

[0784] R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0785] R 2d is selected from halogen or cyano;

[0786] R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide;

[0787] R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0788] R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0789] The above-mentioned radicals are optionally deuterated, up to fully deuterated.

[0790] In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0791] R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or 5-6 membered heteroaryl, preferably C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace;

[0792] R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6Haloalkyl; preferably selected from H, F, Me, NH2 or NHCH3; preferably H, F or Me;

[0793] R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide;

[0794] R 2b Selected from H, D, C 1-4 Alkyl or C 1-4 alkyl halide;

[0795] R 2c is selected from H, D or halogen;

[0796] R 2d is selected from halogen or cyano;

[0797] R 3a is a halogen;

[0798] R 3f C 1-6 Alkyl or C 1-6 alkyl halide;

[0799] R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0800] In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein when R 1a When the atom connected to S is a chiral carbon atom, for

[0801] In a more specific embodiment, the present invention provides a compound of formula (IV-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0802] Selected from: Preferably Preferably Preferably Preferably, for

[0803] R 2a is H, F or Me;

[0804] R 2b is H or Me;

[0805] R 2c is H, F or Cl;

[0806] R 2d is Cl or CN;

[0807] R 3a is Cl;

[0808] R 3f For Me.

[0809] In a more specific embodiment, Selected from: Preferably Preferably

[0810] 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, wherein the compound is selected from the following:

[0811] 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.

[0812] 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.

[0813] For example, in formula (I) of the present invention, the compound represented when Y is N and X is NH, and the compounds represented by formulas (II), (III-1), (III-2), (III-3), (IV-1), (IV-2) and (IV-3), etc., include the following tautomers:

[0814] For example, in formula (I) of the present invention, when Y is CH and X is NH, the compound includes the following tautomers:

[0815] For example, the compound of Example 1 of the present invention includes the following tautomers:

[0816] 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.

[0817] 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.

[0818] 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, hemihydrate (R·0.5H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0819] 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.

[0820] 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.

[0821] 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.

[0822] 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.

[0823] 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.

[0824] Pharmaceutical compositions and kits

[0825] 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.

[0826] 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.

[0827] 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.

[0828] 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.

[0829] Drug administration

[0830] 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.

[0831] 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.

[0832] 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.

[0833] 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.

[0834] 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.

[0835] 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.

[0836] 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.

[0837] 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.

[0838] 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.

[0839] 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.

[0840] 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.

[0841] 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.

[0842] 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.

[0843] 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.

[0844] 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.

[0845] 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%).

[0846] Indications

[0847] For diseases caused by viral infection, the development of 3C-like protease inhibitors can provide therapeutic benefits to a large number of patients. The compounds of the present invention exert their therapeutic effects by negatively regulating the activity of 3C-like proteases in viruses, especially those with viruses that have a P132H mutation in the 3C-like protease.

[0848] 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.

[0849] 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.

[0850] More specifically, these compounds can be used for the above-mentioned diseases or symptoms caused by SARS-CoV-2 infection.

[0851] Combination therapy

[0852] 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.

[0853] Example

[0854] 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.

[0855] 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.

[0856] Example 1

[0857] Synthesis of intermediates 1-3

[0858] 1-(Bromomethyl)-2,4,5-trifluorotoluene (8.46 g, 37.6 mmol) was added to a mixture of 1-1 (5.73 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 extraction was performed with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 2:1) to afford 1-3 as a white solid (8.3 g, yield: 89%).

[0859] LCMS (ESI) m / z: 318.0 [M+H-56] + .

[0860] Synthesis of intermediates 1-4

[0861] 1-3 (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 1-4, which was used directly in the next reaction.

[0862] LCMS (ESI) m / z: 318.0 [M+H] + .

[0863] Synthesis of intermediates 1-6

[0864] To a solution of 1-4 (250 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) were added triethylamine (398 mg, 3.94 mmol), 1-5 (362 mg, 2.37 mmol), copper acetate (242 mg, 1.35 mmol) and molecular sieves (300 mg) at room temperature. The mixed solution was stirred at 60°C under 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 1-6 (120 mg, yield: 42.1%) as a yellow oil.

[0865] LCMS (ESI) m / z: 425.1 [M+H] + .

[0866] Synthesis of compound 1

[0867] To a solution of 1-6 (110 mg, 0.26 mmol) in tetrahydrofuran (2 mL) was added 1-7 (56.7 mg, 0.31 mmol) under ice-cooling. Under nitrogen protection, lithium bis(trimethylsilyl)amide (0.65 mL) was added at 0°C and stirred for 2 hours. After the reaction was completed, the mixed solution was quenched by adding 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 was concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography ((Chromatographic column: -Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN--H2O (0.1% FA). Gradient: 35-45)) to give compound 1 (49.3 mg, yield: 35.2%) as a white solid.

[0868] LCMS (ESI) m / z: 544.1 [M+H] + .

[0869] 1 H NMR(400MHz,CD3OD)δ8.30(d,J=2.6Hz,1H),8.18(s,2H),7.75(s,1H),7.66(d, J=9.6Hz,1H),7.55(s,1H),7.23(s,2H),5.39(s,2H),4.21(s,3H),3.91(s,3H).

[0870] The compounds shown in Table A below were synthesized in the same manner as above.

[0871] Table A

[0872] Example 15 Synthesis of Compound 15

[0873] Synthesis of intermediate 15-6c

[0874] Triphenylphosphine (11.3 g, 43.1 mmol) was dissolved in tetrahydrofuran (100 mL) under ice-cooling, and diisopropyl azodicarboxylate (8.71 g, 43.1 mmol) was added. The mixture was stirred under ice-cooling for 15 minutes until a large amount of white solid precipitated. 15-6a (5.0 g, 28.7 mmol) was then added under ice-cooling, and stirred at this temperature for 15 minutes. 15-6b (2.53 g, 28.7 mmol) was then added, and the mixed solution was stirred at 20°C under nitrogen for 16 hours. After completion of the reaction, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether, ethyl acetate = 1:2) to give 15-6c as a yellow oil (6.46 g, yield: 92.3%).

[0875] LCMS (ESI) m / z: 244.0 [M+H] + .

[0876] Synthesis of intermediate 15-6

[0877] Intermediate 15-6c (6.4 g, 26.2 mmol) was dissolved in 1,4-dioxane (100 mL) at room temperature. Diboron (9.98 g, 39.3 mmol), potassium acetate (7.71 g, 78.6 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (1.92 g, 2.62 mmol) were added. The mixture was stirred at 80°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and petroleum ether (500 mL) was added. The resulting solution was stirred at room temperature for 1 hour and then filtered through celite. The filter cake was washed with petroleum ether, and the filtrate was concentrated to dryness. The crude product was purified by reverse phase column chromatography (C18, water (0.1% trifluoroacetic acid): acetonitrile = 5:95 to 15 / 85) to give a yellow solid 15-6 (3.8 g, yield: 69.9%).

[0878] LCMS (ESI) m / z: 210.1 [M+H] + .

[0879] Synthesis of intermediate 15-2

[0880] Intermediate 15-1 (5.0 g, 26.0 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. A 1 M solution of borane in tetrahydrofuran (52 mL, 52.0 mmol) was added, and the mixture was stirred at 60°C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and methanol (50 mL) was slowly added dropwise in an ice bath. The resulting mixture was stirred at 60°C for 1 hour and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 5:1) to obtain 2-2 as a yellow oil (4.4 g, yield: 94.6%).

[0881] LCMS (ESI) m / z: 161.4 [M-18+H] + .

[0882] Synthesis of intermediate 15-3

[0883] To a solution of 15-2 (4.4 g, 24.6 mmol) in dichloromethane (50 mL) was added triphenylphosphine (9.68 g, 36.9 mmol) and carbon tetrabromide (8.97 g, 27.1 mmol) under ice-cooling. The mixture was stirred at 20°C for 4 hours. Extraction was performed with water (50 mL) and then twice with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 15-3 as a pale yellow oil (5.6 g, yield: 94.3%).

[0884] 1 H NMR (400MHz, CDCl3) δ7.50–7.43 (m, 1H), 6.96–6.90 (m, 1H), 4.42 (d, J = 0.9Hz, 2H).

[0885] Synthesis of intermediate 15-4

[0886] To a solution of 15-3 (5.6 g, 23.2 mmol) in acetonitrile (60 mL) were added potassium carbonate (6.41 g, 46.4 mmol) and compound 1-1 (3.99 g, 17.4 mmol) at room temperature. The mixture was stirred at 80°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford 15-4 (5.4 g, 79.7% yield) as a pale yellow solid.

[0887] LCMS (ESI) m / z: 412.1 [M+Na] + .

[0888] Synthesis of intermediate 15-5

[0889] 15-4 (7.2 g, 18.5 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid (30 mL) solution at room temperature, and the mixed solution was stirred at 20°C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a light yellow solid 15-5 (6.15 g, crude product).

[0890] LCMS (ESI) m / z: 334.0 [M+H] + .

[0891] Synthesis of intermediate 15-7

[0892] Compound 15-6 (3.76 g, 18.0 mmol) was added to N,N-dimethylformamide (50 mL) of 15-6 (2.0 g, 6.0 mmol) at room temperature, followed by the addition of triethylamine (3.04 g, 30.0 mmol), copper acetate (2.18 g, 12.0 mmol) and 4A molecular sieves (13.2 g, 30.0 mmol). The mixed solution was stirred at 60 ° C for 16 hours under an oxygen atmosphere. After the reaction was complete, ethyl acetate (250 mL) and water (250 mL) were added to the reaction solution to precipitate a large amount of solid, which was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the organic phase was separated from the filtrate. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane:methanol=10:1) to give a light yellow solid 15-7 (2.4 g, yield: 79.7%).

[0893] LCMS (ESI) m / z: 497.0 [M+H] + .

[0894] Synthesis of compound 15

[0895] At room temperature, 15-7 (2.5 g, 5.0 mmol) and compound 1-7 (0.95 g, 5.25 mmol) were dissolved in tetrahydrofuran (25 mL) and cooled to -60°C under nitrogen protection. Subsequently, a tetrahydrofuran solution of potassium tert-butoxide (8.3 mL, 15.0 mmol, 1.8 M) was added dropwise to the reaction solution. The resulting solution was stirred at this temperature for 1 hour. After the reaction was complete, saturated brine (50 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (50 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain a light yellow solid compound 15 (0.4914 g, yield: 16.0%).

[0896] LCMS (ESI) m / z: 615.9 [M+H] + .

[0897] 1 H NMR (400MHz, CD3OD) δ8.33(s,1H),8.25(s,1H),8.18(s,1H),7.81(t,J=7.8Hz,1H),7.71(s,1H),7.69–7.67(m,1H),7.45(br,1H),7.18(t,J= 9.5Hz,1H),5.35(s,2H),5.11(d,J=1.4Hz,1H),4.18(s,3H),3.95(d,J=3.1Hz,3H),3.87-3.83(m,1H),2.32-2.23(m,1H),2.16–2.09(m,1H).

[0898] The same method as above was used to synthesize the compounds shown in Table B below

[0899] Table B

[0900] Example 27 Synthesis of Compound 27

[0901] Synthesis of intermediate 27-2c

[0902] To a solution of 27-1a (1.00 g, 5.68 mmol) in N-methylpyrrolidone (10 mL) was added 27-2b (1.54 g, 12.5 mmol) at room temperature. The mixture was stirred in a microwave reactor at 200°C for 4 hours. Water (40 mL) and dichloromethane (40 mL x 3) were added to the mixture and 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 = 20:1) to afford compound 27-2c (1.20 g, 86.9% yield) as a pale yellow oil.

[0903] LCMS (ESI) m / z: 241.0 [M+H] + .

[0904] Synthesis of intermediate 27-2d

[0905] To a solution of 27-2c (3.48 g, 14.4 mmol) in tetrahydrofuran (35 mL) were added triethylamine (4.37 g, 43.2 mmol), di-tert-butyl dicarbonate (7.86 g, 36 mmol), and 4-dimethylaminopyridine (0.18 g, 1.44 mmol) at room temperature. Under nitrogen, the mixed solution was stirred at 65°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 20:1) to afford compound 27-2d (1.41 g, 28.5% yield) as a pale yellow oil.

[0906] LCMS (ESI) m / z: 343.1 [M+H] + .

[0907] Synthesis of Intermediate 27-2

[0908] To a solution of 27-2d (1.00 g, 2.91 mmol) and isopropyl pinacol borate (2.16 g, 11.6 mmol) in tetrahydrofuran (10 mL) was added dropwise n-butyl lithium (4.8 mL, 11.6 mmol) at -78°C. Under nitrogen, the mixed solution was stirred at -78°C for 2 hours. After the reaction was complete, the mixed solution 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 (dichloromethane:methanol = 20:1) to obtain compound 27-2 (0.76 g, yield: 85.0%) as a pale yellow solid.

[0909] LCMS (ESI) m / z: 309.1 [M+H] + .

[0910] Synthesis of intermediate 27-3

[0911] To a solution of 27-1 (250 mg, 0.75 mmol) in N,N-dimethylformamide (3 mL) at room temperature were added 27-2 (278 mg, 0.90 mmol), copper acetate (272 mg, 1.50 mmol), and triethylamine (379 mg, 3.75 mmol). The mixture was stirred at room temperature under oxygen protection for 16 hours. After completion of the reaction, the mixture was washed sequentially with water (10 mL) and saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol = 10:1) to afford 27-3 as a yellow oil (179 mg, yield: 40.2%).

[0912] LCMS (ESI) m / z: 596.0 [M+H] + .

[0913] Synthesis of intermediate 27-4

[0914] To a solution of 27-3- (200 mg, 0.36 mmol) in tetrahydrofuran (2 mL) at -40°C was added 1-7 (73.0 mg, 0.40 mmol). Potassium tert-butoxide solution (1 mL) was added to the mixed solution under nitrogen. Stir at -40°C for 2 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added to the mixed solution for extraction. The organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to afford 27-4 as a yellow oil (96.6 mg, yield: 37.5%).

[0915] LCMS (ESI) m / z: 715.0 [M+H] + .

[0916] Synthesis of compound 27

[0917] 27-4- (100 mg, 0.15 mmol) was added to a 1 / 1 dichloromethane / trifluoroacetic acid solution (2 mL) at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH = 7 with sodium carbonate solution in an ice bath. The mixed solution was extracted with dichloromethane (10 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (chromatographic column: Gemini-C18 150 x 21.2 mm, 5 μm. Mobile phase: ACN-H2O (0.1% FA). Gradient: 30-50) to obtain white solid compound 27 (SWD0309) (27.1 mg, yield: 29.4%).

[0918] LCMS (ESI) m / z: 615.0 [M+H] + .

[0919] 1 H NMR (400MHz, CD3OD) δ8.23(s,2H),8.03(d,J=15.6Hz,2H),7.85(s,1H),7.76(s,1H),7.53(s,1H),7.24(s,1H),5.40(s,2H) ,4.23(s,3H),4.15(s,1H),3.98-3.94(m,2H),3.90-3.85(m,1H),3.75-3.72(m,1H),2.37-2.28(m,1H),1.94-1.91(m,1H).

[0920] The same method as above was used to synthesize the compounds shown in Table C below:

[0921] Table C

[0922] Example 32 Synthesis of Compound 32

[0923] Synthesis of intermediate 32-2c

[0924] Triphenylphosphine (11.3 g, 43.1 mmol) was dissolved in tetrahydrofuran (100 mL) under an ice bath, and diisopropyl azodicarboxylate (8.71 g, 43.1 mmol) was added. The mixture was stirred under an ice bath for 15 minutes until a large amount of white solid precipitated. Compound 32-2a (5.45 g, 28.7 mmol) was then added under an ice bath and stirred at this temperature for 15 minutes. Compound 32-2b (2.53 g, 28.7 mmol) was then added, and the mixture was stirred at 20°C under nitrogen for 16 hours. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:2) to obtain compound 32-2c (6.9 g, yield: 92.3%) as a yellow oil.

[0925] LCMS (ESI) m / z: 260.0 [M+H] + .

[0926] Synthesis of intermediate 32-2

[0927] Intermediate 32-1c (6.8 g, 26.2 mmol) was dissolved in 1,4-dioxane (100 mL) at room temperature. Diboron (9.98 g, 39.3 mmol), potassium acetate (7.71 g, 78.6 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (1.92 g, 2.62 mmol) were added. The mixture was stirred at 80°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and petroleum ether (500 mL) was added. The resulting solution was stirred at room temperature for 1 hour, then filtered through celite. The filter cake was washed with petroleum ether, and the filtrate was concentrated to dryness. The crude product was purified by reverse phase column chromatography (C18, water (0.1% trifluoroacetic acid): acetonitrile = 5:95 to 15 / 85) to give a yellow solid 32-2 (4.12 g, yield: 69.9%).

[0928] LCMS (ESI) m / z: 226.1 [M+H] + .

[0929] Synthesis of intermediate 32-3

[0930] To a solution of 32-1 (0.2 g, 0.6 mmol) in N,N-dimethylformamide (5 mL) were added compound 32-2 (0.405 g, 1.8 mmol), triethylamine (0.304 g, 3.0 mmol), copper acetate (0.218 g, 1.2 mmol), and 4A molecular sieves (1.32 g, 3.0 mmol) at room temperature. The mixed solution was stirred at 60°C under an oxygen atmosphere for 16 hours. Ethyl acetate (25 mL) and water (25 mL) were added to the reaction solution, which was filtered and the filter cake washed with ethyl acetate. The resulting filtrate was separated into an organic phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain 4-32-3 (0.25 g, 80% yield) as a pale yellow solid.

[0931] LCMS (ESI) m / z: 513.1 [M+H] + .

[0932] Synthesis of compound 32

[0933] At room temperature, 32-3 (2.5 g, 5.0 mmol) and compound 1-7 (0.95 g, 5.25 mmol) were dissolved in tetrahydrofuran (25 mL). The mixture was cooled to -60°C under nitrogen, and a solution of potassium tert-butoxide in tetrahydrofuran (8.3 mL, 15.0 mmol, 1.8 M) was then added dropwise. The resulting solution was stirred at this temperature for 1 hour. The mixture was quenched by the addition of saturated brine (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 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)) to afford compound 32 as a pale yellow solid (0.474 g, yield: 15.0%).

[0934] LCMS (ESI) m / z: 632.1 [M+H] + .

[0935] 1 H NMR (400MHz, DMSO-d6) δ11.26 (s, 0.56H), 9.73 (s, 0.44H), 8.57 (d, J = 16.5Hz ,1H),8.47(s,1H),8.33(d,J=50.2Hz,1H),8.09–7.68(m,3.5H),7.59(dt,J= 40.5,9.5Hz,1H),7.13(s,0.5H),5.25(d,J=31.6Hz,2H),4.34–3.94(m,5H), 3.89–3.70(m,2H),3.59–3.51(m,1H),2.43–2.31(m,1H),1.86–1.73(m,1H).

[0936] The same method as above was used to synthesize the compounds shown in Table D below:

[0937] Table D

[0938] Example 35 Synthesis of Compound 35

[0939] Refer to Example 32 to synthesize intermediate 35-2.

[0940] LCMS (ESI) m / z: 213.1 [M+H] + .

[0941] Synthesis of intermediate 32-3

[0942] To a solution of 35-1 (0.2 g, 0.6 mmol) in N,N-dimethylformamide (5 mL) were added compound 35-2 (0.383 g, 1.8 mmol), triethylamine (0.304 g, 3.0 mmol), copper acetate (0.218 g, 1.2 mmol), and 4A molecular sieves (1.32 g, 3.0 mmol) at room temperature. The mixed solution was stirred at 60°C under an oxygen atmosphere for 16 hours. Ethyl acetate (25 mL) and water (25 mL) were added to the reaction solution, which was filtered and the filter cake washed with ethyl acetate. The resulting filtrate was separated into an organic phase, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to afford 35-3 (0.25 g, 82% yield) as a pale yellow solid.

[0943] LCMS (ESI) m / z: 513.1 [M+H] + .

[0944] Synthesis of compound 35

[0945] At room temperature, 35-3 (2.5 g, 5.0 mmol) and compound 1-7 (0.95 g, 5.25 mmol) were dissolved in tetrahydrofuran (25 mL). The mixture was cooled to -60°C under nitrogen, and a solution of potassium tert-butoxide in tetrahydrofuran (8.3 mL, 15.0 mmol, 1.8 M) was added dropwise. The resulting solution was stirred at this temperature for 1 hour. The mixture was quenched by the addition of saturated brine (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 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)) to afford compound 35 as a pale yellow solid (0.434 g, yield: 14.0%).

[0946] LCMS (ESI) m / z: 620.1 [M+H] + .

[0947] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.58-8.52(m,1H),8.47-8.42(m,1H),8.26(s,1H),7.97-7.79( m,2H),7.87-7.51(m,3H),5.24-5.21(m,2H),4.16-4.13(m,3H),3.58-3.52(m,2H),3.28–3.17(m,5H).

[0948] The same method as above was used to synthesize the compounds shown in Table E below:

[0949] Table E

[0950] Experimental Example 1

[0951] 1. Biochemical IC against SARS-Cov-2 50 Test Method

[0952] Assay system (120ul):

[0953] Protease (108ul): (150nM) WT or P132H

[0954] Substrate (10ul final concentration: 20uM)

[0955] Small molecules (2ul; 3-fold serial dilution)

[0956] substrate

[0957] Fluorescent substrate MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2; universal primer for main protease

[0958] Reaction Buffer: 50 mM Tris pH 7.4, 1 mM EDTA, 0.01% triton X-100

[0959] After incubation for 30 minutes, the enzyme was detected by enzyme marker

[0960] ELISA detection: excitation 320nm; emission 405nm

[0961] The inhibition rate of the representative compound on the main protease was determined by using the ratio of the initial reaction rate of the enzyme at different drug concentrations to the initial reaction rate of the control group.

[0962] GraphPad Prism was used to calculate the IC50 value using nonlinear curve fitting.

[0963] Formula 1: Inhibition rate (%) = (RFU 100% enzyme activity control - RFU sample) / (RFU 100% enzyme activity control - RFU blank control) × 100%

[0964] Formula 2: Inhibition rate (%) = (NC initial velocity V0 - sample initial velocity V0) / NC initial velocity × 100

[0965] NC is the DMSO-added control, and the enzyme activity is set as 100%.

[0966] Initial velocity calculation = Slope (RFU within 200s: time s)

[0967] 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).

[0968] 2. Cell ECs against SARS-Cov-2 50 Test Method

[0969] (1) Experimental materials

[0970] 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).

[0971] Virus strain: 2019-nCoV-WIV04 (IVCAS 6.7512)

[0972] Infectious dose: MOI = 0.01

[0973] (2) Experimental methods

[0974] 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;

[0975] 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.

[0976] 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%.

[0977] 4) Calculate EC using four-parameter fitting based on the inhibition rate results 50 .

[0978] The test results are shown in Table 1.

[0979] Table 1

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; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 1s for -C(O)NR 1b R 1c or L 1a Selected from chemical bonds, O, S or NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a 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 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b R c 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; n3 is 0, 1, 2, or 3; L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ; R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; m1 is 0, 1, or 2; R 4c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace; R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、 C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ; R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace; R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SR a 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl; L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl; wherein each of the above groups is optionally deuterated, up to fully deuterated; Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

2. A compound of formula (I) according to 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; Ring A is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R 1s for or -C(O)NR 1b R 1c ; L 1a Selected from O, S or NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L 1c -OR a 、-L 1c -SR a 、-L 1c -NR b R c 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R' 1s Independently selected from H, D, halogen, cyano, -L 1d -OR a 、-L 1d -SR a 、-L 1d -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; n3 is 0, 1, 2, or 3; L2 is selected from -(CR 4a R 4b ) m1 -, O, S, or NR 4c ; R 4a and R 4b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; m1 is 0, 1, or 2; R 4c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R2 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 2s replace; R 2s Independently selected from H, D, halogen, cyano, -L 2a -OR a 、-L 2a -SR a 、-L 2a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; L3 is selected from chemical bonds, CR 6a R 6b , O, S or NR 6c ; R 6a and R 6b Each independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R 6c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2, 3, 4 or 5 R 3s replace; R 3s Independently selected from H, D, halogen, cyano, -L 3a -OR a 、-L 3a -SR a 、-L 3a -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; Or two adjacent R 3s and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, halogen, cyano, -L 3b -OR a 、-L 3b -SR a 、-L 3b -NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 3-10 Aryl or 3-10 membered heteroaryl; L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, which is optionally substituted by 1, 2 or 3 atoms selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 radical substitution of alkynyl groups; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl; wherein each of the above groups is optionally deuterated, up to fully deuterated; Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A haloalkyl group; and the compound is not of the following structure:

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Y is N.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably 5-6 membered heteroaryl, preferably pyridyl or thiazolyl; preferably pyridyl; preferably More preferably 5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1s Selected from Preferably selected from Preferably selected from Preferably selected from More preferably not 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH; preferably O or NH; preferably O or S; preferably O; preferably S.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 1b is a chemical bond; Preferably, L 1b Selected from O, S or NR 5b ; preferably selected from O or NR 5b ; preferably selected from O, S or NMe; preferably selected from O or S; preferably selected from O or NMe; preferably O.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; preferably selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; preferably selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from Me, Preferably selected from Me, Preferably Me; Preferably, R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably 3-7 membered heterocyclic group; preferably 4-5 membered heterocyclic group; preferably 5 membered heterocyclic group; preferably selected from Preferably 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a SR a NR b R c 、C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: n1 is selected from 0, 1, 2 or 3; preferably selected from 0, 1 or 2; preferably selected from 1, 2 or 3; preferably 0; preferably 1; preferably 2.

11. A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: n2 is selected from 0, 1, 2 or 3; preferably selected from 0 or 1; preferably 0.

12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 5a is H or Me; preferably H.

13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 5b Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

14. A compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 1b is H; Preferably, R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

15. The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R' 1s Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

16. A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: n3 is 0 or 1; preferably 0.

17. A compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein n3 is 1, 2 or 3; preferably 0 or 1; preferably 0.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L2 is -(CR 4a R 4b ) m1 -; preferably methylene; Preferably, m1 is 1; Preferably, R 4a and R 4b For H.

19. A compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R2 is selected from C 6-10 Aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably phenyl; Preferably, R2 is optionally replaced by 1, 2, 3 or 4 R 2s replace; Preferably, R2 is optionally replaced by 2 or 3 R 2s replace; Preferably, R2 is selected from Preferably selected from Preferably selected from 20. A compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, cyano or C 1-6 Alkyl; preferably selected from H, F, Cl, CN, Me, CHF2 or CF3; preferably selected from H, F, Cl, CN or Me.

21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L3 for NR 6c ; preferably NH; Preferably, R 6a and R 6b For H.

22. A compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R3 is selected from C 6-10 Aryl or 5-10 membered heteroaryl; preferably 23. A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 3s Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, OR a 、C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, Cl, OMe or Me; preferably Cl or Me.

24. A compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Two adjacent R 3s and the atoms they connect to form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably forming a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl; preferably forming a pyrazolyl or dihydrofuranyl; preferably forming Preferred Formation 25. A compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R 3ss Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me.

26. A compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 1c , L 1d , L 2a , L 3a and L 3b Each independently selected from a chemical bond or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 Alkyl or C 1-6 The group of haloalkyl is substituted; preferably selected from chemical bonds or C 1-3 Alkylene.

27. A compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-6 Alkyl or C 1-6 alkyl halide; or R b 、R c Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group; preferably a 3-7 membered heterocyclic group.

28. A compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, having the following structural formula: in, m2 is 1, 2, 3 or 4; X1 for CR 3b or N, X2 is CR 3c or N; Or X1 is C(O), X2 is NH; R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 3b Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; or R 3b With R 3c and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2d is selected from H, D, halogen or cyano; R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; The remaining groups are as defined in claims 1-27.

29. The compound of formula (II) according to claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R 1s for or -C(O)NR 1b R 1c ; L 1a Selected from O, S or NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR a SR a NR b R c 、C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; n1 and n2 are independently selected from 0, 1, 2, 3, 4, 5 or 6; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 1c Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R' 1s Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n3 is 0, 1, 2, or 3; R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; m2 is 1, 2, 3 or 4; X1 for CR 3b or N, X2 is CR 3c or N; Or X1 is C(O), X2 is NH; R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 3b Selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; or R 3b With R 3c and the atoms they connect to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, halogen, cyano, OR a SR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 3-10 membered heterocyclic group; wherein each of the above groups is optionally deuterated, up to fully deuterated; Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A halogenated alkyl group, and the compound is not of the following structure:

30. The compound of formula (II) according to claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring A is phenyl or a 5-6 membered heteroaryl group; R 1s for or -C(O)NHR 1c ; preferably L 1a Selected from O, S or NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; n1 and n2 are independently selected from 0, 1, 2 or 3; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; R 1c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R' 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n3 is 0 or 1; R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 alkyl halide; m2 is 1, 2, 3 or 4; X1 for CR 3b , X2 is CR 3c ; Or X1 is C(O), X2 is NH; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3b Selected from OR a SR a or NR b R c ; preferably OR a or SR a ; R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; or R 3b With R 3c and the atoms they connect to form C 5-7 Cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; or R b 、R c and the atoms to which they are attached together form a 3-7 membered heterocyclic group.

31. The compound of formula (II) according to claim 29 or 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring A is a 5-6 membered heteroaryl group, preferably a pyridyl group or a thiazolyl group; R 1s for or -C(O)NHR 1c ; preferably L 1a Selected from O, S, NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n1 is selected from 0, 1 or 2; n2 is selected from 0 or 1; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; preferably R 5b C 1-6 Alkyl or C 1-6 Haloalkyl, preferably Me; R 1c Selected from C 1-6 Alkyl or C 1-6 alkyl halide; n3 is 0; R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl; m2 is 2 or 3; X1 for CR 3b , X2 is CR 3c ; Or X1 is C(O), X2 is NH; R 3a is a halogen; R 3b is OR a ; R 3c 、R 3d and R 3e independently H or D; or R 3b With R 3c and the atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, preferably a pyrazolyl or dihydrofuranyl, which is optionally substituted by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R a Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-6 Alkyl or C 1-6 Halogenated alkyl.

32. The compound of formula (II) according to any one of claims 29 to 31, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: Ring A is R 1s for Or C(O)NHCH3; preferably L 1a Selected from O, S, NH or NMe; preferably selected from O, S or NH; L 1b Selected from O, S or NMe; R 1a Selected from Me, n1 is selected from 0, 1 or 2; n2 is selected from 0 or 1; n3 is 0; R 2s Independently selected from H, F, Cl, CN, Me, CHF2 or CF3, preferably selected from H, F, Cl, CN or Me; m2 is 2 or 3; X1 for CR 3b , X2 is CR 3c ; Or X1 is C(O), X2 is NH; R 3a is Cl; R 3b OMe R 3c 、R 3d and R 3e is H; or R 3b With R 3c and the atoms they connect to form Preferably, R 1s Selected from Preferably, ring A and the substituents thereon together form: Preferably, Selected from Preferably, Selected from 33. The compound of formula (III-1) according to claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L 1a Selected from O, S or NR 5a ; L 1b Selected from O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; n1 is selected from 1, 2, 3, 4, 5 or 6; n2 is selected from 0, 1, 2, 3, 4, 5 or 6; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 2d is selected from H, D, halogen or cyano; R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

34. The compound of formula (III-1) according to claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; preferably S; L 1b Selected from O, S or NR 5b ; preferably O or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n1 is selected from 1, 2 or 3; preferably 2; n2 is selected from 0, 1, 2 or 3; preferably 0 or 1; R 5b Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably C 1-3 Alkyl or C 1-3 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, R 2a Selected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2b is H; R 2c is selected from H, D or halogen; R 2d is selected from halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

35. The compound of formula (III-1) according to claim 33 or 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; L 1b Selected from O or S; R 1a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; n1 is 2; n2 is 0 or 1; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

36. The compound of formula (III-1) according to any one of claims 33 to 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; L 1b is O; R 1a Selected from C 1-6 Alkyl or C 1-6 alkyl halide; n1 is 2; n2 is 0; R 2a 、R 2c and R 2d are independently halogen; R 2b H or D; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

37. The compound of formula (III-1) according to any one of claims 33 to 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; L 1b Selected from O or NMe; preferably O; R 1a Selected from Me, Preferably Me; n1 is 2; n2 is 0 or 1; preferably 0; R 2a Selected from F or Me; preferably F; R 2b is H; R 2c Selected from H or F; more preferably F; R 2d Selected from F, Cl or CN; preferably F or Cl; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably Preferably, Selected from: Preferably 38. The compound of formula (III-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L 1a Selected from O, S or NR 5a ; R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; n1 is selected from 1, 2, 3, 4, 5 or 6; R 5a Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 2d is selected from H, D, halogen or cyano; R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

39. The compound of formula (III-2) according to claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; preferably S; R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n1 is selected from 1, 2 or 3; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

40. The compound of formula (III-2) according to claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; R 1a is a 3-7 membered heterocyclic group, preferably a 4-5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Selected from H, D, C 1-6 Alkyl or C 1-6 Halogenated alkyl; preferably Me; n1 is 1; R 2a 、R 2c and R 2d are independently halogen; R 2b H or D; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

41. The compound of formula (III-2) according to any one of claims 38 to 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; R 1a Selected from n1 is 1; for R 3a is Cl; R 3f for Me; Preferably, Selected from:

42. The compound of formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein in, L 1a Selected from O, S or NR 5a ; R 1a Selected from C 3-10 Cycloalkyl or 3-10 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or 3-10 membered heterocyclic group; R 5a Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 2d is selected from H, D, halogen or cyano; R 3a Selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; R 3f Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

43. The compound of formula (III-3) of claim 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O, S or NH; preferably O or NH; preferably S; R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

44. The compound of formula (III-3) according to claim 42 or 43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O, S or NH; preferably O or NH; R 1a is a 4-6 membered heterocyclic group, preferably a 5 membered heterocyclic group, preferably a tetrahydrofuranyl group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2b is selected from H, D or halogen; R 2c is a halogen; R 2d is selected from halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

45. The compound of formula (III-3) according to any one of claims 42 to 44, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein When R 1a With L 1a When the connecting atom of is a chiral carbon atom, for 46. ​​The compound of formula (III-3) according to any one of claims 44 to 45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O, S or NH; preferably O or NH; R 1a Selected from Preferably More preferably R 2a is H, F, Cl or Me; R 2b H or F; R 2c is F or Cl; preferably F; R 2d is F, Cl or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably not More preferably Preferably, Selected from: Preferably selected from 47. The compound of formula (II) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, Ring A is phenyl or a 5-6 membered heteroaryl group; R 1s for -C(O)NHR 1c or L 1a Selected from chemical bonds, O, S or NR 5a ; L 1b Selected from chemical bonds, O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, cyano, OR a NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; n1 and n2 are independently selected from 0, 1, 2 or 3; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; R 1c Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R' 1s Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n3 is 0 or 1; R 2s Independently selected from H, D, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or m2 is 1, 2, 3 or 4; X1 for CR 3b , X2 is CR 3c ; Or X1 is C(O), X2 is NH; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3b Selected from OR a SR a or NR b R c ; preferably OR a or SR a ; R 3c 、R 3d and R 3e Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; or R 3b With R 3c and the atoms they connect to form C 5-7 cycloalkyl, 5-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, It is optionally replaced by 1, 2 or 3 R 3ss replace; R 3ss Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; wherein each of the above groups is optionally deuterated, up to fully deuterated; Provided that, when ring A is pyridyl, L 1a For NH, L 1b When it is a chemical bond, R 1a Not for C 1-6 Alkyl or C 1-6 A halogenated alkyl group, and the compound is not of the following structure:

48. The compound of formula (II) of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Ring A is a 5-6 membered heteroaryl group, preferably a pyridyl group or a thiazolyl group, preferably a pyridyl group, preferably R 1s for Preferably L 1a Selected from O, S, NR 5a ; L 1b Selected from chemical bonds, O or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; n1 is selected from 0, 1 or 2; n2 is selected from 0, 1 or 2; R 5a and R 5b Independently selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; preferably R 5a is H; preferably R 5b C 1-3 Alkyl or C 1-3 alkyl halide; n3 is 0; R 2s Independently selected from H, D, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 haloalkoxy; m2 is 2 or 3; X1 for CR 3b , X2 is CR 3c ; Or X1 is C(O), X2 is NH; R 3a is a halogen; R 3b OR a ; preferably OMe; R 3c 、R 3d and R 3e independently H or D; or R 3b With R 3c and the atoms to which they are attached together form a 5-7 membered heterocyclyl or a 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss Substitution; preferably forming R 3ss Independently selected from H, D, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; Preferably, Selected from Preferred Preferred Preferably, when L 1b When it is a chemical bond, R 1a C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.

49. The compound of formula (III-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L 1a Selected from O or S; L 1b Selected from O, S or NR 5b ; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl or 3-7 membered heterocyclic group; preferably selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; n1 is selected from 1, 2 or 3; n2 is selected from 0, 1, 2 or 3; R 5b Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a Selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from H, D, halogen or cyano; preferably halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

50. The compound of formula (III-1) of claim 49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; L 1b O or NR 5b ; preferably O; R 1a Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclic group; preferably C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-5 Cycloalkyl; preferably C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-5 Cycloalkyl; n1 is 2; n2 is 0, 1, or 2; R 5b C 1-3 Alkyl or C 1-3 Haloalkyl, preferably Me; R 2a Selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy; preferably halogen, C 1-4 Alkyl or C 1-4 alkoxy; R 2b is H, D or halogen; R 2c is selected from H, D or halogen; R 2d is halogen or CN; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

51. The compound of formula (III-1) according to claim 49 or 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O or S; preferably O; L 1b Selected from O or NMe; preferably O; R 1a Selected from Me, OMe, cyclopropyl or Preferably Me, OMe or cyclopropyl; Preferably Me or cyclopropyl; n1 is 2; n2 is 0, 1 or 2; preferably 0 or 1; R 2a Selected from H, F, Me, CF3, OMe or OCHF2; preferably F, Me or OMe; R 2b H or F; R 2c is selected from H, F or Cl; more preferably H or F; R 2d Selected from F, Cl or CN; preferably Cl or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably Preferably Preferably, Selected from: Preferably 52. The compound of formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, L 1a Selected from O, S or NR 5a ; R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 5a Selected from H, C 1-3 Alkyl or C 1-3 Haloalkyl; preferably R 5a is H; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

53. The compound of formula (III-3) of claim 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O, S or NH; R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, F, Me, NH2, -NHCH3 or -NH(CH3)2; preferably selected from H, F, Me, NH2 or -NHCH3; R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 2b Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 2c is H, D or halogen; R 2d is halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 alkyl halide; R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

54. The compound of formula (III-3) of claim 52 or 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein When R 1a With L 1a When the connecting atom of is a chiral carbon atom, for 55. The compound of formula (III-3) according to any one of claims 52 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein: L 1a Selected from O, S or NH; R 1a Selected from Preferably selected from: Preferably, for R 2a is H, F, Cl or Me; R 2b is H, F or Me; R 2c is H, F or Cl; R 2d is F, Cl or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably selected from: Preferably, for Preferably, for Preferably, for Preferably, Selected from:

56. The compound of formula (IV-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2a and R 2b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

57. The compound of formula (IV-1) of claim 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably selected from H, D or NR b R c ; preferably selected from H, NH2 or -N(CH3)2; preferably selected from H or NH2; R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 2b is selected from H, D or halogen; R 2c is a halogen; R 2d is selected from halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 alkyl halide; R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably H.

58. The compound of formula (IV-1) according to claim 56 or 57, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein When R 1a When the atom connected to O is a chiral carbon atom, for 59. The compound of formula (IV-1) according to any one of claims 56 to 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L 1a Selected from O, S or NH; preferably O or NH; Selected from: Preferably: Preferably Preferably, for R 2a is H, F, Cl or Me; preferably H, Cl or Me; R 2b is H or F; preferably H; R 2c is F; R 2d is F, Cl or CN; preferably Cl or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably selected from Preferably selected from 60. The compound of formula (IV-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, R 1a C 3-7 Cycloalkyl or 3-7 membered heterocyclic group, preferably 3-7 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a and R 2b Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2c Selected from halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

61. The compound of formula (IV-2) of claim 60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1a is a 4-6 membered heterocyclic group, preferably a 5 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 Haloalkyl; preferably selected from H, D or halogen; R 2b Selected from H or D; R 2c is a halogen; R 2d is selected from halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 Halogenated alkyl.

62. The compound of formula (IV-2) of claim 60 or 61, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein When R 1a When the connecting atom to NH is a chiral carbon atom, for 63. The compound of formula (IV-2) according to any one of claims 60 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Selected from: Preferably R 2a is H, F, Cl or Me; preferably H or F; R 2b is H; R 2c is F; R 2d is F, Cl or CN; preferably F or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably selected from Preferably 64. The compound of formula (IV-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in, R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, OR a NR b R c 、C 1-6 Alkyl or C 1-6 alkyl halide; R 2a 、R 2b and R 2c Independently selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 2d is selected from halogen or cyano; R 3a Selected from H, D, halogen, C 1-6 Alkyl or C 1-6 alkyl halide; R 3f Selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; R a 、R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 alkyl halide; The above-mentioned radicals are optionally deuterated, up to fully deuterated.

65. The compound of formula (IV-3) of claim 64, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein R 1a C 3-7 Cycloalkyl, 3-7 membered heterocyclic group or 5-6 membered heteroaryl, preferably C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as replace; R 1as Independently selected from H, D, halogen, NR b R c 、C 1-6 Alkyl or C 1-6 Haloalkyl; preferably selected from H, F, Me, NH2 or NHCH3; preferably H, F or Me; R 2a Selected from H, D, halogen, C 1-4 Alkyl or C 1-4 alkyl halide; R 2b Selected from H, D, C 1-4 Alkyl or C 1-4 alkyl halide; R 2c is selected from H, D or halogen; R 2d is selected from halogen or cyano; R 3a is a halogen; R 3f C 1-6 Alkyl or C 1-6 alkyl halide; R b and R c Each independently selected from H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

66. The compound of formula (IV-3) of claim 64 or 65, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein When R 1a When the atom connected to S is a chiral carbon atom, for 67. The compound of formula (IV-3) according to any one of claims 64 to 66, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein Selected from: Preferably Preferably Preferably Preferably, for R 2a is H, F or Me; R 2b is H or Me; R 2c is H, F or Cl; R 2d is Cl or CN; R 3a is Cl; R 3f for Me; Preferably, Selected from: Preferably Preferably 68. The compound of formula (I) 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:

69. A pharmaceutical composition comprising a compound according to any one of claims 1 to 68, 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.

70. Use of a compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition according to claim 69 in the preparation of a medicament for treating or preventing a disease caused by a viral infection.

71. 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 1-68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition of claim 69.

72. A compound according to any one of claims 1 to 68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or a pharmaceutical composition according to claim 69, for use in treating or preventing a disease caused by a viral infection.

73. The use of claim 70 or the method of claim 71 or the use of the compound or pharmaceutical composition of claim 72, 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.

74. The use of claim 70 or the method of claim 71 or the use of the compound or pharmaceutical composition of claim 72, 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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