Protein degradation targeting chimera compounds degrading irak4 and applications thereof

Abstract

The present application relates to a protein degradation targeting chimera compound degrading IRAK4 of formula (A) and a preparation method thereof, a pharmaceutical composition comprising the compound, and use of the pharmaceutical composition for treating a disease, disorder or condition associated with IRAK4 protein kinase.

Description

A protein degradation targeting chimeric compound for degrading IRAK4 and its application

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311375410.X filed on October 20, 2023 and Chinese patent application CN202410084340.0 filed on January 19, 2024, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present application relates to a protein degradation targeting chimera (PROTAC) compound for degrading IRAK4 and a preparation method thereof, a pharmaceutical composition comprising the compound, and the use of the pharmaceutical composition for treating diseases, disorders or conditions associated with IRAK4 protein kinase. Background Art

[0004] IRAK4 is a serine / threonine protein kinase that belongs to the interleukin-1 receptor-associated kinase (IRAK) family, which includes four subtypes: IRAK1, IRAK2, IRAK3 (or IRAKM), and IRAK4. IRAK1, IRAK2, and IRAK4 promote the release of inflammatory factors, while IRAK3 is involved in suppressing inflammation. Among the four subtypes, the biological function of IRAK4 has been clearly elucidated. When TLRs or IL-1Rs perceive external signaling, the Myddosome complex formed by IRAK4 activates the MAPK and NF-κB pathways, leading to the release of multiple inflammatory factors.

[0005] Research has confirmed that IRAK4 is highly expressed in various tumor cells and inflammatory models. The development of inhibitors targeting IRAK4 is becoming an increasingly important approach in the treatment of autoimmune diseases and tumors. IRAK4 has both kinase and scaffold activities, both of which play a crucial role in downstream signaling regulation.

[0006] In addition, the protein degradation targeting chimera (PROTAC) technology is a new technology that has emerged in recent years. Since its advent in 2001, the technology has attracted much attention. At present, many drug developments based on this technology have entered the clinical research stage, and some have entered clinical phase 2. PROTAC, as a heterogeneous bifunctional molecule, consists of three parts: a small molecule inhibitor that can recognize the target protein at one end, a connecting chain, and a ligand that can recognize E3 ubiquitin ligase at the other end. This bifunctional molecule recognizes and brings the target protein and E3 ubiquitin ligase together in the body to form a ternary complex, and then ubiquitin-tags the target protein, thereby initiating a degradation pathway that depends on ubiquitin-proteasome. Compared with conventional small molecule inhibitors, PROTAC technology achieves simultaneous inhibition of the two functions of IRAK4 by degrading the IRAK4 protein, which can effectively solve the problem of insufficient small molecule activity or mutation.

[0007] Therefore, it is of great significance to develop new PROTAC molecules targeting IRAK4.

[0008] Summary of the Invention

[0009] The present invention provides PROTAC compounds targeting IRAK4, which are used to recruit IRAK4 kinase to E3 ubiquitin ligase for degradation. In other words, the bifunctional PROTAC compounds of the present invention have the utility of a regulator of targeted ubiquitination of IRAK4 kinase, which is degraded and / or otherwise inhibited by the bifunctional compounds as described herein. The inventors of the present application have shown that the compounds of the present invention can effectively degrade IRAK4 kinase. The compounds of the present invention can be used to treat diseases, disorders or conditions associated with IRAK4 protein kinase. In addition, the compounds of the present invention have better physicochemical properties (such as solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiotoxicity) and / or less side effects), less prone to drug resistance and other more excellent properties.

[0010] In one aspect, the present invention provides a compound of formula (A) as defined below:

[0011] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present invention provides a method for targeted degradation of IRAK4 protein kinase, comprising contacting the IRAK4 protein kinase with a compound of formula (A) of the present invention in the presence of an E3 ubiquitin ligase.

[0013] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (A) of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0014] In another aspect, the present invention provides a compound of formula (A) of the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating a disease, disorder or condition associated with IRAK4 protein kinase.

[0015] In another aspect, the present invention provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) of the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0016] In another aspect, the present invention provides a process for preparing a compound of formula (A) of the present invention. DETAILED DESCRIPTION

[0017] definition

[0018] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0019] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0020] As used herein, the term "hydrocarbyl" means a straight or branched saturated or unsaturated aliphatic hydrocarbon group. Hydrocarbyl groups include alkyl, alkenyl, and alkynyl groups. In some embodiments, the hydrocarbyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Hydrocarbon" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2- 6 hydrocarbon groups", "C 2-5 Hydrocarbon" and "C 1-4 As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from the "alkyl" as defined above. As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0021] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2-6 Alkyl", "C 2-5 Alkyl" and "C 1-4 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term "C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0022] As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from an "alkyl" as defined above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 1-6 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene" and "C 1-4 Alkylene". "C 1-6Examples of "alkylene" include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene and n-hexylene. The term "C 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0023] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above.

[0024] As used herein, the term "heteroalkyl" refers to an alkyl group as defined above wherein one or more, but not all, C atoms in the alkyl chain are replaced by heteroatoms or radicals selected from NR', O, C(O), S, S(O), and S(O), wherein R' is a suitable substituent, such as H, alkyl, or the like. The heteroalkyl group may be attached to the remainder of the molecule via a C atom or such heteroatom or radical. Preferably, the heteroalkyl group is attached to the remainder of the molecule via a C atom.

[0025] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 Alkenyl", such as "C 2-4 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0026] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 Alkynyl", such as "C 2-4The alkynyl group is, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl and 2-methyl-3-pentynyl. The term "alkynylene" is the corresponding divalent group, including, for example, "C 2-6 Alkynylidene", "C 2-4 Specific examples include, but are not limited to, -C≡C-, -CH2C≡C-, -C≡C-CH2-, -CH2-C≡C-CH2-, pentynylene, hexynylene, and the like.

[0027] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0028] As used herein, the term "bridge" or "bridged" means that two or more ring structures share two non-adjacent atoms with each other.

[0029] As used herein, the term "spiro" or "spiro-connected" means that two or more ring structures share 1 atom with each other.

[0030] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to a saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-12 (suitably having 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. It includes, but is not limited to, cyclopropyl (ring), cyclobutyl (ring), cyclopentyl (ring), cyclohexyl (ring), cycloheptyl (ring), cyclooctyl (ring), cyclononyl (ring), cyclobutenyl (ring), cyclopentenyl (ring), cyclohexenyl (ring), cycloheptenyl (ring), cyclooctenyl (ring), cyclononenyl (ring), etc. In some embodiments, the cycloalkyl group includes an aromatic-fused cycloalkyl group, as long as the entire ring system is non-aromatic.

[0031] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). The cycloalkyl group has 3-15 carbon atoms, suitably 3-12, 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6 carbon atoms. For example, the term "C 3-6 Cycloalkyl" and "C 3-6 "Cycloalkylene" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0032] The terms "spirocycloalkyl" and "spirocycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share one carbon atom. For example, "C 7-12 Spirocycloalkyl" and "C 7-12 "Spirocycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 5-12 or 7-11) carbon atoms and formed by at least two rings sharing one atom.

[0033] The terms "fused cycloalkyl" and "fused cycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share two adjacent carbon atoms. For example, "C 4-10 Fused cycloalkyl" and "C 4-10 "Fused cycloalkylene" refers to a fused ring containing from 4 to 10 (e.g., 6-10 or 8-10) ring carbon atoms and formed from two or more rings that share two adjacent carbon atoms.

[0034] The terms "bridged cycloalkyl" and "bridged cycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share two non-adjacent carbon atoms. For example, "C 7-10 Bridged cycloalkyl" and "C 7-10 "Cycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms and formed by two rings that share two non-adjacent atoms.

[0035] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6.

[0036] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monocyclic or bicyclic ring structures having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(═O), S(═O)2, and NR' in the ring, wherein R ’ As defined above. The heterocyclic ring may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-12 membered heterocyclic ring is a group having 3-12 (e.g., 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11, or 8-12) carbon atoms and heteroatoms in the ring. Examples that may be mentioned include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

[0037] As used herein, the heterocycles described above include nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles. For example, a "nitrogen-containing heterocycle" has at least one nitrogen atom, which may also optionally have one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O). The nitrogen-containing heterocycle may be attached to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 12-membered nitrogen-containing heterocycle is a group having 3-12 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0038] As used herein, the heterocycles described above include monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., monocyclic heterocycles, bridged heterocycles, spiro heterocycles, and fused heterocycles. The point of attachment of the bridged heterocycles, spiro heterocycles, and fused heterocycles to other groups can be on any ring in the structure.

[0039] As used herein, fused heterocycle refers to a polycyclic (such as bicyclic) heterocycle as defined above, wherein any two connected rings share two adjacent atoms. Fused heterocycles include, but are not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example, 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl. Preferably, the fused heterocycle is 6 to 10-membered, and more preferably 8-10-membered. Examples of fused heterocycles include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, fused heterocyclyls also include heteroaryl-fused heterocyclyls or cycloalkyls, and aryl-fused heterocyclyls, as long as the entire ring system is non-aromatic. In some embodiments, fused heterocyclyls include 5-6 membered monocyclic heteroaryl-fused C 5-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl fused 5-6 membered monocyclic heterocyclyl, and phenyl fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl and imidazotetrahydropyridinyl.

[0040] As used herein, spiro heterocycle refers to polycyclic (such as bicyclic) heterocycle defined above, wherein any two connected rings share a carbon atom.Preferably, spiro heterocycle is 5-12 yuan, and more preferably 7-11 yuan.According to the number of shared spiral atoms, spiro heterocycle is divided into single spiral heterocycle, two spiral heterocycles or many spiral heterocycles, and preferably refers to single spiral heterocycle or two spiral heterocycles, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocycles.

[0041] As used herein, bridged heterocycle or bridged heterocycle refers to a polycyclic (such as bicyclic) heterocycle as defined above, wherein any two connected rings share two non-adjacent atoms. One or more rings of the bridged heterocycle may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocycle is 6 to 9 members, and more preferably 6-8 members. Depending on the number of member rings, bridged heterocycles are divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycles, and preferably refer to bicyclic, tricyclic or tetracyclic bridged heterocycles, and more preferably bicyclic or tricyclic bridged heterocycles.

[0042] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0043] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O). One or more ring carbon atoms in a heteroaryl group may be replaced by C(O). A heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzo furanyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

[0044] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0045] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0046] As used herein, the term "haloalkenyl" refers to an alkenyl group substituted with one or more (such as 1 to 3) the same or different halogen atoms, as defined herein. 2-8 Halogenated alkenyl, "C 2-6 Halogenated alkenyl" and "C 2-4 The term "haloalkenyl" refers to haloalkenyl groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, and 2 to 4 carbon atoms, respectively.

[0047] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0048] If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0049] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0050] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0051] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0052] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any ring atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0053] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0054] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0055] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0056] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0057] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0058] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0059] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0060] In this paper, solid lines (——), dashed bars (——) Solid rod Solid wedge or virtual wedge Depicting chemical bonds of the compounds of the present invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. Isomers resulting from the inability to rotate freely about single bonds of ring atoms are depicted as dashed or solid sticks to indicate whether two substituents on a ring atom are located on the same or opposite sides, e.g. represents the cis configuration, represents the trans configuration. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and diastereomeric pairs.

[0061] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0062] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0063] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0064] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0065] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0066] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0067] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0068] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0069] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0070] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0071] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0072] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0073] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0074] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0075] Compound

[0076] In one aspect, the present invention provides compounds of formula (A):

[0077] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:

[0078] L A Selected from bonds and straight or branched C 1-4 Alkylene, the C 1-4 The alkylene group is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2 is substituted with a substituent;

[0079] L B A group selected from the following groups (1) to (21):

[0080] (1)–CyL1–,

[0081] (2)–CyL1–La–,

[0082] (3)–CyL1–Lb–,

[0083] (4)–CyL1–La–CyL2–La–,

[0084] (5)–CyL1–NR L1 –,

[0085] (6)–CyL1–C(O)–,

[0086] (7)–CyL1–C(O)-NR L1 –,

[0087] (8)–CyL1–NR L1 -C(O)–,

[0088] (9)–CyL1–CyL2–,

[0089] (10)–NR L1 -CyL1-La–,

[0090] (11)–NR L1 -CyL1-Lb–,

[0091] (12)–NR L1 -CyL3-NR L2 –,

[0092] (13)–NR L1 -CyL3-La-NRL2 –,

[0093] (14)–NR L1 -CyL1-C(O)–,

[0094] (15)–NR L1 -La-CyL1-La–,

[0095] (16)–La–CyL1–,

[0096] (17)–O-La–,

[0097] (18)–S-La–,

[0098] (19)–NR L1 -La–,

[0099] (20)–CyL1–La–CyL2-, and

[0100] (21)–CyL1–Lc–CyL4-,

[0101] in:

[0102] In the groups (1) to (21), the leftmost extending bond of each group is connected to L A and the rightmost key is connected to the part, or the leftmost bond of each group is connected to the The rightmost key is connected to the L A ,

[0103] CyL1 and CyL2 are each independently selected from C 3-12 cycloalkylene or 3-12 membered heterocycloalkylene, wherein the heterocycloalkylene preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S,

[0104] CyL3 is independently selected at each occurrence from C 3-12 Cycloalkylene,

[0105] CyL4 is independently selected at each occurrence from a 5-12 membered heteroarylene group,

[0106] La is independently selected at each occurrence from C 1-4 alkylene,

[0107] Lb is independently selected at each occurrence from a linear C 2-4 Hydrocarbylene, wherein the straight chain C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O),

[0108] Lc is independently selected at each occurrence from a bond or C 1-4 alkylene,

[0109] CyL1, CyL2, CyL3, CyL4, La, Lb and Lc are each optionally substituted with one or more groups independently selected from the following: 1-4 Alkyl, C 1-4 Haloalkyl, halogen, OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2, preferably methyl, ethyl, F, Cl, Br, OH, CN and NH 2, more preferably methyl, F, Cl and OH; and

[0110] R L1 and R L2 Each is independently selected at each occurrence from H and C 1-4 alkyl;

[0111] In some embodiments,

[0112] CyL1 and CyL2 are each independently selected at each occurrence from a 3-12 membered heterocycloalkylene group, wherein the heterocycloalkylene group preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S;

[0113] Lb is independently selected at each occurrence from a linear C 2-4 Alkylene, wherein the linear C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O);

[0114] described The part has the structure of formula (1): in:

[0115] X1, X2, X3, X4, X5, X6, X7, X8 and X9 can each independently be C, CR or N, provided that the valences of all atoms are satisfied and X4 and X5 are not N at the same time;

[0116] R, R 1 、R 4 and R 5 Each independently selected from: hydrogen, deuterium, R 7 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e 、-C(O)NR 1f -OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e and -NR 1f -S(O)2R 1f ,

[0117] p is 1, 2, or 3;

[0118] n is 0, 1 or 2, wherein when n is 1 or 2, R 4 available ring members connected to ring D; and

[0119] R 5 Available ring members connected to ring C;

[0120] R 2Selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-7 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkyl or heterocyclyl group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form a saturated or partially unsaturated optionally substituted C 3-7 cycloalkyl or 3-7 membered saturated or partially unsaturated optionally substituted heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0121] R 3 and R 6 Each independently selected from: H, R 8 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2R 3f 、-S(O)R 3f 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-P(O)(OR 3f )2、-P(O)(NR 3d R 3e )2、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-(CR 3a R 3b ) q -OR 3f 、-(CR 3a R3b ) q -C(O)OR 3f 、-(CR 3a R 3b ) q -NR 3d R 3e 、-C(O)R 3f 、-C(O)OR 3f and -C(O)NR 3d R 3e ,

[0122] q is 1, 2, or 3; and

[0123] m is 0, 1, 2 or 3, wherein when m is 1, 2 or 3, R 6 Available ring members connected to ring B;

[0124] R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 ;

[0125] R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e 、R 7d and R 7e are each independently selected from hydrogen, deuterium, R 11 、C 1-6 Alkyl and C 1-6 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 ;

[0126] R 1f 、R 2f and R 3f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ;

[0127] R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-12 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents substituted;

[0128] R 10 is selected from: a 3-7 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-10 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e and

[0129] R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0130] described The part is the ligase binding part.

[0131] In some embodiments,

[0132] R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents substituted;

[0133] R 10 is selected from: a 3-7 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-10 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e Substituents substituted;

[0134] Linking group L A

[0135] In some embodiments, the present invention provides compounds of formula (A) according to the present invention, which have L as defined above. A group.

[0136] In some embodiments, L A Selected from bond, C 1-2 Alkylene, the C 1-2 The alkylene group is optionally substituted by one or more independently selected C 1-2 Alkyl, C 1-2 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-2alkyl) and -N(C 1-2 alkyl)2 is substituted with a substituent.

[0137] In some embodiments, L A Selected from bond, C 1-2 Alkylene, the C 1-2 Alkylene is optionally selected from C 1-2 The substituents of alkyl, halogen, and oxo (=O) are substituted.

[0138] In some embodiments, L A is selected from a bond, -CH2-, -CH2-CH2-, -CH(CH3)- and -C(=O)-.

[0139] In some embodiments, L A It is a bond, -CH2- or -CH2-CH2-, preferably -CH2-.

[0140] IRAK4 ligands

[0141] In some embodiments, the present invention provides a compound of formula (1) according to the present invention, which has an IRAK ligand as defined above.

[0142] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 1 and R 4 Not hydrogen or deuterium at the same time.

[0143] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 1a 、R 1b 、R 3a and R 3b Each independently selected from hydrogen, halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 .

[0144] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 1d 、R 1e 、R 2d 、R 2e 、R 3d 、R 3e、R 7d and R 7e are each independently selected from hydrogen, R 11 、C 1-4 Alkyl and C 1-4 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are commonly attached, form R 10 .

[0145] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 1f 、R 2f and R 3f are independently selected from hydrogen, C 1- 4 alkyl, C 1-4 Haloalkyl and R 12 .

[0146] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 7 、R 8 、R 9 、R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-6 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0147] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 10is selected from: a 3-6 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, oxo, C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e substituted by a substituent.

[0148] In some embodiments, the present invention provides an IRAK ligand as described above, wherein R 8d 、R 8e 、R 10d and R 10e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0149] In a first sub-aspect, the present invention provides an IRAK ligand as described above, wherein R 1 Not hydrogen.

[0150] In some embodiments, R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R 1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e 、-C(O)NR 1f -OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e or -NR 1f -S(O)2R 1f .

[0151] In some embodiments, R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-CF(R 1f )2、-CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or

[0152] In some embodiments, R 1 Selected from: R 7 、Halogen、CN、-OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0153] In some embodiments, R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0154] In some embodiments, R 7 Selected from: C 3-6 cycloalkyl; 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e substituted by a substituent.

[0155] In some embodiments, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or, preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0156] In some embodiments, R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0157] In some embodiments, R 7 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0158] In some embodiments, R 7 Selected from: azetidinyl, pyrrolidinyl and piperidinyl.

[0159] In some embodiments, p is 1.

[0160] In some embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-6 alkyl.

[0161] In some embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl.

[0162] In some embodiments, R 1a and R 1b are each independently hydrogen.

[0163] In some embodiments, R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0164] In some embodiments, R 9 Selected from: C 3-6Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0165] In some embodiments, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0166] In some embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, -NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0167] In some embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0168] In some embodiments, R 9 It is cyclopropyl.

[0169] In some embodiments, R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-6 alkyl.

[0170] In some embodiments, R1d and R 1e are each independently selected from hydrogen, R 11 and C 1-4 alkyl.

[0171] In some embodiments, R 1d and R 1e are each independently selected from hydrogen, R 11 , methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0172] In some embodiments, R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0173] In some embodiments, R 11 Selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0174] In some embodiments, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0175] In some embodiments, R 11 Selected from: C 3-6 and 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4alkyl)2 is substituted with a substituent.

[0176] In some embodiments, R 11 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0177] In some embodiments, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from F and Cl.

[0178] In some embodiments, R 11 Selected from cyclopropyl and

[0179] In some embodiments, R 10 is selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0180] In some embodiments, R 10is selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0181] In some embodiments, R 10 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0182] In some embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0183] In some embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0184] In some embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0185] In some embodiments, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0186] In some embodiments, R 1f Selected from hydrogen and C 1-6 alkyl.

[0187] In some embodiments, R 1f Selected from hydrogen and C 1-4 alkyl.

[0188] In some embodiments, R 1f For hydrogen.

[0189] In some embodiments, wherein R 1 Selected from: F, Cl, Br, CN, OH, NH2, -NHCH3, -C(O)OH, -C(O)NH2, -CH2NH2, -CH2OH,

[0190] In some embodiments, R 1 Selected from -CN, -C(O)NH2, F, -NHCH3, -C(O)OH,

[0191] In some embodiments according to the first sub-aspect, the Part has the structure of formula (I-1):

[0192] Where n is 0 or 1.

[0193] In a second sub-aspect, the present invention provides an IRAK ligand as described above, wherein R 1 is selected from hydrogen and deuterium, and n is 1 or 2.

[0194] In some embodiments, R 1is hydrogen, and n is 1.

[0195] In some embodiments according to the second sub-aspect, the Part has the structure of formula (I-2):

[0196] The conditions are: R 4 Not hydrogen or deuterium.

[0197] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 4 Selected from: hydrogen, R 7 、Halogen、CN、NO2、-OR 1f 、-SR 1f and -NR 1d R 1e ; The condition is that when R 1 When it is hydrogen and deuterium, R 4 Not hydrogen.

[0198] In some embodiments, R 1d and R 1e are each independently selected from hydrogen and C 1-6 alkyl.

[0199] In some embodiments, R 1d and R 1e are each independently selected from hydrogen and C 1-4 alkyl.

[0200] In some embodiments, R 1f Selected from hydrogen and C 1-6 alkyl.

[0201] In some embodiments, R 1f Selected from hydrogen and C 1-4 alkyl.

[0202] In some embodiments, R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; provided that when R 1 When it is hydrogen and deuterium, R 4 Not hydrogen.

[0203] In some embodiments, R 4 Selected from: hydrogen, R 7 and CN; the condition is that when R 1 When it is hydrogen and deuterium, R 4 Not hydrogen.

[0204] In some embodiments, R 7is selected from: 4-6 membered saturated monocyclic heterocyclic group, 8-10 membered saturated fused bicyclic heterocyclic group, 6-11 membered saturated spiro heterocyclic group and 7-10 membered saturated bridged heterocyclic group, each of which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e substituted by a substituent.

[0205] In some embodiments, R 7 Selected from: 4-6 membered saturated monocyclic heterocyclic groups and 7-10 membered saturated bridged heterocyclic groups, said monocyclic heterocyclic groups and bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -NR 8d R 8e substituted by a substituent.

[0206] In some embodiments, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl.

[0207] In some embodiments, R 7 is selected from: a 4-6 membered saturated monocyclic heterocyclic group (e.g., azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl) and a 7-10 membered saturated bridged heterocyclic group, wherein the monocyclic heterocyclic group and the bridged heterocyclic group have 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0208] In some embodiments, R7 Selected from: Each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2, and wherein X 10 is CH2, (CH2)2 or (CH2)3.

[0209] In some embodiments, R 7 Selected from:

[0210] In some embodiments, R 4 Selected from: hydrogen, CN, The condition is: when R 1 When it is hydrogen or deuterium, R 4 Not hydrogen.

[0211] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R and R 5 are each independently selected from hydrogen.

[0212] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 2 Selected from: C 3-6 Cycloalkylene; 4-6 membered saturated or partially unsaturated heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl groups having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 1, 2 or more groups independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocyclylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein preferably, R2d and R 2e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl, and / or R 2f Selected from hydrogen and C 1-6 alkyl.

[0213] In some embodiments, R 2 Selected from: Sub-C 3-6 cycloalkyl; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-4 Alkyl, -C(O)OH, -C(O)OC 1-4 Alkyl, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)NH(C 1-4 alkyl)2, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0214] In some embodiments, R 2Selected from: cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylene, pyrrolylene, oxazolylene, thiazolylidene, pyrazolylene, imidazolylidene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally substituted by 1, 2 or more independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl, isopropyl, tert-butyl, thiazolyl, oxadiazolyl, thiadiazolyl ... wherein the substituents are substituted with a substituent selected from the group consisting of -C(O)-butyl, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)NH2, -C(O)NHCH3 and -C(O)N(CH3)2, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylidene, pyrrolylidene, oxazolidinylidene, thiazolidinylidene, pyrazolidinylidene, imidazolidinylidene, piperidinylidene, piperazinylidene, hexahydropyrimidinylidene, morpholinylidene or thiomorpholinylidene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C ... 3-6 Cycloalkyl.

[0215] In some embodiments, R 2 is selected from the group consisting of cyclohexylidene, pyrrolidylene, piperidylene, phenylene and pyridylene, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, OH, NH2 and methyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclohexylidene, pyrrolidylene or piperidylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0216] In some embodiments, R 2 Selected from:

[0217] Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0218] In some embodiments, R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0219] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e .

[0220] In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e .

[0221] In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e .

[0222] In some embodiments, R 3d and R 3e are each independently selected from hydrogen, deuterium, R 11 、C1-4 Alkyl and C 1-4 In some embodiments, wherein R 11 Preferably selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent, wherein preferably, R 8d and R 8e are each independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0223] In some embodiments, R 3d and R 3e are each independently selected from hydrogen, methyl and ethyl.

[0224] In some embodiments, R 3f Selected from hydrogen and C 1-6 alkyl.

[0225] In some embodiments, R 3f Selected from hydrogen and C 1-4 alkyl.

[0226] In some embodiments, R 3d and R 3e Together with the nitrogen atom to which they are attached, they form R 10 In some embodiments, wherein R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0227] In some embodiments, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0228] In some embodiments, R 3 Selected from: F, Cl, Br, OH, NH2, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -N(CH3)2, -CHF2, -CHCl2 and -C(O)NH2.

[0229] In some embodiments, R 6 Selected from: halogen, CN, NO2, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ) and -CCl3, where R 3f Preferably selected from hydrogen and C 1-6 Alkyl, or R 3f Preferably selected from hydrogen and C 1-4 alkyl.

[0230] In some embodiments, R 6 Selected from: F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0231] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein m is 0.

[0232] In some embodiments, the present invention provides a compound according to any of the embodiments described above, wherein at least two of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time.

[0233] In some embodiments, three of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time.

[0234] In some embodiments, four of X1, X2, X3, X4, and X5 are N, provided that X4 and X5 are not N at the same time.

[0235] In some embodiments, X1 is N.

[0236] In some embodiments, at least two of X6, X7, X8 and X9 are N.

[0237] In some embodiments, at least three of X6, X7, X8 and X9 are N.

[0238] In some embodiments, at least four of X6, X7, X8 and X9 are N.

[0239] In some embodiments, X8 and X9 are each N.

[0240] In some embodiments, the present invention provides a compound according to any of the embodiments described above, 2 or 3 of X1, X2, X3, X4 and X5 are N, and X1 is N, provided that X4 and X5 are not N at the same time; and

[0241] Three or four of X6, X7, X8, and X9 are N, and X8 and X9 are each N.

[0242] In a third aspect, the present invention provides the compounds according to formula (I), formula (I-1) and formula (I-2) described above. moiety, wherein X1 and X2 are each N; X3 is CH; X4 and X5 are each C; X6, X8, and X9 are each N; and X7 is CH.

[0243] In some embodiments, the The moiety has the structure of formula (Ii) or formula (I-ii):

[0244] Where: R 1 、R 2 、R 3 and R 4 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that:1 Not hydrogen or deuterium;

[0245] Where: R 2 、R 3 and R 4 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0246] In some embodiments, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0247] In some embodiments, R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0248] In some embodiments, p is 1.

[0249] In some embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0250] In some embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0251] In some embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0252] In some embodiments, R 9 is cyclopropyl;

[0253] In some embodiments, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0254] In some embodiments, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0255] In some embodiments, R 11is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0256] In some embodiments, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0257] In some embodiments, R 11 Selected from cyclopropyl and

[0258] In some embodiments, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0259] In some embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0260] In some embodiments, R 10 Selected from: Preferred Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0261] In some embodiments, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen.

[0262] In some embodiments, R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, -C(O)NH2,

[0263] In some embodiments, R 1 Selected from CN and -C(O)NH2.

[0264] In some embodiments, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0265] In some embodiments, R 2is selected from the group consisting of: cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylidene, pyrrolylidene, oxazolylidene, thiazolylidene, pyrazolylidene, imidazolylidene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally substituted by 1 or 2 independently selected from F, Cl, Br, CN, OH, NH2, wherein the substituents are substituted with a substituent of N02 and C1-C4 alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0266] In some embodiments, R 2 is selected from cyclopentylidene, cyclohexylidene, pyrrolidinylene, piperidylene, phenylene and pyridylene, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopentylidene, cyclohexylidene, pyrrolidinylene or piperidylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0267] In some embodiments, R 2 Selected from:

[0268] Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0269] In some embodiments, R 2 Selected from Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0270] In some embodiments, R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to LA .

[0271] In some embodiments, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0272] In some embodiments, R 3 is -CHF2.

[0273] In some embodiments, R 4 Selected from: hydrogen, R 7 , halogens, CN, NO2, OH and NH2.

[0274] In some embodiments, R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2.

[0275] In some embodiments, R 7 Selected from: 4-6 membered saturated monocyclic heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0276] In some embodiments, R 7 Selected from:

[0277] In some embodiments, R 4 Selected from: hydrogen, CN and The condition is: when R 1 When it is hydrogen, R 4 Not hydrogen.

[0278] In a fourth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) described above, wherein X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6, X8 and X9 are each N; and X7 is CH.

[0279] In some embodiments, the present invention The moiety has the structure of formula (I-iii):

[0280] Where: R 1 、R 2 and R 3 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0281] In some embodiments, R 1 Selected from: R 7 、Halogen、NO2、-OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0282] In some embodiments, R 1 Selected from: R 7 , halogen, -NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e .

[0283] In some embodiments, p is 1.

[0284] In some embodiments, R 7is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0285] In some embodiments, R 7 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0286] In some embodiments, R 7 It is a piperidinyl group.

[0287] In some embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 The alkyl groups are preferably each independently hydrogen.

[0288] In some embodiments, R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0289] In some embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0290] In some embodiments, R 9Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0291] In some embodiments, R 1d and R 1e are each independently selected from hydrogen, C 1-4 Alkyl and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0292] In some embodiments, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0293] In some embodiments, R 11 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0294] In some embodiments, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0295] In some embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0296] In some embodiments, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen;

[0297] In some embodiments, R 1 Selected from: F, Cl, Br, OH, NH2, -NHCH3, C(O)OH, -C(O)NH2, -CH2OH,

[0298] In some embodiments, R 1 Selected from -CN and -C(O)NH2.

[0299] In some embodiments, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0300] In some embodiments, R 2is selected from the group consisting of: cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally replaced by 1 or 2 independently selected from F, C wherein the substituents are substituted with a substituent selected from the group consisting of 1, Br, CN, OH, NH2, NO2 and C1-C4 alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylidene, pyrrolylidene, oxazolylidene, thiazolylidene, pyrazolylidene, imidazolylidene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0301] In some embodiments, R 2 is selected from the group consisting of cyclopentylidene, cyclohexylidene, pyrrolidinylidene, piperidylidene, phenylene and pyridylidene, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopentylidene, cyclohexylidene, pyrrolidinylidene or piperidylidene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0302] In some embodiments, R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0303] In some embodiments, R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0304] In some embodiments, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-SR 3f、-NR 3d R 3e 、-CF(R 3f )2、-CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e .

[0305] In some embodiments, R 3d and R 3e are each independently selected from hydrogen and C 1-4 Alkyl groups, preferably hydrogen and methyl.

[0306] In some embodiments, R 3f Selected from hydrogen and C 1-4 Alkyl groups, preferably hydrogen and methyl.

[0307] In some embodiments, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2、-CHF2、-CH2F、-CF3、-CH2Cl、-CHCl2、-CCl3、-C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2.

[0308] In some embodiments, R 3 Selected from: F, OH, NH2, CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

[0309] In some embodiments, R 3 Selected from: F, CN, methyl, isopropyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

[0310] In a fifth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) described above, wherein X1, X3 and X4 are each N; X2 and X5 are C; X6, X8 and X9 are each N; and X7 is CH.

[0311] In some embodiments, the The moiety has the structure of formula (I-iv):

[0312] Where: R 1 、R 2 and R 3 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0313] In some embodiments, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e or-C(O)OR 1f .

[0314] In some embodiments, R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f , or -C(O)OR 1f .

[0315] In some embodiments, p is 1.

[0316] In some embodiments, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 .

[0317] In some embodiments, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0318] In some embodiments, R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0319] In some embodiments, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 .

[0320] In some embodiments, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0321] In some embodiments, R 11 is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2.

[0322] In some embodiments, R 10is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0323] In some embodiments, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more groups independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

[0324] In some embodiments, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen.

[0325] In some embodiments, R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH,

[0326] In some embodiments, R 1 For CN.

[0327] In some embodiments, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl.

[0328] In some embodiments, R 2 is selected from the group consisting of: cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally replaced by 1 or 2 independently selected from F, C wherein the substituents are substituted with a substituent selected from the group consisting of 1, Br, CN, OH, NH2, NO2 and C1-C4 alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylidene, pyrrolylidene, oxazolylidene, thiazolylidene, pyrazolylidene, imidazolylidene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C1-C4 alkyl group. 3-6 Cycloalkyl.

[0329] In some embodiments, R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0330] In some embodiments, R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A . .

[0331] In some embodiments, R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A .

[0332] In some embodiments, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3.

[0333] In some embodiments, R 3 is -CHF2.

[0334] In a sixth sub-aspect, the present invention provides compounds according to formula (I), formula (I-1) and formula (I-2) described above, wherein X1 and X5 are each N; X2 and X4 are C; and X3 is CH; X6 is CH; and X7, X8 and X9 are each N.

[0335] In some embodiments, the The moiety has the structure of formula (IV):

[0336] Among them, R 1 、R 2 and R 3 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0337] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any embodiment according to the third, fourth and / or fifth sub-aspect.

[0338] In some embodiments, R 1 is -C(O)NH2; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2.

[0339] In a seventh aspect, the present invention is based on the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the moiety, wherein X1 and X5 are each N; X2 and X4 are C; X3 is CH; and X6, X7, X8 and X9 are each N.

[0340] In some embodiments, the present invention The portion has the structure of formula (I-vi):

[0341] Among them, R 1 、R 2 and R 3 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0342] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any embodiment according to the third, fourth and / or fifth sub-aspect.

[0343] In some embodiments, R 1 is -C(O)NH2; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2;

[0344] In an eighth aspect, the present invention is based on the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the moiety, wherein: X1 and X2 are each N; X3 is CH; X4 and X5 are each C; and X6, X7, X8 and X9 are each N.

[0345] In some embodiments, the The moiety has the structure of formula (I-vii):

[0346] Among them, R 1 、R 2 and R 3 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0347] In some embodiments, R 1 、R 2 and R 3 Each is as defined in any embodiment according to the third, fourth and / or fifth sub-aspect.

[0348] In some embodiments, R 1 is -CN; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2.

[0349] In a ninth aspect, the present invention is based on the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, wherein: X1, X3 and X4 are each N; X2 and X5 are C; and X6, X7, X8 and X9 are each N.

[0350] In some embodiments, the present invention The moiety has the structure of formula (I-viii):

[0351] Among them, R 2 、R 3 and R 4 Each of the above-mentioned formula (I), formula (I-1) and formula (I-2) As defined in any embodiment of the present invention, provided that: 1 Not hydrogen or deuterium.

[0352] In some embodiments, R 2 、R 3 and R 4 Each is as defined in any embodiment according to the third, fourth and / or fifth sub-aspect.

[0353] In some embodiments, R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or, in some embodiments, R 3 is -CHF2.

[0354] In some embodiments, R 4 Selected from: R 7 , halogens, CN, NO2, OH and NH2.

[0355] In some embodiments, R 4 Selected from: R 7 , F, Cl, Br, CN, NO2, OH and NH2.

[0356] In some embodiments, R 7 Selected from: 7-10 membered saturated bridged heterocyclic groups having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent.

[0357] In some embodiments, R 7 Selected from: where X 10 is CH2, (CH2)2 or (CH2)3.

[0358] In some embodiments, R 4 Selected from: CN and More preferred

[0359] In some embodiments, the present invention provides a compound of formula (A), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: Some selected from: (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ) (Preferred ).

[0360] Linking group L B

[0361] In some embodiments, the present invention provides compounds of formula (A) according to the present invention, which have L as defined above. B group.

[0362] In some embodiments, the CyL1 and CyL2 groups are each independently selected at each occurrence from C 4-11 Cycloalkylene, 4-11 membered heterocycloalkylene, preferably C 4-7 Monocyclic cycloalkylene, 4-7 membered monocyclic heterocycloalkylene, 6-10 membered fused bicyclic heterocycloalkylene, 6-9 membered bridged heterocycloalkylene and 5-12 membered spiro heterocycloalkylene, more preferably C 4-6 Monocyclic cycloalkylene, 4-6 membered monocyclic heterocycloalkylene, 8-10 membered fused bicyclic heterocycloalkylene, 6-8 membered bridged heterocycloalkylene and 7-11 membered spiro heterocycloalkylene, further preferably, CyL1 is independently selected from C 5-6 monocyclic cycloalkylene, 4-6 membered monocyclic heterocycloalkylene, 8-10 membered fused bicyclic heterocycloalkylene, 7-8 membered bridged bicyclic heterocycloalkylene, 7-11 membered spiro bicyclic heterocycloalkylene, CyL2 is independently selected at each occurrence from 4-6 membered monocyclic heterocycloalkylene, wherein any of the above heterocycloalkylene preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0363] In some embodiments, the CyL1 and CyL2 groups are each independently selected at each occurrence from a 4-11 membered heterocycloalkylene group, preferably a 4-7 membered monocyclic heterocycloalkylene group, a 6-10 membered fused bicyclic heterocycloalkylene group, a 6-9 membered bridged heterocycloalkylene group, and a 5-12 membered spiro heterocycloalkylene group, more preferably a 4-6 membered monocyclic heterocycloalkylene group, an 8-10 membered fused bicyclic heterocycloalkylene group, a 6-8 membered bridged heterocycloalkylene group, and a 7-11 membered spiro heterocycloalkylene group, wherein any of the above heterocycloalkylene groups preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0364] In some embodiments, the CyL3 group is independently selected at each occurrence from C 4-11 Cycloalkylene, preferably C 4-6 Monocyclic cycloalkylene, C 6-10 Fused bicyclic cycloalkylene, C 6-9 Cycloalkylene and C 5-12 Spirocycloalkylene, more preferably C 5-6 Monocyclic cycloalkylene, C 8-10 Fused bicyclic cycloalkylene, C 6-8 Cycloalkylene and C 7-11 Spirocycloalkylene.

[0365] In some embodiments, the CyL3 group is independently selected at each occurrence from C 5-6 Monocyclic cycloalkylene, C 7-11 Spirobicyclic cycloalkylene.

[0366] In some embodiments, the CyL4 group is independently selected at each occurrence from a 5-10 membered heteroarylene group, preferably a 5-6 membered heteroarylene group, and more preferably a 5-6 membered nitrogen-containing heteroarylene group.

[0367] In some embodiments, La at each occurrence is independently selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkynylene, preferably -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2-, -CH2CH2-C≡C- and -CH2-C≡C-CH2-, more preferably -CH2-, -(CH2)2-, -(CH2)3-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2- and -CH2CH2-C≡C-.

[0368] In some embodiments, Lb is independently selected at each occurrence from -O- linear C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-O-, -OC 2-3 Alkenylene-, -C 2-3 Alkenylene-O-, -OC 2-3 Alkynylidene-, -C 2-3 Alkynylidene-O-, -NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -、-NR 8’ -C(O)-straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-NR 8’ -C(O)-, -C(O)- straight chain C 1-3 Alkylene- and - straight-chain C 1-3Alkylene-C(O)-, preferably -OC 2-3 Alkynylidene-、-NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -C(O)- and -C(O)- straight chain C 1-3 Alkylene-, where R 8’ independently selected at each occurrence from H and C 1-4 alkyl.

[0369] In some embodiments, Lb is independently selected at each occurrence from -O- linear C 1-3 Alkylene, - straight chain C 1-3 Alkylene-O-, -OC 2-3 Alkenylene, -C 2-3 Alkenylene-O-, -OC 2-3 Alkynylidene, -C 2-3 Alkynylidene-O-, -NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -、-NR 8’ -C(O)-straight chain C 1-2 Alkylene-, -C(O)- straight chain C 1-3 Alkylene- and - straight-chain C 1-3 Alkylene-C(O)-, where R 8’ independently selected at each occurrence from H and C 1-4 alkyl.

[0370] In some embodiments, Lc is independently selected at each occurrence from a bond or a linear C 1-3 The alkylene group is preferably a bond, a methylene group or an ethylene group, and more preferably a bond or a methylene group.

[0371] In some embodiments, R L1 、R L2and R 8’ Each at each occurrence is independently selected from H, methyl and ethyl, more preferably H and methyl.

[0372] In some embodiments, L B A group selected from the following groups (1) to (21):

[0373] (1) (Preferred ), (Preferred ), (Preferred ),

[0374] (2)

[0375] (3) (Preferred ),

[0376] (4)

[0377] (5)

[0378] (6)

[0379] (7)

[0380] (8)

[0381] (9) (Preferred ), (Preferred Further optimization ), (Preferred ),

[0382] (10)

[0383] (11)

[0384] (12) (Preferred )

[0385] (13)

[0386] (14)

[0387] (15)

[0388] (16)

[0389] (17)

[0390] (18)

[0391] (19)

[0392] (20) (Preferred ) as well as

[0393] (twenty one)

[0394] Preferably, in any of the groups (1) to (21) above, the bond identified by "u" is connected to the LA, and the bond identified by "v" is connected to the part.

[0395] Ligase binding part

[0396] In some embodiments, the present invention provides a compound of formula (A) according to the present invention, wherein Some are E3 ubiquitin ligase ligands.

[0397] In some embodiments, the Some selected from:

[0398] in:

[0399] Ring Aa is a 5-membered heterocyclic group or a 5-membered heteroaryl group, preferably a 5-membered heterocyclic group or a 5-membered heteroaryl group having 1, 2 or more N heteroatoms, wherein the 5-membered heterocyclic group and the 5-membered heteroaryl group are optionally substituted by one or more independently selected from H, halogen, OH, NH2, CN, oxo and C 1-4 Alkyl substituents are substituted,

[0400] Preferably, Partially selected The bond marked with "z" is connected to X 5 ;

[0401] Each ring are independently phenyl or 5-6 membered heteroaryl, preferably phenyl;

[0402] X 5 CR L7 or N;

[0403] t is 0 or 1, preferably 1;

[0404] R L1 、R L5 and R L6 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl;

[0405] R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together they form an oxo group;

[0406] R L4 and R L7 Each is independently selected at each occurrence from H, halogen, OH, NH2, CN and C 1-4 Alkyl, preferably H, F, Cl, Br and C 1-2 Alkyl, more preferably H, F, Cl and methyl;

[0407] m5 is 0, 1, 2, 3 or 4, preferably 1 or 2.

[0408] In some embodiments, m5 is selected from 0 or 1.

[0409] In some embodiments, the Partially selected

[0410] More preferably, the Partially selected

[0411] More preferably, the Partially selected

[0412] In some embodiments, wherein Some selected from:

[0413] In some embodiments, wherein Some selected from:

[0414] In some preferred embodiments, the compound of the present invention has a structure shown in formula (B0):

[0415] Among them, R 1 , L B , Aa, R L1 、R L2 、R L3 、R L4 、X 5 , t, m5 are as defined in any of the preceding embodiments;

[0416] Preferably, R 1 Selected from CN, R 7 、-C(O)OR 1f or -C(O)NR 1d R 1e More preferably, R 1 Selected from -C(O)NR 1d R 1e ;

[0417] in:

[0418] Preferably, R 7 is selected from: a 4-7 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or

[0419] R 7 is selected from the group consisting of: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, and 2-oxa-5-azabicyclo[2.2.1]heptane, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or

[0420] R 7 is selected from piperidinyl, morpholinyl and 2-oxa-5-azabicyclo[2.2.1]heptane; and / or

[0421] Preferably, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; and / or

[0422] Preferably, R 1d and R 1e are each independently selected from hydrogen, C 1-6 Alkyl and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ;

[0423] in:

[0424] Preferably, R 11 Selected from: C 3-6 Cycloalkyl; wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 alkyl) and N(C 1-4 alkyl)2 is substituted with a substituent; or

[0425] R 11 is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; and / or

[0426] R 10 Selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2 is substituted with a substituent; or

[0427] R 10 Selected from: piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, oxo, C 1-4 Alkyl, C1-4 Halogenated alkyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2 is substituted with a substituent;

[0428] Preferably, R 1 Selected from CN, -C(O)OH, -C(O)NH2, More preferably, R 1 Selected from -C(O)NH2; and / or

[0429] L B Selected from:

[0430] (1) -CyL1-, wherein CyL1 is selected from 4-7 membered monocyclic heterocycloalkylene, 7-11 membered spiro bicyclic heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene, 9-11 membered spiro bicyclic heterocycloalkylene; wherein any of the heterocycloalkylene groups each has 1 or 2, preferably 2, nitrogen heteroatoms, and any of the heterocycloalkylene groups is optionally substituted by one or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0431] (3) –CyL1–Lb–, wherein CyL1 is selected from 4-7 membered monocyclic heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene; Lb group is selected from -OC 2-3 Alkynylidene;

[0432] (9) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 5-6 membered monocyclic heterocycloalkylene, wherein any of the heterocycloalkylene groups each has 1 or 2 nitrogen heteroatoms and is optionally substituted by one or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0433] (12)–NR L1 -CyL3-NR L2 –, wherein the CyL3 group is selected from C 5-6 Monocyclic cycloalkylene, R L1 、R L2 The groups are each independently selected from H and C 1-4 Alkyl, preferably H and methyl;

[0434] (20)-CyL1-La-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from a 4-7 membered monocyclic heterocycloalkylene group or a C 4-7 Monocyclic cycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene or C 5-6 Monocyclic cycloalkylene; La is independently selected from C 1-4 Alkylene, preferably methylene and ethylene;

[0435] (21) –CyL1–Lc–CyL4-, wherein the CyL1 group is selected from a 4-7 membered heterocycloalkylene group, preferably a 5-6 membered heterocycloalkylene group; the CyL4 group is selected from a 5-6 membered monocyclic heteroarylene group, preferably a 5 membered monocyclic nitrogen-containing heteroarylene group; the Lc group is selected from a bond or C 1-4 Alkylene, preferably a bond, methylene or ethylene; or

[0436] L B Selected from: (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), wherein in any of the above groups, the bond identified by "u" is connected to the CH2 portion, and the bond identified by "v" is connected to the portion where the phenyl group is located; and / or

[0437] Preferably, Partially selected The bond marked with "z" is connected to X 5 ;

[0438] in:

[0439] Preferably, R L4 Selected from H, halogen and C 1-4 Alkyl, more preferably H, F, Cl and methyl; and / or

[0440] Preferably, R L6 Selected from H and C 1-4 Alkyl, more preferably H and methyl; and / or

[0441] Preferably, m5 is selected from 0 or 1, more preferably 0; and / or

[0442] X 5 CR L7 or N;

[0443] Where: R L7 Selected from H, halogen and C 1-4 Alkyl, more preferably H; and / or

[0444] t is preferably 1; and / or

[0445] Preferably, R L1 Selected from H and C 1-4 Alkyl, more preferably H and methyl; and / or

[0446] Preferably, R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together form an oxo group; more preferably R L2 and R L3 Together they form an oxo group;

[0447] Preferably, the formula (B0) is selected from the structures represented by formula (B0-1), (B0-2) or (B0-3):

[0448] In some preferred embodiments, the present invention provides a compound of formula (A), wherein the compound has a structure shown in formula (B):

[0449] in:

[0450] L B Selected from:

[0451] (1) -CyL1-, wherein the CyL1 group is selected from 5-9 membered heterocycloalkylene, 7-11 membered spiro heterocycloalkylene, preferably 5-6 membered heterocycloalkylene, 9-11 membered spiro heterocycloalkylene; more preferably 9-11 membered spiro heterocycloalkylene; wherein the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene each have 1 or 2, preferably 2 nitrogen heteroatoms, and the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene are optionally substituted by one or more groups independently selected from the following: C 1-4alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; wherein the 5-9 membered heterocycloalkylene and the 5-6 membered heterocycloalkylene each have 1 or 2, preferably 2 nitrogen heteroatoms, and the 5-9 membered heterocycloalkylene and the 5-6 membered heterocycloalkylene are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0452] (2) –CyL1–Lb–, wherein the CyL1 group is selected from a 5-9 membered heterocycloalkylene group, more preferably a 5-6 membered heterocycloalkylene group; and the Lb group is selected from -OC 2-3 Alkynylidene;

[0453] (3) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, wherein the 4-7 membered monocyclic heterocycloalkylene and the 4-6 membered monocyclic heterocycloalkylene each have 1 or 2 nitrogen heteroatoms, and are optionally substituted by one or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0454] (4)–NR L1 -CyL3-NR L2 –, wherein the CyL3 group is selected from C 4-6 Monocyclic cycloalkylene, R L1 、R L2 The groups are each independently selected from H, methyl and ethyl, preferably H and methyl;

[0455] (5) –CyL1–La–CyL2, wherein the CyL1 and CyL2 groups are each independently selected from a 4-7 membered monocyclic heterocycloalkylene group or a C 4-7 Monocyclic cycloalkylene; La is independently selected from C 1-4 Alkylene, preferably methylene and ethylene;

[0456] (6) –CyL1–Lc–CyL4-, where the CyL1 group is selected from C 4-6 Monocyclic heterocycloalkylene, preferably CyL1 group is selected from 5-6 membered monocyclic heterocycloalkylene; CyL4 group here is selected from 5-6 membered monocyclic heteroarylene, preferably 5 membered monocyclic nitrogen-containing heteroarylene, where Lc group is selected from bond or C 1-4 alkylene, preferably a bond, methylene or ethylene;

[0457] And, R 1is selected from a 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, CN, -C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e ;

[0458] R 1d 、R 1e are each independently selected from hydrogen, deuterium, R 11 、C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably hydrogen, R 11 、C 1-3 Alkyl and C 1- 3 haloalkyl;

[0459] R 1f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ; preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl and R 12 ;

[0460] R 11 、R 12 Independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more independently selected C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group are substituted; preferably saturated C 3-7 Cycloalkyl; 3-10 membered saturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably the cycloalkyl and heterocyclic groups are optionally substituted by one or more independently selected C 1-3 Alkyl, C 1-3 Substitution of haloalkyl groups;

[0461] R 1 Preferably selected from -CONH2, -CN, -COOH, More preferably R 1 Preferably it is selected from -CONH2.

[0462] In some embodiments, in the structure represented by formula (B), wherein:

[0463] L B Selected from:

[0464] (1) -CyL1-, wherein the CyL1 group is selected from 5-9 membered monocyclic heterocycloalkylene, 7-11 membered spiro heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene, 9-11 membered spiro heterocycloalkylene; more preferably 9-11 membered spiro heterocycloalkylene; wherein the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene each have 1 or 2, preferably 2, nitrogen heteroatoms, and the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene are optionally substituted by one or more groups independently selected from the following: C 1-4 alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; wherein the 5-9 membered monocyclic heterocycloalkylene and the 5-6 membered monocyclic heterocycloalkylene each have 1 or 2, preferably 2 nitrogen heteroatoms, and the 5-9 membered monocyclic heterocycloalkylene and the 5-6 membered monocyclic heterocycloalkylene are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0465] (2) –CyL1–Lb–, wherein the CyL1 group is selected from a 5-9 membered monocyclic heterocycloalkylene group, more preferably a 5-6 membered monocyclic heterocycloalkylene group; and the Lb group is selected from -OC 2-3 Alkynylidene;

[0466] (3) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, wherein the 4-7 membered monocyclic heterocycloalkylene and the 4-6 membered monocyclic heterocycloalkylene each have 1 or 2 nitrogen heteroatoms, and are optionally substituted by one or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0467] (4)–NR L1 -CyL3-NR L2 –, wherein the CyL3 group is selected from C 4-6 Monocyclic cycloalkylene, R L1 、R L2 The groups are each independently selected from H, methyl and ethyl, preferably H and methyl;

[0468] (5) –CyL1–La–CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from a 4-7 membered monocyclic heterocycloalkylene group or a C 4-7 Monocyclic cycloalkylene; La is independently selected from C 1-4 Alkylene, preferably methylene and ethylene;

[0469] (6) –CyL1–Lc–CyL4-, wherein the CyL1 group is selected from a 4-6 membered monocyclic heterocycloalkylene group, preferably a 5-6 membered monocyclic heterocycloalkylene group; the CyL4 group is selected from a 5-6 membered monocyclic heteroarylene group, preferably a 5 membered monocyclic nitrogen-containing heteroarylene group; the Lc group is selected from a bond or C 1-4 The alkylene group is preferably a bond, a methylene group or an ethylene group.

[0470] In some embodiments, L B Selected from: (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), Preferred More preferred (Preferred ), (Preferred ), (Preferred ), Preferred and, wherein in any of the above groups, the bond identified by "u" is connected to the CH2 portion, and the bond identified by "v" is connected to the portion where the phenyl group is located.

[0471] In some embodiments, R 1 Selected from -CONR Na R Nb , where R Na 、R Nb Each independently is H or C 1-4 Alkyl, preferably -CONH2.

[0472] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0473] In some embodiments, the present invention provides a compound of formula (A), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following Table 1:

[0474] In some preferred embodiments, the compound is selected from Compound 1 to Compound 22.

[0475] Pharmaceutical compositions and uses

[0476] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0477] In another aspect, the present invention provides a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or the use of a pharmaceutical composition of the present invention for the preparation of a medicament.

[0478] In some embodiments, the compound of the invention, the pharmaceutical composition of the invention, or the medicament is used to treat a disease, disorder, or condition associated with IRAK4 protein kinase.

[0479] In another aspect, the present invention also provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, alleviating its symptoms, delaying its development or onset, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0480] In another aspect, the present invention provides a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, for use in treating a disease, disorder or condition associated with IRAK4 protein kinase.

[0481] In another aspect, the present invention also provides the use of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention for the preparation of a medicament as an IRAK4 inhibitor.

[0482] In another aspect, the present invention provides a method of inhibiting IRAK4 activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0483] In another aspect, the present invention provides a method for targeted degradation of IRAK4 protein kinase, comprising contacting the IRAK4 protein kinase with a compound of formula (A) according to the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof in the presence of an E3 ubiquitin ligase. In some embodiments, the method is performed in vitro or ex vivo. In other embodiments, the method is performed in vivo.

[0484] In some embodiments, the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: an autoimmune disorder, an inflammatory disorder, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction, and metabolic syndrome.

[0485] In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fever, atopic dermatitis, hidradenitis suppurativa, chronic nephritis, allergic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma, and allergies, preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, and chronic nephritis.

[0486] In some embodiments, the autoimmune disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis, and systemic juvenile idiopathic arthritis, preferably psoriasis.

[0487] In some embodiments, the transplant rejection is selected from graft-versus-host disease and allograft rejection.

[0488] In some embodiments, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma Myeloma, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

[0489] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0490] As used herein, unless otherwise indicated, the terms "treat," ...

[0491] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0492] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0493] Example

[0494] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0495] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0496] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0497] High-performance liquid chromatography (HPLC) assay conditions: Gilson GX-281, C18 column (10 μM, 19 mm x 250 mm), UV detection at 220 and 254 nm, elution with a gradient of 5–95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate) over 15 min.

[0498] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0499] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0500] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0501] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0502] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0503] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0504] Synthesis Example

[0505] Example 1

[0506] 1) Step 1: Compound 1a (14.2 g, 49.9 mmol, prepared by the method disclosed in the intermediate ARD of page 586, item 001207 of the specification of patent application "WO2020264499A1") was dissolved in dichloromethane (150 mL), and imidazole (6.80 g, 99.9 mmol) and tert-butyldiphenylsilyl chloride (16.5 g, 59.9 mmol) were added. The reaction was stirred at 20 ° C for 2 hours, water (300 mL) was added to the reaction mixture, and then extracted with ethyl acetate (100 mL × 3), the organic phases were combined and dried, filtered, and concentrated under reduced pressure. The crude product was stirred with petroleum ether (200 mL), filtered, the solid was collected, and vacuum dried to obtain compound 1b. 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=8.1Hz,2H),7.61–7.58(m,4H),7.47–7.43(m,8H),4.71(s,1H),3.4 7(d,J=6.0Hz,2H),2.42(s,3H),1.75–1.65(m,2H),1.60–1.44(m,5H),1.32–1.20(m,2H),1.00(s,9H).

[0507] 2) Step 2: Compound 1c (300 mg, 2.10 mmol, prepared using the method disclosed for the intermediate pyrrolo[1,2-b]pyndazine-3-carbonitrile on page 75 of the specification of patent application "WO2015117563A1") and N-iodosuccinimide (707 mg, 3.14 mmol) were added to acetonitrile (10 mL) at room temperature. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature, and saturated sodium sulfite solution (10 mL) was carefully added to the reaction mixture. The mixture was then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 1d. 1 H NMR (400MHz, CDCl3): δ8.27(d,J=2.1Hz,1H), 8.05(d,J=2.1Hz,1H), 7.24(d,J=4.7Hz,1H), 6.95(d,J=4.7Hz,1H).

[0508] 3) Step 3: Compound 1d (1.50 g, 5.58 mmol) was dissolved in a mixture of ethanol (15 mL) and dimethyl sulfoxide (3 mL). Aqueous hydrogen peroxide (35%, 3 mL) and aqueous sodium hydroxide (0.5 M, 13.4 mL, 6.69 mmol) were added at 0°C, and the mixture was stirred at 0°C for 30 minutes. A large amount of solid precipitated, which was directly filtered. The filter cake was washed twice with PE / EA (1 / 1, 10 mL), filtered, and used directly as the starting material for the next step without further purification to obtain compound 1e. MS m / z (ESI): 287.9 ​​[M+1]. + .

[0509] 4) Step 4: At room temperature, compound 1f (200 mg, 0.590 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623A"), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (301 mg, 1.18 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl ( 55.0mg, 0.120mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (25.0mg, 30.0μmol) were dissolved in toluene (3mL), and under nitrogen protection, lithium bis(trimethylsilyl)amide (3mL, 3.00mmol, 1.0M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, water (20mL) was added, and the aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15mL×3). The combined organic phase was washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol=100 / 1 to 10 / 1) to obtain compound 1g. MS m / z(ESI):510.4[M-1] - .

[0510] 5) Step 5: Dissolve 1 g (120 mg, 0.210 mmol) in dichloromethane (2 mL) at room temperature, add trifluoroacetic acid (2 mL), and stir the reaction mixture at 25°C for 1 hour. Remove the solvent under reduced pressure to obtain compound 1h without purification. MS m / z (ESI): 412.6 [M+1] + .

[0511] 6) Step 6: Compound 1i (7.20 g, 26.5 mmol) and 1b (18.0 g, 34.4 mmol) were dissolved in N,N-dimethylformamide (150 mL) and cesium carbonate (25.9 g, 79.4 mmol, Bid) was added at 25°C. The reaction solution was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, the residue was diluted with dichloromethane (100 mL) and water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL×2). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with (petroleum ether / ethyl acetate = 100 / 1 to 2 / 5) to obtain the crude product of compound 1j. MS m / z (ESI): 385.6 [M+H] + .

[0512] 7) Step 7: The crude product of compound 1j (11.5 g, 15.0 mmol) was dissolved in glacial acetic acid (100 mL) and water (20 mL). The reaction solution was stirred at 25 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane (100 mL), and saturated sodium bicarbonate (80 mL) was slowly added dropwise. After the aqueous phase was separated, it was extracted with dichloromethane (100 mL×2). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure and purified to obtain the crude product of compound 1l. MS m / z (ESI): 339.9 [M+H] + .

[0513] 8) Step 8: The crude product of compound 11 (9.70 g, 14.3 mmol), 4-dimethylaminopyridine (180 mg, 1.43 mmol, Bid) and triethylamine (6.00 mL, 43.0 mmol, Bid) were dissolved in dichloromethane (150 mL). Acetyl chloride (1.58 g, 20.1 mmol, Bid) was slowly added dropwise at 0°C. The reaction solution was stirred at 0°C for 1 hour. The reaction solution was quenched with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 100 / 1 to 10 / 1). The resulting compound was identified as compound 1n by two-dimensional nuclear magnetic resonance spectroscopy. MS m / z (ESI): 380.0 [M+H] + . 1 H NMR (400MHz, CDCl3): δ10.22(s,1H),8.84(s,1H),8.39(s,1H),4.67–4.54(m,1H),4.02(d, J=6.4Hz,2H),2.27–2.14(m,4H),2.12–2.06(m,5H),1.92–1.83(m,1H),1.41–1.32(m,2H).

[0514] 9) Step 9: Compound 1n (2.40 g, 6.31 mmol) was dissolved in dichloromethane (40 mL) and diethylaminosulfur trifluoride (5.80 mL, 44.2 mmol, Bid) was slowly added dropwise at 0°C. The reaction solution was warmed to 25°C and stirred at this temperature for 4 hours. The reaction solution was slowly poured into a cooled saturated aqueous sodium bicarbonate solution (100 mL). The aqueous phase was separated and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with (petroleum ether / tetrahydrofuran=100 / 1 to 10 / 1) to obtain compound 1o. MS m / z(ESI):403.8[M+H] + . 1 H NMR (400MHz, CDCl3): δ8.81(d,J=1.0Hz,1H),8.01(s,1H),6.96(t,J=54.3Hz,1H),4.56–4.46(m,1H) ,4.00(d,J=6.4Hz,2H),2.20–2.14(m,2H),2.12–2.04(m,6H),1.89–1.78(m,1H),1.39–1.25(m,3H).

[0515] 10) Step 10: Compound 1o (1.00 g, 2.49 mmol), hexa-n-butylditin (1.6 mL, 3.23 mmol, Bidex), lithium chloride (0.530 g, 12.4 mmol, Bidex), tris(dibenzylideneacetone)dipalladium (230 mg, 0.250 mmol, Bidex), and tricyclohexylphosphine (140 mg, 0.500 mmol, Bidex) were dissolved in 1,4-dioxane (15 mL). The reaction mixture was purged with nitrogen three times and stirred at 100°C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to provide compound 1p. MS m / z (ESI): 614.3 [M+H] + . 1 H NMR (400MHz, CDCl3): δ9.22(d,J=1.3Hz,1H),7.89(s,1H),6.99(t,J=54.5Hz,1H),4.58–4.47(m,1H),4.00(d,J=6.4Hz,2H),2.20– 2.12(m,3H),2.11–2.01(m,6H),1.88–1.81(m,1H),1.66–1.54(m,8H),1.38–1.31(m,8H),1.19–1.15(m,4H),0.89(t,J=7.3Hz,9H).

[0516] 11) Step 11: Compound 1p (660 mg, 1.08 mmol), compound 1e (371 mg, 1.29 mmol), cuprous iodide (41.1 mg, 0.220 mmol, Bidex), and tetrakis(triphenylphosphine)palladium (125 mg, 0.110 mmol, Bidex) were dissolved in dioxane (10 mL). The reaction solution was sparged with nitrogen for 1 minute and stirred at 100°C for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1 to 1 / 1) to provide compound 1q. MS m / z (ESI): 483.2 [M+H] + .

[0517] 12) Step 12: Compound 1q (900 mg, 1.87 mmol) was dissolved in methanol (10 mL) and potassium carbonate (773 mg, 5.60 mmol, Bis-Des) was added at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (50 mL) and methanol (5 mL). The mixture was acidified with ethanolic hydrochloric acid (4.0 M) to a pH of approximately 6-7. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 1r. MS m / z (ESI): 441.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ9.48(d,J=1.2Hz,1H),9.18(s,1H),8.88(d,J=2.3Hz ,1H),8.64(d,J=2.3Hz,1H),8.23–7.95(m,1H),7.82(d,J=4.7Hz,1H),7.63–7 .33(m,2H),7.04(d,J=4.7Hz,1H),4.95–4.85(m,1H),4.54(t,J=5.3Hz,1H),3 .17(d,J=5.3Hz,2H),2.17–2.09(m,2H),1.99–1.89(m,4H),1.28–1.21(m,3H).

[0518] 13) Step 13: Compound 1r (150 mg, 0.340 mmol) was dissolved in N,N-dimethylformamide (3 mL) and dichloromethane (3 mL). Dess-Martin periodinane (289 mg, 0.680 mmol, Bis-Decanone) was added at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 15 / 1) to obtain compound 1s. MS m / z (ESI): 439.1 [M+H] + .

[0519] 14) Step 14: Compound 1h (134 mg, 0.330 mmol) was dissolved in N,N-dimethylformamide (2 mL). Triethylamine (25.4 mg, 0.250 mmol, Bid) was added at 25°C. The reaction mixture was stirred at 25°C for 5 minutes, followed by the addition of acetic acid (15.1 mg, 0.250 mmol, Bid) and sodium acetate borohydride (237 mg, 1.13 mmol, Bid). The reaction mixture was stirred for 5 minutes, followed by the addition of compound 1s (110 mg, 0.250 mmol), and the reaction mixture was stirred for 3 hours. A drop of water was added to the reaction mixture to quench the reaction. The residue was filtered and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 1. MS m / z (ESI): 832.6 [MH] - . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.48(s,1H),9.18(s,1H),8.88(d,J=1.9Hz,1H),8.64(d,J=2.1Hz,1H),8 .16–8.05(m,1H),7.82(d,J=4.7Hz,1H),7.62–7.34(m,2H),7.04(d,J=4.7Hz,1H),6.99–6.94(m,2H),6.89–6.84 (m,1H),5.36–5.31(m,1H),4.94–4.84(m,1H),3.63(s,3H),2.88(s,6H),2.70–2.61(m,3H),2.43–2.36(m,4H),2 .25–2.19(m,2H),2.14–2.08(m,2H),2.02–1.94(m,5H),1.71–1.65(m,3H),1.54–1.40(m,4H),1.25–1.20(m,2H).

[0520] Example 2

[0521] 1) Step 1: Compound 2a (398 mg, 1.48 mmol, Bid) was dissolved in toluene (5 mL), and compound 1f (500 mg, 1.48 mmol, prepared using the method disclosed in step 3 on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (138 mg, 0.300 mmol), and (2-amino-[1,1-biphenyl]-2-yl)(dicyclohexyl(2,6-diisopropoxy-[1,1-biphenyl]-2-yl)phosphoryl)palladium chloride (230 mg, 0.300 mmol) were added. Under nitrogen protection, lithium bis(trimethylsilyl)amide (7.40 mL, 7.40 mmol, 1.0 M tetrahydrofuran solution) was added dropwise. The reaction mixture was reacted at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 2b. MS m / z (ESI): 527.3 [M+1] + .

[0522] 2) Step 2: Compound 2b (60.0 mg, 0.110 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 2c. MS m / z (ESI): 427.3 [M+1] + .

[0523] 3) Step 3: Compound 2c (24.3 mg, 0.057 mmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). Triethylamine (5.77 mg, 0.057 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Then, 1s (25.0 mg, 0.06 mmol) and acetic acid (6.85 mg, 0.11 mmol) were added and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (36.1 mg, 0.17 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction system was directly concentrated and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the formate salt of compound 2. MS m / z(ESI):849.6[M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.49(d,J=1.2Hz,1H),9.19(s,1H),8.89(d,J=2.3Hz,1H),8.65(d,J=2.3Hz,1H),8. 17(s,1H),7.83(d,J=4.7Hz,1H),7.63–7.36(m,2H),7.04(d,J=4.7Hz,1H),6.99–6.94(m,1H),6.91–6.85(m,2H),5.39–5.3 1(m,1H),4.96–4.86(m,1H),3.63(s,3H),3.17–3.12(m,2H),2.97–2.83(m,2H),2.72–2.60(m,6H),2.45–2.39(m,2H),2.36 –2.29(m,2H),2.20–2.16(m,2H),2.14–2.09(m,2H),2.03–1.86(m,8H),1.76(s,1H),1.70–1.58(m,3H),1.25–1.15(m,2H).

[0524] Example 3

[0525] 1) The first step: Compound 1f (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification of patent application "WO2022012623 A"), compound 3a (533 mg, 2.22 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl) palladium (II) (248 mg, 0.300 mmol, Bid) and 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl (138 mg, 0.300 mmol, Bid) were dissolved in toluene (5 mL) and lithium bistrimethylsilylamide (7.40 mL, 7.40 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 3b. MS m / z (ESI): 498.4 [M+1] + .

[0526] 2) Step 2: Dissolve compound 3b (80.0 mg, 0.160 mmol) in dichloromethane (2 mL) and add trifluoroacetic acid (1 mL). Stir the reaction at 25°C for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain compound 3c.

[0527] MS m / z(ESI):398.5[M+1] +

[0528] 3) Step 3: Compound 3c (36.3 mg, 0.091 mmol) was dissolved in N,N-dimethylformamide (1 mL), and sodium acetate borohydride (76.9 mg, 0.361 mmol, Bidler) was added. The reaction mixture was stirred at 25°C for 5 minutes, and then 1s (40.1 mg, 0.091 mmol) was added. The reaction mixture was stirred at 25°C for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 3. MS m / z (ESI): 820.5 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.49(s,1H),9.19(s,1H),8.89(d,J=2.2Hz,1H),8.65(d,J=2.1Hz,1H),8.36(s,1H) ,8.11(s,1H),7.83(d,J=4.7Hz,1H),7.65–7.33(m,2H),7.05(d,J=4.7Hz,1H),6.99–6.94(m,2H),6.89–6.83(m,1H),5.38–5 .30(m,1H),4.97–4.86(m,1H),3.61(s,3H),3.11–3.04(m,2H),2.90(s,3H),2.75–2.58(m,3H),2.43–2.36(m,3H),2.35–2.3 2(m,1H),2.20–2.15(m,2H),2.15–2.08(m,2H),2.05–1.95(m,5H),1.78–1.74(m,2H),1.70–1.60(m,4H),1.27–1.13(m,2H).

[0529] Example 4

[0530] Compound 4a (28.2 mg, 0.091 mmol, prepared using the method disclosed for intermediate GS on page 550 of the specification of patent application "WO2022236058 A1") was dissolved in N,N-dimethylformamide (1 mL), and sodium acetate borohydride (57.7 mg, 0.271 mmol, Bidler) was added. The reaction solution was stirred at 25°C for 5 minutes, and then 1s (30.1 mg, 0.071 mmol) was added. The reaction solution was stirred at 25°C for an additional 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the formate salt of compound 4. MS m / z(ESI):766.4[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.10(s,1H),9.51(d,J=1.2Hz,1H),9.20(s,1H),8.90(d,J=2.3Hz,1H),8.65(d,J= 2.3Hz,1H),8.45(s,1H),8.11(s,1H),7.83(d,J=4.7Hz,1H),7.66–7.33(m,2H),7.05(d,J=4.7Hz,1H),7.02– 6.94(m,2H),6.92–6.87(m,1H),5.48–5.26(m,1H),5.01–4.85(m,1H),3.65(s,3H),3.06–2.86(m,8H),2.75– 2.68(m,2H),2.30–2.26(m,2H),2.21–2.10(m,3H),2.07–1.97(m,5H),1.79–1.69(m,1H),1.32–1.19(m,2H).

[0531] Example 5

[0532] 1) Step 1: Compound 1f (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 5a (179 mg, 0.660 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (111 mg, 0.130 mmol, adamas) were dissolved in toluene (5 mL) and lithium bis(trimethylsilyl)amide (2.6 mL, 2.60 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 5b. MS m / z (ESI): 527.3 [M+1] + .

[0533] 2) Step 2: Compound 5b (78.0 mg, 0.150 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain compound 5c. MS m / z (ESI): 427.3 [M+1] + .

[0534] 3) Step 3: Compound 5c (46.7 mg, 0.110 mmol) was dissolved in N,N-dimethylformamide (1 mL) and triethylamine (9.23 mg, 91 μmol) was added at 25°C. The reaction solution was stirred at 25°C for 5 minutes, followed by the addition of acetic acid (5.48 mg, 91 μmol) and sodium acetate borohydride (115 mg, 0.540 mmol, Bid). The reaction solution was stirred for 5 minutes, followed by the addition of compound 1s (40.0 mg, 91 μmol), and the reaction solution was stirred for 3 hours. A drop of water was added to the reaction mixture to quench the reaction. The residue was filtered and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 5. MS m / z (ESI): 425.2 [M / 2+H] + .1 H NMR (400MHz, DMSO-d6): δ11.08(s,1H),9.49(d,J=1.1Hz,1H),9.18(s,1H),8.89(d,J=2.2Hz,1H),8.64 (d,J=2.3Hz,1H),8.10(s,1H),7.82(d,J=4.7Hz,1H),7.65–7.30(m,2H),7.04(d,J=4.7H z,1H),7.01–6.95(m,1H),6.94–6.90(m,1H),6.89–6.85(m,1H),5.38–5.32(m,1H),4.96– 4.84(m,1H),3.62(s,3H),2.95–2.80(m,7H),2.75–2.57(m,3H),2.25–2.10(m,5H),2.03– 1.85(m,8H),1.81–1.75(m,2H),1.72–1.64(m,1H),1.51–1.42(m,2H),1.28–1.12(m,4H).

[0535] Example 6

[0536] 1) Step 1: Compound 1f (300 mg, 0.890 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 6a (426 mg, 1.77 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (149 mg, 0.180 mmol, adamas) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (83.0 mg, 0.180 mmol, Bid) were dissolved in toluene (3 mL). Under nitrogen protection, lithium bistrimethylsilylamide (4.4 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction mixture was incubated at 80°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 6b. MS m / z (ESI): 498.3 [M+1] + .

[0537] 2) Step 2: Dissolve compound 6b (100 mg, 0.200 mmol) in dichloromethane (2 mL) and add trifluoroacetic acid (1 mL). Stir the reaction mixture at 20°C for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain crude compound 6c. MS m / z (ESI): 398.2 [M+1] + .

[0538] 3) Step 3: Compound 6c (55.0 mg, 0.14 mmol) and triethylamine (7.00 mg, 0.069 mmol) were added to N,N-diisopropylethylamine (3 mL) at room temperature and stirred for 2 minutes. Acetic acid (8.00 mg, 0.13 mmol), sodium acetate borohydride (43.0 mg, 0.20 mmol), and compound 1s (30.0 mg, 0.068 mmol) were added, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to water (10 mL) and extracted with ethyl acetate (3 mL x 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 10%-90%, flow rate: 25 mL / min) to obtain the formate salt of compound 6. MS m / z (ESI): 821.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.50–9.47(m,1H),9.19(s,1H),8.89(d,J=2.3Hz,1H),8.65(d,J= 2.3Hz,1H),8.11(s,1H),7.83(d,J=4.6Hz,1H),7.67–7.30(m,2H),7.05(d,J=4.7Hz,1H),7.01–6.97(m, 2H),6.88–6.86(m,1H),5.38–5.33(m,1H),4.95–4.88(m,1H),3.65(s,3H),2.99–2.85(m,4H),2.77–2.6 5(m,5H),2.38–2.33(m,3H),2.18–2.12(m,2H),2.03–2.00(m,5H),1.80–1.60(m,8H),1.24–1.21(m,2H).

[0539] Example 7

[0540] 1) Step 1: Compound 1f (518 mg, 1.53 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 7a (698 mg, 3.06 mmol, prepared by the method disclosed in patent application "US 2019 / 0192668A1" prepared by the method disclosed in intermediate 4 on page 858 of the specification), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (140 mg, 0.300 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.2 mg, 90.0 μmol, adamas) was dissolved in toluene (8 mL), and lithium bistrimethylsilylamide (8.9 mL, 8.87 mmol, 1 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction solution was reacted at 80 ° C under a nitrogen atmosphere for 1 hour. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 7b. MS m / z (ESI): 486.4 [M+1]. + .

[0541] 2) Step 2: Compound 7b (350 mg, 0.721 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was incubated at 25°C for 2 hours and then concentrated under reduced pressure to obtain compound 7c. MS m / z (ESI): 386.7 [M+1] + .

[0542] 3) Step 3: Compound 7c (26.3 mg, 0.068 mmol) was dissolved in N,N-dimethylformamide (1 mL), and sodium acetate borohydride (57.7 mg, 0.271 mmol, Bidler) was added. The reaction mixture was stirred at 25°C for 5 minutes, and then 1s (30.1 mg, 0.071 mmol) was added. The reaction mixture was stirred at 25°C for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 7. MS m / z (ESI): 808.5 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.07(s,1H),9.49(d,J=1.2Hz,1H),9.19(s,1H),8.89(d,J=2.2Hz,1H),8.65(d,J=2.3Hz,1H), 8.33(s,1H),8.11(s,1H),7.83(d,J=4.6Hz,1H),7.66–7.32(m,2H),7.05(d,J=4.7Hz,1H),6.91–6.83(m,1H),6.57–6.47( m,2H),5.34–5.25(m,1H),4.97–4.85(m,1H),4.60–4.53(m,1H),3.62(s,3H),2.99–2.81(m,2H),2.70–2.61(m,2H),2.36– 2.25(m,3H),2.24(s,3H),2.15–2.05(m,4H),2.03–1.94(m,5H),1.81–1.74(m,2H),1.64–1.53(m,1H),1.44–1.15(m,6H).

[0543] Example 8

[0544] Compound 8a (36.2 mg, 0.091 mmol, prepared using the method disclosed for intermediate APT on page 91 of the specification of patent application "WO2021247899 A1") was dissolved in N,N-dimethylformamide (1 mL), and sodium acetate borohydride (76.9 mg, 0.361 mmol, Bidler) was added. The reaction solution was stirred at 25°C for 5 minutes, and then 1s (40.1 mg, 0.091 mmol) was added. The reaction solution was stirred at 25°C for an additional 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 8. MS m / z(ESI):819.5[M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.13(s,1H),9.49(s,1H),9.19(s,1H),8.89(d,J=2.2H z,1H),8.65(d,J=2.2Hz,1H),8.41(s,1H),8.11(s,1H),7.83(d,J=4.7Hz,1H),7. 64–7.35(m,2H),7.21–7.16(m,1H),7.15–7.11(m,1H),7.07–7.01(m,2H),5.45–5 .37(m,1H),4.95–4.83(m,1H),4.49(s,2H),3.66(s,3H),3.60–3.53(m,1H),2.94 –2.68(m,4H),2.20–2.09(m,5H),2.05–1.90(m,8H),1.77–1.59(m,2H),1.56–1.45(m,2H),1.24–1.15(m,2H).

[0545] Example 9

[0546] 1) Step 1: Compound 1f (200 mg, 0.590 mmol, prepared using the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 9a (355 mg, 1.77 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (55.0 mg, 0.120 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.0 mg, 90.0 μmol) were dissolved in toluene (3 mL). Under nitrogen protection, lithium bistrimethylsilylamide (4 mL, 4.00 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 9b. MS m / z (ESI): 458.3 [M+1] + .

[0547] 2) Step 2: Compound 9b (110 mg, 0.240 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain compound 9c. MS m / z (ESI): 358.4 [M+1] + .

[0548] 3) Step 3: Compound 9c (56.3 mg, 0.16 mmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). Triethylamine (15.9 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 1s (69.0 mg, 0.16 mmol) and acetic acid (18.9 mg, 0.31 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (166 mg, 0.79 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction system was directly concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 9. MS m / z(ESI):780.7[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.49(s,1H),9.19(s,1H),8.89(s,1H),8.65( s,1H),8.11(s,1H),7.87–7.77(m,1H),7.61–7.33(m,2H),7.07–6.86(m,4H),5.42–5. 29(m,1H),5.00–4.87(m,1H),3.65(s,3H),3.11–2.81(m,5H),2.72–2.58(m,3H),2.3 2–2.05(m,5H),2.03–1.91(m,4H),1.75–1.65(m,1H),1.27–1.19(m,5H),1.07(s,2H).

[0549] Example 10

[0550] 1) Step 1: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (88.0 mg, 120 μmol) was added to a solution containing compound 10a (600 mg, 1.20 mmol, prepared by the method disclosed in step 00146 on page 48 of the specification of patent application "WO2021262812A1"), compound 10b (905.0 mg, 2.40 mmol, Bid), potassium carbonate (500 mg, 3.60 mmol), dioxane (10 mL) and water (2 mL). The reaction solution was stirred at 110 ° C. under a nitrogen atmosphere for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate (50 mL × 3), washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-30% petroleum ether / ethyl acetate) to obtain compound 10c. MS m / z(ESI):671.0[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.87(d,J=8.1Hz,1H),7.69(s,1H),7.61(d,J=8 .1Hz,1H),7.51–7.46(m,2H),7.44–7.27(m,8H),7.20–7.15(m,1H),7.07–6.99(m,1H ),6.61(d,J=8.1Hz,1H),5.45(d,J=2.7Hz,4H),4.48–4.38(m,1H),4.13–3.98(m,2H) ,3.78(s,3H),3.07–2.84(m,2H),2.13–2.02(m,2H),1.93–1.79(m,2H),1.43(s,9H).

[0551] 2) Step 2: Palladium on carbon (30 mg, 10%) was added to a solution containing compound 10c (300.0 mg, 450 μmol), ethyl acetate (3 mL), and ethanol (3 mL) at room temperature. The reaction was purged with hydrogen three times and then allowed to react at 25°C for 12 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to yield compound 10d, which was used directly in the next step without purification. MS m / z (ESI): 493.4 [M+1] + .

[0552] 3) Step 3: Trifluoroacetic acid (1 mL) was added to a solution containing compound 10d (140.0 mg, 280 μmol) and dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound 10e, which was used directly in the next step without purification. MS m / z (ESI): 393.6 [M+1]+ .

[0553] 4) Step 4: Triethylamine (0.30 mL, 2.26 mmol) was added to a solution containing compound 10e (80.0 mg, 200 μmol), tetrahydrofuran (1 mL), and N,N-dimethylformamide (2 mL) and stirred for 30 minutes. Compound 1s (108.0 mg, 240 μmol) and acetic acid (0.5 mL) were then added to the solution and stirred for 30 minutes. Finally, sodium triacetoxyborohydride (129.0 mg, 610 μmol) was added to the reaction mixture. The reaction was also stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (A: 0.1% FA / H2O B: ACN, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to obtain the formate salt of compound 10. MS m / z (ESI): 815.6 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.50(d,J=1.2Hz,1H),9.19(s,1H),8.89(d,J=2.3Hz,1H),8.65(d,J=2.3Hz,1H),8 .10(s,2H),7.83(d,J=4.7Hz,1H),7.71–7.66(m,2H),7.63–7.34(m,2H),7.23–7.19(m,1H),7.16–7.10(m,1H),7.05(d,J =4.7Hz,1H),4.97–4.87(m,1H),4.44–4.37(m,1H),4.28–4.20(m,1H),3.73(s,3H),3.01(d,J=10.5Hz,2H),2.74–2.60(m ,2H),2.43–2.33(m,1H),2.27–2.22(m,2H),2.15–2.05(m,8H),2.03–1.96(m,5H),1.83–1.66(m,1H),1.29–1.20(m,2H).

[0554] Example 11

[0555] 1) Step 1: Compound 1f (400 mg, 1.18 mmol, using patent application "WO2022012623 A "prepared by the method disclosed in step 3 product on page 88 of the specification of the invention) was dissolved in a mixed solution of dioxane (10 mL) and water (1 mL), and 10b (580 mg, 1.54 mmol, Bid), potassium phosphate (753 mg, 3.55 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (150 mg, 0.18 mmol) were added. After stirring at 60 ° C for 3 hours, the reaction solution was poured into an aqueous solution (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 11a. MS m / z(ESI):453.3[M-55] + .

[0556] 2) Step 2: Compound 11a (100 mg, 0.20 mmol) was dissolved in dichloromethane (4 mL). Hydrogen chloride / dioxane (4 M, 4 mL) was added. After stirring at room temperature for 1 hour, the reaction solution was directly concentrated under reduced pressure to obtain compound 11b. MS m / z (ESI): 409.7 [M+1] + .

[0557] 3) Step 3: Compound 11b (55.9 mg, 0.14 mmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). Triethylamine (13.9 mg, 0.14 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 1s (60.0 mg, 0.14 mmol) and acetic acid (16.4 mg, 0.27 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (144 mg, 0.68 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction system was directly concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mM formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 11. MS m / z(ESI):416.2[M / 2+1] + . 1H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.52–9.47(m,1H),9.19(s,1H),8.89(d,J=2.3Hz,1H),8.64(d,J=2.3Hz,1H) ,8.10(s,1H),8.03(m,1H),7.82(d,J=4.7Hz,1H),7.62–7.35(m,3H),7.15–7.08(m,1H),7.07–7.01(m,2H),6.92–6.8 8(m,1H),5.44–5.39(m,1H),4.96–4.86(m,1H),4.25–4.16(m,1H),3.06(s,3H),3.02–2.97(m,2H),2.94–2.87(m,1H) ,2.79–2.70(m,1H),2.67–2.60(m,1H),2.27–2.20(m,2H),2.14–1.96(m,13H),1.76–1.67(m,1H),1.28–1.16(m,2H).

[0558] Example 12

[0559] 1) Step 1: To a solution of compound 12a (5.15 g, 25.7 mmol) in methanol (50 mL) at room temperature were added 1-benzyloxycarbonyl-4-piperidone (5.00 g, 21.4 mmol) and acetic acid (4.90 mL, 85.7 mmol). The mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (6.73 g, 107 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was quenched by addition of water (1 mL). The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 12b. MS m / z (ESI): 418.7 [M+1] + .

[0560] 2) Step 2: To a solution of compound 12b (2.00 g, 4.79 mmol) in methanol (30 mL) at room temperature was added wet palladium on carbon (50.0 mg, 10%). The system was purged with hydrogen three times, and the reaction was stirred under hydrogen for 18 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was used directly in the next reaction without further purification to obtain compound 12c. MS m / z (ESI): 284.3 [M+1] + .

[0561] 3) Step 3: To a solution of compound 12c (754 mg, 2.66 mmol) in toluene (10 mL) were added compound 1f (600 mg, 1.78 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (82.8 mg, 0.18 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II) (148 mg, 0.18 mmol), and lithium bis(trimethylsilyl)amide (8.87 mL, 8.87 mmol, 1 M tetrahydrofuran solution) at room temperature. The system was purged with nitrogen three times, and the reaction was stirred at 80°C for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 12d. MS m / z (ESI): 541.5 [M+1] + .

[0562] 4) Step 4: Trifluoroacetic acid (1 mL) was added to a solution containing compound 12d (100.0 mg, 185 μmol) and dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 12e, which was used directly in the next step without purification.

[0563] 5) Step 5: Compound 12e (42.2 mg, 0.120 mmol) was dissolved in N,N-dimethylformamide (1 mL), and triethylamine (9.69 mg, 0.100 mmol) was added. The reaction mixture was stirred at 25°C for 5 minutes. Acetic acid (5.66 mg, 0.100 mmol) and sodium acetate borohydride (101 mg, 0.480 mmol) were added. After stirring for 5 minutes, compound 1t (35.0 mg, 80.0 μmol) was finally added. The reaction mixture was stirred for 1 hour. Two drops of water were added to quench the reaction mixture, and the residue was filtered and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 12. MS m / z(ESI):863.8[M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.08(s,1H),9.48(s,1H),9.18(s,1H),8.89(d,J=2.3Hz,1H),8.64(d,J=2.2Hz,1H),8.10(s ,1H),7.82(d,J=4.6Hz,1H),7.70–7.29(m,2H),7.04(d,J=4.7Hz,1H),6.99–6.93(m,1H),6.92–6.84(m,2H),5.37–5.3 2(m,1H),4.98–4.82(m,1H),3.62(s,3H),3.16–3.11(m,2H),2.91–2.81(m,2H),2.77–2.59(m,6H),2.35–2.26(m,3H), 2.17–2.08(m,4H),2.05–1.96(m,5H),1.91–1.84(m,3H),1.69–1.55(m,3H),1.25–1.21(m,3H),1.01(d,J=6.0Hz,3H).

[0564] Example 13

[0565] 1) Step 1: Compound 9a (4.50 g, 22.5 mmol) and 1-benzyloxycarbonyl-4-piperidone (5.00 g, 21.4 mmol) were dissolved in methanol (80 mL), and acetic acid (2 mL) was added to the reaction solution. After the reaction solution was stirred at 25°C for 1 hour, sodium cyanoborohydride (3.00 g, 62.8 mmol) was added. The reaction solution was stirred for 2 hours. The reaction solution was poured into water (100 mL) and extracted three times with ethyl acetate (80 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 15 / 1) to obtain compound 13a. MS m / z (ESI): 418.7 [M+H] + .

[0566] 2) Step 2: Compound 13a (2.80 g, 2.71 mmol) was dissolved in methanol (30 mL), and wet palladium on carbon (200 mg, 10%) was added to the reaction mixture. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (1 atm) for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13b, which was used directly in the next reaction without purification. MS m / z (ESI): 284.2 [M+H] + .

[0567] 3) The third step: Compound 1f (450 mg, 1.33 mmol), 13b (565.7 mg, 2.01 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (124 mg, 0.27 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (223 mg, 0.27 mmol) were added to the mixture. ol) was dissolved in toluene (8 mL), and lithium bistrimethylsilylamide (6.65 mL, 6.65 mmol, 1 M solution in tetrahydrofuran) was added. The reaction was carried out at 80°C under a nitrogen atmosphere for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 13c. MS m / z (ESI): 541.6 [M+1]. + .

[0568] 4) Step 4: Compound 13c (90 mg, 0.171 mmol) was dissolved in dioxane (0.5 mL), and hydrogen chloride / dioxane (2 mL, 4 M) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 13d. MS m / z (ESI): 441.4 [M+1] + ;

[0569] 5) Step 5: Compound 13d (50.2 mg, 0.111 mmol) was dissolved in N,N-dimethylformamide (1 mL), and sodium acetate borohydride (72.5 mg, 0.341 mmol) was added. The reaction mixture was stirred at 25°C for 5 minutes, and then 1t (50 mg, 0.111 mmol) was added. The reaction mixture was stirred at 25°C for an additional 30 minutes. After concentration under reduced pressure, the residue was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 13. MS m / z (ESI): 863.8 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.49(s,1H),9.19(s,1H),8.89(d,J=2.2Hz,1H),8.65(d,J=2.3Hz,1H),8.11(s,1H) ,7.83(d,J=4.7Hz,1H),7.65–7.33(m,2H),7.05(d,J=4.7Hz,1H),6.97(d,J=7.8Hz,1H),6.93–6.84(m,2H),5.41–5.32(m,1H ),4.98–4.86(m,1H),3.63(s,3H),3.18–3.12(m,2H),2.94–2.84(m,2H),2.81–2.55(m,7H),2.39–2.23(m,4H),2.19–2.08(m ,4H),2.05–1.96(m,4H),1.95–1.83(m,4H),1.66–1.58(m,2H),1.32–1.22(m,1H),1.19–1.07(m,1H),1.01(d,J=6.1Hz,3H).

[0570] Example 14

[0571] 1) Step 1: Compound 15a (100 mg, 309 μmol, prepared by the method disclosed in product B25 of step 5 on page 209 of the specification of patent application "WO2023083194 A1") was dissolved in a mixed solution of dioxane (4 mL) and water (0.5 mL), and 15a-1 (234 mg, 618 μmol), potassium carbonate (128 mg, 927 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (II) (22.6 mg, 30.9 μmol) were added. The nitrogen atmosphere was replaced three times, and the reaction was stirred at 100 ° C. for 2 hours. The reaction solution was poured into an aqueous solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 15b. MS m / z(ESI):516.3[M+23] + .

[0572] 2) Step 2: Compound 15b (100 mg, 203 μmol) was dissolved in dichloromethane (4 mL). Hydrogen chloride / dioxane (4 mL, 4 M) was added and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to afford compound 15c, which was used directly as the starting material for the next step without purification. MS m / z (ESI): 394.6 [M+1]+ .

[0573] 3) Step 3: Compound 15c (44.9 mg, 114 μmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). Triethylamine (11.5 mg, 114 μmol) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 1t (50.0 mg, 114 μmol) and acetic acid (13.7 mg, 228 μmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (120 mg, 570 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction system was directly concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 15. MS m / z(ESI):816.6[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.57(s,1H),9.50–9.48(m,1H),9.19(s,1H),8.89(d,J=2.3Hz,1H),8.64(d,J=2.3 Hz,1H),8.16–8.03(m,2H),7.89–7.78(m,1H),7.67(s,1H),7.63–7.34(m,3H),7.28–7.20(m,1H),7.18–7.10( m,1H),7.07–7.01(m,1H),5.05–4.81(m,1H),4.33–4.17(m,1H),3.90(t,J=6.7Hz,2H),3.72(s,3H),3.12–2.9 3(m,2H),2.78(t,J=6.7Hz,2H),2.29–2.21(m,2H),2.16–1.93(m,12H),1.79–1.66(m,1H),1.38–1.08(m,2H).

[0574] Example 15

[0575] 1) Step 1: Compound 1-Cbz-4-piperidone (5.00 g, 21.4 mmol), compound 16a (5.15 g, 25.7 mmol), anhydrous methanol (100 mL), and acetic acid (1.21 mL, 21.4 mmol) were added to a single-necked flask and stirred until dissolved. Sodium cyanoborohydride (2.69 g, 42.8 mmol) was added, and the reaction solution was stirred at 45°C for 18 hours. Aqueous sodium hydroxide solution (1 M) was added dropwise to adjust the pH to approximately 7. The solution was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by reverse phase purification (acetonitrile / aqueous formic acid solution (0.1%) = 0-100%) to obtain compound 16b. MS m / z (ESI): 418.4 [M+1] + .

[0576] 2) Step 2: Compound 16b (1.50 g, 3.59 mmol) and anhydrous methanol (30 mL) were added to a single-necked flask and stirred until dissolved. Wet palladium on carbon (150 mg, 10%) was added, and the reaction system was replaced with hydrogen three times. Under a hydrogen atmosphere (15 psi), the reaction mixture was stirred at room temperature for 18 hours. The reaction solution was filtered through celite, and the filter cake was washed with methanol (10 mL x 3). The filtrates were combined and evaporated to dryness under reduced pressure to obtain compound 16c. MS m / z (ESI): 284.2 [M+1] + .

[0577] 3) Step 3: Compound 16c (1.02 g, 3.59 mmol), compound 1f (950 mg, 2.81 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.26 g, 0.56 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (0.47 g, 0.56 mmol) and anhydrous toluene (20 mL) were added to a three-necked flask, and the reaction system was replaced with nitrogen three times. Lithium bistrimethylsilylamide (14.1 mL, 14.1 mmol, 1 M tetrahydrofuran solution) was added, and the reaction mixture was reacted at 80°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 16d. MS m / z (ESI): 541.4 [M+1]. + .

[0578] 4) Step 4: Trifluoroacetic acid (1 mL) was added to a solution containing compound 16d (100.0 mg, 185 μmol) and dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 16e, which was used directly in the next step without purification. MS m / z (ESI): 441.3 [M+1] + .

[0579] 5) Step 5: Triethylamine (0.20 mL, 1.44 mmol) was added to a solution containing compound 16e (50.0 mg, 110 μmol), tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL) and stirred for 30 minutes. Then, compound 1t (60.0 mg, 137 μmol) and acetic acid (0.5 mL) were added to the above solution and stirred for 30 minutes. Finally, sodium triacetoxyborohydride (73.0 mg, 340 μmol) was added to the reaction mixture, followed by stirring at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (A: 0.1% FA / H2O B: ACN, column: Waters-SunFire-C18-10μm-19×250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to obtain the formate salt of compound 16. MS m / z (ESI): 863.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.50(d,J=1.3Hz,1H),9.19(d,J=1.2Hz,1H),8.89(d,J=2.3Hz,1H),8.65( d,J=2.3Hz,1H),7.85–7.81(m,1H),7.64–7.33(m,2H),7.05(d,J=4.7Hz,1H),7.01–6.85(m,3H),5.38–5.33(m,1H ),4.96–4.86(m,1H),3.64(s,3H),3.19–3.11(m,2H),2.81–2.60(m,8H),2.17–2.11(m,4H),2.02–1.97(m,4H),1 .89–1.73(m,3H),1.73–1.55(m,3H),1.51–1.39(m,1H),1.27–1.19(m,6H),1.10–1.01(m,3H),0.92–0.81(m,1H).

[0580] Example 16

[0581] 1) Step 1: Compound 17a (2.27 g, 8.92 mmol, using the synthesis method of compound R-3 on page 225 of the specification of patent application "WO2021055756 A1"), anhydrous acetonitrile (20 mL) and water (20 mL) were added to a single-necked flask and stirred until dissolved. Sodium carbonate (2.84 g, 26.8 mmol) and benzyl chloroformate (2.54 mL, 17.9 mmol) were added, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was separated by reverse phase column (acetonitrile / 0.1% formic acid aqueous solution = 0-100%) to obtain compound 17b. MS m / z (ESI): 333.2 [M-55] + .

[0582] 2) Step 2: Compound 17b (2.05 g, 5.28 mmol) was dissolved in a hydrogen chloride / dioxane solution (4.0 M, 20 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 17c. MS m / z (ESI): 289.6 [M+H] + .

[0583] 3) Step 3: Compound 1f (1.20 g, 3.55 mmol), compound 17c (1.54 g, 5.32 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (170 mg, 0.350 mmol, Bidex), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (300 mg, 0.350 mmol, Bidex) were dissolved in toluene (20 mL). The reaction mixture was purged with nitrogen three times at 25°C, and lithium bis(trimethylsilyl)amide (17.7 mL, 17.7 mmol, 1.0 M solution in tetrahydrofuran, Bidex) was added under a nitrogen atmosphere. The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction solution was poured into a cooled saturated aqueous ammonium chloride solution (50 mL) and diluted with dichloromethane (100 mL). The aqueous phase was separated and extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 50 / 1) to obtain compound 17d. MS m / z (ESI): 546.4 [M+H] + . 1H NMR (400MHz, DMSO-d6): δ11.10–11.07(m,1H),7.43–7.23(m,4H),7.20–6.84(m,4H),5.38–5.31(m,1H),5.09–5.02(m,1H),3.86(s,1H) ,3.62(s,2H),3.32(s,4H),3.20–2.80(m,4H),2.74–2.58(m,3H),2.49–2.31(m,2H),2.06–1.89(m,2H),1.68–1.42(m,3H),1.24(s,3H).

[0584] 4) Step 4: Compound 17d (860 mg, 1.58 mmol) and wet palladium on carbon (168 mg, 10%) were mixed with methanol (15 mL). The mixture was replaced with hydrogen three times at 25°C and stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanolic ammonia solution (7.0 M) = 100 / 1 to 10 / 1) to obtain compound 17e. MS m / z (ESI): 412.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.02–6.96(m,1H),6.93–6.88(m,1H),6.56(d,J=7.2Hz,1H),5.23–5.02(m,1H),3.77(s,3H),3.30–3.23(m ,1H),3.05(s,2H),2.87–2.72(m,4H),2.47–2.34(m,4H),2.24–2.19(m,1H),1.90–1.73(m,3H),1.71–1.55(m,2H),1.21(s,3H).

[0585] 5) Step 5: Compound 17e (70.1 mg, 0.171 mmol) was dissolved in N,N-dimethylformamide (2 mL), and sodium acetate borohydride (180.1 mg, 0.851 mmol, Bidler) was added. The reaction mixture was stirred at 25°C for 5 minutes, and then 1t (74.5 mg, 0.171 mmol) was added. The reaction mixture was stirred at 25°C for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain the formate salt of compound 17. MS m / z (ESI): 832.8 [M-1] - ;1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.50(s,1H),9.20(s,1H),8.89(d,J=2.2Hz,1H),8.65(d,J=2 .2Hz,1H),8.15(s,1H),8.12(s,1H),7.83(d,J=4.7Hz,1H),7.66–7.32(m,2H),7.07–6.85(m,4H),5. 41–5.30(m,1H),4.99–4.86(m,1H),3.65(s,3H),3.08–2.96(m,2H),2.95–2.76(m,3H),2.75–2.58(m ,4H),2.27–2.06(m,5H),2.06–1.82(m,6H),1.81–1.66(m,4H),1.61–1.27(m,3H),1.25–1.05(m,4H).

[0586] Example 17

[0587] 1) Step 1: Compound 18a (3.00 g, 13.7 mmol, Anaiji) was dissolved in dichloromethane (35 mL), cooled to 0°C, and Dess-Martin periodinane (8.70 g, 20.5 mmol) was added. The reaction was stirred at room temperature for 16 hours, and then the reaction system was poured into an aqueous sodium bicarbonate solution (100 mL), extracted with dichloromethane (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 4 / 1) to obtain compound 18b. 1 H NMR (400MHz, DMSO-d6): δ5.18–5.02(m,1H),4.36–4.25(m,1H),4.06–3.98(m ,1H),3.30–3.18(m,2H),2.60–2.54(m,1H),2.40–2.35(m,3H),1.45(s,9H).

[0588] 2) Step 2: Compound 18b (2.00 g, 9.21 mmol) was dissolved in 1,2-dichloroethane (40 mL), and benzyl-1-piperazine carbonate (4.06 g, 18.4 mmol) and acetic acid (1.11 g, 18.4 mmol) were added. The reaction was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (3.90 g, 18.4 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction system was poured into aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain compound 18c. MS m / z (ESI): 422.7 [M+1] + .

[0589] 3) Step 3: Compound 18c (1.60 g, 3.80 mmol) was dissolved in dichloromethane (10 mL). Hydrogen chloride / dioxane (4 M, 10 mL) was added and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to afford compound 18d, which was used directly in the next step without purification. MS m / z (ESI): 322.6 [M+1] + .

[0590] 4) Step 4: Compound 1f (300 mg, 887 μmol), 18d (570 mg, 1.77 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41.4 mg, 88.7 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.2 mg, 88.7 μmol) were dissolved in toluene (15 mL). Under nitrogen, lithium bis(trimethylsilyl)amide (4.44 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and water (40 mL) was added. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 18e. MS m / z (ESI): 579.4 [M+1]. + .

[0591] 5) Step 5: Compound 18e (100 mg, 173 μmol) was dissolved in methanol (10 mL), and palladium on carbon (10%, 100 mg) was added. The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere (1 atm) for 18 hours. The reaction mixture was filtered, and the organic phase was concentrated. The residue was used directly as the starting material for the next step without purification to obtain compound 18f. MS m / z (ESI): 445.5 [M+1] + .

[0592] 6) Step 6: Compound 18f (30.4 mg, 68.4 μmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). 1t (30.0 mg, 68.4 μmol) and acetic acid (8.22 mg, 137 μmol) were added and stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (72.2 mg, 342 μmol) was added and stirred at room temperature for 30 minutes. The reaction system was directly concentrated and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 18. MS m / z (ESI): 867.8 [M+1]. + . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.54–9.45(m,1H),9.28–9.15(m,1H),8.89(d,J=2.3Hz,1H) ,8.64(d,J=2.3Hz,1H),8.10(s,1H),7.89–7.78(m,1H),7.67–7.34(m,2H),7.09–7.02(m,1H),7.02– 6.88(m,3H),5.42–5.29(m,1H),5.16–4.99(m,1H),4.96–4.84(m,1H),3.65(s,3H),3.21–2.78(m,5 H),2.75–2.58(m,5H),2.48–2.31(m,4H),2.28–1.92(m,11H),1.82–1.62(m,2H),1.27–1.11(m,3H).

[0593] Example 18

[0594] 1) Step 1: Compound 10a (800 mg, 1.60 mmol) was added to a single-necked flask at room temperature and stirred with toluene (5 mL). Compound 2a (862 mg, 3.20 mmol), tris(dibenzylideneacetone)dipalladium (147 mg, 0.16 mmol), sodium tert-butoxide (460.0 mg, 4.80 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (100.0 mg, 0.16 mmol) were then added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-5% dichloromethane / methanol) to obtain compound 19a. MS m / z (ESI): 690.0 [M+1]. + .

[0595] 2) Step 2: 10% palladium on carbon (20 mg) was added to a solution containing compound 19a (120.0 mg, 170 μmol), ethyl acetate (2 mL), and ethanol (2 mL) at room temperature. The reaction was purged with hydrogen three times and then allowed to react at 25°C for 16 hours. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to yield compound 19b.

[0596] 3) Step 3: Trifluoroacetic acid (1 mL) was added to a solution containing compound 19b (80.0 mg, 160 μmol) and dichloromethane (2 mL). The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude compound 19c. MS m / z (ESI): 411.7 [M+1] + .

[0597] 4) Step 4: Triethylamine (0.30 mL, 2.15 mmol) was added to a solution containing compound 19c (50.0 mg, 120 μmol), tetrahydrofuran (2 mL), and N,N-dimethylformamide (1 mL) and stirred for 30 minutes. Compound 1t (81.0 mg, 180 μmol) and acetic acid (0.5 mL) were then added to the solution and stirred for 30 minutes. Finally, sodium triacetylborohydride (77.0 mg, 360 μmol) was added and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain the formate salt of compound 19. MS m / z(ESI):833.7[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),9.50(d,J=1.3Hz,1H),9.19(d,J=1.3Hz,1H),8.89(d,J=2.3Hz, 1H),8.65(d,J=2.3Hz,1H),8.35(s,1H),7.83(d,J=4.7Hz,1H),7.65–7.34(m,3H),7.05–7.01(m,3H), 4.95–4.89(m,1H),4.37–4.31(m,1H),4.25(s,3H),3.29–3.26(m,1H),2.73–2.55(m,8H),2.44–2.30( m,6H),2.25–2.10(m,6H),2.08–1.95(m,6H),1.75–1.62(m,3H),1.51–1.39(m,1H),0.93–0.82(m,1H).

[0598] Example 19

[0599] 1) Step 1: Tris(dibenzylideneacetone)dipalladium (64 mg, 0.070 mmol) was added to a mixture containing compound 10a (350 mg, 0.70 mmol), compound 6a (252 mg, 1.05 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (44 mg, 0.07 mmol), sodium tert-butoxide (134 mg, 1.40 mmol), and toluene (20 mL). The atmosphere was purged with nitrogen three times and then stirred at 80°C for 18 hours under nitrogen. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to provide compound 20a. MS m / z (ESI): 660.6 [M+1]+. 1 H NMR(400MHz, DMSO-d6)δ7.85(d,J=8.0Hz,1H),7.51–7.45(m,2H),7.43–7.23(m,10H),6.96–6.90(m,1H),6.59(d,J=8.0Hz,1H),5.5 1–5.35(m,4H),4.33(s,3H),3.26(s,2H),3.22–3.04(m,3H),2.89–2.66(m,2H),2.58–2.52(m,1H),1.91–1.59(m,6H),1.42(s,9H).

[0600] 2) Step 2: Under nitrogen, palladium on carbon (10 mg, 10%) was added to a solution containing compound 20a (90 mg, 0.14 mmol), ethanol (2 mL), and ethyl acetate (2 mL) at room temperature. The mixture was replaced with hydrogen three times, and then stirred at 25°C under hydrogen (15 psi) for 18 hours. The reaction mixture was filtered, and the filter cake was washed twice with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to yield compound 20b. MS m / z (ESI): 482.4 [M+1] + .

[0601] 3) Step 3: Compound 20b (65 mg, 0.13 mmol) was mixed with hydrogen chloride / dioxane (3 mL, 4 M) and stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 20c. MS m / z (ESI): 382.6 [M+1] + ;

[0602] 4) Step 4: Compound 20c (39 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (3 mL), and triethylamine (10.4 mg, 0.103 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Acetic acid (9.2 mg, 0.15 mmol) and sodium triacetoxyborohydride (56 mg, 0.26 mmol) were then added. The mixture was stirred at room temperature for 10 minutes. Finally, compound 1t (45 mg, 0.103 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The reaction system was then concentrated and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 20. MS m / z (ESI): 804.7 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.89(s,1H),9.50(s,1H),9.19(s,1H),8.93–8.87(m,1H),8.68–8.6 2(m,1H),8.11(s,1H),7.86–7.81(m,1H),7.65–7.33(m,3H),7.08–6.98(m,3H),4.99–4.87(m, 1H),4.36–4.31(m,1H),4.26(s,3H),3.15–3.08(m,2H),2.84–2.71(m,2H),2.70–2.56(m,5H), 2.43–2.27(m,4H),2.20–2.09(m,3H),2.06–1.95(m,4H),1.84–1.62(m,7H),1.29–1.16(m,2H).

[0603] Example 20

[0604] 1) The first step: Compound 21a (3.30 g, 13.0 mmol, prepared by the method disclosed in the product of step R-3 on page 225 of the specification of "WO2021055756A1") was dissolved in a mixed solution of water (15 mL) and acetonitrile (15 mL), and sodium carbonate (4.13 g, 38.9 mmol) was added, cooled to 0 ° C, and benzyl chloroformate (3.69 mL, 26.0 mmol) was added dropwise. After stirring at room temperature for 5 hours, the reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on silica gel plates (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 21b.

[0605] 2) Step 2: Compound 21b (1.10 g, 2.83 mmol) was dissolved in dichloromethane (5 mL). Hydrogen chloride / dioxane (5 mL, 4 M) was added and stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to afford compound 21c, which was used directly in the next step without purification. MS m / z (ESI): 289.4 [M+1] + .

[0606] 3) Step 3: Compound 1f (300 mg, 887 μmol), 21c (512 mg, 1.77 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41.4 mg, 88.7 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.2 mg, 88.7 μmol) were dissolved in toluene (15 mL). Under nitrogen, lithium bis(trimethylsilyl)amide (4.44 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 20 / 1) to obtain compound 21d. MS m / z (ESI): 546.4 [M+1]. + .

[0607] 4) Step 4: Compound 21d (60 mg, 110 μmol) was dissolved in methanol (5 mL), and palladium on carbon (10%, 60 mg) was added. The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere (1 atm) for 3 hours. The reaction mixture was filtered, and the organic phase was concentrated. The residue was used directly as the starting material for the next step without purification to obtain compound 21e. MS m / z (ESI): 412.4 [M+1] + .

[0608] 5) Step 5: Compound 21e (28.2 mg, 68.4 μmol) was dissolved in a mixture of N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL). Compound 1t (30.0 mg, 68.4 μmol) and acetic acid (8.22 mg, 137 μmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetoxyborohydride (72.3 mg, 342 μmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction system was then concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30 × 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 21. MS m / z (ESI): 833.7 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.08(s,1H),9.55–9.46(m,1H),9.21–9.15(m,1H),8.89(d,J=2.3Hz,1H) ,8.64(d,J=2.3Hz,1H),8.10(s,1H),7.87–7.79(m,1H),7.61–7.35(m,2H),7.06–7.02(m,1H),7.00– 6.85(m,2H),5.46–5.27(m,1H),4.97–4.82(m,1H),3.69–3.61(m,3H),3.45(s,1H),3.07–2.82(m,4 H),2.78–2.57(m,3H),2.48–2.26(m,2H),2.23–1.58(m,17H),1.35–1.22(m,2H),1.12–0.99(m,3H).

[0609] Example 21

[0610] 1) Step 1: Compound 22a (440 mg, 1.55 mmol, prepared by the method disclosed in Preparation 23 on page 45 of the specification of patent application "WO2013163262A1"), compound 1f (350 mg, 1.04 mmol, prepared by the method disclosed in Step 3 on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (100 mg, 0.214 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (175 mg, 0.209 mmol) and toluene (10 mL) were added to a three-necked flask, and the reaction system was replaced with nitrogen. Three times, lithium bis(trimethylsilylamide) (5.20 mL, 5.20 mmol, 1 M tetrahydrofuran solution) was added. The reaction solution was reacted at 80°C for 2 hours, then poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 22b. MS m / z (ESI): 541.6 [M+1]. + .

[0611] 2) Step 2: Compound 22b (250 mg, 0.462 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 22c, which was used directly in the next step without purification. MS m / z (ESI): 441.5 [M+1] + .

[0612] 3) Step 3: Compound 22c (150 mg, 0.340 mmol) and compound 1t (150 mg, 0.342 mmol) were dissolved in N,N-dimethylformamide (5 mL). Acetic acid (0.5 mL) and sodium acetate borohydride (300 mg, 1.42 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (A: 0.1% FA / H2O B: ACN, column: Waters-SunFire-C18-10μm-19×250mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to obtain the formate salt of compound 22. MS m / z (ESI): 863.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.49(s,1H),9.19(s,1H),8.89(d,J=2.2Hz,1H),8.65(d,J=2.2Hz,1H),8. 11(s,1H),7.83(d,J=4.6Hz,1H),7.62–7.37(m,2H),7.05(d,J=4.7Hz,1H),7.00–6.94(m,1H),6.93–6.89(m,1H), 6.89–6.85(m,1H),5.40–5.31(m,1H),4.96–4.86(m,1H),3.64(s,3H),3.18–3.12(m,2H),2.97–2.75(m,5H),2.74 –2.52(m,6H),2.23–2.08(m,5H),2.05–1.94(m,6H),1.87–1.59(m,5H),1.24–1.15(m,2H),1.06(d,J=6.1Hz,3H).

[0613] Biological tests:

[0614] Experimental Example 1: Hibit fluorescence detection of protein degradation

[0615] TM 9DNA Transfection Reagent (Roche #06365787001), 1 μg of IRAK4 plasmid was added to 200 μL of Opti-MEM (Gibico 31985062) and gently mixed. The 6-well plate was removed from the overnight incubation, allowed to stand at room temperature for 15 minutes, and then added dropwise to the 6-well plate. Six hours after transient transfection, cells were digested with trypsin (Gibco, 25200-056) for one minute and centrifuged at 1000 rpm for 3 minutes. 5000 HEK293T cells were seeded into 384-well plates (Corning 3765) with 40 μL of DMEM medium and placed in a 37°C, 5% CO2 incubator overnight. Then, 40 nL of compound was added to the 384-well plate using an Echo 655 Liquid Handler. The final concentration was 10 μM, and a 1:3 serial dilution was performed for a total of 10 concentrations. Incubate at 37°C, 5% CO2 for 24 hours. Remove the 384-well plate and equilibrate to room temperature. Add 40 μL of HiBiT Lytic Detection System (Promega N3030) was used for incubation at room temperature for 15 minutes, and fluorescence values ​​were recorded using an EnVision Xcite Multilabel Reader (PerkinElmer 2105-0020). Data were analyzed using Prism 9.3 software using a nonlinear, four-parameter (non-liner inhibitor (Bell-shaped)) fitting method with the following parameters:

[0616] Span1=Plateau1-Dip

[0617] Span2=Plateau2-Dip

[0618] Section1=Span1 / (1+10^((LogEC50_1-X)*nH1))

[0619] Section2=Span2 / (1+10^((X-LogEC50_2)*nH2))

[0620] The equation is as follows: Y=Dip+Section1+Section2.

[0621] Some Hibit test results are shown in Table 2.

[0622] Table 2 Note: Hibit DC 50≤0.5nM is A, 0.5nM<DC 50 ≤1nM is B, 1nM<DC 50 ≤5nM is C, 5nM<DC 50 Hibit D max ≥80% is A, 70% ≤ D max <80% is B, 60%≤D max <70% is C, D max <60% is D.

[0623] Experimental Example 2: WB detection of protein degradation

[0624] Western blot analysis was used to assess IRAK4 degradation in THP-1 cells. One million THP-1 cells were seeded in a 12-well plate (Corning 3513) with 1 mL per well. A 1000X serial dilution of compound stock was prepared, with a maximum concentration of 300 μM. The stock solution was serially diluted 1:3 in DMSO for a total of nine doses. The 1000X serial dilution of compound was added to the 12-well plate at 1 μL per well. The cells were incubated at 37°C, 5% CO₂ for 24 hours. The cells were harvested into a 2 mL centrifuge tube and centrifuged at 5000 rpm for 5 minutes. The supernatant was removed. 100 μL of RIPA lysis buffer (Beyotime, P0013C) was added, mixed, and the cells were lysed on ice for 10 minutes. The cells were then centrifuged at 14000 rpm for 10 minutes at 4°C, and the supernatant was collected. Protein content was determined using BCA assay (Solarbio, PC0020-10*50T). Take 75 μL of supernatant and add 25 μL NuPAGE LDS Sample Buffer (4X) (Thermo B0007) to each tube (add 5% β-mercaptoethanol before use) to prepare the sample, and boil it in a metal bath at 100°C for 5 minutes. Take 20 μL and load it on a 4-12% Bis-Tris gel (Invitrogen, WG1402BOX) to prepare a 1x NuPAGE. TM MOPS buffer (Invitrogen, NP0001) was used, and the electrophoresis apparatus was set to a constant voltage of 120 V for 1.5 hours. 1x NuPAGE was prepared. TMMOPS SDS electrophoresis buffer (20X) (Invitrogen, NP0001), the electrophoresis instrument was set to a constant current of 300 mA for 100 minutes, and the protein was transferred to a PVDF membrane (Millipore, IPVH00010). The PVDF membrane was blocked with blocking solution (Licor, 927-60001) at room temperature for 1 hour, and the IRAK4 antibody (Abcam ab32511) was diluted at 1:1000, and the GAPDH (Abcam ab8245) was diluted at 1:3000, and then incubated with the antibody at 4°C overnight. The next day, the membrane was washed three times with 1x TBST (Elabscience E-BC-R335), each time for 5 minutes. The secondary antibody IR Dye 800CW Goat anti-rabbit (Licor#926-32211) was diluted at 1:10000 and Incubate with 680RD Goat anti-Mouse (Licor #926-68070) at room temperature in the dark for 1 hour. Wash the membrane three times with TBST (5 minutes each). Signals were detected and data analyzed using the Licor Odyssey CLx imaging system. Data were analyzed using GraphPad (Prism 9.3) software, using a nonlinear four-parameter fit (non-liner inhibitor (Bell-shaped)) with the following parameters:

[0625] Span1=Plateau1-Dip

[0626] Span2=Plateau2-Dip

[0627] Section1=Span1 / (1+10^((LogEC50_1-X)*nH1))

[0628] Section2=Span2 / (1+10^((X-LogEC50_2)*nH2))

[0629] The equation is as follows: Y=Dip+Section1+Section2.

[0630] Some WB test activity results are shown in Table 3.

[0631] Table 3 Note: WB DC 50 ≤10nM is A, 10nM<DC 50 ≤30nM is B, 30nM<DC 50 C; WB D max ≥70% is A, 60% ≤ D max <70% is B, Dmax <60% is C.

[0632] The results of this test example show that the compound of the present application exhibits excellent target protein degradation in the experiment of detecting IRAK4 degradation in THP-1 cells based on Western Blot technology.

[0633] The results show that the compound of the present invention has good IRAK4 protein degradation ability and has the efficacy of being a protein degradation targeting chimera of IRAK4 kinase.

[0634] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula (A): or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, in: L A Selected from bonds and straight or branched C 1-4 Alkylene, the C 1-4 The alkylene group is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 Alkyl)2 is substituted by a substituent; L B A group selected from the following groups (1) to (21): (1)–CyL1–, (2)–CyL1–La–, (3)–CyL1–Lb–, (4)–CyL1–La–CyL2–La–, (5)–CyL1–NR L1 –, (6)–CyL1–C(O)–, (7)–CyL1–C(O)-NR L1 –, (8)–CyL1–NR L1 -C(O)–, (9)–CyL1–CyL2–, (10)–NR L1 -CyL1-La–, (11)–NR L1 -CyL1-Lb–, (12)–NR L1 -CyL3-NR L2 –, (13)–NR L1 -CyL3-La-NR L2 –, (14)–NR L1 -CyL1-C(O)–, (15)–NR L1 -La-CyL1-La–, (16)–La–CyL1–, (17)–O-La–, (18)–S-La–, (19)–NR L1 -To–, (20)–CyL1–La–CyL2-, and (21)–CyL1–Lc–CyL4-, in: In the groups (1) to (21), the leftmost extending bond of each group is connected to L A The rightmost key is connected to the part, or the leftmost bond of each group is connected to the The rightmost key is connected to the L A , CyL1 and CyL2 are each independently selected from C 3-12 cycloalkylene or 3-12 membered heterocycloalkylene, wherein the heterocycloalkylene preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S, CyL3 is independently selected from C at each occurrence 3-12 Cycloalkylene, CyL4 is independently selected at each occurrence from a 5-12 membered heteroarylene group, La is independently selected at each occurrence from C 1-4 Hydrocarbylene, Lb is independently selected at each occurrence from a linear C 2-4 Hydrocarbylene, wherein the straight chain C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O), Lc is independently selected at each occurrence from a bond or C 1-4 Hydrocarbylene, CyL1, CyL2, CyL3, CyL4, La, Lb and Lc are each optionally substituted by one or more groups independently selected from the following: 1-4 Alkyl, C 1-4 Haloalkyl, halogen, OH, CN, NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2, preferably methyl, ethyl, F, Cl, Br, OH, CN and NH2, more preferably methyl, F, Cl and OH; and R L1 and R L2 Each is independently selected at each occurrence from H and C 1-4 alkyl; Said The part has the structure of formula (1): Wherein: X1, X2, X3, X4, X5, X6, X7, X8 and X9 can each independently be C, CR or N, provided that the valence of all atoms is satisfied, and X4 and X5 are not N at the same time; R, R 1 , R 4 and R 5 Each independently selected from: hydrogen, deuterium, R 7 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-S(O)2R 1f 、-S(O)R 1f 、-S(O)2-NR 1d R 1e 、-S(O)-NR 1d R 1e 、-P(O)(OR 1f )2、-P(O)(NR 1d R 1e )2. -CF(R 1f )2, -CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e 、-C(O)NR 1f -OR 1f 、-OC(O)R 1f 、-OC(O)NR 1d R 1e 、-NR 1f -C(O)OR 1f 、-NR 1f -C(O)R 1f 、-NR 1f -C(O)NR 1d R 1e and-NR 1f -S(O)2R 1f , p is 1, 2, or 3; n is 0, 1 or 2, wherein when n is 1 or 2, R 4 an available ring member connected to ring D; and R 5 Available ring members connected to ring C; R 2 Selected from: saturated or partially unsaturated C 3-7 Cycloalkylene; 3-7 membered saturated or partially unsaturated heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroarylene groups having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene groups are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocyclylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form a saturated or partially unsaturated optionally substituted C 3-7 Cycloalkyl or 3-7 membered saturated or partially unsaturated optionally substituted heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 and R 6 Each independently selected from: H, R 8 、Halogen、CN、NO2、C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2R 3f 、-S(O)R 3f 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-P(O)(OR 3f )2、-P(O)(NR 3d R 3e )2. -CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-(CR 3a R 3b ) q -OR 3f 、-(CR 3a R 3b ) q -C(O)OR 3f 、-(CR 3a R 3b ) q -NR 3d R 3e 、-C(O)R 3f 、-C(O)OR 3f and -C(O)NR 3d R 3e , q is 1, 2, or 3; and m is 0, 1, 2 or 3, wherein when m is 1, 2 or 3, R 6 Available ring members connected to ring B; R 1a , R 1b , R 3a and R 3b Each independently selected from hydrogen, deuterium, halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 ; R 1d , R 1e , R 2d , R 2e , R 3d , R 3e , R 7d and R 7e are each independently selected from hydrogen, deuterium, R 11 , C 1-6 Alkyl and C 1-6 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are attached, form R 10 ; R 1f , R 2f and R 3f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ; R 7 , R 8 , R 9 , R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; a 3-12 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents are substituted; R 10 is selected from: a 3-7 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-10 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, oxo (=O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e substituted with a substituent; and R 8d , R 8e , R 10d and R 10e are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 1-6 haloalkyl; and Said The part is the ligase binding part.

2. The compound according to claim 1, wherein L A Select from key, C 1-2 Alkylene, the C 1-2 The alkylene group is optionally substituted by one or more independently selected from C 1-2 Alkyl, C 1-2 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-2 Alkyl) and -N(C 1-2 alkyl) 2 is substituted with a substituent; preferably, L A Select from key, C 1-2 Alkylene, the C 1-2 The alkylene group is optionally substituted by one or more independently selected from C 1-2 alkyl, halogen, oxo (=O) substituent; further preferably, L A is selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)- and -C(=O)-; further preferably, L A It is a bond, -CH2- or -CH2-CH2-, more preferably -CH2-.

3. The compound according to any one of claims 1 or 2, wherein The part has the structure of formula (1), wherein: R 1 and R 4 Not simultaneously hydrogen or deuterium; and / or R 1a , R 1b , R 3a and R 3b Each is independently selected from hydrogen, halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 7d R 7e ; or R 1a and R 1b , or R 3a and R 3b , together with the carbon atom to which they are attached, form R 9 ; and / or R 1d , R 1e , R 2d , R 2e , R 3d , R 3e , R 7d and R 7e are each independently selected from hydrogen, R 11 , C 1-4 Alkyl and C 1-4 haloalkyl; or, R 1d and R 1e , or R 2d and R 2e , or R 3d and R 3e , or R 7d and R 7e , together with the nitrogen atom to which they are attached, form R 10 ; and / or R 1f , R 2f and R 3f are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl and R 12 ; and / or R 7 , R 8 , R 9 , R 11 and R 12 Each independently selected from: saturated or partially unsaturated C 3-6 Cycloalkyl; a 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e Substituents are substituted; and / or R 10 is selected from: a 3-6 membered saturated or partially unsaturated heterocyclyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, oxo (=O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 10d R 10e Substituents are substituted; and / or R 8d , R 8e , R 10d and R 10e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

4. The compound according to any one of claims 1 to 3, wherein the The part has the structure of formula (1), wherein: R 1 is not hydrogen; or R 1 Selected from: R 7 , halogen, CN, NO2, C 1-4 alkyl, -OR 1f , -SR 1f , -NR 1d R 1e , -S(O)2R 1f , -S(O)R 1f , -S(O)2-NR 1d R 1e , -S(O)-NR 1d R 1e , -P(O)(OR 1f )2, -P(O)(NR 1d R 1e )2, -CF(R 1f )2, -CF2(R 1f ), -CF3, -CCl(R 1f )2, -CCl2(R 1f ), -CCl3, -(CR 1a R 1b ) p -OR 1f , -(CR 1a R 1b ) p -C(O)OR 1f , -(CR 1a R 1b ) p -NR 1d R 1e , -C(O)R 1f , -C(O)OR 1f , -C(O)NR 1d R 1e , -C(O)NR 1f -OR 1f , -OC(O)R 1f , -OC(O)NR 1d R 1e , -NR 1f -C(O)OR 1f , -NR 1f -C(O)R 1f , -NR 1f -C(O)NR 1d R 1e or -NR 1f -S(O)2R 1f ; or R 1 Selected from: R 7 、Halogen、CN、NO2、C 1-4 Alkyl, -OR 1f 、-SR 1f 、-NR 1d R 1e 、-CF(R 1f )2, -CF2(R 1f )、-CF3、-CCl(R 1f )2、-CCl2(R 1f )、-CCl3、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: R 7 、halogen, CN, -OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e 。 5. The compound according to any one of claims 1 to 4, wherein the The part has the structure of formula (1), wherein: R 7 Selected from: C 3-6 Cycloalkyl; 4-6 membered saturated or partially unsaturated cycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur heterocyclyl; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e or R 7 Selected from: C 3-6 Cycloalkyl; 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -NR 8d R 8e Substituents are substituted; Where: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or, preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 7 is selected from the group consisting of azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or R 7 Selected from: azetidinyl, pyrrolidinyl and piperidinyl.

6. The compound according to any one of claims 1 to 5, wherein the The part has the structure of formula (1), wherein: p is 1; and / or R 1a and R 1b are each independently selected from hydrogen and C 1-6 Alkyl; or R 1a and R 1b are each independently selected from hydrogen and C 1-4 Alkyl; or R 1a and R 1b are each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: R 9 Selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e Substituents are substituted; Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, -NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 9 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 9 It is cyclopropyl.

7. A compound according to any one of claims 1 to 6, wherein the The part has the structure of formula (1), wherein: R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-6 Alkyl; or R 1d and R 1e are each independently selected from hydrogen, R 11 and C 1-4 Alkyl; or R 1d and R 1e are each independently selected from hydrogen, R 11 , methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl; a 3-6 membered saturated or partially cycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated heterocyclic group; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1- 4 alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e Substituents are substituted; More preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or Preferably, R 11 Selected from: C 3-6 cycloalkyl; and 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl and piperidinyl, each of which is optionally substituted with one or more substituents independently selected from F and Cl; or Preferably, R 11 Selected from cyclopropyl and and / or Preferably, R 10 is selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 10 is selected from the group consisting of azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1- 4 alkyl)2 substituent; or Preferably, R 10 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 10 Selected from: Each of them is optionally substituted by one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, oxo, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2.

8. A compound according to any one of claims 1 to 7, wherein the The part has the structure of formula (1), wherein: R 1f Selected from hydrogen and C 1-6 Alkyl; or R 1f Selected from hydrogen and C 1-4 Alkyl; or R 1f For hydrogen.

9. A compound according to any one of claims 1 to 8, wherein the The part has the structure of formula (1), wherein R 1 Selected from: F, Cl, Br, CN, OH, NH2, -NHCH3, -C(O)OH, -C(O)NH2, -CH2NH2, -CH2OH, Or, R 1 Selected from -CN, -C(O)NH2, F, -NHCH3, -C(O)OH, 10. The compound according to any one of claims 1 to 9, wherein the The part has the structure of formula (I-1): in, n is 0 or 1.

11. A compound according to any one of claims 1 to 9, wherein: R 1 is selected from hydrogen and deuterium, and n is 1 or 2; or R 1 is hydrogen, and n is 1; or Said Part has the structure of formula (I-2): The conditions are: R 4 Not hydrogen or deuterium.

12. A compound according to any one of claims 1 to 11, wherein: R 4 Selected from: hydrogen, R 7 、Halogen、CN、NO2、-OR 1f 、-SR 1f and-NR 1d R 1e ; Preferably, R 1d and R 1e are each independently selected from hydrogen and C 1-6 Alkyl; or Preferably, R 1d and R 1e are each independently selected from hydrogen and C 1-4 alkyl; and / or Preferably, R 1f Selected from hydrogen and C 1-6 Alkyl; or preferably, R 1f Selected from hydrogen and C 1-4 alkyl; or R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; or R 4 Selected from: hydrogen, R 7 and CN; in: Preferably, R 7 is selected from: 4-6 membered saturated monocyclic heterocyclic group, 8-10 membered saturated fused bicyclic heterocyclic group, 6-11 membered saturated spiro heterocyclic group and 7-10 membered saturated bridged heterocyclic group, each of which has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and -NR 8d R 8e or Preferably, R 7 is selected from: 4-6 membered saturated monocyclic heterocyclic groups and 7-10 membered saturated bridged heterocyclic groups, wherein the monocyclic heterocyclic groups and bridged heterocyclic groups have 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -NR 8d R 8e Substituents are substituted; Where: Preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-6 Alkyl; or preferably, R 8d and R 8e are each independently selected from hydrogen and C 1-4 alkyl; or Preferably, R 7 is selected from: a 4-6 membered saturated monocyclic heterocyclic group (e.g., azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl or thiomorpholinyl) and a 7-10 membered saturated bridged heterocyclic group, wherein the monocyclic heterocyclic group and the bridged heterocyclic group have 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CHCl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 7 Selected from: Each of them is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2, and wherein X 10 is CH2, (CH2)2 or (CH2)3; or Preferably, R 7 Selected from: Preferably, R 4 Selected from: hydrogen, CN, The condition is: when R 1 When it is hydrogen or deuterium, R 4 Not hydrogen.

13. A compound according to any one of claims 1 to 12, wherein: R and R 5 are each independently selected from hydrogen; and / or R 2 Selected from: C 3-6 Cycloalkylene; a 4-6 membered saturated or partially unsaturated heterocyclylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroarylene groups having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene groups are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -NR 2d R 2e 、-C(O)OR 2f and -C(O)NR 2d R 2e and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocyclylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein preferably, R 2d and R 2e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl, and / or R 2f Selected from hydrogen and C 1-6 Alkyl; or R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-4 Alkyl, -C(O)OH, -C(O)OC 1-4 alkyl, -C(O)NH2、-C(O)NH(C 1-4 alkyl) and -C(O)NH(C 1-4 alkyl)2, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 Selected from: cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylene, pyrrolylene, oxazoleylene, thiazolylene, pyrazolylene, imidazoleylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally substituted by 1, 2 or more independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl, isopropyl, tert-butyl wherein the substituents are substituted with a substituent selected from the group consisting of -C(O)OH, -C(O)OCH, -C(O)OCHCH, -C(O)NH, -C(O)NHCH and -C(O)N(CH), and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylidene, pyrrolylidene, oxazolylidene, thiazolylidene, pyrazolylidene, imidazolylidene, piperidinylidene, piperazinylidene, hexahydropyrimidinylidene, triazinylidene, morpholinylidene or thiomorpholinylidene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from the group consisting of cyclohexylidene, pyrrolidinylene, piperidinylene, phenylene and pyridinylene, each of which is optionally substituted with 1 or 2 substituents independently selected from F, Cl, Br, OH, NH2 and methyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclohexylidene, pyrrolidinylene or piperidinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 Selected from: or R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-S(O)2-NR 3d R 3e 、-S(O)-NR 3d R 3e 、-CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e ;or R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f )、-CCl3、-C(O)OR 3f and -C(O)NR 3d R 3e ;or R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-NR 3d R 3e 、-CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e ; Where: Preferably, R 3d and R 3e are each independently selected from hydrogen, deuterium, R 11 , C 1-4 Alkyl and C 1-4 A haloalkyl group, wherein R 11 Preferably selected from: C 3-6 Cycloalkyl; a 4-6 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 6-10 and 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio and -NR 8d R 8e substituted by a substituent, wherein preferably, R 8d and R 8e are each independently selected from hydrogen, C 1-4 Alkyl and C 1-4 haloalkyl; or Preferably, R 3d and R 3e are each independently selected from hydrogen, methyl and ethyl; and / or in: Preferably, R 3f Selected from hydrogen and C 1-6 Alkyl; or preferably, R 3f Selected from hydrogen and C 1-4 alkyl; or in: Preferably, R 3d and R 3e Together with the nitrogen atom to which they are attached, they form R 10 , where R 10 Preferably selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl and heteroaryl are optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 Alkyl)2 is substituted by a substituent; or R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, -CHF2, -CH2F, -CF3, -CH2Cl, -CHCl2, -CCl3, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)N(C 1-4 Alkyl)2; or R 3 Selected from: F, Cl, Br, OH, NH2, CN, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -N(CH3)2, -CHF2, -CHCl2 and -C(O)NH2; and / or R 6 Selected from: halogen, CN, NO2, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ) and -CCl3, where R 3f Preferably selected from hydrogen and C 1-6 Alkyl, or R 3f Preferably selected from hydrogen and C 1-4 Alkyl; or R 6 Selected from: F, Cl, Br, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2 and -CCl3; and / or m is 0.

14. A compound according to any one of claims 1 to 13, wherein: At least two of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time; or Three of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time; or Four of X1, X2, X3, X4 and X5 are N, provided that X4 and X5 are not N at the same time; Preferably, X1 is N; and / or At least 2 of X6, X7, X8 and X9 are N; or At least three of X6, X7, X8 and X9 are N; At least 4 of X6, X7, X8 and X9 are N; Preferably, X8 and X9 are each N; Preferably, 2 or 3 of X1, X2, X3, X4 and X5 are N, and X1 is N, provided that X4 and X5 are not N at the same time; and Three or four of X6, X7, X8, and X9 are N, and X8 and X9 are each N.

15. A compound according to any one of claims 1 to 14, wherein: X1 and X2 are each N; X3 is CH; X4 and X5 are each C; X6, X8 and X9 are each N; and X7 is CH; and / or Said The moiety has the structure of formula (Ii) or formula (I-ii): in: R 1 , R 2 , R 3 and R 4 Each as defined in any one of claims 1 to 14, provided that: R 1 Not hydrogen or deuterium; in: R 2 , R 3 and R 4 Each as defined in any one of claims 1 to 13, provided that: R 4 Not hydrogen or deuterium; Preferably, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e ; More preferably, p is 1; and / or Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 9 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 9 is cyclopropyl; and / or Preferably, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; or R 11 Selected from cyclopropyl and and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or Preferably, R 10 Selected from: Best Each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; or R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, -C(O)NH2, Preferably, R 1 Selected from CN and -C(O)NH2; and / or Preferably, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from the group consisting of cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally replaced by 1 or 2 independently selected from F, C wherein the substituents are substituted with a substituent selected from the group consisting of 1-C alkyl, 2-Br, 2-Br, 2-CN, OH, NH, NO, and C-C alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from cyclopentylidene, cyclohexylidene, pyrrolylene, piperidylene, phenylene and pyridylene, each of which is optionally substituted by 1 or 2 substituents independently selected from F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl. wherein the two substituents are attached to the same ring carbon atom of the cyclopentylidene, cyclohexylidene, pyrrolidinylene or piperidinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 Selected from: or R 2 Selected from or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or Preferably, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, and -CCl3; or R 3 is -CHF2; and / or Preferably, R 4 Selected from: hydrogen, R 7 , halogens, CN, NO2, OH and NH2; or R 4 Selected from: hydrogen, R 7 , F, Cl, Br, CN, NO2, OH and NH2; Where: Preferably, R 7 is selected from: a 4-6 membered saturated monocyclic heterocyclic group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 7 Selected from: Preferably, R 4 Selected from: hydrogen, CN and The condition is: when R 1 When it is hydrogen, R 4 Not hydrogen.

16. A compound according to any one of claims 1 to 14, wherein: X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6, X8 and X9 are each N; and X7 is CH; and / or Said The part has the structure of formula (I-iii): in: R 1 , R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 Selected from: R 7 、Halogen、NO2、-OR 1f 、-NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e 、-C(O)OR 1f or -C(O)NR 1d R 1e ;or R 1 Selected from: R 7 , halogen, -NR 1d R 1e 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-C(O)OR 1f or -C(O)NR 1d R 1e ; in: Preferably, p is 1; and / or in: Preferably, R 7 is selected from: a 4-6 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 7 is selected from the group consisting of azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, and NH2; or R 7 is piperidinyl; and / or in: Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: Preferably, R 1d and R 1e are each independently selected from hydrogen, C 1-4 Alkyl and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, NO2, Methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; Preferably, R 1 Selected from: F, Cl, Br, OH, NH2, -NHCH3, C(O)OH, -C(O)NH2, -CH2OH, More preferably, R 1 Selected from -CN and -C(O)NH2; and / or in: Preferably, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from the group consisting of cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally replaced by 1 or 2 independently selected from F, C wherein the substituents are substituted with a substituent selected from the group consisting of 1-C alkyl, 2-Br, 2-Br, 2-CN, OH, NH, NO, and C-C alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from the group consisting of cyclopentylidene, cyclohexylidene, pyrrolidinylidene, piperidinylidene, phenylene and pyridinylene, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NH2, NO2, methyl, ethyl and isopropyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopentylidene, cyclohexylidene, pyrrolidinylidene or piperidinylidene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 Selected from: or R 2 Selected from: Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or in: Preferably, R 3 Selected from: halogen, CN, C 1-4 Alkyl, -OR 3f 、-SR 3f 、-NR 3d R 3e 、-CF(R 3f )2, -CF2(R 3f )、-CF3、-CCl(R 3f )2、-CCl2(R 3f ), -CCl3 and -C(O)NR 3d R 3e ; Where: Preferably, R 3d and R 3e are each independently selected from hydrogen and C 1-4 Alkyl, preferably hydrogen and methyl; and / or Preferably, R 3f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen and methyl; Preferably, R 3 Selected from: halogen, OH, SH, NH2, CN, C 1-4 Alkyl, -OC 1-4 Alkyl, -NH(C 1-4 Alkyl), -N(C 1- 4 alkyl)2, -CHF2, -CH2F, -CF3, -CH2Cl, -CHCl2, -CCl3, -C(O)NH2, -C(O)NH(C 1-4 alkyl) and -C(O)N(C 1- 4 alkyl)2; or R 3 is selected from the group consisting of: F, OH, NH2, CN, methyl, ethyl, isopropyl, tert-butyl, methoxy, -N(CH3)2, -CHF2, and -C(O)NH2; or R 3 Selected from: F, CN, methyl, isopropyl, methoxy, -N(CH3)2, -CHF2 and -C(O)NH2.

17. A compound according to any one of claims 1 to 14, wherein: X1, X3 and X4 are each N; X2 and X5 are C; X6, X8 and X9 are each N; and X7 is CH; and / or Said The part has the structure of formula (I-iv): in: R 1 , R 2 and R 3 Each as defined in any one of claims 1 to 13, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 Selected from: halogen, CN, NO2, -OR 1f 、-(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f 、-(CR 1a R 1b ) p -NR 1d R 1e or-C(O)OR 1f ;or R 1 Selected from: halogen, CN, -(CR 1a R 1b ) p -OR 1f 、-(CR 1a R 1b ) p -C(O)OR 1f , or -C(O)OR 1f ; in: Preferably, p is 1; and / or Preferably, R 1a and R 1b are each independently selected from hydrogen and C 1-4 alkyl, preferably each independently hydrogen; or R 1a and R 1b Together with the carbon atom to which they are attached, they form R 9 ; in: Preferably, R 9 Selected from: C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, SH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, NH2, NH(C 1-4 Alkyl) and N(C 1-4 Alkyl)2 or R 9 Selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: Preferably, R 1d and R 1e are each independently selected from hydrogen and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl, and 3-6 membered heterocycloalkyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocycloalkyl are optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 11 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; and / or Preferably, R 10 is selected from: a 3-6 membered heterocycloalkyl group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or Preferably, R 10 Selected from: azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, triazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted with one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; and / or in: R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; or R 1 Selected from: F, Cl, Br, CN, OH, NH2, C(O)OH, or R 1 is CN; and / or in: Preferably, R 2 Selected from: C 3-6 cycloalkylene; 4-6 membered heterocycloalkylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; phenylene; and 5-6 membered heteroarylene having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the cycloalkylene, heterocycloalkylene, phenylene and heteroarylene are optionally substituted by 1, 2 or more independently selected from halogen, CN, OH, NH2, NO2, C 1-6 Alkyl and C 1-6 wherein the substituents are substituted with a substituent of the alkoxy group, and in the case where two substituents are attached to the same ring carbon atom of the cycloalkylene or heterocycloalkylene group, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 is selected from the group consisting of cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, thiomorpholinylene, phenylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, oxadiazolylene, thiadiazolylene, pyridinylene, pyrazinylene, pyridazinylene and pyrimidinylene, each of which is optionally replaced by 1 or 2 independently selected from F, C wherein the substituents are substituted with a substituent selected from the group consisting of 1-C alkyl, 2-Br, 2-Br, 2-CN, OH, NH, NO, and C-C alkyl, and in the case where two substituents are attached to the same ring carbon atom of the cyclopropylidene, cyclobutylidene, cyclopentylene, cyclohexylene, azetidinylene, pyrrolylene, oxazolylene, thiazolylene, pyrazolylene, imidazolylene, piperidinylene, piperazinylene, hexahydropyrimidinylene, triazinylene, morpholinylene, or thiomorpholinylene, the two substituents are optionally taken together with the ring carbon atom to which they are attached to form an optionally substituted C 3-6 Cycloalkyl; or R 2 Selected from: or R 2 Selected from: or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or in: Preferably, R 3 Selected from: halogen, CN, NO2, C 1-6 Alkyl, OH, NH2, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, and -CCl3; or R 3 is -CHF2.

18. A compound according to any one of claims 1 to 14, wherein: X1 and X5 are each N; X2 and X4 are C; X3 is CH; X6 is CH; and X7, X8 and X9 are each N; and / or Said The moiety has the structure of formula (IV): in: R 1 , R 2 and R 3 Each as defined in any one of claims 1 to 17, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 , R 2 and R 3 as defined in claim 15, 16 or 17 respectively; or R 1 is -C(O)NH2; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2; or in: X1 and X5 are each N; X2 and X4 are C; X3 is CH; and X6, X7, X8 and X9 are each N; and / or Said The part has the structure of formula (I-vi): R 1 , R 2 and R 3 Each as defined in any one of claims 1 to 17, provided that: R 1 Not hydrogen or deuterium; in: Preferably, R 1 , R 2 and R 3 as defined in claim 15, 16 or 17 respectively; or R 1 is -C(O)NH2; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2; or in: X1 and X2 are each N; X3 is CH; X4 and X5 are each C; and X6, X7, X8 and X9 are each N; and / or Said The part has the structure of formula (I-vii): in: R 1 , R 2 and R 3 Each as defined in any one of claims 1 to 17, provided that: R 1 Not hydrogen or deuterium; Preferably, R 1 , R 2 and R 3 as defined in claim 15, 16 or 17 respectively; or R 1 is -CN; and / or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2.

19. A compound according to any one of claims 1 to 14, wherein: X1, X3 and X4 are each N; X2 and X5 are C; and X6, X7, X8 and X9 are each N; and / or Said The part has the structure of formula (I-viii): in: R 2 , R 3 and R 4 Each as defined in any one of claims 1 to 17, provided that: R 4 Not hydrogen or deuterium; Preferably, R 2 and R 3 as defined in claim 15, 16 or 17 respectively; or R 2 for Among them, the wavy line Represents the attachment site, with the bond indicated by * connected to L A ; and / or R 3 is -CHF2; and / or Preferably, R 4 Selected from: R 7 , halogens, CN, NO2, OH and NH2; or R 4 Selected from: R 7 , F, Cl, Br, CN, NO2, OH and NH2; among which: in: Preferably, R 7 is selected from: a 7-10 membered saturated bridged heterocyclic group having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 7 Selected from: Where X 10 is CH2, (CH2)2 or (CH2)3; Preferably, R 4 Selected from: CN and More preferred 20. The compound according to claim 1, wherein Some selected from: (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred )and (Preferred ).

21. A compound according to any one of claims 1 to 20, wherein: The CyL1 and CyL2 groups are each independently selected at each occurrence from C 4-11 Cycloalkylene, 4-11 membered heterocycloalkylene, preferably C 4-7 Monocyclic cycloalkylene, 4-7 membered monocyclic heterocycloalkylene, 6-10 membered fused bicyclic heterocycloalkylene, 6-9 membered bridged heterocycloalkylene and 5-12 membered spiro heterocycloalkylene, more preferably C 4-6 Monocyclic cycloalkylene, 4-6 membered monocyclic heterocycloalkylene, 8-10 membered fused bicyclic heterocycloalkylene, 6-8 membered bridged heterocycloalkylene and 7-11 membered spiro heterocycloalkylene, further preferably, CyL1 is independently selected at each occurrence from C 5- 6-membered monocyclic cycloalkylene, 4-6-membered monocyclic heterocycloalkylene, 8-10-membered fused bicyclic heterocycloalkylene, 7-8-membered bridged bicyclic heterocycloalkylene, 7-11-membered spiro bicyclic heterocycloalkylene, CyL2 is independently selected at each occurrence from 4-6-membered monocyclic heterocycloalkylene, any of the above heterocycloalkylene preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S; and / or The CyL3 group is independently selected at each occurrence from C 4-11 Cycloalkylene, preferably C 4-6 Monocyclic cycloalkylene, C 6-10 Fused bicyclic cycloalkylene, C 6-9 Cycloalkylene and C 5-12 Spirocycloalkylene, more preferably C 5-6 Monocyclic cycloalkylene, C 8-10 Fused bicyclic cycloalkylene, C 6-8 Cycloalkylene and C 7-11 Spirocycloalkylene, further preferably C 5-6 Monocyclic cycloalkylene, C 7-11 spirobicyclic cycloalkylene; and / or The CyL4 group is independently selected at each occurrence from a 5-10 membered heteroarylene group, preferably a 5-6 membered heteroarylene group, more preferably a 5-6 membered nitrogen-containing heteroarylene group; and / or La is independently selected at each occurrence from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkyne, preferably -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2-, -CH2CH2-C≡C- and -CH2-C≡C-CH2-, more preferably -CH2-, -(CH2)2-, -(CH2)3-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2- and -CH2CH2-C≡C-; and / or Lb is independently selected at each occurrence from -O- straight chain C 1-3 Alkylene-, -straight-chain C 1-3 Alkylene-O-, -OC 2-3 Alkenylene-, -C 2-3 Alkenylene-O-, -OC 2-3 Alkynylidene-, -C 2-3 Alkynylidene-O-, -NR 8’ - Straight chain C 1-3 Alkylene-, -straight-chain C 1-3 Alkylene-NR 8’ -,- Straight chain C 1-2 Alkylene-NR 8’ - Straight chain C 1-2 Alkylene-, -straight-chain C 1-2 Alkylene-C(O)-NR 8’ -、-NR 8’ -C(O)-straight chain C 1-2 Alkylene-, -straight-chain C 1-2 Alkylene-NR 8’ -C(O)-, -C(O)- straight chain C 1-3 Alkylene- and -straight-chain C 1-3 Alkylene-C(O)-, preferably -OC 2-3 Alkynylidene-、-NR 8’ - Straight chain C 1-3 Alkylene-, -straight-chain C 1-3 Alkylene-NR 8’ -,- Straight chain C 1-2 Alkylene-NR 8’ - Straight chain C 1-2 Alkylene-, -straight-chain C 1-2 Alkylene-C(O)-NR 8’ -,- Straight chain C 1-2 Alkylene-NR 8’ -C(O)- and -C(O)- straight chain C 1-3 Alkylene-, where R 8’ is independently selected at each occurrence from H and C 1-4 alkyl; and / or Lc is independently selected at each occurrence from a bond or a linear C 1-3 Alkylene, preferably a bond, methylene or ethylene, more preferably a bond or methylene; and / or R L1 , R L2 and R 8’ each at each occurrence is independently selected from H, methyl and ethyl, more preferably H and methyl; and / or L B A group selected from the following groups (1) to (21): (1) (Preferred )、 (Preferred )、 (Preferred )、 (2) (3) (Preferred )、 (4) (5) (6) (7) (8) (9) (Preferred )、 (Preferred Further optimization )、 (Preferred )、 (10) (11) (12) (Preferred ) (13) (14) (15) (16) (17) (18) (19) (20) (Preferred )and as well as (21) Preferably, in any of the groups (1) to (21) above, the bond marked with "u" is connected to the L A , and the key marked with "v" is connected to the part.

22. A compound according to any one of claims 1 to 21, wherein: Said Some are E3 ubiquitin ligase ligands, Preferably, the Some selected from: in: Ring Aa is a 5-membered heterocyclic group or a 5-membered heteroaryl group, preferably a 5-membered heterocyclic group or a 5-membered heteroaryl group having 1, 2 or more N heteroatoms, wherein the 5-membered heterocyclic group and the 5-membered heteroaryl group are optionally substituted by one or more independently selected from H, halogen, OH, NH2, CN, oxo and C 1-4 Alkyl substituents are substituted, Preferably, Partially selected The bond marked with "z" is connected to X 5 ; Each ring are independently phenyl or 5-6 membered heteroaryl, preferably phenyl; X 5 CR L7 or N; t is 0 or 1, preferably 1; R L1 , R L5 and R L6 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together they form an oxo group; R L4 and R L7 Each is independently selected at each occurrence from H, halogen, OH, NH2, CN and C 1-4 Alkyl, preferably H, F, Cl, Br and C 1-2 Alkyl, more preferably H, F, Cl and methyl; m5 is 0, 1, 2, 3 or 4, preferably 0 or 1; Preferably, the Some selected from: More preferably, the Partially selected More preferably, the Partially selected 23. A compound according to any one of claims 1 to 22, wherein Some selected from:

24. The compound according to claim 1, wherein the compound is selected from the compounds listed in Table 1 in the specification.

25. The compound according to any one of claims 1 to 23, wherein the compound has a structure shown in formula (B0): in, R 1 , L B , Aa, R L1 , R L2 , R L3 , R L4 , X 5 , t, m5 as defined in any one of claims 1 to 23; Preferably, R 1 Selected from CN, R 7 、-C(O)OR 1f or -C(O)NR 1d R 1e More preferably, R 1 Selected from -C(O)NR 1d R 1e ; in: Preferably, R 7 is selected from: a 4-7 membered heterocycloalkyl group having 1 N atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl group is optionally replaced by one or more independently selected from F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 7 is selected from the group consisting of azetidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl and 2-oxa-5-azabicyclo[2.2.1]heptane, each of which is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, CN, OH, NO2, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CHF2, CH2F, CF3, CHCl2, CH2Cl, CCl3, methoxy, ethoxy and NH2; or R 7 is selected from piperidinyl, morpholinyl and 2-oxa-5-azabicyclo[2.2.1]heptane; and / or Preferably, R 1f Selected from hydrogen and C 1-4 Alkyl, preferably hydrogen; and / or Preferably, R 1d and R 1e are each independently selected from hydrogen, C 1-6 Alkyl and R 11 ; or R 1d and R 1e Together with the nitrogen atom to which they are attached, they form R 10 ; in: Preferably, R 11 Selected from: C 3-6 Cycloalkyl; wherein the cycloalkyl is optionally substituted by one or more independently selected from halogen, CN, OH, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, NH2, NH(C 1-4 Alkyl) and N(C 1-4 alkyl)2 is substituted by a substituent; or R 11 Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, CN, OH, NO2 and NH2; and / or R 10 Selected from: 3-6 membered heterocycloalkyl having 1 nitrogen heteroatom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocycloalkyl is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl)2 is substituted by a substituent; or R 10 Selected from: piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which is optionally substituted by one or more independently selected from F, Cl, Br, CN, OH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 Alkyl)2 is substituted by a substituent; Preferably, R 1 Selected from CN, -C(O)OH、-C(O)NH2、 More preferably, R 1 Selected from -C(O)NH2; and / or L B Selected from: (1) -CyL1-, wherein CyL1 is selected from 4-7 membered monocyclic heterocycloalkylene, 7-11 membered spiro bicyclic heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene, 9-11 membered spiro bicyclic heterocycloalkylene; wherein any of the heterocycloalkylenes each has 1 or 2, preferably 2, nitrogen heteroatoms, and any of the heterocycloalkylenes is optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; (3) -CyL1-Lb-, wherein CyL1 is selected from 4-7 membered monocyclic heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene; Lb group is selected from -OC 2-3 Alkyne; (9) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 5-6 membered monocyclic heterocycloalkylene, wherein any of the heterocycloalkylene groups each has 1 or 2 nitrogen heteroatoms, and is optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; (12)–NR L1 -CyL3-NR L2 –, wherein the CyL3 group is selected from C 5-6 Monocyclic cycloalkylene, R L1 , R L2 The groups are each independently selected from H and C 1-4 Alkyl, preferably H and methyl; (20)-CyL1-La-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from a 4-7 membered monocyclic heterocycloalkylene group or a C 4-7 Monocyclic cycloalkylene; preferably 5-6-membered monocyclic heterocycloalkylene or C 5-6 Monocyclic cycloalkylene; La is independently selected from C 1-4 Alkylene, preferably methylene and ethylene; (21) –CyL1–Lc–CyL4-, wherein the CyL1 group is selected from a 4-7 membered heterocycloalkylene group, preferably a 5-6 membered heterocycloalkylene group; the CyL4 group is selected from a 5-6 membered monocyclic heteroarylene group, preferably a 5 membered monocyclic nitrogen-containing heteroarylene group; the Lc group is selected from a bond or C 1-4 Alkylene, preferably a bond, methylene or ethylene; or L B Selected from: (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 wherein in any of the above groups, the bond marked with "u" is connected to the CH2 portion, and the bond marked with "v" is connected to the phenyl portion; and / or Preferably, Partially selected The bond marked with "z" is connected to X 5 ; in: Preferably, R L4 Selected from H, halogen and C 1-4 Alkyl, more preferably H, F, Cl and methyl; and / or Preferably, R L6 Selected from H and C 1-4 Alkyl, more preferably H and methyl; and / or Preferably, m5 is selected from 0 or 1, more preferably 0; and / or X 5 CR L7 or N; Where: R L7 Selected from H, halogen and C 1-4 Alkyl, more preferably H; and / or t is preferably 1; and / or Preferably, R L1 Selected from H and C 1-4 Alkyl, more preferably H and methyl; and / or Preferably, R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together form an oxo group; more preferably R L2 and R L3 Together they form an oxo group; Preferably, the formula (B0) is selected from the structures shown in formula (B0-1), (B0-2) or (B0-3):

26. The compound according to claim 1, wherein the compound has a structure shown in formula (B): in: L B Selected from: (1) -CyL1-, wherein the CyL1 group is selected from 5-9 membered monocyclic heterocycloalkylene, 7-11 membered spiro heterocycloalkylene; preferably 5-6 membered monocyclic heterocycloalkylene, 9-11 membered spiro heterocycloalkylene; more preferably 9-11 membered spiro heterocycloalkylene; wherein the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene each have 1 or 2, preferably 2 nitrogen heteroatoms, and the 7-11 membered spiro heterocycloalkylene and the 9-11 membered spiro heterocycloalkylene are optionally substituted by 1 or more groups independently selected from the following: C 1-4 alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; wherein the 5-9 membered monocyclic heterocycloalkylene and the 5-6 membered monocyclic heterocycloalkylene each have 1 or 2, preferably 2 nitrogen heteroatoms, and the 5-9 membered monocyclic heterocycloalkylene and the 5-6 membered monocyclic heterocycloalkylene are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; (2) -CyL1-Lb-, wherein the CyL1 group is selected from a 5-9-membered monocyclic heterocycloalkylene group, more preferably a 5-6-membered monocyclic heterocycloalkylene group; and the Lb group is selected from -OC 2-3 Alkyne; (3) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, wherein the 4-7 membered monocyclic heterocycloalkylene and the 4-6 membered monocyclic heterocycloalkylene each have 1 or 2 nitrogen heteroatoms, and are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; (4)–NR L1 -CyL3-NR L2 –, wherein the CyL3 group is selected from C 4-6 Monocyclic cycloalkylene, R L1 , R L2 The groups are each independently selected from H, methyl and ethyl, preferably H and methyl; (5) -CyL1-La-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from a 4-7 membered monocyclic heterocycloalkylene group or a C 4-7 Monocyclic cycloalkylene; La is independently selected from C 1-4 Alkylene, preferably methylene and ethylene; (6) –CyL1–Lc–CyL4-, wherein the CyL1 group is selected from a 4-6-membered monocyclic heterocycloalkylene group, preferably a 5-6-membered monocyclic heterocycloalkylene group; the CyL4 group is selected from a 5-6-membered monocyclic heteroarylene group, preferably a 5-membered monocyclic nitrogen-containing heteroarylene group; the Lc group is selected from a bond or C 1-4 Hydrocarbylene, preferably a bond, methylene or ethylene; And, R 1 is selected from a 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, CN, -C(O)R 1f 、-C(O)OR 1f 、-C(O)NR 1d R 1e ; R 1d , R 1e are each independently selected from hydrogen, deuterium, R 11 , C 1-6 Alkyl and C 1-6 haloalkyl; preferably hydrogen, R 11 , C 1-3 Alkyl and C 1- 3 haloalkyl; R 1f independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and R 12 ; preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl and R 12 ; R 11 , R 12 Independently selected from: saturated or partially unsaturated C 3-7 Cycloalkyl; 3-10 membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more independently selected from C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group are substituted; preferably saturated C 3-7 Cycloalkyl; 3-10 membered saturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; preferably the cycloalkyl and heterocyclic groups are optionally substituted by one or more independently selected from C 1-3 Alkyl, C 1-3 Substitution of haloalkyl groups; R 1 Preferably selected from -CONH2, -CN, -COOH, More preferably R 1 Preferably it is selected from -CONH2.

27. The compound according to claim 25 or 26, wherein L B Selected from: (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 Preferred ( ) More preferred (Preferred )、 (Preferred )、 (Preferred )、 Preferred ( ) and, wherein in any of the above groups, the bond identified by "u" is connected to the CH2 portion, and the bond identified by "v" is connected to the portion where the phenyl group is located; and / or R 1 Selected from -CONR Na R Nb , where R Na , R Nb Each independently is H or C 1-4 Alkyl, preferably -CONH2.

28. The compound according to any one of claims 25 to 27, wherein the compound is selected from:

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

30. Use of a compound according to any one of claims 1 to 28 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition according to claim 29 in the preparation of a medicament for treating a disease, disorder or condition associated with IRAK4 protein kinase.

31. A method for treating a disease, disorder or condition associated with IRAK4 protein kinase, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 28, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 29.

32. The use according to claim 30, or the method according to claim 31, wherein the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: autoimmune disorders, inflammatory disorders, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction and metabolic syndrome; in: Preferably, the inflammatory disorder is selected from the group consisting of osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fever, atopic dermatitis, hidradenitis suppurativa, chronic nephritis, allergic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma and allergies, preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa and chronic nephritis; and / or Preferably, the autoimmune disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis and systemic juvenile idiopathic arthritis, preferably psoriasis; and / or Preferably, the transplant rejection is selected from graft-versus-host disease and allogeneic transplant rejection; and / or Preferably, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma tumors, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

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