IRAK4-degrading proteolytic targeting chimeric compounds and their applications

Abstract

This application relates to a proteolytic targeting chimeric compound that degrades IRAK4 of formula (A), a method for producing the same, a pharmaceutical composition containing the compound, and uses of the pharmaceutical composition to treat diseases, disorders, or conditions related to IRAK4 protein kinase. [Case 1] JPEG2026528824000527.jpg28106

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to Chinese patent applications CN202311018650.4 filed on 11 August 2023, CN202311038908.7 filed on 16 August 2023, CN202311618951.0 filed on 29 November 2023, and CN202410120222.0 filed on 26 January 2024, all of which are incorporated by reference into this application and used for all purposes.

[0002] This application relates to a proteolytic targeting chimeric (PROTAC) compound that degrades IRAK4, a method for producing the same, a pharmaceutical composition containing the compound, and uses of the pharmaceutical composition to treat diseases, disorders, or conditions related to IRAK4 protein kinase. [Background technology]

[0003] IRAK4 is a serine / threonine protein kinase belonging to the interleukin-1 receptor-associated kinase family, which includes four subtypes: IRAK1, IRAK2, IRAK3 (also known as "IRAKM"), and IRAK4. IRAK1, IRAK2, and IRAK4 promote the release of inflammatory factors, while IRAK3 is involved in anti-inflammatory processes. The biological functions of IRAK4 are clearly elucidated in all four subtypes. When TLR or IL-1R senses an external signaling stimulus, the Myddosome complex formed by IRAK4 activates the MAPK and NF-κB pathways, ultimately leading to the release of several inflammatory factors.

[0004] Research has shown that IRAK4 is highly expressed in various tumor cells and inflammation models, and the research and development of IRAK4-targeted inhibitors is becoming an important direction in the treatment of autoimmune diseases and tumors. IRAK4 has two functions: kinase activity and scaffold activity, both of which play important roles in downstream signaling regulation. Conventional small molecule IRAK4 kinase inhibitors only inhibit kinase activity and fail to achieve ideal therapeutic effects, and there are subsequent problems such as drug resistance due to mutations in the target protein.

[0005] The ubiquitin-proteasome pathway (UPP) is a major pathway for regulating important regulatory proteins and for degrading misfolded or abnormal proteins. UPP plays a central role in multiple cellular processes, and when defects or imbalances are present, they are involved in the pathogenesis of various diseases. Covalent bonding between ubiquitin and specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0006] Proteolysis Targeting Chimera (PROTAC) technology is a relatively new technology that has attracted considerable attention since its first report in 2001. Currently, several drug development projects based on this technology are in the clinical research stage, with some progressing to Phase II clinical trials. PROTAC is a heterobifunctional molecule composed of three parts: a small molecule inhibitor that can recognize a target protein at one end, a ligator at the other end, and a ligand that can recognize an E3 ubiquitin ligase. Such a bifunctional molecule recognizes the target protein in vivo, brings the target protein and the E3 ubiquitin ligase into close proximity to form a ternary complex, ubiquitinated the target protein, and subsequently initiated a ubiquitin-proteasome-dependent degradation pathway. Compared to conventional small molecule inhibitors, PROTAC technology can effectively solve the problems of insufficient activity of small molecule inhibitors or mutations of target proteins by simultaneously inhibiting both functions of IRAK4 through its degradation.

[0007] There is a need to research and develop novel IRAK4-degrading PROTAC compounds to treat diseases, disorders, or conditions related to IRAK4 protein kinase. [Overview of the project]

[0008] The present invention provides a PROTAC compound that targets IRAK4, which is used to recruit and degrade IRAK4 kinase to E3 ubiquitin ligase. In other words, the bifunctional PROTAC compound of the present invention has utility as a modulator of targeted ubiquitination of IRAK4 kinase, and the IRAK4 kinase is degraded and / or otherwise inhibited by the bifunctional compound described herein. The inventors of this application have demonstrated 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 related to IRAK4 protein kinase. Furthermore, the compounds of the present invention have better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, appropriate half-life and duration of action), improved safety (reduced toxicity (e.g., reduced cardiotoxicity and / or fewer side effects), and less susceptibility to drug tolerance).

[0009] In one embodiment, the present invention relates to a compound of formula (A) as defined below, [ka] The present invention provides stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts thereof.

[0010] In another embodiment, the present invention provides a method for targeted degradation of IRAK4 protein kinase, the method comprising contacting the IRAK4 protein kinase with a compound of formula (A) of the present invention in the presence of an E3 ubiquitin ligase.

[0011] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (A) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, and pharmaceutically acceptable excipients, carriers or diluents. The pharmaceutical composition is preferably a solid formulation, a liquid formulation or a transdermal formulation.

[0012] In another aspect, the present invention provides uses for a compound of formula (A) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, in the manufacture of a drug for treating a disease, disorder, or condition related to IRAK4 protein kinase.

[0013] In another embodiment, the present invention provides a method for treating a disease, disorder or condition related to IRAK4 protein kinase, the method comprising administering to an individual in need a therapeutically effective amount of the compound of formula (A) of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention.

[0014] In another embodiment, the present invention provides a method for producing a compound of formula (A) of the present invention. [Brief explanation of the drawing]

[0015] [Figure 1] This figure shows the effect of Test Example 3 (positive control) and Example 146 of this application on the degradation level of IRAK4 protein in Balb / c mouse spleen. [Figure 2] This is a data map of the inhibition of LPS inducing hPBMCs to secrete multiple cytokines, as shown in Test Example 6 (positive control) and Example 146 of this application. [Modes for carrying out the invention]

[0016] definition Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to mean technology commonly understood in the art, including modifications or substitutions of technology that would be obvious to those skilled in the art. The following terms are considered to be well understood by those skilled in the art, but their definitions are provided below for better interpretation of the present invention.

[0017] The terms “inclusive,” “including,” “possessing,” “containing,” or “related to,” and other variations thereof herein, are inclusive or open and do not exclude other elements or method steps not enumerated (i.e., these terms also cover “substantially consisting of” and “consisting of”).

[0018] As used herein, the term “hydrocarbon group” means a linear or branched saturated or unsaturated aliphatic hydrocarbon group. Hydrocarbon groups include alkyl groups, alkenyl groups and alkynyl groups. In some embodiments, the hydrocarbon group has 1 to 12 carbon atoms, for example, 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6). For example, as used herein, the term “C 1-6 A "hydrocarbon group" refers to a linear or branched group having 1 to 6 carbon atoms. 2-6 "Hydroxide group", "C 2-5 "Hydroxide group" and "C1-4 It contains a "hydrocarbon group". As used herein, the term "alkylene group" refers to a group obtained after the "hydrocarbon group" defined above further loses one hydrogen atom.

[0019] As used herein, the term "alkane" means a straight-chain or branched-chain saturated aliphatic hydrocarbon.

[0020] As used herein, the term "alkyl group" means a straight-chain or branched-chain monovalent saturated aliphatic hydrocarbon group, which may be regarded as a group obtained after an alkane loses one hydrogen atom. In some embodiments, the alkyl group has 1 to 12 carbon atoms, for example 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 group" refers to a straight-chain or branched-chain group having 1 to 6 carbon atoms, and "C 2-6 alkyl group", "C 2-5 alkyl group" and "C 1-4 alkyl group" are included. "C 1-6 alkyl group" examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group and n-hexyl group. The term "C 1-4 alkyl group" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group or tert-butyl group).

[0021] As used herein, the term "alkylene group" refers to a group obtained after the "alkyl group" defined above further loses one hydrogen atom. 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 group", "C 2-6 alkylene group", "C 2-5 alkylene group" and "C 1-4 alkylene group". "C1-6 Examples of alkylene groups include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, and n-hexylene groups. 1-4 An "alkylene group" refers to an alkylene group that has 1 to 4 carbon atoms.

[0022] As used herein, the term “alkoxy group” refers to an -O-alkyl group, where the alkyl group is as defined above.

[0023] As used herein, the term “heteroalkyl group” refers to the alkyl group defined above, where one or more but not all of the carbon atoms in the alkyl chain are substituted with heteroatoms or groups of atoms selected from the group consisting of NR', O, C(O), S, S(O), S(O)2, where R' is a suitable substituent, such as H, an alkyl group, etc. The heteroalkyl group can be linked to the rest of the molecule via carbon atoms or the heteroatoms or groups of atoms. Preferably, the heteroalkyl group is linked to the rest of the molecule via carbon atoms.

[0024] As used herein, the term “alkenyl group” refers to a monovalent aliphatic hydrocarbon group, either linear or branched, which contains one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, or 6 carbon atoms ("C"). 2-6 "Alkenyl group", for example, "C 2-4The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-2-propenyl group, and 4-methyl-3-pentenyl group. When the compound of the present invention contains an alkenyl group, the compound may exist in a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof. The term "alkenylene group" refers to the corresponding divalent group, for example, "C 2-6 "Alkenylene group", "C 2-4 This includes, but is not limited to, alkenylene groups such as -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene group, pentenylene group, hexenylene group, cyclopentenylene group, and cyclohexenylene group.

[0025] As used herein, the term “alkynyl group” refers to a monovalent aliphatic hydrocarbon group, either linear or branched, which contains one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C"). 2-6 "Alkynyl group", for example, "C 2-4 The alkynyl group is, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 3-methyl-2-butynyl group, and 2-methyl-3-pentynyl group. The term "alkynylene group" refers to the corresponding divalent group, for example, "C 2-6 "Alkynylene group", "C 2-4 This includes groups such as the "alkynylene group," and specific examples include, but are not limited to, -C≡C-, -CH2C≡C-, -C≡C-CH2-, -CH2-C≡C-CH2-, pentynylene group, and hexylene group.

[0026] As used herein, the term “condensation” refers to a condition in which two or more cyclic structures share two adjacent atoms with one another.

[0027] As used herein, the term “crosslinking” or “crosslinking bond” refers to a situation in which two or more cyclic structures share two non-adjacent atoms with one another.

[0028] As used herein, the term “spiro” or “spiro bond” refers to a configuration in which two or more cyclic structures share one atom with one another.

[0029] As used herein, the terms “cyclic hydrocarbon group,” “hydrocarbon ring,” and “cycloalkylene group” refer to monocyclic or polycyclic hydrocarbon rings that are saturated (i.e., “cycloalkyl group” and “cycloalkylene group”) or partially unsaturated (i.e., have one or more double bonds (i.e., “cycloalkenyl group” and “cycloalkenylene group”) and / or triple bonds within the ring, for example, 3 to 12 (appropriately 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 6 or 5 to 6) ring carbon atoms, and that include (ylidene)cyclopropyl group This includes, but is not limited to, (ring), (ylidene)cyclobutyl group (ring), (ylidene)cyclopentyl group (ring), (ylidene)cyclohexyl group (ring), (ylidene)cycloheptyl group (ring), (ylidene)cyclooctyl group (ring), (ylidene)cyclononyl group (ring), (ylidene)cyclobutenyl group (ring), (ylidene)cyclopentenyl group (ring), (ylidene)cyclohexenyl group (ring), (ylidene)cycloheptenyl group (ring), (ylidene)cyclooctenyl group (ring), (ylidene)cyclononenyl group (ring), etc. In some embodiments, the cyclic hydrocarbon group includes a cyclic hydrocarbon group into which an aryl group is fused, as long as the entire ring system is non-aromatic.

[0030] As used herein, the terms “cycloalkyl group” and “cycloalkylene group” refer to saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon rings (e.g., monocyclic, e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or bicyclic, e.g., spirocycle, condensed or crosslinked system (e.g., bicyclic[1.1.1]pentyl group, bicyclic[2.2.1]heptyl group, bicyclic[3.2.1]octyl group, or bicyclic[5.2.0]nonyl group, decahydronaphthalenyl group, etc.)). The cycloalkyl group has 3 to 15 carbon atoms, and preferably 3 to 12, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 6 or 5 to 6 carbon atoms. For example, the term “C 3-6 "Cycloalkyl group" and "C 3-6 A "cycloalkylene group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., a cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group).

[0031] The terms "spirocycloalkyl group" and "spirocycloalkylene group" refer to the polycyclic (e.g., bicyclic) "cycloalkyl group" and "cycloalkylene group" defined above, where any two linked rings share one carbon atom. For example, "C 7-12 "Spirocycloalkyl group" and "C 7-12 A "spirocycloalkylene group" refers to a cyclic structure that contains 7 to 12 carbon atoms (for example, 5 to 12 or 7 to 11) and is formed by at least two rings sharing one atom.

[0032] The terms "condensed cycloalkyl group" and "condensed cycloalkylene group" refer to the polycyclic (e.g., bicyclic) "cycloalkyl group" and "cycloalkylene group" defined above, where any two linked rings share two adjacent carbon atoms. For example, "C 4-10 "Condensed cycloalkyl group" and "C 4-10A "condensed cycloalkylene group" refers to a condensed ring formed by two or more rings containing 4 to 10 (e.g., 6 to 10 or 8 to 10) ring carbon atoms and sharing two adjacent carbon atoms.

[0033] The terms "crosslinked cycloalkyl group" and "crosslinked cycloalkylene group" refer to the polycyclic (e.g., bicyclic) "cycloalkyl group" and "cycloalkylene group" defined above, where any two linked rings share two non-adjacent carbon atoms. For example, "C 7-10 "Cross-linked cycloalkyl group" and "C 7-10 A "bridged cycloalkylene group" refers to a cyclic structure formed by two rings containing 7 to 12 carbon atoms (for example, 6 to 10, 6 to 9, or 6 to 8) and sharing two non-adjacent atoms.

[0034] As used herein, the terms “cycloalkenyl group” and “cycloalkenylene group” refer to monocyclic or polycyclic (e.g., bicyclic) fused hydrocarbon rings having one or more double bonds within the ring (e.g., monocyclic, e.g., cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group, cyclopentadienyl group, cycloheptenyl group, cyclooctenyl group, cyclononenyl group, or bicyclic). The cycloalkenyl group and “cycloalkenylene group” have 3 to 10 carbon atoms, preferably 3 to 8, for example, 3 to 7, 3 to 6, 4 to 6, or 5 to 6.

[0035] As used herein, the terms “heterocyclyl group,” “heterocycle,” and “heterocyclylene group” refer to monocyclic or polycyclic (e.g., bicyclic) cyclic structures that are saturated (i.e., “heterocycloalkyl group” and “heterocycloalkylene group”) or partially unsaturated (e.g., having one or more double bonds in the ring (i.e., “heterocycloalkenyl group” and “heterocycloalkenylene group”), having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from the group consisting of O, S, S(=O), S(=O)2, NR', where R ’ The above definition applies. The heterocycle may be linked to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). In particular, a 3- to 12-membered heterocycle is a group having 3 to 12 carbon atoms and heteroatoms (e.g., 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 11, 4 to 9, 4 to 7, 4 to 6, 5 to 12, 5 to 6, 6 to 10, 6 to 9, 6 to 8, 7 to 11, or 8 to 12) within the ring. Examples include, but are not limited to, oxyranyl group, azilidinyl group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dioxolinyl group, pyrrolidinyl group, pyrrolidonyl group, oxazolidine, thiazolidinyl group, pyrazolidinyl group, imidazolidinyl group, pyrazolidinyl group, pyrrolidinyl group, tetrahydropyranyl group, piperidinyl group, hexahydropyrimidinyl group, triazinyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, piperazinyl group, trithianyl group, azacyclooctanyl group, dihydropyrrolyl group, dihydroimidazolyl group, and azacyclooctenyl group.

[0036] 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 and may further optionally have one or more (e.g., one, two, three, or four) ring members selected from the group consisting of N, O, C=O, S, S=O, and S(=O)2. The nitrogen-containing heterocycle can be linked to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocycle. In particular, 3- to 12-membered nitrogen-containing heterocycles are groups having 3 to 12 carbon atoms and heteroatoms (where at least one is a nitrogen atom) within the ring, and include, but are not limited to, 3-membered nitrogen-containing heterocycles (e.g., azilidinyl group), 4-membered nitrogen-containing heterocycles (e.g., azetidinyl group), 5-membered nitrogen-containing heterocycles (e.g., pyrrolyl group, pyrrolidine group (pyrrolidine ring), pyrrolinyl group, pyrrolidonyl group, imidazolyl group, imidazolidinyl group, imidazolinyl group, pyrazolyl group, pyrazolinyl group), 6-membered nitrogen-containing heterocycles (e.g., piperidinyl group (piperidine ring), morpholinyl group, thiomorpholinyl group, piperazinyl group), and 7-membered nitrogen-containing heterocycles.

[0037] As used herein, the heterocycles described above include monocycles, fused heterocycles, bridging heterocycles, and spirocycles, i.e., monocyclic heterocycles, bridging heterocycles, spiroheterocycles, and fused heterocycles. The linkage between the bridging heterocycle, spiroheterocycle, and fused heterocycle and other groups may be on any one of the rings in the above structure.

[0038] As used herein, a condensed heterocycle refers to a polycyclic (e.g., bicyclic) heterocycle as defined above, where any two linked rings share two adjacent atoms. A condensed heterocycle is a heterocyclyl group condensed with a heterocyclyl group, a heterocyclyl group condensed with a cycloalkyl group, a monoheterocyclyl group condensed with a monoheterocyclyl group, a monoheterocyclyl group condensed with a monocycloalkyl group, for example, a 3-7 member (mono)heterocyclyl group condensed with a 3-7 member (mono)heterocyclyl group, a 3-7 member (mono)heterocyclyl group condensed with a (mono)cycloalkyl group, or a 3-7 member (mono)heterocyclyl group condensed with a C4-6 The (mono)cycloalkyl groups are included, but not limited to, (mono)cycloalkyl groups. Preferably, the condensed heterocycle has 6 to 10 members, and more preferably 8 to 10 members. Examples of condensed heterocycles include pyrrolidinyl group condensed cyclopropyl group, cyclopentyl group condensed azacyclopropyl group, pyrrolidinyl group condensed cyclobutyl group, pyrrolidinyl group condensed pyrrolidinyl group, pyrrolidinyl group condensed piperidinyl group, pyrrolidinyl group condensed piperazinyl group, piperidinyl group condensed morpholinyl group, [ka] This includes, but is not limited to, the following. In some embodiments, the condensed heterocyclyl group further includes a heterocyclyl group or cyclic hydrocarbon group fused with a heteroaryl group, and a heterocyclyl group fused with an aryl group, as long as the entire ring system is non-aromatic. In some embodiments, the condensed heterocyclyl group is a C fused with a 5-6 membered monocyclic heteroaryl group. 5-6 This includes monocyclic cyclic hydrocarbon groups, 5-6 membered monocyclic heterocyclyl groups formed by the condensation of 5-6 membered monocyclic heteroaryl groups, and 5-6 membered monocyclic heterocyclyl groups formed by the condensation of phenyl groups, such as pyrrolotetrahydropyridyl groups, pyrazolotetrahydropyridyl groups, and imidazotetrahydropyridyl groups.

[0039] As used herein, a spiroheterocycle refers to a polycyclic (e.g., bicyclic) heterocycle as defined above, where any two linked rings share one carbon atom. Preferably, a spiroheterocycle is 5 to 12-membered, and more preferably 7 to 11-membered. Depending on the number of spiro atoms shared, a spiroheterocycle is divided into a monospiroheterocycle, a bisspiroheterocycle, or a polyspiroheterocycle, and preferably refers to a monospiroheterocycle or a bisspiroheterocycle, and more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycle.

[0040] As used herein, a bridging heterocycle or bridging heterocycle refers to a polycyclic (e.g., bicyclic) heterocycle as defined above, where any two linked rings share two non-adjacent atoms. One or more rings in a bridging heterocycle may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, a bridging heterocycle has 6 to 9 members, and more preferably 6 to 8 members. Depending on the number of ring members, a bridging heterocycle is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocycle, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridging heterocycle, and more preferably to a bicyclic or tricyclic bridging heterocycle.

[0041] As used herein, the term “aryl group” 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 An "aryl group" refers to an aromatic group having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group.

[0042] As used herein, the term “heteroaryl group” 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, and in particular 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 the group consisting of N, O, S, and S(O)2. One or more ring carbon atoms in the heteroaryl group may be replaced by C(O). The heteroaryl group may be a benzo-condensed group. Examples of heteroaryl groups include pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridadinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl, quinolyl, indolyl, pyrrolopyridazinyl, benzofuranyl, and benzothiazolyl. This group includes, but is not limited to, an enyl group, an indazolyl group, a benzoxazolyl group, a benzoisoxazolyl group, a quinazolinyl group, a pyrrolopyridyl group, a pyrazolopyrimidinyl group, an imidazopyridazinyl group, a pyrazolopyridyl group, a triazolopyridyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, a benzimidazoyl group, a cinnolyl group, an indolidinyl group, a phthalazinyl group, an isoindolyl group, a pteridinyl group, a prinyl group, a flazanyl group, a benzoflazanyl group, a quinoxalyl group, a naphthilidinyl group, or a flopyridyl group.

[0043] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0044] As used herein, the term “haloalkyl group” refers to an alkyl group substituted with one or more (e.g., 1 to 3) identical or different halogen atoms, said alkyl group as defined herein. 1-8"Haloalkyl group", "C 1-6 "Haloalkyl" and "C 1-4 A "haloalkyl group" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0045] As used herein, the term “haloalkenyl group” refers to an alkenyl group substituted with one or more (e.g., 1 to 3) identical or different halogen atoms, the alkenyl group as defined herein. 2-8 "Haloalkenyl group", "C 2-6 "haloalkenyl group" and "C 2-4 A "haloalkenyl group" refers to a haloalkenyl group having 2 to 8 carbon atoms, 2 to 6 carbon atoms, and 2 to 4 carbon atoms, respectively.

[0046] The term "substitution" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a designated atom by a specified group, provided that the substitution does not exceed the normal valence of the designated atom in its current state and that the substitution forms a stable compound. A combination of substituents and / or variables is permitted only if the combination forms a stable compound.

[0047] Where a group is described as "optionally substituted with..." or "optionally substituted," the group may be (1) unsubstituted or (2) substituted. Where a carbon of a group is described as being optionally substituted with one or more of the substituents in the substituent list, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced with optional substituents that are independently selected individually and / or together. Where a nitrogen of a group is described as being optionally substituted with one or more of the substituents in the substituent list, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may be replaced with optional substituents that are independently selected.

[0048] When substituents are described as being "selected independently" from one group, each substituent is selected independently from the other. Therefore, each substituent may be the same as or different from another substituent.

[0049] As used herein, the term “one or more” means one or more in reasonable terms, for example, two, three, four, five or ten.

[0050] Unless otherwise specified, the linking points of substituents may be any suitable position on the substituent, as used herein.

[0051] Where it is shown that a substituent bond passes through a bond that connects two atoms in a ring ("dangling bond"), unless otherwise specified, such substituent may bond to any one of the ring-forming atoms in the substituteable ring. Where it is shown that an available ring member has a substituteable hydrogen atom, when the dangling bond bonds to the available ring member, the substituteable hydrogen atom is substantially substituted (i.e., absent).

[0052] The present invention further comprises all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but different atomic masses or mass numbers from those predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention are isotopes of hydrogen (e.g., deuterium (D), 2 H), tritium (T, 3 H), carbon isotopes (for example) 11 C, 13 C and 14 C) Isotopes of chlorine (for example) 36 Cl), fluorine isotopes (e.g., 18 F), isotopes of iodine (for example) 123 I and 125 I) Nitrogen isotopes (e.g. 13 N and 15 N), oxygen isotopes (e.g.)15 O, 17 O and 18 O), phosphorus isotopes (e.g., 32 P), and sulfur isotopes (e.g., 35 Contains (but is not limited to) S). Several isotope-labeled compounds of the present invention (e.g., those incorporating radioactive isotopes) can be used in tissue distribution studies (e.g., analysis) of drugs and / or substrates. Tritium (i.e., the radioactive isotope) 3 H) and carbon-14 (i.e.) 14 C) can be used in particular for this purpose because it is easy to incorporate and easy to detect. Positron-emitting isotopes (e.g.) 11 C, 18 F, 15 O and 13 Substitution with N) can be used to verify substrate receptor occupancy in positron emission tomography (PET) studies. The isotope-labeled compounds of the present invention can be prepared by using suitable isotope-labeled reagents instead of previously used unlabeled reagents by the accompanying routes and / or similar methods described in the examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, e.g., D2O, acetone-d6, or DMSO-d6. In some embodiments, the isotope-labeled compounds of the present invention are deuterated compounds.

[0053] The term "stereoisomer" refers to an isomer formed by at least one asymmetric center, which has the same chemical composition but differs in the configuration of atoms or groups. In a compound having one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention may exist as a rapidly equilibrium mixture of two or more structurally different forms (generally called tautomers). Typical examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0054] A "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods, such as electrophoresis and chromatography.

[0055] An "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0056] The term "chiral" refers to a non-superimposing molecule that has a mirror image pair, while the term "achiral" refers to a molecule that can be superimposed on those mirror image pairs.

[0057] The compounds of the present invention can be prepared in racemic form, or a single enantiomer can be prepared by selective synthesis or division of the enantiomer.

[0058] As used herein, the terms “cis-trans isomer” or “geometric isomer” result from the inability of a single bond to freely rotate due to a double bond or a ring-forming carbon atom. The compounds herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof.

[0059] In this specification, solid lines [ka] Solid line wedge shape [ka] Or a dotted wedge shape [ka] The chemical bonds of the compounds of the present invention can be depicted using the following. Using a solid line to depict bonds to a chiral carbon atom is intended to indicate the presence of all possible stereoisomers present at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Using a solid wedge or dotted wedge to depict bonds to a chiral carbon atom is intended to indicate the presence of the stereoisomers shown. In the case of a racemic mixture, a solid wedge or dotted wedge is used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist in the form of stereoisomers (it is intended that they may exist in the form of 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 one or more types of isomerization phenomena and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0060] It should be understood that some of the compounds of the present invention may exist in a free form for therapeutic purposes, or, when appropriate, in a pharmaceutically acceptable derivative form. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, and may directly or indirectly provide the compounds of the present invention or their metabolites or residues after administration to patients who require them. Therefore, when "compounds of the present invention" is referred to herein, it is also intended to include the various derivative forms of the compounds described above.

[0061] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or with the mammal being treated.

[0062] The pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0063] Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Examples include aspartates, benzoates, bicarbonates / carbonates, bisulfates / sulfates, fumarates, glucoheptonates, glucons, glucurons, hexafluorophosphates, hydrobroms / bromides, hydroiodides / iodides, maleates, malons, methylsulfates, naphthylates, nicotinates, nitrates, orotates, oxalates, palmitates, and other similar salts.

[0064] A suitable base addition salt is formed from a base that forms a pharmaceutically acceptable salt. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.

[0065] 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 present invention are known to those skilled in the art.

[0066] As used herein, the term “ester” means an ester derived from each of the general formulas of this application, which includes physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention themselves may be esters.

[0067] The present invention covers all possible crystalline forms or polymorphs of the compound of the present invention, which may be a single polymorph or a mixture of any proportion of more than one polymorph.

[0068] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention include a polar solvent, particularly water, methanol, or ethanol, as structural elements of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

[0069] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides, as nitrogen requires a lone pair of electrons useful for oxidation to oxides, and will be able to identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will further recognize that tertiary amines can form N-oxides. Synthetic methods for producing N-oxides from heterocycles and tertiary amines are well known to those skilled in the art and involve oxidizing the heterocycle and tertiary amine with peracids, such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides, such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes, such as dimethyldioxirane. These methods for producing N-oxides are widely described and reviewed in the literature; see, for example, TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750, ARKatritzky and AJBoulton, Eds., Academic Press, and GWHCheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, ARKatritzky and AJBoulton, Eds., Academic Press.

[0070] The scope of the present invention further includes metabolites of the compounds of the present invention, i.e., substances formed in the body when the compounds of the present invention are administered. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic hydrolysis of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention and compounds produced by a method of exposing the compounds of the present invention to mammals for a sufficient time to produce their metabolites.

[0071] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are derivatives of the compounds of the present invention that themselves have little or no pharmacological activity and can be converted to the compounds of the present invention having the desired activity by, for example, cleavage by hydrolysis when administered in or onto the body. Generally, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo to the desired therapeutically active compounds. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, American Pharmaceutical Association). Prodrugs of the present invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the present invention with parts of a "pro-moiety" (e.g., described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)) that are known to those skilled in the art.

[0072] The present invention further comprises compounds of the present invention containing protecting groups. In any process of producing the compounds of the present invention, it is necessary and / or desirable to protect any sensitive or reactive groups on any relevant molecules, thereby forming a form of chemical protection of the compounds of the present invention. This can be achieved by common protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973, and T. Greene & P. ​​G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, these references are incorporated herein by reference. The protecting group can be removed in an appropriate subsequent step using methods known in the art.

[0073] As used herein, the term “about” means within ±10%, preferably within ±5%, and more preferably within ±2% of the given value.

[0074] compound In one embodiment, the present invention relates to a compound of formula (A), [ka] Or provide stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts thereof. Here, The aforementioned [ka] The part is an IRAK4 ligand that can bind to IRAK4, The aforementioned [ka] This part is the ligase binding portion, -L A -L B - is the above [ka] part and the above [ka] It is a divalent part that connects parts.

[0075] In some embodiments, the present invention provides a compound of formula (A), where, L A The bond and the linear or branched chain of C 1-4 Selected alkylene group, the C 1-4 The alkylene group can be optionally C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, halogen, oxo group (=O), OH, CN, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Substituted with one or more substituents independently selected from the group consisting of alkyl)2, L B The elements are 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 -La-, (20)-CyL1-La-CyL3-, and (21)-CyL1-Lc-CyL4-, Here, In the groups (1) to (21) above, the leftmost protruding bond of each group is the L A It is connected to the above, and the rightmost protruding connection is the above [ka] The portion is connected, or the leftmost protruding bond of each unit is the [ka] The connection is made to the L A It is connected to, CyL1 and CyL2 are independently selected from a 3- to 12-membered heterocycloalkylene group each time they appear, where the heterocycloalkylene group preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. CyL3, each time it appears, C 3-12 A cycloalkylene group and a 3- to 12-membered heterocycloalkylene group are independently selected. Each time CyL4 appears, it is independently selected from a 5- to 12-membered heteroarylene group. La is independently selected from alkylene groups each time it appears, and C 1-4 is independently selected from alkylene groups, Lb is independently selected from linear C 2-4 alkylene groups each time it appears, where one or two, but not all, of the CH2 groups in the linear C 2-4 alkylene groups are substituted with one or two groups selected from the group consisting of O, S, NR L1 , C(O). Lc is independently selected from a bond or C 1-4 alkylene groups each time it appears, CyL1, CyL2, CyL3, CyL4, La, Lb, Lc are each optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl group, C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​k C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, R p R q N-, C 1-6 Haloalkyl group, C 1-6 Heteroalkyl groups (e.g., C 1-6 Alkoxy groups), 4-9 membered heterocyclyl groups (e.g., 5-6 membered saturated heterocycloalkyl groups), C 6-10 Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, R p , R q Each of them is independent of C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Selected from the group consisting of haloalkyl groups, Ring B [ka] The following group (1) to (3) is selected: (1) [ka] Here, R 4 is hydrogen, C 1-6 Alkyl alkyl group, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Alkyl-, -NR Na R Nb Selected from the group consisting of (where R Na and R Nb These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 3-6 Selected from the group consisting of cycloalkyl groups, the C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups can optionally include halogens, hydroxyl groups, and C 3-6 Cycloalkyl groups, C 3-6The C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Alkyl- is optionally C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, halogen, hydroxyl group, hydroxy-C 1-6 Alkylene-, cyano group, oxo, -NH2, -NH(C) 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, R 5 is hydrogen, cyano group, C 1-6 Alkyl alkyl groups, -C(O)NH2, -NR l R m Selected from the group consisting of, R l , R m Each of them is independent of C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups, (2) [ka] Here, R 22 is hydrogen, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Selected from the group consisting of alkyl-, R 23 is hydrogen, C 1-6 Alkyl group, cyano group, carboxyl group, -C(O)NH2, -NR l R m , [ka] Selected from the group consisting of R l , R m Each of them is independent of C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups, (3) [ka] Here, R 25 is hydrogen, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Selected from the group consisting of alkyl-, R 26 is hydrogen, C 1-6 Selected from the group consisting of alkyl groups, cyano groups, carboxyl groups, and -C(O)NH2, L 1 Direct bond, C 1-6 Selected from the group consisting of alkyl groups, -NH-, -O-, and -S-, R 13 C 1-6 Alkyl alkyl group, C 1-6 Selected from haloalkyl groups, R 14 C 3-6 Selected from the group consisting of a cycloalkylene group, a 5-12 membered spiroheterocycloalkylene group, and a piperidinylene group, the C 3-6 Cycloalkylene groups, 5-12 membered spiroheterocycloalkylene groups, and piperidinylene groups are optionally hydroxyl C 1-6 Alkyl group (e.g., hydroxymethyl), formyl group, C 1-6 Substituted with one or two substituents selected from the group consisting of alkyl groups, Or, (II) Structure of Equation (2) [ka] Here, Ring A' [ka] It is selected from 5-10 membered heteroaryl groups, X 1 , X 2 , X 3 and X 4 Each is independently N or CH, and X 1 , X 2 , X 3 and X 4 At least one of them is not N, Z is CR 4’ And, The letters "a" and "b" refer to the bonds between the ring carbon atom linked to Z and the two adjacent ring carbon atoms, respectively. [ka] The part is expressed by the structure of equation (i) or equation (ii) below, [ka] L 1’ This involves direct bonding and NR 7’ Selected from, R 1’ is, -L 2’ -R 1a And, L 2’ is -S(O)2NR 1b -*, -C(O)-NR 1b -*, -NR 1b -C(O)-* or -NR 1b -S(O)2-*, where the bond indicated by * is R 1a It is connected to, R 1a C 6-10 Selected from an aryl group and a 5-10 membered heteroaryl group, where the C 6-10The aryl group and the 5-10 membered heteroaryl group can be optionally associated with halogens, OH, SH, and -NR groups, respectively. 1e R 1f , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN and -C 1-6 Alkilen-NR 1e R 1f It is substituted with one or more substituents independently selected from the base, Each R 2’ These are independently H, halogen, OH, SH, and -NR. 2a R 2b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 2a R 2b Selected from the group consisting of, m2 is 0, 1, 2, or 3. R 3’ and R 7’These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 3a R 3b Selected from the group consisting of, R 4’ H, D, halogen, OH, SH, -NR 4a R 4b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 4a R 4b Selected from the group consisting of, R 5’ C 3-10 Selected from a cycloalkylene group and a 3-10 membered heterocyclene group, where the C 3-10 The cycloalkylene group and the 3-10 membered heterocyclene group can be optionally assigned halogen, OH, SH, or -NR groups, respectively. 5a R 5b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN and -C 1-6 Alkilen-NR 5a R 5b It is substituted with one or more substituents independently selected from the base, R 6’ H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 6a R 6b Selected from the group consisting of, n2 is 0, 1, 2, 3 or 4, and R 1b , R 1e , R 1f , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b Each time it appears, H and C 1-6 Selected independently of alkyl groups, and The aforementioned [ka] This part is the ligase binding site.

[0076] In some embodiments, the compound of formula (A), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts are provided. Here, L A The bond and the linear or branched chain of C 1-4 Selected alkylene group, the C 1-4 The alkylene group can be optionally C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, halogen, oxo group (=O), OH, CN, NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 Substituted with one or more substituents independently selected from the group consisting of alkyl)2, L B The elements are selected from the following groups (1) to (19): (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-NRL2 -, (14)-NR L1 -CyL1-C(O)-, (15)-NR L1 -La-CyL1-La-, (16)-La-CyL1-, (17)-O-La-, (18)-S-La-, and (19)-NR L1 -La-, Here, In the aforementioned groups (1) to (19), the leftmost protruding bond of each group is the L A It is connected to the above, and the rightmost protruding connection is the above [ka] The portion is connected, or the leftmost protruding bond of each unit is the [ka] The connection is made to the L A It is connected to, CyL1 and CyL2 are independently selected from a 3- to 12-membered heterocycloalkylene group each time they appear, where the heterocycloalkylene group preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. CyL3, each time it appears, C 3-12 Independently selected from the cycloalkylene group, Each time CyL4 appears, it is independently selected from a 5- to 12-membered heteroarylene group. Each time La appears, C 1-4 Independently selected from alkylene groups, Each time Lb appears, it is a linear C 2-4 A group independently selected from alkylene groups, where the linear C 2-4 CH2, which consists of one or two but not all alkylene groups, is O, S, NR L1, substituted with one or two groups selected from the group consisting of C(O), Each time Lc appears, it is bound or C 1-4 Independently selected from alkylene groups, CyL1, CyL2, CyL3, CyL4, La, Lb, and Lc are each optionally C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl groups, halogens, OH, CN, NH2, -NH(C) 1-4 Alkyl), -N(C 1-4 Substituted with one or more groups independently selected from the group consisting of alkyl)2, preferably a methyl group, an ethyl group, F, Cl, Br, OH, CN, and NH2, more preferably a methyl group, F, Cl, and OH. R L1 and R L2 Each time they appear, H and C 1-4 Selected independently of alkyl groups, The aforementioned [ka] The part has the following: (I) Structure of equation (1): [ka] Here, Ring A [ka] The substituent R is selected from a 5-6 member heteroaryl group, and the 5-6 member heteroaryl group is optionally substituted R k Replaced by, R k C 1-6 Alkyl alkyl group, C 3-7 Cycloalkyl groups, R p R q N-, C 1-6 Haloalkyl group, C 1-6 Heteroalkyl groups (e.g., C 1-6Alkoxy groups), 4-9 membered heterocyclyl groups (e.g., 5-6 membered saturated heterocycloalkyl groups), C 6-10 Selected from the group consisting of aryl groups and 5-10 membered heteroaryl groups, R p , R q Each of them is independent of C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Selected from the group consisting of haloalkyl groups, Ring B [ka] The following group (1) to (3) is selected: (1) [ka] Here, R 4 is hydrogen, C 1-6 Alkyl alkyl group, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Alkyl-, -NR Na R Nb Selected from the group consisting of (where R Na and R Nb These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 3-6 Selected from the group consisting of cycloalkyl groups, the C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups can optionally include halogens, hydroxyl groups, and C 3-6 Cycloalkyl groups, C 3-6 The C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Alkyl- is optionally C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, halogen, hydroxyl group, hydroxy-C 1-6 Alkylene-, cyano group, oxo, -NH2, -NH(C) 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, R 5 is hydrogen, cyano group, C 1-6 Alkyl alkyl groups, -C(O)NH2, -NR l R m Selected from the group consisting of, R l , R m Each of them is independent of C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups, (2) [ka] Here, R 22 is hydrogen, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Selected from the group consisting of alkyl-, R 23 is hydrogen, C 1-6 Alkyl group, cyano group, carboxyl group, -C(O)NH2, -NR l R m , [ka] Selected from the group consisting of R l , R mEach of them is independent of C 1-6 Alkyl alkyl group, C 3-6 Selected from cycloalkyl groups, (3) [ka] Here, R 25 is hydrogen, C 4-9 Cycloalkyl groups, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C 1-6 Selected from the group consisting of alkyl-, R 26 is hydrogen, C 1-6 Selected from the group consisting of alkyl groups, cyano groups, carboxyl groups, and -C(O)NH2, L 1 Direct bond, C 1-6 Selected from the group consisting of alkyl groups, -NH-, -O-, and -S-, R 13 C 1-6 Selected from haloalkyl groups, R 14 C 3-6 Selected from the group consisting of a cycloalkylene group, a 5-12 membered spiroheterocycloalkylene group, and a piperidinylene group, the C 3-6 Cycloalkylene groups, 5-12 membered spiroheterocycloalkylene groups, and piperidinylene groups are optionally hydroxyl C 1-6 Alkyl group (e.g., hydroxymethyl), formyl group, C 1-6 Substituted with one or two substituents selected from the group consisting of alkyl groups, Or, (II) Structure of Equation (2) [ka] Here, Ring A' [ka] It is selected from 5-10 membered heteroaryl groups, X 1 , X 2 , X 3 and X 4 Each is independently N or CH, and X 1 , X 2 , X 3 and X 4 At least one of them is not N, Z is CR 4’ And, The letters "a" and "b" refer to the bonds between the ring carbon atom linked to Z and the two adjacent ring carbon atoms, respectively. [ka] The part is expressed by the structure of equation (i) or equation (ii) below, [ka] Selected from, L 1’ This involves direct bonding and NR 7’ Selected from, R 1’ is, -L 2’ -R 1a And, L 2’ is -S(O)2NR 1b -*, -C(O)-NR 1b -*, -NR 1b -C(O)-* or -NR 1b -S(O)2-*, where the bond indicated by * is R 1a It is connected to, R 1a C 6-10 Selected from an aryl group and a 5-10 membered heteroaryl group, where the C 6-10 The aryl group and the 5-10 membered heteroaryl group can be optionally associated with halogens, OH, SH, and -NR groups, respectively. 1e R 1f , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN and -C 1-6 Alkilen-NR 1e R 1f It is substituted with one or more substituents independently selected from the base, Each R 2’ These are independently H, halogen, OH, SH, and -NR. 2a R 2b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 2a R 2b Selected from the group consisting of, m2 is 0, 1, 2, or 3. R 3’ and R 7’ These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -C 1-6 Alkylene-OC 1-6 Alkyl, -C1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 3a R 3b Selected from the group consisting of, R 4’ H, D, halogen, OH, SH, -NR 4a R 4b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -C 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 4a R 4b Selected from the group consisting of, R 5’ C 3-10 Selected from a cycloalkylene group and a 3-10 membered heterocyclene group, where the C 3-10 The cycloalkylene group and the 3-10 membered heterocyclene group can be optionally assigned halogen, OH, SH, or -NR groups, respectively. 5a R 5b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN and -C 1-6 Alkilen-NR 5a R5b It is substituted with one or more substituents independently selected from the base, R 6’ H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Haloalkenyl group, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, -OC 1-6 Alkylene-OC 1-6 Alkyl, -C 1-6 Alkylene-OH,-C 1-6 Alkylene-SH, -C 1-6 Alkylene-CN, -C 1-6 Alkilen-NR 6a R 6b Selected from the group consisting of, n2 is 0, 1, 2, 3 or 4, and R 1b , R 1e , R 1f , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a and R 6b Each time it appears, H and C 1-6 Selected independently of alkyl groups, The aforementioned [ka] This part is the ligase binding site.

[0077] Linking group L A In some embodiments, the present invention provides a compound of formula (A) according to the present invention, which is defined as L A It has a base.

[0078] In some embodiments, L A is a bond and C 1-2 Selected alkylene group, the C 1-2 The alkylene group can be optionally C 1-2 Alkyl alkyl group, C 1-2 Haloalkyl group, halogen, oxo group, OH, CN, NH2, -NH(C) 1-2 Alkyl), -N(C 1-2 It is substituted with one or more substituents independently selected from the group consisting of alkyl)2.

[0079] In some embodiments, L A is a bond and C 1-2 Selected alkylene group, the C 1-2 The alkylene group can be optionally C 1-2 It is substituted with a substituent selected from the group consisting of alkyl groups, halogens, and oxo groups.

[0080] In some embodiments, L A The group is selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, and -C(O)-. In some preferred embodiments, L A is -CH2- or -CH2-CH2-, and more preferably -CH2-.

[0081] IRAK4 ligand I) IRAK ligand having the structure of formula (1) above In some embodiments, the present invention provides a compound of formula (A) according to the present invention, where the [ka] The part has the structure of formula (1) above.

[0082] In some embodiments, the ring A is selected from a 5-membered heteroaryl group, the 5-membered heteroaryl group contains at least one N atom, and the 5-membered heteroaryl group is optionally substituted with R k It will be replaced with.

[0083] In some embodiments, the ring A is selected from a 5-membered heteroaryl group, the 5-membered heteroaryl group containing 2 to 3 heteroatoms, at least 2 of which are N atoms, and the 5-membered heteroaryl group optionally has a substituent R k It will be replaced with.

[0084] In some preferred embodiments, ring A is selected from the group consisting of a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a pyrazolyl group, an imidazolyl group, a 1,3,4-thiadiazolyl group, and a 1,3,4-oxadiazolyl group.

[0085] More preferably, the ring A is [ka] Selected from the group consisting of, where #C is, [ka] $L represents the connecting part that is connected to the part, 1 L 1 This represents the connecting part that is connected to the other.

[0086] More preferably, the ring A is [ka] Selected from, where #C is, [ka] $L represents the connecting part that is connected to the part, 1 L1 This represents the connecting part that is connected to the other.

[0087] In some embodiments, R k C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups, R p R q N-, C 1-6 The group is selected from haloalkyl groups and 4- to 9-membered saturated heterocycloalkyl groups (for example, 5- to 6-membered saturated heterocycloalkyl groups).

[0088] Preferably, R k C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups, R p R q N-, C 1-6 Selected from the group consisting of haloalkyl groups and morpholinyl groups.

[0089] In some embodiments, R p , R q These are, independently, hydrogen and C 1-6 Selected from alkyl groups.

[0090] In some preferred embodiments, R k isopropyl group, cyclopropyl group, dimethylamino group, difluoromethyl group, [ka] It is selected from the group consisting of the following.

[0091] In some embodiments, L 1 The bond is selected from direct bonding and -NH-, and is preferably direct bonding.

[0092] In some embodiments, R 13 C 1-4 Selected from a haloalkyl group, preferably -CHF2 and a trifluoromethyl group, and more preferably -CHF2.

[0093] In some embodiments, the structure of formula (1) is represented by the following formulas (1-1) or (1-2): [ka] It is represented by [this].

[0094] In some embodiments, ring B is selected from the following groups (1) to (3).

[0095] In some embodiments, group (1) [ka] In, R 4 This includes hydrogen, 4-7 member saturated monocyclic heterocycloalkyl groups, 6-9 member saturated cross-linked heterocycloalkyl groups, 6-9 member saturated spiroheterocycloalkyl groups, and 4-7 member saturated monocyclic heterocycloalkyl groups - C 1-4 Alkyl-, 6-9 member saturated crosslinked heterocycloalkyl-C 1-4 Alkyl-, -NR Na R Nb Selected from the group consisting of (where R Na and R Nb These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 3-6 Selected from the group consisting of cycloalkyl groups, the C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups can optionally include halogens, hydroxyl groups, and C 3-6 Cycloalkyl groups, C 3-6 Halocycloalkyl groups (which may be substituted with 1 to 3 substituents selected from the group consisting of 4-7 membered heterocyclyl groups), the 4-7 membered saturated monocyclic heterocycloalkyl groups, 6-9 membered saturated crosslinked heterocycloalkyl groups, 6-9 membered saturated spiroheterocycloalkyl groups, 4-7 membered saturated monocyclic heterocycloalkyl groups - C 1-4 Alkyl-, 6-9 member saturated crosslinked heterocycloalkyl-C 1-4 Alkyl- is optionally C1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, halogen, hydroxyl group, hydroxy-C 1-6 Alkylene-, oxo, -NH2, -NH(C) 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, In some embodiments, R 4 These are hydrogen, 4-7 member saturated monocyclic heterocycloalkyl groups, 6-9 member saturated cross-linked heterocycloalkyl groups, 6-9 member saturated spiroheterocycloalkyl groups, and -NR. Na R Nb Selected from the group consisting of (where R Na and R Nb These are H and C, respectively, independently. 1-6 Alkyl alkyl group, C 3-6 Selected from the group consisting of cycloalkyl groups, the C 1-6 Alkyl alkyl group, C 3-6 Cycloalkyl groups can optionally include a hydroxyl group and a C group. 3-6 The 4-7 member saturated monocyclic heterocycloalkyl group, the 6-9 member saturated crosslinked heterocycloalkyl group, and the 6-9 member saturated spiroheterocycloalkyl group may be optionally substituted with one, two, or three substituents selected from cycloalkyl groups. 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group, hydroxyl group, hydroxy-C 1-6 Alkylene-,-NH2,-NH(C) 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 Substituted with one, two, or three substituents selected from the group consisting of alkyl groups, R 4 is hydrogen, [ka] Selected from the group consisting of the above, [ka] C is optional. 1-6 Alkyl alkyl, halogen, hydroxyl group, hydroxy(C) 1-6 Alkyl)-, cyano group, -NH2, -N(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 The molecule is substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, where m1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0, and n1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0 or 1.

[0096] In some embodiments, R 4 is hydrogen, [ka] Selected from the group consisting of the above, [ka] C is optional. 1-6 Alkyl alkyl, halogen, hydroxyl group, hydroxy(C) 1-6 Alkyl)-, cyano group, -NH2, -N(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 The molecule is substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, where m1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0, and n1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0 or 1.

[0097] In some embodiments, R 4 is hydrogen, [ka] Selected from the group consisting of the above, [ka] C is optional. 1-6 Alkyl group, hydroxyl group, -NH2, hydroxy(C 1-6 It is substituted with one, two, or three substituents selected from the group consisting of alkyl)-.

[0098] In some embodiments, R 4 is hydrogen, [ka] It is selected from the group consisting of the following.

[0099] In some embodiments, R 4 is hydrogen, [ka] It is selected from the group consisting of the following.

[0100] In some embodiments, R 5 This is hydrogen, cyano group, -C(O)NH2, -NR l R m It is selected from the group consisting of the following.

[0101] In some embodiments, R l , R m Each of them is independent of C 1-6 Selected from alkyl groups.

[0102] In some embodiments, R 5 The group is selected from hydrogen and cyano groups.

[0103] In some embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0104] In some preferred embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0105] In some embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0106] In some embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0107] In some embodiments, group (2) [ka] In, R 22 is hydrogen and [ka] m4 is selected from the group consisting of 0, 1, 2, and 3, and n4 is selected from the group consisting of 0, 1, 2, and 3.

[0108] Preferably, R 22 is hydrogen and [ka] Selected from.

[0109] Comfortable, R 22 It is selected from hydrogen.

[0110] In some embodiments, R 23 is hydrogen, C 1-6 Alkyl group, cyano group, carboxyl group, -C(O)NH2, -NR l R m It is selected from the group consisting of the following.

[0111] Preferably, R 23 These are hydrogen, cyano group, carboxyl group, -C(O)NH2, -NR l R m It is selected from the group consisting of the following.

[0112] Comfortable, R 23 This is hydrogen, cyano group, -C(O)NH2, -NR l R m It is selected from the group consisting of the following.

[0113] More preferably, R 23 It is selected from -C(O)NH2.

[0114] In some embodiments, R l , R m These are, independently, hydrogen and C 1-6 Selected from alkyl groups.

[0115] In some preferred embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0116] more, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0117] more, [ka] Overall, [ka] That is the case.

[0118] In some embodiments, group (3) [ka] In, R 25 is hydrogen, [ka] m6 is selected from the group consisting of 0, 1, 2, and 3, and n6 is selected from the group consisting of 0, 1, 2, and 3.

[0119] Preferably, R 25 is hydrogen, [ka] Selected from.

[0120] Comfortable, R 25 It is hydrogen.

[0121] In some embodiments, R 26 is hydrogen, C 1-6 Selected from the group consisting of alkyl groups, cyano groups, and -C(O)NH2.

[0122] Preferably, R 26 is hydrogen, C 1-6 Selected from the group consisting of alkyl groups and -C(O)NH2.

[0123] Comfortable, R 26 It is selected from -C(O)NH2.

[0124] In some preferred embodiments, [ka] Overall, [ka] It is selected from the group consisting of the following.

[0125] In some preferred embodiments, [ka] Overall, [ka] That is the case.

[0126] In some embodiments, R 14 C 3-6 Selected from cycloalkylene groups, the C3-6 The cycloalkylene group can optionally be hydroxy C 1-6 It is substituted with one or two substituents selected from alkyl groups (e.g., hydroxymethyl group) and formyl group. Preferably, R 14 teeth, [ka] p is selected from the group consisting of 0, 1, and 2, R g is hydrogen, hydroxyl C 1-6 Selected from the group consisting of alkyl groups and formyl groups. Preferably, R g It is selected from hydrogen.

[0127] In some other embodiments, R 14 The group is selected from 7-11 member spiroheterocycloalkylene groups, and the 7-11 member spiroheterocycloalkylene group is optionally hydroxy C 1-6 Alkyl group (e.g., hydroxymethyl group), formyl group, C 1-3 It is substituted with one or two substituents selected from the group consisting of alkyl groups. Preferably, R 14 The group is selected from 9-11 membered spiroheterocycloalkylene groups, the 9-11 membered spiroheterocycloalkylene group having 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0128] In some other embodiments, R 14 The group is selected from piperidinylene groups, and the piperidinylene group is optionally composed of 1 to 2 carbon atoms. 1-3 It is substituted with an alkyl group (preferably a methyl group).

[0129] In some preferred embodiments, R 14 teeth, [ka] Selected from the group consisting of, more preferably, [ka] And moreover, [ka] Here, the bond indicated by x is linked to the pyrazole ring, and the bond indicated by y is the L A It is connected to.

[0130] In some embodiments, the [ka] The part is, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0131] In some preferred embodiments, [ka] The part is, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0132] In some preferred embodiments, [ka] The part is, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0133] II) IRAK4 ligand having the structure of formula (2) above In some embodiments, the present invention provides a compound of formula (A) according to the present invention, where the [ka] The part has the structure of formula (2) above.

[0134] In some embodiments, R 3’ H, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH,-C 1-4 Alkylene-SH, -C 1-4 Alkylene-CN, -C 1-4 Alkilen-NR 3a R 3b Selected from the group consisting of R. Preferably, R 3’ H and C 1-4 Selected from alkyl groups, more preferably H and a methyl group. Even more preferably H.

[0135] In some embodiments, the structure of formula (2) is as follows: [ka] It is represented by [this].

[0136] In some embodiments, n2 is 0 or 1.

[0137] In some embodiments, R 5’ C 3-10 Selected from a cycloalkylene group and a 3-10 membered heterocyclene group, where the C 3-10 The cycloalkylene group and the 3-10 membered heterocyclene group can be optionally assigned halogen, OH, SH, or -NR groups, respectively. 5a R 5b , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH,-C 1-4 Alkylene-SH, -C 1-4 Alkylene-CN and -C 1-4 Alkilen-NR 5a R 5b It is substituted with one or more substituents independently selected from the group.

[0138] Preferably, R 5’ C 3-6 Selected from a cycloalkylene group and a 5-10 membered heterocycloalkylene group, where the C 3-6The cycloalkylene group and the 5-10 membered heterocycloalkylene group can be optionally assigned halogen, OH, SH, or -NR groups, respectively. 5a R 5b , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH,-C 1-4 Alkylene-SH, -C 1-4 Alkylene-CN and -C 1-4 Alkilen-NR 5a R 5b It is substituted with one or more substituents independently selected from the group.

[0139] Comfortable, R 5’ C 3-6 Selected from a cycloalkylene group and a 5-10 membered heterocycloalkylene group, where the C 3-6 The cycloalkylene group and the 5-10 membered heterocycloalkylene group are each optionally C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH,-C 1-4 Alkylene-SH, -C 1-4 Alkylene-CN and -C 1-4 Alkilen-NR 5a R 5b It is substituted with one or more substituents independently selected from the group.

[0140] In some even more preferred embodiments, R5’ teeth, [ka] Selected from the group consisting of, Preferably, [ka] And, more, [ka] And, Here, the bond indicated by "c" is L A The bond connected to and indicated by "d" is connected to the ring A', or preferably, the bond indicated by "c" is connected to the ring A', and the bond indicated by "d" is connected to the L A It is connected to.

[0141] In some embodiments, the ring A' is selected from a 5-10 membered monocyclic or fused bicyclic heteroaryl group.

[0142] Preferably, the ring A' is selected from a 5-6 member monocyclic heteroaryl group and a 9-10 member fused bicyclic heteroaryl group.

[0143] More preferably, the ring A' is selected from a 5-6 membered monocyclic heteroaryl group and a benzo 5-6 membered monocyclic heteroaryl group, where preferably, the ring A' is connected to the L via the 5-6 membered monocyclic heteroaryl group. 1’ It is connected to.

[0144] More preferably, the ring A' is selected from a 5-membered monocyclic heteroaryl group and a benzo 5-membered monocyclic heteroaryl group, where preferably, the ring A' is connected to the L via the 5-membered monocyclic heteroaryl group. 1 It is connected to.

[0145] In some preferred embodiments, any of the above five-membered monocyclic heteroaryl groups is selected from the group consisting of a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, and a tetrazolyl group.

[0146] In some preferred embodiments, the ring A' is selected from the group consisting of a pyrazolyl group, a benzofuryl group, a benzothienyl group, and an indolyl group. Preferably, the benzofuryl group is connected to the L via a furan ring. 1 The benzothienyl group is linked to the L via the thiophene ring. 1 The indolyl group is connected to the L via the pyrrole ring. 1 It is connected to.

[0147] In some preferred embodiments, the ring A' is [ka] It is selected from the group consisting of the following.

[0148] In some preferred embodiments, [ka] The part is, [ka] Selected from the group consisting of, more preferably, [ka] That is the case.

[0149] In some preferred embodiments, [ka] The part is, [ka] Selected from.

[0150] In some embodiments, X 1 , X 2 and X 3 These are CH and X respectively. 1 is N and X 2 and X 3 These are CH and X respectively. 2 is N and X 1 and X 3 These are CH and X respectively. 3 is N and X 1 and X 2 These are CH and X respectively. 1 and X 2 Each of these is N, and X 3 is CH, or X 1 and X 3 Each of these is N, and X 2 is CH, or X 2 and X 3 Each of these is N, and X 1 is CH, or X 1 , X 2 and X 3 These are N, respectively.

[0151] In some preferred embodiments, the structure of formula (2) is as follows: [ka] As shown, More preferably, formulas (2-5)-(2-8): [ka] As shown.

[0152] In some embodiments, R 4’ H, D, halogen, OH, SH, -NR 4a R 4b , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene-OH,-C 1-4 Alkylene-SH, -C 1-4 Alkylene-CN, -C 1-4 Alkilen-NR 4a R 4b It is selected from the group consisting of the following.

[0153] Preferably, R 4’ H, D, halogen, OH, -NR 4a R 4b , CN, C 1-4 Alkyl alkyl group, C 1-4 Selected from the group consisting of haloalkyl groups.

[0154] Comfortable, R 4’ The group is selected from the group consisting of H, D, F, Cl, OH, -NH2, CN, methyl group, ethyl group, -CHF2, and -CF3.

[0155] Comfortable, R 4’ is selected from the group consisting of H, D, F, Cl, a methyl group, and an ethyl group, and more preferably H.

[0156] In some embodiments, R 6’ H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -SC 1-4Alkyl, -C 1-4 Alkylene - O - C 1-4 Alkyl, -OC 1-4 Alkylene - OC 1-4 Alkyl, -C 1-4 Alkylene - OH, -C 1-4 Alkylene - SH, -C 1-4 Alkylene - CN, -C 1-4 Alkylene - NR 6a R 6b is selected from the group consisting of.

[0157] Preferably, R 6’ is H, halogen, OH, SH, -NR 6a R 6b CN, C 1-4 alkyl group, C 1-4 haloalkyl group, -C 1-4 alkylene - OH, -C 1-4 alkylene - SH, -C 1-4 alkylene - CN, -C 1-4 alkylene - NR 6a R 6b is selected from the group consisting of.

[0158] More preferably, R 6’ is selected from the group consisting of H, F, Cl, OH, -NH2, -NHCH3, -N(CH3)2, CN, methyl group, ethyl group, -CHF2, -CF3.

[0159] More preferably, R 6’ is selected from the group consisting of H, -NH2, -NHCH3, -N(CH3)2, methyl group, ethyl group, -CHF2, -CF; even more preferably, it is H, methyl group, ethyl group and -CHF2.

[0160] In some embodiments, R 7’ is H, C 1-4 alkyl group, C 1-4 haloalkyl group, C 2-4 alkenyl group, C 2-4 haloalkenyl group, -C 1-4 alkylene - O - C 1-4 alkyl, -C1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, -C 1-4 alkylene-NR 3a R 3b is selected from the group consisting of.

[0161] Preferably, R 7’ is selected from H and C 1-4 alkyl groups, more preferably H and methyl groups, even more preferably H.

[0162] In some embodiments, the structure of formula (2) is formula (2-9)-(2-12):

Chemical formula

[0163] In some embodiments, R 1a is a C 6-10 aryl group and a 5- to 10-member heteroaryl group, where the C 6-10 aryl group and the 5- to 10-member heteroaryl group are each optionally halogen, OH, SH, -NR 1e R 1f CN, C 1-4 alkyl group, C 1-4 haloalkyl group, C 2-4 alkenyl group, C 2-4 haloalkenyl group, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl, -S-C 1-4 alkyl, -C 1-4 alkylene-O-C 1-4 alkyl, -OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN and -C 1-4 alkylene-NR 1e R 1fIt is substituted with one or more substituents independently selected from the base, Preferably, R 1a is a phenyl group, where the phenyl group can optionally be a halogen, OH, or -NR. 1e R 1f , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, -OC 1-4 Alkyl and -OC 1-4 The group is substituted with one or more substituents independently selected from the haloalkyl group, preferably F, Cl, OH, -NH2, CN, a methyl group, and an ethyl group.

[0164] Comfortable, R 1a teeth, [ka] Selected from.

[0165] In some embodiments, L 2’ is -S(O)2NR 1b -*, -C(O)-NR 1b -* or -NR 1b It is -C(O)-*, preferably -S(O)2NR 1b -*, where the bond indicated by * is R 1a It is connected to.

[0166] In some embodiments, each R 2’ These are independently H, halogen, OH, SH, and -NR. 2a R 2b , CN, C 1-4 Alkyl alkyl group, C 1-4 Haloalkyl group, C 2-4 Alkenyl group, C 2-4 Haloalkenyl group, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl, -SC 1-4 Alkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4 Alkylene-OC1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-SH, -C 1-4 alkylene-CN, -C 1-4 alkylene-NR 2a R 2b is selected from the group consisting of. Preferably, each R 2’ is, independently, H.

[0167] In some embodiments, R 1b , R 1e , R 1f , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , R 6b is, each time it appears, independently selected from H and C 1-4 alkyl groups, preferably H, methyl groups, and ethyl groups.

[0168] In some preferred embodiments,

Chemical formula

Chemical formula

[0169] Linking group L B In some embodiments, the present invention provides a compound of formula (A) according to the present invention, which has an L B group as defined above.

[0170] In some embodiments, the CyL1 and CyL2 groups are independently selected from 4- to 11-membered heterocycloalkylene groups each time they appear, preferably 4- to 7-membered monocyclic heterocycloalkylene groups, 6- to 10-membered condensed bicyclic heterocycloalkylene groups, 6- to 9-membered bridged heterocycloalkylene groups, and 5- to 12-membered spiroheterocycloalkylene groups, more preferably 4- to 6-membered monocyclic heterocycloalkylene groups, 8- to 10-membered condensed bicyclic heterocycloalkylene groups, 6- to 8-membered bridged heterocycloalkylene groups, and 7- to 11-membered spiroheterocycloalkylene groups. In some preferred embodiments, any one of the above heterocycloalkylene groups has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0171] In some embodiments, each time the CyL3 group appears, C 4-11 A cycloalkylene group and a 4- to 11-membered heterocycloalkylene group are independently selected, preferably C 4-6 Monocyclic cycloalkylene group, C 6-10 Condensed bicyclic cycloalkylene group, C 6-9 Crosslinked cycloalkylene group, C 5-12 The group is a spirocycloalkylene group, a 4-7 member monocyclic heterocycloalkylene group, a 6-10 member condensed bicyclic heterocycloalkylene group, a 6-9 member bridged heterocycloalkylene group, and a 5-12 member spiroheterocycloalkylene group, more preferably C 5-6 Monocyclic cycloalkylene group, C 8-10 Condensed bicyclic cycloalkylene group, C 6-8 Crosslinked cycloalkylene group, C 7-11 The groups are spirocycloalkylene groups, 4-6 membered monocyclic heterocycloalkylene groups, 8-10 membered condensed bicyclic heterocycloalkylene groups, 6-8 membered bridged heterocycloalkylene groups, and 7-11 membered spiroheterocycloalkylene groups, where any one of the above heterocycloalkylene groups preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0172] In some embodiments, each time the CyL3 group appears, C 4-11 A group independently selected from cycloalkylene groups, preferably C 4-6 Monocyclic cycloalkylene group, C 6-10 Condensed bicyclic cycloalkylene group, C 6-9 Crosslinked cycloalkylene group and C 5-12 A spirocycloalkylene group, more preferably C 5-6 Monocyclic cycloalkylene group, C 8-10 Condensed bicyclic cycloalkylene group, C 6-8 Crosslinked cycloalkylene group and C 7-11 It is a spirocycloalkylene group.

[0173] In some embodiments, each time the CyL3 group appears, C 5-6 Monocyclic cycloalkylene group, C 9-11 It is independently selected from the spirocycloalkylene group.

[0174] In some embodiments, the CyL4 group is independently selected from 5- to 10-membered heteroarylene groups each time it appears, preferably a 5- to 6-membered heteroarylene group, and more preferably a 5- to 6-membered nitrogen-containing heteroarylene group. In some embodiments, each time La appears, C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 It is independently selected from the group consisting of alkynylene groups.

[0175] Preferably, each time La appears, it is independently selected from the group consisting of -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-.

[0176] More specifically, each time La appears, it is independently selected from the group consisting of -CH2-, -(CH2)2-, -(CH2)3-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2-, and -CH2CH2-C≡C-.

[0177] In some embodiments, Lb is a -O-linear C whenever it appears. 1-3 Alkylene, -straight chain C 1-3 Alkylene-O-,-OC 2-3 Alkenylene, -C 2-3 Alkenylene-O-,-OC 2-3 Alkinylene, -C 2-3 Alkynylene-O-,-NR 8’ - Straight chain C 1-3 Alkylene-,-linear C 1-3 Alkilen-NR 8’ -, - Linear C 1-2 Alkilen-NR 8’ - Straight chain C 1-2 Alkylene-,-linear C 1-2 Alkylene-C(O)-NR 8’ -, -NR 8’ -C(O)- Linear C 1-2 Alkylene-, -C(O)- straight chain C 1-3 Alkylene-,-linear C 1-3 Alkylene -C(O)-, -linear carbon chain 1-2 Alkilen-NR 8’ -C(O)-, -C(O)-NR 8’ - Straight chain C 1-2 It is independently selected from the group consisting of alkylenes.

[0178] In some embodiments, Lb is a -O-linear C whenever it appears. 1-3 Alkylene, -straight chain C 1-3 Alkylene-O-,-OC 2-3 Alkenylene, -C 2-3 Alkenylene-O-,-OC 2-3 Alkinylene, -C 2-3 Alkynylene-O-,-NR 8’ - Straight chain C 1-3 Alkylene-,-linear C1-3 Alkilen-NR 8’ -, - Linear C 1-2 Alkilen-NR 8’ - Straight chain C 1-2 Alkylene-,-linear C 1-2 Alkylene-C(O)-NR 8’ -, -NR 8’ -C(O)- Linear C 1-2 Alkylene-, -C(O)- straight chain C 1-3 Alkylene-,-linear C 1-3 Independently selected from the group consisting of alkylene-C(O)-, where R 8’ Each time it appears, H and C 1-4 It is selected independently of alkyl groups.

[0179] In some embodiments, Lb is -OC each time it appears. 2-3 Alkynylene, -NR 8’ - Straight chain C 1-3 Alkylene-,-linear C 1-3 Alkilen-NR 8’ -, - Linear C 1-2 Alkilen-NR 8’ - Straight chain C 1-2 Alkylene-,-linear C 1-2 Alkylene-C(O)-NR 8’ -, -C(O)- straight chain C 1-3 It is independently selected from the group consisting of alkylenes.

[0180] In some embodiments, each time Lc appears, it is bound to or connected to a linear C chain. 1-3 Independently selected from alkylene groups, preferably a bond, a methylene group, or an ethylene group, more preferably a bond or a methylene group. In some embodiments, R L1 , R L2 and R 8’ Each instance of this group is independently selected from the group consisting of H, a methyl group, and an ethyl group, and more preferably H and a methyl group.

[0181] In some preferred embodiments, L BThe elements are selected from the following groups (1) to (21): (1) [ka] (2) [ka] (3) [ka] (4) [ka] (5) [ka] (6) [ka] (7) [ka] (8) [ka] (9) [ka] (10) [ka] (11) [ka] (12) [ka] (13) [ka] (14) [ka] (15) [ka] (16) [ka] (17) [ka] (18) [ka] (19) [ka] (20) [ka] (twenty one) [ka] Here, preferably, in any one of the groups (1) to (21) above, the bond indicated by "u" is linked to the LA, and the bond indicated by "v" is [ka] It is connected to the part.

[0182] In some preferred embodiments, L B The elements are selected from the following groups (1) to (21): (1) [ka] (2) [ka] (3) [ka] (4) [ka] (5) [ka] (6) [ka] (7) [ka] (8) [ka] (9) [ka] (10) [ka] (11) [ka] (12) [ka] (13) [ka] (14) [ka] (15) [ka] (16) [ka] (17) [ka] (18) [ka] (19) [ka] (20) [ka] (twenty one) [ka] Here, preferably, in any one of the groups (1) to (21) above, the bond indicated by "u" is linked to the LA, and the bond indicated by "v" is [ka] It is connected to the part.

[0183] In some preferred embodiments, L B The elements are selected from the following groups (1) to (19): (1) [ka] (2) [ka] (3) [ka] (4) [ka] (5) [ka] (6) [ka] (7) [ka] (8) [ka] (9) [ka] (10) [ka] (11) [ka] (12) [ka] (13) [ka] (14) [ka] (15) [ka] (16) [ka] (17) [ka] (18) [ka] (19) [ka] Here, preferably, in any one of the groups (1) to (19) above, the bond indicated by "u" is linked to the LA, and the bond indicated by "v" is [ka] It is connected to the part.

[0184] Ligase binding part In some embodiments, the present invention provides a compound of formula (A) according to the present invention, where the [ka] The component is the E3 ubiquitin ligase ligand.

[0185] In some preferred embodiments, [ka] The part is, [ka] Selected from the group consisting of, Here, Ring Aa [ka] is a 5-membered heterocyclyl group or a 5-membered heteroaryl group, preferably a 5-membered heterocyclyl group or a 5-membered heteroaryl group having 1, 2 or more N heteroatoms, where the 5-membered heterocyclyl group and the 5-membered heteroaryl group can optionally be H, halogen, OH, NH2, CN, oxo group, C 1-4 Substituted with one or more substituents independently selected from the group consisting of alkyl groups, Preferably, [ka] The part is, [ka] A group consisting of is selected, where the combination denoted by "z" is X 5 It is connected to, each ring [ka] These are independently a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group. X 5 CR L7 or N, t is 0 or 1, preferably 1. R L1 , R L5 and R L6 Each time they appear, H and C 1-4 Independently selected from alkyl groups, preferably H and a methyl group, R L2 and R L3 Each time they appear, H and C 1-4 Independently selected from alkyl groups, preferably H and a methyl group, or R L2 and R L3 They combine to form an oxo group, R L4 and R L7 Each of these is H, halogen, OH, NH2, CN, and C, as they appear. 1-4 Independently selected from the group consisting of alkyl groups, preferably H, F, Cl, Br, and C 1-2 It is an alkyl group, more preferably H, F, Cl and a methyl group, m5 is 0, 1, 2, 3, or 4, preferably 1 or 2.

[0186] In some preferred embodiments, [ka] The part is, [ka] It is selected from the group consisting of the following.

[0187] In some preferred embodiments, [ka] The part is, [ka] It is selected from the group consisting of the following.

[0188] In some preferred embodiments, [ka] The part is, [ka] It is selected from the group consisting of the following.

[0189] In some preferred embodiments, the present invention provides a compound of formula (A), wherein the compound has the structure shown in formula (B), [ka] Here, L B The following can be selected: (1)-CyL1-, where the CyL1 group is selected from 7-11 member spiroheterocycloalkylene groups, more preferably a 9-11 member spiroheterocycloalkylene group, where the 7-11 member spiroheterocycloalkylene group and the 9-11 member spiroheterocycloalkylene group each have 1 or 2, preferably 2 nitrogen heteroatoms, and optionally C 1-4 Substituted with one or more groups independently selected from alkyl groups and halogens, preferably a methyl group, F and Cl, more preferably a methyl group and F, or (2)-CyL1-CyL2-, where CyL1 and CyL2 groups are independently selected from 4- to 7-membered monocyclic heterocycloalkylene groups, more preferably 4- to 6-membered monocyclic heterocycloalkylene groups, where the 4- to 7-membered monocyclic heterocycloalkylene group and the 4- to 6-membered monocyclic heterocycloalkylene group each have one or two nitrogen heteroatoms, and optionally C 1-4 Substituted with one or more groups independently selected from alkyl groups and halogens, preferably a methyl group, F and Cl, more preferably a methyl group and F. R 4 These are 4-6 member saturated monocyclic heterocycloalkyl groups and -NR Na R Nb Selected from, where R Na H and C 1-6 Selected from alkyl groups, and R Nb C 3-6 Selected from cycloalkyl groups, wherein the 4-6 member saturated monocyclic heterocycloalkyl group and the C 3-6 The cycloalkyl group is substituted with 1 to 3 substituents selected from halogens and hydroxyl groups, R 5 It is hydrogen.

[0190] In some embodiments, L B teeth, [ka] Selected from the group consisting of, more preferably, [ka] And here, in any one of the above groups, the bond indicated by "u" is, [ka] A connection that is linked to a part and is indicated by "v" is [ka] It is connected to the part.

[0191] In some preferred embodiments, L B teeth, [ka] Selected from the group consisting of, more preferably, [ka] And here, in any one of the above groups, the bond indicated by "u" is, [ka] A connection that is linked to a part and is indicated by "v" is [ka] It is connected to the part.

[0192] In some preferred embodiments, R 4 This consists of a 4-6 member saturated monocyclic nitrogen-containing heterocycloalkyl group (preferably a piperidinyl group) and -NR Na R Nb Selected from, where R Na is H and R Nb C 3-6 Selected from cycloalkyl groups (preferably cyclohexyl groups), wherein the 4-6 member saturated monocyclic nitrogen-containing heterocycloalkyl group and the C 3-6 A cycloalkyl group is substituted with one hydroxyl group.

[0193] In some preferred embodiments, R 4 teeth, [ka] Selected from, more preferably, [ka] That is the case.

[0194] This invention covers compounds that can be obtained by arbitrarily combining each embodiment.

[0195] In some embodiments, the present invention provides compounds of formula (A), or stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterides), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts thereof, wherein the compounds are selected from Table 1 below.

[0196] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0197] In some embodiments, the present invention provides a compound of formula (A), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound is selected from compound 1 to compound 282.

[0198] In some preferred embodiments, the compound is [ka] It is selected from the group consisting of the following.

[0199] Pharmaceutical compositions and uses In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid formulation, a liquid formulation, or a transdermal formulation.

[0200] In another aspect, the present invention provides uses for the manufacture of drugs of the compounds of the present invention or their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical compositions of the present invention.

[0201] In some embodiments, the compounds of the present invention, the pharmaceutical compositions of the present invention, or the drugs are used to treat diseases, disorders, or conditions related to IRAK4 protein kinase.

[0202] In another embodiment, the present invention further provides a method for treating, alleviating, or delaying the progression or onset of a disease, disorder, or condition related to IRAK4 protein kinase, the method comprising administering to an individual in need an effective amount of the compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions of the present invention.

[0203] In another aspect, the present invention provides compounds of the present invention or their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions of the present invention, for treating diseases, disorders, or conditions related to IRAK4 protein kinase.

[0204] In another aspect, the present invention further provides uses for the manufacture of drugs as IRAK4 inhibitors of the compounds of the present invention or their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical compositions of the present invention.

[0205] In yet another aspect, the present invention provides a method for inhibiting IRAK4 activity in an organism, the method comprising administering to an organism in need of such inhibition an effective amount of the compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention.

[0206] In another embodiment, the present invention provides a method for targeted degradation of IRAK4 protein kinase, the method comprising contacting the IRAK4 protein kinase with the compound of formula (A) described above or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts in the presence of an E3 ubiquitin ligase. In some embodiments, the method is carried out in vitro or ex vivo. In some other embodiments, the method is carried out in vivo.

[0207] In some embodiments, the disease, disorder, or condition associated with IRAK4 protein kinase is selected from the group consisting of autoimmune diseases, inflammatory diseases, cancer, graft rejection, thromboembolism, atherosclerosis, myocardial infarction, and metabolic syndrome.

[0208] In some embodiments, the inflammatory disease 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 allergy, and is preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, and chronic nephritis.

[0209] In some embodiments, the autoimmune disease 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, and is preferably psoriasis.

[0210] In some embodiments, the graft rejection reaction is selected from graft-versus-host disease and allograft rejection.

[0211] In some embodiments, the cancers include brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumors, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, head and neck tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminomas, melanoma, acute myeloid leukemia, and chronic bone cancer. The diagnosis is selected from the following group: myelin leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, pre-B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

[0212] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or medium administered together with a therapeutic agent, which, to the extent of reasonable medical judgment, is suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications that constitute a reasonable benefit / risk ratio.

[0213] Unless otherwise stated herein, the term “treatment” as used herein means reversing, mitigating, inhibiting the progression of a disease or condition to which such term applies, or one or more symptoms of such disease or condition, or preventing such disease or condition, or one or more symptoms of such disease or condition.

[0214] As used herein, “individual” includes humans and non-human animals. An exemplary human individual includes a human individual suffering from a disease (referred to as a patient) or a healthy individual. “Non-human animals” in the present invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, dairy cows, pigs, etc.).

[0215] In another embodiment, the pharmaceutical composition of the present invention may further comprise one or more other therapeutic or prophylactic agents.

[0216] Examples The embodiments of the present invention will be described in detail below, linking them to examples. However, those skilled in the art will understand that the following examples are merely illustrative and not intended to limit the scope of the present invention. Unless otherwise specified in the examples, the procedures were carried out under conventional or manufacturer-suggested conditions. Unless otherwise specified, the reagents or equipment used were all commercially available, standard products.

[0217] NMR was measured using a Bruker Avance III 400 nuclear magnetometer, and the chemical shift (δ) was 10 -6 The values ​​were given in units of ppm. The solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeutate dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0218] Mass spectroscopy (MS) was performed using Agilent (ESI) mass spectrometers (Agilent 1260, Agilent 6125B).

[0219] High-performance liquid chromatography (HPLC) measurement conditions: Gilson high-pressure liquid chromatograph (Gilson GX-281), C18 column (10 μM, 19 mm x 250 mm), UV detection bands at 220 and 254 nm, and gradient elution for 15 minutes with 5-95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate).

[0220] Reverse-phase purification was performed using the Biotage Isolera high-speed purification system.

[0221] For separation and purification by thin-layer chromatography, thin-layer chromatography silica gel plates (Meck aluminum plates (20cm x 20cm x 1mm) or Yantai GF 254) were used.

[0222] The microwave reaction was carried out using a Biotage Initiator + (400W, RT~300℃) microwave reactor.

[0223] Reaction monitoring was generally performed using TLC or LCMS. Commonly used developing agent systems included dichloromethane / methanol, n-hexane / ethyl acetate, and petroleum ether / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound, or by adding triethylamine or the like.

[0224] The silica gel used in column chromatography was generally 100-200 mesh silica gel. Commonly used eluent systems were dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of triethylamine may also be added.

[0225] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, An Naiji, Bailingwei Technology, Shanghai Bide Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Taitan Technology Co., Ltd.

[0226] Synthesis Examples Example 1: 3-(4-((R)-3-((1-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)oxy)buto-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(1) [ka] 1) Step 1: At room temperature, compound 1c-1 (5.00 g, 32.56 mmol) and acetonitrile (50 mL) were sequentially added to a 250 mL single-necked flask and stirred until dissolved. Morpholine (4.25 g, 48.8 mmol) and N,N-diisopropylethylamine (12.6 g, 97.7 mmol) were sequentially added. The mixture was purged three times with nitrogen gas and stirred at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100 / 1) to obtain compound 1c-2. MS m / z (ESI): 205.4 [M+H] + .

[0227] 2) Step 2: At room temperature, compound 1c-2 (2.00 g, 9.79 mmol) and acetonitrile (25 mL) were added to a 100 mL single-necked flask and stirred until dissolved. N-iodosuccinimide (3.30 g, 14.7 mmol) was added, the mixture was purged three times with nitrogen gas, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100 / 1) to obtain compound 1c-3. MS m / z (ESI): 330.9 [M+H] + .

[0228] 3) Step 3: At room temperature, compound 1c-3 (500 mg, 1.51 mmol) and tetrahydrofuran (10 mL) were sequentially added to a 100 mL single-necked flask and stirred until dissolved. Trimethylsilylacetylene (1.07 mL, 7.57 mmol), cuprous iodide (28.8 mg, 0.150 mmol), triethylamine (460 mg, 4.54 mmol), and bistriphenylphosphine dichloride palladium (106.31 mg, 0.15 mmol) were sequentially added. The mixture was purged three times with nitrogen gas and stirred at 30°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / petroleum ether = 50 / 1) to obtain compound 1c-4. MS m / z (ESI): 300.8 [M+H] + .

[0229] 4) Step 4: At room temperature, compound 1c-4 (300 mg, 1.00 mmol) and anhydrous methanol (10 mL) were sequentially added to a 50 mL single-necked flask and stirred until dissolved. Potassium carbonate (276 mg, 2.00 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and it was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saline solution (20 mL), dried over sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain a product containing compound 1c, which was then used to carry out the subsequent reaction directly. MS m / z (ESI): 228.9 [M + H] + .

[0230] 5) Step 5: Compound 1a (3.00 g, 12.2 mmol, prepared by the method disclosed in step 6 of the intermediate compound on page 137 of the specification in patent application "WO2022161414A1") was dissolved in acetonitrile (35 mL), and isoamyl nitrite (2.10 g, 17.9 mmol, Bi-de) was added at 0°C. After stirring the reaction mixture for 30 minutes, trimethylsilyl azide (2.00 g, 17.4 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was poured into water (30 mL), and the aqueous phase was 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 to obtain compound 1b. MS m / z (ESI): 272.1 [M + H] + .

[0231] 6) Step 6: Compound 1b (2.20 g, 8.11 mmol) was dissolved in ethanol (30 mL) and water (10 mL). Sodium vitamin C (0.33 g, 1.67 mmol, aneji), copper sulfate pentahydrate (0.41 g, 1.64 mmol, aneji), and compound 1c (1.86 g, 8.15 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was filtered, the solid was collected, and beaten with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 30 mL) to obtain compound 1d. 1 H NMR(400MHz,DMSO-d6):δ 8.76(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),6.81(d,J=7.9Hz,1H),4.50(s,1H),4.27(t ,J=11.9Hz,1H),3.73(s,8H),3.28(d,J=5.7Hz,2H),2.19-2.07(m,2H),1.93-1.76(m,4H),1.54-1.38(m,1H),1.20-1.07(m,2H).

[0232] 7) Step 7: Compound 1d (3.20 g, 6.41 mmol) was dissolved in dichloromethane (50 mL), and Dessmartin oxidizing agent (4.10 g, 9.67 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (80 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was beaten with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 30 mL) to obtain compound 1e. 1 H NMR(400MHz,DMSO-d6):δ 9.63(s,1H),8.76(d,J=7.9Hz,1H),8.67(s,1H),8.54(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),6.81(d,J=7.9Hz,1H),4. 39-4.26(m,1H),3.73(s,8H),2.45-2.36(m,1H),2.24-2.16(m,2H),2.16-2.07(m,2H),1.94-1.84(m,2H),1.49-1.35(m,2H).

[0233] 8) Step 8: Compound 1f (50.0 mg, 0.12 mmol, prepared by the method disclosed in Intermediate AVF on page 1148 of the specification in patent application "CN113423427") is dissolved in a mixed solution of tetrahydrofuran (1 mL) and N,N-dimethylcarboxamide (1 mL), and triethylamine (0.03 mL, 0.23 mmol), acetic acid (0.03 mL, 0.45 mmol), sodium triacetoxyborohydride (25.8 mg, 0.12 mmol), and compound 1e (60.6 mg, 0.12 mmol) are added, and 2 After stirring for a specified time, water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 1. MS m / z (ESI): 892.7 [M+1] + . 1 1H NMR (400 MHz, CDCl3): δ 8.61(s,1H),8.57(s,1H),8.38(d,J=7.6Hz,1H),8.11(s,1H),7.25-7.20( m,1H),7.18-6.77(m,3H),6.39(d,J=7.6Hz,1H),5.27-5.20(m,1H),4.60- 4.50(m,1H),4.25-4.15(m,1H),3.87-3.76(m,13H),2.95-2.81(m,5H),2. 28-2.21 (m, 10H), 1.81-1.61 (m, 4H), 1.56-1.54 (m, 6H), 1.27-1.00 (m, 1H).

[0234] Example 2: 3-(4-(3-((S)-2-((((4-(-3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-ylcyclohexyl)methyl)amino)methyl)morpholinyl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(2) [ka] Compound 2a (80.0 mg, 0.190 mmol, prepared by the method disclosed in intermediate SR on page 934 of the specification in patent application "US20190192668A1") and compound 1e (95.8 mg, 0.190 mmol) were dissolved in ethanol (2 mL), acetic acid (0.10 mL, 1.75 mmol) was added, and the reaction mixture was stirred at 25°C for 10 minutes, after which sodium cyanoborohydride (48.4 mg, 0.770 mmol) was added. The reaction mixture was stirred for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 2. MS m / z (ESI): 897.6 [M+1] + .

[0235] Example 3: 3-(4-((((1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)methyl)(methyl)amino)methyl)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(3) [ka] 1) Step 1: Compound 3a (100 mg, 0.320 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") was dissolved in acetonitrile (5 mL), compound 3b (74.0 mg, 0.320 mmol, Bi De) and potassium carbonate (135 mg, 0.970 mmol) were added, and the reaction mixture was stirred at 80°C for 2 hours. Then, water (10 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 3c.

[0236] 2) Step 2: Compound 3c (50 mg, 0.100 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. After that, the reaction mixture was concentrated under reduced pressure, and the residue was used directly as the starting material for the next step without purification to obtain compound 3d. MS m / z (ESI): 400.2 [M+1] + .

[0237] 3) Step 3: Compound 3d (35.0 mg, 90.0 μmol) and compound 1e (45.0 mg, 90.0 μmol) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (60.0 mg, 0.280 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography 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 3. MSm / z(ESI): 441.6 [M / 2+1] + .

[0238] Example 4: 3-(4-(2-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)amino)-7-azaspiro[3.5]nonane-7-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione(4) [ka] 1) Step 1: Compound 3a (160 mg, 0.520 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 4a (162 mg, 0.680 mmol, Bi De) were dissolved in acetonitrile (6 mL), and potassium carbonate (138 mg, 1.04 mmol) was added. The reaction mixture was heated to 80°C under a nitrogen gas atmosphere and reacted for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 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 using an eluent system (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 4b. MS m / z (ESI): 512.2 [M+1] + .

[0239] 2) Step 2: Compound 4b (120 mg, 0.230 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 4c. MS m / z (ESI): 412.2 [M+1] + .

[0240] 3) Step 3: Compound 4c (60.0 mg, 0.150 mmol) and compound 1e (75.0 mg, 0.150 mmol) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (90.0 mg, 0.430 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated saline solution (20 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% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 4. MS m / z (ESI): 893.6 [M+1] + .

[0241] Example 5: 3-(4-(4-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione(5) [ka] 1) Step 1: Compound 3a (100 mg, 0.320 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 5a (100 mg, 0.390 mmol, Bi De) were dissolved in acetonitrile (5 mL), and potassium carbonate (150 mg, 1.09 mmol) was added. The reaction mixture was heated to 80°C under a nitrogen gas atmosphere and reacted for 18 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 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 using an eluent system (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 5b. MS m / z (ESI): 528.7 [M+1] + .

[0242] 2) Step 2: Compound 5b (100 mg, 0.190 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 5c. MS m / z (ESI): 428.2 [M+1] + .

[0243] 3) Step 3: Compound 5c (50.0 mg, 0.120 mmol) and compound 1e (65.0 mg, 0.130 mmol) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (75.0 mg, 0.360 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated saline solution (20 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% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 5. MS m / z (ESI): 909.4 [M+1] + .

[0244] Example 6: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)amino)piperidine-1-carbonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione(6) [ka] Compound 6a (80.0 mg, 0.190 mmol, prepared by the method disclosed in intermediate CA on page 411 of the specification in patent application "WO2022236058A1") and compound 1e (100 mg, 0.200 mmol) were dissolved in tetrahydrofuran (3 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.2 mL) and sodium borohydride acetate (120 mg, 0.570 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated saline solution (20 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% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 30%~70%, flow rate: 25 mL / min) to obtain compound 6. MS m / z (ESI): 907.6 [M+1] + .

[0245] Example 7: 3-(4-(3-(1-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)oxy)propyl-1-alkynyl)3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione(7) [ka] Compound 7a (50.0 mg, 0.130 mmol, prepared by the method disclosed in the intermediate APT on page 91 of the specification in patent application "WO2021247899A1") and compound 1e (65.0 mg, 0.130 mmol) were dissolved in tetrahydrofuran (1 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (75.0 mg, 0.360 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated saline solution (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19 × 250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 40%~75%, flow rate: 25 mL / min) to obtain compound 7. MS m / z (ESI): 439.9 [M / 2 + 1] + .

[0246] Example 8: 3-(4-(1-(((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazole[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexylmethyl)piperidine-4-yl)methyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(8) [ka] 1) Step 1: Compound 8a (240 mg, 0.670 mmol, prepared by the method disclosed in the intermediate step AVW compound on page 639 of the specification in patent application "WO2020 / 264499Al") was dissolved in dichloromethane (10 mL), and triethylamine (0.20 mL, 1.35 mmol), compound 8b (144 mg, 0.670 mmol, Bi De), acetic acid (0.08 mL, 1.35 mmol), and sodium borohydride acetate (428 mg, 2.02 mmol) were added. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (GILSON-215, chromatography column: Boston-Prime C18, 30 × 150 mm, 5 μm, mobile phase: water (containing 0.05% ammonium hydroxide) and acetonitrile, gradient ratio: acetonitrile 45%~65%, flow rate: 35 mL / min) to obtain compound 8c. MS m / z (ESI): 554.3 [M+1] + .

[0247] 2) Step 2: Compound 8c (10.0 mg, 0.200 mmol) was dissolved in dichloromethane (0.5 mL). Trifluoroacetic acid (0.5 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 8d. MS m / z (ESI): 454.4 [M+1] + .

[0248] 3) Step 3: Compound 8d (8.00 mg, 20.0 μmol) was dissolved in tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL). Triethylamine (1.78 mg, 20.0 μmol), compound 1e (8.78 mg, 20.0 μmol), and acetic acid (1.06 mg, 20.0 μmol) were added, and the mixture was reacted at room temperature for 1 hour. Next, sodium triacetylborohydride (22.4 mg, 110 μmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel plate chromatography using an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 8. MS m / z (ESI): 935.5 [M+1].

[0249] Example 9: 3-(4-(7-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-7-azaspiro[3.5]nonane-2-ylmethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione(9) [ka] Compound 9a (40.0 mg, 0.100 mmol, prepared by the method disclosed in intermediate BAQ on page 786 of the specification in patent application "WO2020264499") was dissolved in 1,2-dichloroethane (2 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.1 mL) was added, and the mixture was stirred for 0.5 hours. Compound 1e (59.0 mg, 90.0 μmol) and acetic acid (0.1 mL) were added to the reaction mixture and the mixture was stirred for 0.5 hours. Sodium cyanoborohydride (19.0 mg, 0.300 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 9. MS m / z (ESI): 893.5 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 11.06(s,1H),8.77(d,J=7.9Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),7.19(t,J=53.0Hz, 1H),6.86-6.81(m,2H),6.50(d,J=8.5Hz,1H),6.42(d,J=8.3Hz,1H),5.32-5.27(m,1H),4.93-4 .87(m,1H),4.32-4.25(m,1H),3.73(s,8H),3.61(s,3H),3.10-3.02(m,2H),2.72-2.60(m,3H), 2.59-2.55(m,2H),2.40-2.30(m,3H),2.25-1.75(m,12H),1.70-1.50(m,6H),1.10-1.00(m,2H).

[0250] Example 10: 3-(4-(((7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl(cyclohexyl)methyl)-7-azaspiro[3.5]non-2-yl)amino)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(10) [ka] 1) Step 1: Compound 1e (120 mg, 0.240 mmol) was dissolved in dichloromethane (6 mL), and compound 4a (74.9 mg, 0.310 mmol, bisulfite) and acetic acid (14.4 mg, 0.240 mmol) were added. The reaction mixture was stirred at 25°C for 10 minutes, and then sodium triacetoxyborohydride (306 mg, 1.45 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 10 / 1) to obtain compound 10a. MS m / z (ESI): 722.4 [M+1] + .

[0251] 2) Step 2: Compound 10a (40.0 mg, 60.0 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 10b. MS m / z (ESI): 622.7 [M+1] + .

[0252] 3) Step 3: Compound 10b (80.0 mg, 0.130 mmol) was dissolved in tetrahydrofuran (1 mL), and compound 10c (36.9 mg, 0.130 mmol, prepared by the method disclosed in the intermediates on page 171 of the specification in patent application "WO2022140472A1") and tetraethyl orthotitanate (0.050 mL, 0.26 mmol) were added. The reaction mixture was stirred at 80°C for 18 hours, then returned to room temperature, sodium triacetoxyborohydride (40.9 mg, 0.190 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phase was washed with saturated saline solution (10 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% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 10. MS m / z (ESI): 893.6 [M+1] + .

[0253] Example 11: 3-(4-(1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (11) [ka] Compound 11a (165 mg, 0.480 mmol, prepared by the method disclosed in intermediate 199 on page 222 of the specification in patent application "WO2021158634A1") was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL), and triethylamine (40.7 mg, 0.400 mmol) was added. After stirring the reaction mixture at 25°C for 10 minutes, acetic acid (24.1 mg, 0.400 mmol) and compound 1e (200 mg, 0.400 mmol) were added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, sodium borohydride acetate (511 mg, 2.41 mmol) was added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (8 mL) and dichloromethane (10 mL). After separating the aqueous phase, it was extracted with dichloromethane (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 11. MS m / z (ESI): 824.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.10(s,1H),8.76(d,J=4.0Hz,1H),8.65(s,1H),8.54(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H) ,7.05-6.94(m,3H),6.81(d,J=4.0Hz,1H),5.42-5.28(m,1H),4.34-4.26(m,1H),3.72(s,8H),3.58 (s,3H),3.27-3.21(m,2H),3.06-3.00(m,2H),2.93-2.85(m,1H),2.72-2.59(m,2H),2.30-2.23(m, 2H), 2.20-2.11 (m, 4H), 2.02-1.94 (m, 3H), 1.85-1.77 (m, 5H), 1.69-1.62 (m, 1H), 1.17-1.06 (m, 2H).

[0254] Example 12: 3-(4-((6-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(12) [ka] 1) Step 1: Compound 3a (120 mg, 0.390 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 12a (92.8 mg, 0.470 mmol, Bi-de) were dissolved in acetonitrile (8 mL), potassium carbonate (55.0 mg, 0.390 mmol) was added, and the mixture was stirred at 80°C for 1.5 hours. After adding water (50 mL) to the reaction mixture, the mixture was extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated brine, the organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 12b. MS m / z (ESI): 470.6 [M+1] + .

[0255] 2) Step 2: Compound 12b (120 mg, 0.260 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.8 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, compound 12c was obtained. MS m / z (ESI): 370 [M+1] + .

[0256] 3) Step 3: Compound 12c (66.8 mg, 0.181 mmol) was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL). Triethylamine (18.3 mg, 0.181 mmol) was added until the pH value exceeded 8, and the mixture was stirred at 25°C for 10 minutes. The reaction mixture was cooled to -10°C, acetic acid (50.3 mg, 0.271 mmol) was added, and compound 1e (90.0 mg, 0.181 mmol) was added. The reaction mixture was heated to 25°C and stirred at this temperature for 20 minutes, after which sodium borohydride acetate (76.7 mg, 0.361 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-T C18, 30*150 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%~45%, flow rate: 30 mL / min) to obtain compound 12. MS m / z (ESI): 851.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.10(s,1H),8.76(d,J=7.9Hz,1H),8.64(s,1H),8.53(d,J=3.9Hz,1H),8.20(s,1H),7.34-7.02(m,2H),7.00-6.8 8(m,2H),6.81(d,J=7.9Hz,1H),5.37(dd,J=12.6,5.3Hz,1H),4.25(t,J=11.7Hz,1H),3.76-3.71(m,10H),3.63(s,3 H),3.35-3.27(m,4H),3.24(s,4H),2.94-2.85(m,1H),2.74-2.59(m,2H),2.31(d,J=6.5Hz,2H),2.17-2.05(m,2H) ,2.03-1.97(m,1H),1.91-1.81(m,2H),1.79-1.72(m,1H),1.68-1.48(m,1H),1.46-1.24(m,1H),1.20-0.94(m,2H).

[0257] Example 13: 3-(4-((7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(13) [ka] 1) Step 1: Compound 3a (100 mg, 0.321 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 13a (73.5 mg, 0.321 mmol, Bi De) were dissolved in acetonitrile (8 mL), potassium carbonate (112 mg, 0.810 mmol) was added, and the reaction mixture was stirred at 80°C for 1.5 hours. Then, water (50 mL) was added to the reaction mixture, and it was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 13b. MS m / z (ESI): 498.6 [M+1] + .

[0258] 2) Step 2: Compound 13b (25.0 mg, 51.0 μmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (0.8 mL) was added, and the reaction mixture was allowed to react at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, compound 13c was obtained. MS m / z (ESI): 398 [M+1] + .

[0259] 3) Step 3: Compound 13c (25.0 mg, 61.0 μmol) was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL). Triethylamine (8.12 mg, 81.00 μmol) was added until the pH value exceeded 8, and the reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was cooled to -10°C, and acetic acid (186 mg, 91.0 μmol) and compound 1e (30.0 mg, 61.0 μmol) were added. The reaction mixture was raised to 25°C and stirred at this temperature for 20 minutes, after which sodium borohydride acetate (25.7 mg, 0.121 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-T C18, 30×150 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%~45%, flow rate: 30 mL / min) to obtain compound 13. MS m / z (ESI): 879.5 [M+1] + .

[0260] Example 14: 3-(4-(2-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (14) [ka] 1) Step 1: Compound 3a (100 mg, 0.321 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 14a (100 mg, 0.440 mmol, Bi De) were dissolved in acetonitrile (2 mL), and potassium carbonate (122 mg, 0.880 mmol) was added. The reaction mixture was purged three times with nitrogen gas and reacted at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 14b. MS m / z (ESI): 498 [M+1] + .

[0261] 2) Step 2: Compound 14b (80.0 mg, 0.160 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, compound 14c was obtained. MS m / z (ESI): 398.2 [M+1] + .

[0262] 3) Step 3: Compound 14c (35.0 mg, 90.0 μmol) was dissolved in a solution of 1,2-dichloroethane (2 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.05 mL) was added, and the reaction mixture was stirred for 0.5 hours. Then, compound 1e (54.0 mg, 0.110 mmol) and acetic acid (0.1 mL) were added to the reaction mixture and stirred for another 0.5 hours. Sodium borohydride acetate (17.0 mg, 0.270 mmol, AN-NAI) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours, then concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 14. MS m / z (ESI): 879.6 [M+1] + . 1 HNMR(400MHz,DMSO-d6):δ11.10(s,1H),8.76(d,J=7.9Hz,1H),8.64(s,1H),8.53(s,1H),8.38(s,1H),7.32-7.05(m ,3H),6.95(t,J=7.7Hz,1H),6.86(d,J=7.2Hz,1H),6.81(d,J=7.7Hz,1H),6.65(s,1H),5.40-5.30(m,2H),4.31-4.20 (m,1H),3.72(s,8H),3.67(s,3H),3.58(s,2H),2.90(s,3H),2.70-2.62(m,2H),2.30-2.26(m,2H),2.13-2.07(m,2H) ),2.01-1.98(m,3H),1.80-1.72(m,2H),1.65-1.61(m,3H),1.47-1.42(m,2H),1.13-1.01(m,2H),0.90-0.80(m,3H).

[0263] Example 15: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)piperidine-1-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (15) [ka] 1) Step 1: Compound 3a (80.0 mg, 0.260 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") and compound 15a (67.0 mg, 0.310 mmol, Bi De) were dissolved in acetonitrile (5 mL), and potassium carbonate (71.0 mg, 0.520 mmol) was added. The reaction mixture was purged three times with nitrogen gas and reacted at 80°C for 2 hours. The reaction mixture was diluted with aqueous ammonium chloride (20 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 15b. MS m / z (ESI): 486.7 [M+1] + .

[0264] 2) Step 2: Compound 15b (80.0 mg, 0.160 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the crude product compound 15c was obtained. MS m / z (ESI): 368.2 [M+1] + .

[0265] 3) Step 3: Compound 15c (30.0 mg, 80.0 μmol) was dissolved in 1,2-dichloroethane (2 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.1 mL) was added, and the mixture was stirred for 0.5 hours. Compound 1e (47.0 mg, 90.0 μmol) and glacial acetic acid (0.1 mL) were added to the reaction mixture, and the mixture was stirred for 0.5 hours. Finally, sodium borohydride acetate (15.0 mg, 0.230 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19*250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 15. MS m / z (ESI): 867.7 [M+1] + . 1 HNMR(400MHz,DMSO-d6):δ 11.13(s,1H),8.77(d,J=7.9Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),8.16(s,1H),7.20(t,J=47.8Hz,1H),7.09-7.04(m ,1H),6.96(t,J=7.7Hz,1H),6.89-6.82(m,1H),6.82(d,J=7.9Hz,1H),5.39(dd,J=12.5,5.4Hz,1H),4.31-4.21(m,1H),3.72(s, 8H),3.68(s,3H),3.62(s,2H),2.92-2.84(m,3H),2.77-2.69(m,1H),2.68-2.56(m,2H),2.44-2.38(m,1H),2.31-2.27(m,2H), 2.23(s,3H),2.15-2.09(m,2H),2.01-1.91(m,4H),1.84-1.75(m,2H),1.70-1.62(m,2H),1.47-1.34(m,2H),1.11-0.99(m,2H).

[0266] Example 16: 3-(4-(3-(2-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)-3-oxopropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (16) [ka] 1) Step 1: Compound 16a (100 mg, 0.300 mmol, prepared by the method disclosed in intermediate B-116 on page 171 of the specification in patent application "WO2023019166A1") and N,N-diisopropylethylamine (0.2 mL, 1.21 mmol) were dissolved in N,N-dimethylcarboxamide (2.5 mL), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.360 mmol) was added. After the reaction mixture was allowed to react at 25°C for 10 minutes, compound 16b (88.8 mg, 0.390 mmol) was added. After stirring the reaction mixture for 1 hour, it was diluted with ethyl acetate (2 mL) and quenched with water (4 mL). After separating the aqueous phase, it was extracted with ethyl acetate (2 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography on a silica gel plate (dichloromethane / methanol = 10 / 1) to obtain compound 16c. MS m / z (ESI): 540.7 [M+1] + .

[0267] 2) Step 2: Compound 16c (45 mg, 80.0 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was allowed to react at 25°C for 30 minutes, after which the reaction mixture was concentrated under reduced pressure to obtain compound 16d. MS m / z (ESI): 440.6 [M+1] + .

[0268] 3) Step 3: Compound 16d (36.0 mg, 80.0 μmol) was dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and triethylamine (7.53 mg, 70.0 μmol) was added. After stirring the reaction mixture at 25°C for 10 minutes, acetic acid (4.47 mg, 70.0 μmol) and compound 1e (37.0 mg, 70.0 μmol) were added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, sodium borohydride acetate (94.6 mg, 0.780 mmol) was added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). After separating the aqueous phase, it was extracted with dichloromethane (3 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 16 (23.5 mg). MS m / z (ESI): 921.8 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),8.76(d,J=7.9Hz,1H),8.70-8.63(m,1H),8.54-8.52(m,1H),8.37(s,1H),7.23(t,J=26.6Hz,1H),6 .98-6.90(m,3H),6.81(d,J=7.9Hz,1H),5.45-5.30(m,1H),4.32-4.19(m,1H),3.72(s,8H),3.57(s,3H),3.28-3. 25(m,2H),3.15-3.11(m,2H),2.91(s,4H),2.70-2.60(m,4H),2.47-2.40(m,2H),2.29-2.27(m,1H),2.14-2.07(m ,2H),2.00-1.95(m,1H),1.92-1.85(m,2H),1.82-1.71(m,2H),1.55(s,6H),1.39-1.29(m,1H),1.15-0.99(m,2H).

[0269] Example 17: 3-(4-(1-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)ethinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (17) [ka] Compound 17a (50.0 mg, 0.140 mmol, prepared by the method disclosed in intermediate YL on page 858 of the specification in patent application "WO2020113233") and triethylamine (14.0 mg, 0.140 mmol) were dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (2 mL) and stirred for 10 minutes. Acetic acid (13.0 mg, 0.220 mmol) and compound 1e (67.0 mg, 0.130 mmol) were added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium borohydride acetate (87.0 mg, 0.410 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 46%~95%, flow rate: 25 mL / min) to obtain compound 17. MS m / z (ESI): 848.6 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),7.20 (t,J=53.2Hz,1H),7.11-7.07(m,1H),7.05-7.01(m,1H),6.99-6.97(m,1H),6.82(d,J=8.0Hz,1H),5.41- 5.37(m,1H),4.28-4.25(m,1H),3.73(s,8H),3.65(s,3H),2.92-2.85(m,1H),2.71-2.60(m,5H),2.15-2. 12(m,6H),2.03-2.00(m,1H),1.92-1.87(m,4H),1.83-1.80(m,2H),1.68-1.65(m,3H),1.09-1.07(m,2H).

[0270] Example 18: 2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-N-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-2,8-diazaspiro[4.5]deca-8-carboxamide (18) [ka] 1) Step 1: Compound 18a (171 mg, 0.620 mmol, prepared by the method disclosed in intermediate 495 on page 172 of the specification in patent application "WO2022068933A1") and N,N-diisopropylethylamine (0.3 mL, 1.87 mmol) were dissolved in tetrahydrofuran (5 mL). A solution of triphosgene (130 mg, 0.440 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at 50°C for 0.5 hours. The reaction mixture was cooled to 25°C, and compound 18b (150 mg, 0.620 mmol, Bi De) was added to the reaction mixture. After reacting the reaction mixture at 25°C for 0.5 hours, the reaction mixture was quenched by adding it dropwise to a mixed solution of saturated sodium bicarbonate aqueous solution (10 mL) and dichloromethane (20 mL). After separating the aqueous phase, it was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 15 / 1) to obtain compound 18c. MS m / z (ESI): 541.4 [M+1] + . 1 H NMR(400MHz,CDCl3):δ 8.69-8.41(m,1H),6.97(t,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),6.71-6.55(m,2H),5.15(dd,J=12.3,5.0Hz,1H),3.54-3.49( m,6H),3.44-3.38(m,2H),3.29-3.18(m,3H),2.81-2.64(m,2H),2.24-2.15(m,1H),1.76(t,J=7.1Hz,2H),1.50-1.38(m,14H).

[0271] 2) Step 2: Compound 18c (171 mg, 0.620 mmol) was dissolved in hydrochloric acid dioxane (2 mL, 4.0 M). The reaction mixture was stirred at 25°C for 1 hour, then concentrated under reduced pressure to obtain the crude compound 18d. MS m / z (ESI): 441.6 [M+1] + . 1H NMR(400MHz,MeOD):δ 7.09-7.01(m,2H),6.87(dd,J=7.4,1.5Hz,1H),5.34(dd,J=12.5,5.4Hz,1H),3.74-3.65(m,2H),3.59-3.53(m,2H),3.51(s, 3H),3.42(t,J=7.5Hz,2H),3.18(s,2H),2.18-2.10(m,1H),2.02(t,J=7.5Hz,2H),1.70(t,J=5.6Hz,4H),1.38-1.26(m,3H).

[0272] 3) Step 3: Compound 18d (58.4 mg, 0.130 mmol) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylcarboxamide (1 mL), and triethylamine (12.2 mg, 0.120 mmol) was added. The reaction mixture was stirred at 25°C for 5 minutes, and acetic acid (7.24 mg, 0.120 mmol) and compound 1e (60.0 mg, 0.120 mmol) were added. After stirring the reaction mixture at 25°C for 0.5 hours, sodium borohydride acetate (127 mg, 0.600 mmol) was added. After stirring the reaction mixture at 25°C for 0.5 hours, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (10 mL). After liquid-liquid separation of the aqueous phase, it was extracted with dichloromethane (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 18 (34.6 mg). MS m / z (ESI): 922.7 [M+1] + .

[0273] Example 19: 3-(4-((R)-3-((1-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)oxy)buto-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (19) [ka] 1) Step 1: At room temperature, compound 19a-1 (300 mg, 2.10 mmol, prepared by the method disclosed in the intermediate pyrrolo[1,2-b]pyndazine-3-carbonitrile on page 75 of the specification in patent application "WO2015117563A1") and N-iodosuccinimide (707 mg, 3.14 mmol) were added to acetonitrile (10 mL). The reaction mixture was stirred at 60°C for 1 hour. The completion of the reaction was monitored by TLC, 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 high-performance chromatography column (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 19a-2. 1 H NMR (400MHz, CDCl3): δ 8.27 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 4.7 Hz, 1H), 6.95 (d, J = 4.7 Hz, 1H).

[0274] 2) Step 2: Compound 19a-2 (1.16 g, 4.31 mmol) was added to tetrahydrofuran (10 mL), cuprous iodide (80 mg, 0.43 mmol), bistriphenylphosphine dichloride palladium (300 mg, 0.43 mmol), and triethylamine (1.20 mL, 8.62 mmol) were added, and the mixture was purged with nitrogen gas. Then trimethylsilylacetylene (6.14 mL, 43.1 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was added to water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 19a-3. 1 H NMR (400MHz, DMSO-d6): δ 8.75 (d, J = 2.2 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 0.27 (s, 9H).

[0275] 3) Step 3: Compound 19a-3 (816 mg, 3.41 mmol) and potassium carbonate (1.41 g, 10.2 mmol) were added to methanol (10 mL) and stirred at room temperature for 2 hours. The reaction system was added to water and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 20) to obtain compound 19a. 1 H NMR(400MHz, CDCl3)δ 8.28(d,J=2.2Hz,1H),8.12(d,J=2.2Hz,1H),7.25(s,1H),6.82(d,J=4.7Hz,1H),3.78(s,1H).

[0276] 4) Step 4: Compound 19a (300 mg, 1.79 mmol) was dissolved in dimethyl sulfoxide (0.6 mL) and ethanol (3 mL). At 0°C, sodium hydroxide (86.0 mg, 2.15 mmol) and hydrogen peroxide (0.2 mL, 30% aqueous solution) were added. The reaction mixture was maintained at 0°C and stirred for 30 minutes. Water (15 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 19b. MS m / z (ESI): 186.1 [M+1] + .

[0277] 5) Step 5: Compound 19b (200 mg, 1.08 mmol) and compound 1b (351 mg, 1.30 mmol) were dissolved in water (4 mL) and ethanol (4 mL). Copper sulfate pentahydrate (27.0 mg, 0.110 mmol, AN-Nai-Gi) and sodium vitamin C (21.0 mg, 0.11 mmol, AN-Nai-Gi) were added, and the reaction mixture was stirred at 25°C for 12 hours. The mixture was then concentrated under reduced pressure to remove the ethanol, and water (15 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and after removing the drying agent, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 19c. MS m / z (ESI): 457.2 [M+1] + .

[0278] 6) Step 6: Compound 19c (33.0 mg, 70.0 μmol) was dissolved in dichloromethane (2 mL), and the reaction mixture was slowly added to Dessmartin oxidizing agent (61.0 mg, 0.140 mmol) at 30°C. The reaction mixture was stirred at 30°C for 30 minutes, after which the reaction system was quenched by adding saturated sodium bicarbonate aqueous solution (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 19d. MS m / z (ESI): 455.1 [M+1] + .

[0279] 7) Step 7: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A") was dissolved in N,N-dimethylcarboxamide (2 mL), compound 19f (104 mg, 0.530 mmol, Bi-de), palladium bistriphenylphosphine dichloride (31.1 mg, 40.0 μmol, Bi-de), and triethylamine (0.3 mL, 1.77 mmol) were added, and the mixture was reacted for 0.5 hours. Then the temperature was raised to 50°C and the mixture was reacted at that temperature for 3 hours. The reaction mixture was returned to 25°C, water (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the drying agent was removed. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain 19 g of the compound. MS m / z (ESI): 453.3 [M-1] - .

[0280] 8) Step 8: 19 g (60.0 mg, 0.130 mmol) of compound was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 19h. MSm / z (ESI): 355.2 [M+1] + .

[0281] 9) Step 9: Compound 19h (60.0 mg, 0.170 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.02 mL, 0.170 mmol) was added, and the mixture was reacted at 25°C for 10 minutes. Then, compound 19d (92.3 mg, 0.200 mmol) and acetic acid (0.02 mL, 0.340 mmol) were added, and the mixture was reacted for 2 hours. Then, sodium triacetoxyborohydride (214 mg, 1.02 mmol) was added, and the reaction mixture was reacted at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 19. MS m / z (ESI): 793.7 [M+1] + . 1 HNMR(400MHz,DMSO-d6):δ 11.13(s,1H),9.04-8.99(m,1H),8.80-8.72(m,2H),8.67-8.65(m,1H),8.15(s,1H),7.67-7.64(m,1H),7.57 (s,1H),7.27-7.13(m,2H),7.12-7.09(m,1H),7.06-7.02(m,2H),6.27(s,1H),5.46-5.36(m,1H),4.39-4.24 (m,1H),3.71-3.63(m,5H),3.16-3.12(m,2H),2.95-2.83(m,1H),2.75-2.63(m,2H),2.37-2.32(m,2H),2.21 -2.11(m,2H),2.06-1.98(m,2H),1.97-1.84(m,3H),1.82-1.78(m,1H),1.64-1.59(m,1H),1.15-1.09(m,1H).

[0282] Example 20: 3-(4-((4-((((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)amino)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (20) [ka] 1) Step 1: Compound 18a (100 mg, 0.361 mol, prepared by the method disclosed in intermediate CD on page 394 of the specification in patent application "WO2021 / 188948A1") and compound 20a (106 mg, 0.471 mmol, Bi De) were dissolved in dioxane (8 mL), and tetraethyl orthotitanate (0.5 mL, 0.721 mmol) was added. The reaction mixture was stirred at 80°C under nitrogen gas protection for 18 hours. The reaction mixture was cooled to 25°C, and sodium borohydride cyanohydride (45.3 mg, 0.721 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, the drying agent was removed, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 15 / 1) to obtain compound 20b. MS m / z (ESI): 486.3 [M+1] + .

[0283] 2) Step 2: Compound 20b (30.0 mg, 0.0610 mmol) was dissolved in hydrochloric acid-dioxane solution (3 mL, 4.0 M), the reaction mixture was allowed to react at 25°C for 2 hours, and the reaction mixture was concentrated under reduced pressure to obtain compound 20c. MS m / z (ESI): 386.5 [M+1] + .

[0284] 3) Step 3: Compound 20c (25.0 mg, 0.0610 mmol) was dissolved in ethanol (3 mL), and triethylamine (8.12 mg, 0.0810 mmol) was added until the pH value exceeded 8. The reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was cooled to -10°C, and acetic acid (186 mg, 0.0910 mmol) and compound 1e (38.7 mg, 0.0810 mmol) were added. The reaction mixture was heated to 25°C and stirred at this temperature for 20 minutes, after which sodium borohydride cyanohydride (10.1 mg, 0.161 mmol, Bi De) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography column: SharpSil-T C18, 30×150 mm, 5 μm, mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%~45%, flow rate: 30 mL / min) to obtain compound 20. MS m / z (ESI): 867.4 [M+1] + .

[0285] Example 21: 3-(4-((((1S,4s)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)methyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(21) [ka] 1) Step 1: Compound 18a (100 mg, 0.360 mmol, prepared by the method disclosed in the product of step 4 on page 171 of the specification in patent application "WO2022068933A1") was dissolved in 1,4-dioxane (5 mL), compound 21a (88.0 mg, 0.360 mmol, Bi De), and tetraethyl orthotitanate (166 mg, 0.730 mmol) were added, and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to 25°C, sodium borohydride cyanohydride (69.0 mg, 1.09 mmol) was added to the reaction mixture, and after stirring for 1 hour, water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 21b. MS m / z (ESI): 522.2 [M+23] + .

[0286] 2) Step 2: Compound 21b (180 mg, 0.360 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, then concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 21c. MS m / z (ESI): 400.2 [M+1] + .

[0287] 3) Step 3: Dissolve compound 21c (75.0 mg, 0.190 mmol) in dichloromethane (3 mL), add triethylamine (0.03 mL, 0.190 mmol), stir the reaction mixture at 25°C for 15 minutes, then add compound 1e (93.0 mg, 0.190 mmol) and glacial acetic acid (0.01 mL, 0.19 mmol), stir the reaction at 25°C for 1 hour, then add sodium cyanoborohydride (35.0 mg After adding 0.560 mmol of the compound and stirring for 1 hour, the reaction system was directly concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 21. MS m / z (ESI): 881.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.07(s,1H),8.76(d,J=7.9Hz,1H),8.74-8.55(m,2H),8.54(s,1H),8.39(s,1H),7.33-7.07(m,1H),6.9 0-6.78(m,2H),6.56-6.32(m,2H),5.38-5.23(m,1H),5.11-4.90(m,1H),4.37-4.26(m,1H),3.73(s,8H), 3.63-3.61(m,2H),3.57-3.55(m,1H),2.93-2.88(m,2H),2.69-2.62(m,2H),2.44-2.37(m,3H),2.17-2.1 1(m,2H),2.01-1.92(m,5H),1.90-1.81(m,4H),1.69-1.53(m,4H),1.37-1.21(m,3H),1.16-1.00(m,4H).

[0288] Example 22: N-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(4-{[4-(2-{[(3Z)-5-[(4-fluorophenyl)sulfamoyl]-2-oxo-2,3-dihydro-1H-indole-3-ylidene]methyl}-3-methyl-1H-indole-6-yl)piperazine-1-yl]methyl}piperidine-1-yl)benzamide(22) [ka] 1) Step 1: Compound 22h-1 (2.00 g, 7.20 mmol) and dimethyl sulfoxide (15 mL) were sequentially added to a single-necked flask and stirred until dissolved. Ethyl isocyanoethyl acetate (895 mg, 7.92 mmol), cuprous iodide (137 mg, 0.72 mmol), and cesium carbonate (4.69 g, 14.4 mmol) were sequentially added. The reaction mixture was stirred at 50°C under nitrogen gas protection for 16 hours. 150 mL of water was added to the reaction mixture and extracted with ethyl acetate (30 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 column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 22h-2. MS m / z (ESI): 284.0 [M+1]+.

[0289] 2) Step 2: Compound 22H-2 (1.20 g, 4.25 mmol) and tetrahydrofuran (18 mL) were added sequentially to a single-necked flask and stirred until dissolved. Compound 22H-3 (1.19 g, 6.38 mmol), tri(dibenzylideneacetone)dipalladium (194.7 mg, 0.21 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (202.76 mg, 0.43 mmol), and sodium tert-butoxide (834.1 mg, 9.36 mmol) were added sequentially. The reaction mixture was stirred at 65°C under nitrogen gas protection for 16 hours. Water (80 mL) was added to the reaction mixture and extracted with ethyl acetate (30 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 column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 22h-4. MS m / z (ESI): 388.1 [M+1] + .

[0290] 3) Step 3: Add lithium aluminum hydride (117.5 mg, 3.10 mmol) and tetrahydrofuran (5 mL) to a single-necked flask, stir, and cool to 0°C. Dissolve compound 22h-4 (600 mg, 1.55 mmol) in tetrahydrofuran (5 mL) and stir until dissolved. At 0°C, slowly add the tetrahydrofuran solution of compound 22h-4 dropwise to the tetrahydrofuran solution of lithium aluminum hydride. Stir the reaction mixture at 0°C for 5 minutes, then stir at 25°C for 20 minutes. Add saturated ammonium chloride (50 mL) to the reaction mixture and extract with ethyl acetate (30 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 22h-5. MS m / z (ESI): 346.1 [M+1] + .

[0291] 4) Step 4: Compound 22h-5 (600 mg, 1.74 mmol) and chloroform (15 mL) were sequentially added to a single-necked flask and stirred until dissolved. Manganese dioxide (1.51 g, 17.37 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 22h-6. MS m / z (ESI): 344.1 [M+1] + .

[0292] 5) Step 5: Compound 22h-7 (1.00 g, 4.32 mmol), pyridine (0.68 g, 8.64 mmol), compound 22h-8 (0.96 g, 8.64 mmol), and tetrahydrofuran (10 mL) were added to a single-necked flask, and the reaction was stirred at 25°C for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was beaten with petroleum ether / ethyl acetate (5 / 1) to obtain compound 22h-9. MS m / z (ESI): 307.0 [M+1] + .

[0293] 6) Step 6: Compound 22h-6 (120 mg, 0.35 mmol) and ethanol (2 mL) were added to a single-necked flask and stirred until dissolved. Next, compound 22h-9 (117.1 mg, 0.38 mmol) and piperidine (29.8 mg, 0.35 mmol) were added sequentially. The reaction mixture was stirred at 70°C for 2 hours. After that, the reaction mixture was filtered at 25°C, the solid was collected and dried to obtain compound 22h-10. MS m / z (ESI): 632.1 [M+1] + .

[0294] 7) Step 7: Compound 22h-10 (180 mg, 0.28 mmol) and tetrahydrofuran (2 mL) were sequentially added to a single-necked flask and stirred until dissolved. Dioxane hydrochloride (4 M, 15 mL) was then added. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated, the residue was dissolved in tetrahydrofuran (40 mL), aqueous ammonia (6 mL) was added, and the solution was stirred at room temperature for 1 hour. After concentration, water (30 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the solid was collected. The solid was dissolved in tetrahydrofuran (15 mL), and petroleum ether (40 mL) was slowly added while stirring. The solid precipitated, and the suspension was stirred for 30 minutes. The mixture was filtered, the solid was collected, and dried to obtain compound 22h. MS m / z (ESI): 532.1 [M+1] + .

[0295] 8) Step 8: Compound 22a (1.50 g, 6.44 mmol, Bi De), 1,4-dioxane (15 mL) were added sequentially to a three-necked flask, followed by compound 22b (1.48 g, 12.9 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (270 mg, 0.320 mmol, Adamas), and cesium carbonate (5.24 g, 16.1 mmol). The reactor was purged three times with nitrogen gas and stirred at 100°C for 2 hours in a nitrogen atmosphere. After the reaction was complete, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the drying agent was removed. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1~5 / 10) to obtain compound 22c. MS m / z (ESI): 268.1 [M+1] + .

[0296] 9) Step 9: Compound 22c (1.00 g, 3.74 mmol) and tetrahydrofuran (10 mL) were added sequentially to a single-necked flask, followed by lithium hydroxide (780 mg, 18.7 mmol) and water (3 mL). The reaction mixture was stirred at 80°C for 5 hours. After the reaction was complete, ethyl acetate (10 mL) was added and the mixture was extracted with water (20 mL x 2). Hydrochloric acid (1.0 M) was slowly added dropwise to the aqueous phase until the pH reached 3, and a solid precipitated. After filtration and washing with water, the filter cake was taken and dried under reduced pressure using an oil pump to obtain compound 22d. 1 H NMR(400MHz,DMSO-d6):δ 12.75-12.01(m,1H),7.66(t,J=9.0Hz,1H),6.77-6.66(m,2H),4.50(s,1H),3.93-3.89(m,2H), 3.27-3.24(m,2H),2.86-2.79(m,2H),1.80-1.65(m,2H),1.65-1.55(m,1H),1.20-1.05(m,2H).

[0297] 10) Step 10: Compound 22d (200 mg, 0.730 mmol) and N,N-dimethylcarboxamide (2 mL) were added sequentially to a single-necked flask, followed by compound 22e (112 mg, 0.730 mmol), 1-hydroxybenzotriazole (147 mg, 1.09 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (348 mg, 1.82 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.18 mmol). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain an oily residue. Three to five drops of dichloromethane were added to the residue, and after standing for 30 minutes, a solid precipitated. The solid was collected to obtain the crude compound 22f.

[0298] 11) Step 11: Compound 22f (100 mg, 0.280 mmol) was dissolved in dichloromethane (1 mL), and Dess Martin's reagent (175 mg, 0.410 mmol) was slowly added little by little. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The organic phase was combined and washed with saturated brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 30 / 1 to 20 / 1) to obtain compound 22 g. MS m / z (ESI): 364.1 [M+1] + .

[0299] 12) Step 12: 22 g of compound (50.0 mg, 0.100 mmol) and N,N-dimethylcarboxamide (0.5 mL) were sequentially added to a single-necked flask, followed by 22 h of compound (51.5 mg, 0.100 mmol) and one drop of glacial acetic acid. The reaction mixture was stirred at 25°C for 1 hour, then sodium borohydride acetate (40.9 mg, 0.190 mmol) was added, and the mixture was stirred at 25°C for 1 hour. After filtering the reaction mixture, the residue was purified by high-performance liquid chromatography (ACSSH-CH, chromatography column: Phenomenex Gemini NX 150 × 30 mm, 5 μm, mobile phase: water (containing formic acid) and acetonitrile, gradient ratio: acetonitrile 24%~64%, flow rate: 60 mL / min) to obtain compound 22. MS m / z (ESI): 877.5 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 12.74(s,1H),11.31(s,1H),10.84(s,1H),8.22(s,1H),8.00(t,J=7.3Hz,1H),7.87(s,1H),7.62(t,J=9.1Hz ,1H),7.53-7.45(m,2H),7.16-7.05(m,4H),6.99-6.92(m,2H),6.86(s,1H),6.83-6.72(m,2H),4.77-4.68(m ,1H),3.93-3.84(m,2H),3.30-3.17(m,8H),2.90-2.80(m,2H),2.79-2.71(m,1H),2.67(s,1H),2.58(s,3H), 2.33(s,1H),2.25-2.18(m,2H),2.15-2.08(m,1H),2.05-1.96(m,1H),1.87-1.76(m,3H),1.25-1.11(m,2H).

[0300] Example 23: 3-(4-((7-((((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)spiro[3.5]non-2-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(23) [ka] 1) Step 1: Compound 18a (200 mg, 0.731 mol, prepared by the method disclosed in intermediate CD on page 394 of the specification in patent application "WO2021 / 188948A1") and compound 23a (307 mg, 1.02 mmol, prepared by the method disclosed in intermediate 00967 on page 374 of the specification in patent application "WO2021 / 188948Al") were dissolved in dioxane (8 mL), and tetraethyl orthotitanate (0.5 mL, 1.46 mmol) was added. The reaction mixture was stirred at 80°C under nitrogen gas protection for 18 hours. The reaction mixture was cooled to room temperature, and sodium borohydride cyanohydride (91.6 mg, 1.46 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. Water (50 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 23b. MS m / z (ESI): 560.0 [M+1] + .

[0301] 2) Step 2: Compound 23b (40.0 mg, 0.0710 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran solution (5 mL), wet palladium carbon (10.0 mg, 10%) was added, the reaction mixture was purged three times with hydrogen gas, stirred at 25°C for 18 hours, filtered, and concentrated to obtain compound 23c. MS m / z (ESI): 426.6 [M+1] + .

[0302] 3) Step 3: Compound 23c (40.0 mg, 0.0910 mmol) and compound 1e (46.8 mg, 0.0910 mmol) were dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and acetic acid (5.41 mg, 0.0910 mmol) was added. The reaction mixture was stirred at 25°C for 20 minutes, and then sodium borohydride acetate (38.2 mg, 0.181 mmol) was added. The reaction mixture was continued to be stirred for 1 hour, and then concentrated under reduced pressure. The mixture was then purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 23. MS m / z (ESI): 907.7 [M+1] + .

[0303] Example 24: 3-(4-((((1R,4r)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)methyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(24) [ka] 1) Step 1: Compound 18a (54.0 mg, 0.200 mmol, prepared by the method disclosed in the product of step 4 on page 171 of the specification in patent application "WO2022068933A1") was dissolved in 1,4-dioxane (5 mL), and compound 24a (95.0 mg, 0.390 mmol, Bi De) and tetraethyl orthotitanate (90.0 mg, 0.390 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to 25°C, sodium borohydride (37.0 mg, 0.590 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 24b. MS m / z (ESI): 444.2 [M-55] + .

[0304] 2) Step 2: Compound 24b (150 mg, 0.360 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. After stirring the reaction mixture at 25°C for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was used directly as the starting material for the next step without purification to obtain compound 24c. MS m / z (ESI): 400.2 [M+1] + .

[0305] 3) Step 3: Dissolve compound 24c (25.0 mg, 60.0 μmol) in a mixed solution of N,N-dimethylcarboxamide (0.5 mL) and tetrahydrofuran (2 mL), add triethylamine (0.01 mL, 60.0 μmol), stir the reaction mixture at 25°C for 15 minutes, then add compound 1e (31.0 mg, 60.0 μmol) and acetic acid (0.01 mL, 0.190 mmol), react for 1 hour, then add sodium cyanohydride. Thorium (12.0 mg, 0.190 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction system was then concentrated, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 24. MS m / z (ESI): 881.3 [M+1] + .

[0306] Example 25: 3-(4-(4-(4-[(4-)(1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl(cyclohexyl)methyl)(methyl)amino)methyl)piperidine-1-yl)buto-1-alkynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(25) [ka] 1) Step 1: Compound 25a (1.00 g, 4.38 mmol, pi de) and compound 25b (0.6 mL, 6.57 mmol, pi de) were dissolved in acetonitrile (20 mL), potassium carbonate (1.81 g, 13.1 mmol) was added, and the reaction mixture was stirred at 80°C for 18 hours. Then, water (20 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 = 5 / 1) to obtain compound 25c. MS m / z (ESI): 281.0 [M+1] + .

[0307] 2) Step 2: Compound 25c (200 mg, 0.710 mmol) and compound 19e (241 mg, 0.710 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A") were dissolved in N,N-dimethylcarboxamide (7 mL), and bistriphenylphosphine dichloride palladium (50.0 mg, 0.0710 mmol, adamas), triethylamine (0.3 mL, 2.14 mmol), and cuprous iodide (13.5 mg, 0.0710 mmol) were added. The reaction was carried out at 80°C for 18 hours under nitrogen gas protection, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 20 / 1) to obtain compound 25e. MS m / z (ESI): 538.0 [M+1] + .

[0308] 3) Step 3: Compound 25e (80.0 mg, 0.145 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was allowed to react at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, 25f was obtained. MS m / z (ESI): 438.0 [M+1] + .

[0309] 4) Step 4: To a solution of compound 25f (61.5 mg, 0.141 mmol) in 1,2-dichloroethane (3 mL) and tetrahydrofuran (5 mL), add triethylamine (14.2 mg, 0.141 mmol) until the pH value exceeds 8, and stir the mixture at 25°C for 10 minutes. Add acetic acid (12.6 mg, 0.212 mmol) at -10°C, and then add compound 1e (70.0 mg, 0.141 mmol). Then stir the mixture at 25°C for 20 minutes, and add sodium borohydride acetate (59.6 mg, 0.282 mmol, Bi De). Stir the mixture at 25°C for a further 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 25. MS m / z (ESI): 919.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.12(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),7.34-7.09(m,2H),7.06-7.03 (m,1H),7.02-6.96(m,1H),6.82(d,J=7.8Hz,1H),5.43-5.34(m,1H),4.35-4.23(m,1H),3.73(s,8H),3.68 (s,3H),2.90(d,J=11.9Hz,3H),2.65(t,J=9.2Hz,3H),2.57(d,J=6.6Hz,2H),2.17-2.06(m,10H),2.00-1. 90(m,5H),1.85-1.77(m,2H),1.75-1.67(m,2H),1.57-1.50(m,1H),1.47-1.39(m,1H),1.11-1.00(m,4H).

[0310] Example 26: 3-(4-((2-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2-azaspiro[3,3]heptan-6-yl)ethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(26) [ka] 1) Step 1: Compound 26a (310 mg, 1.28 mmol, Bi De) was dissolved in dichloromethane (10 mL), and Dess Martin oxidizing agent (1.09 g, 2.57 mmol) was added little by little at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified with neutral aluminum oxide using an eluent system (petroleum ether / ethyl acetate = 100 / 1~3 / 1) to obtain compound 26b. 1 H NMR (400MHz, CDCl3): δ 9.83-9.60(m,1H),3.95(s,2H),3.81(s,2H),2.64-2.51(m,3H),2.44-2.35(m,2H),1.91-1.83(m,2H),1.43(s,9H).

[0311] 2) Step 2: Compound 18a (220 mg, 0.800 mmol, prepared by the method disclosed in intermediate 495 on page 172 of the specification in patent application "WO2022068933A1"), compound 26b (230 mg, 0.960 mmol), and ethyl orthotitanate (0.3 mL, 1.60 mmol) were dissolved in dioxane (10 mL). The reaction mixture was stirred at 100 °C under nitrogen gas protection for 12 hours, and then cooled to 25 °C. Sodium borohydride cyanohydride (252 mg, 4.01 mmol) was added, and the reaction was stirred at 25 °C for 1 hour, after which the reaction mixture was quenched with water (20 mL) and ethyl acetate (20 mL). The reaction mixture was filtered through diatomaceous earth, and the aqueous phase was separated and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 26c. MS m / z (ESI): 520.2 [M+23] + . 1 H NMR(400MHz,CDCl3):δ 8.14(s,1H),7.66-7.55(m,1H),7.10-7.06(m,1H),6.87-6.84(m,1H),5.25-5.19(m,1H),3.88(s,4H),3.7 5(s,2H),3.28-3.21(m,2H),2.26-2.20(m,4H),2.14-2.06(m,3H),1.80-1.71(m,4H),1.43-1.42(m,10H).

[0312] 3) Step 3: Compound 26c (80.0 mg, 0.160 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added at 25°C. After stirring the reaction mixture for 1 hour, it was concentrated under reduced pressure to obtain compound 26d. MS m / z (ESI): 398.2 [M+1] + .

[0313] 4) Step 4: Compound 26d (62.3 mg, 0.160 mmol) was dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and triethylamine (13.2 mg, 0.130 mmol) was added. After stirring the reaction mixture at 25°C for 10 minutes, acetic acid (7.85 mg, 0.130 mmol) and compound 1e (65.0 mg, 0.130 mmol) were added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, sodium borohydride acetate (166 mg, 0.780 mmol) was added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 12 hours, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (10 mL). After separating the aqueous phase, it was extracted with dichloromethane (3 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 26. MS m / z (ESI): 879.4 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 11.05(s,1H),8.76(d,J=7.8Hz,1H),8.63(s,1H),8.53(s,1H),8.37(s,1H),7.18(t,J=53.2Hz,1H),6.88-6.84(m,1H), 6.81(d,J=7.9Hz,1H),6.49(d,J=8.0Hz,1H),6.39(d,J=8.2Hz,1H),5.30-5.24(m,1H),5.04-4.86(m,1H),4.31-4.19(m, 1H),3.72(s,8H),3.60(s,3H),3.13-3.10(m,2H),2.99-2.83(m,5H),2.69-2.65(m,2H),2.34-2.31(m,1H),2.29-2.26(m ,2H),2.23-2.21(m,2H),2.12-2.07(m,2H),2.01-1.92(m,2H),1.88-1.84(m,2H),1.78-1.68(m,5H),1.12-1.03(m,2H).

[0314] Example 27: 3-(4-(1-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)azabuta-3-ylethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (27) [ka]

[0315] 1) Step 1: Compound 19e (120 mg, 0.661 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A") and compound 27a (172 mg, 0.508 mmol, Bi De) were dissolved in N,N-dimethylcarboxamide (2 mL), and triethylamine (0.2 mL, 1.53 mmol), cuprous iodide (19.0 mg, 0.1 mmol), and dichlorobis(triphenylphosphine)palladium(II) (35.8 mg, 51.0 μmol) were added. The reaction mixture was purged with nitrogen gas and stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, water (5 mL) was added, the aqueous phase was extracted with ethyl acetate (5 mL x 3), the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 27b. MS m / z (ESI): 461.1 [M+23] + .

[0316] 2) Step 2: Compound 27b (50.0 mg, 0.114 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography (water / acetonitrile = 25 / 75~80 / 20) to obtain compound 27c. MS m / z (ESI): 339.1 [M+1] + .

[0317] 3) Step 3: Compound 27c (30.0 mg, 88.7 μmol) and compound 1e (44.1 mg, 88.7 μmol) were dissolved in N,N-dimethylcarboxamide (1 mL), triethylamine (8.97 mg, 88.7 μmol) was added, and the mixture was stirred for 5 minutes. Then glacial acetic acid (7.95 mg, 133 μmol) was added, and the reaction mixture was stirred at 40°C for 2 hours. Then sodium borohydride acetate (37.4 mg, 177 μmol) was added, and the mixture was stirred at 40°C for 2 hours. After filtering the reaction, the mixture was purified by high-performance liquid chromatography (ACSSH-CP, chromatography column: C18 150 × 30 mm, mobile phase: water (formic acid) - acetonitrile, gradient ratio: acetonitrile 3%~43%, flow rate: 30 mL / min) to obtain compound 27. MS m / z (ESI): 820.4 [M+1] + .

[0318] Example 28: 4-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexylmethyl)piperazine-1-yl)-N-(2,6-dioxopiperidine-3-yl)-2-fluorobenzamide (28) [ka] Compound 28a (80.0 mg, 220 μmol, prepared by the method disclosed in step 7 of the intermediate compound on page 867 of the specification in patent application "WO2023 / 017446Al"), compound 1e (107 mg, 220 μmol), and triethylamine (0.05 mL) were dissolved in tetrahydrofuran (3 mL) and N,N-dimethylcarboxamide (1.5 mL). The reaction mixture was stirred at 15°C for 10 minutes, after which acetic acid (0.05 mL) and sodium triacetoxyborohydride (136 mg, 0.65 mmol) were added. The reaction mixture was stirred at 15°C for 30 minutes. Water (15 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (15 mL x 3), dried, and concentrated. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: Boston Green ODS 150×30mm, 5um, mobile phase: Waters (FA-CH3CN, gradient mixing ratio: acetonitrile 16%~56%, flow rate: 30 mL / min) to obtain compound 28. MS m / z (ESI): 816.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 10.85(s,1H),8.76(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),8.05(t,J=7. 2Hz,1H),7.63(t,J=9.0Hz,1H),7.34-7.05(m,1H),6.87-6.74(m,3H),4.79-4.67(m,1H), 4.36-4.22(m,1H),3.72(s,8H),3.30(s,8H),2.84-2.70(m,1H),2.47-2.46(m,1H),2.24- 2.06(m,5H),2.05-1.92(m,3H),1.90-1.76(m,2H),1.75-1.60(m,1H),1.20-1.00(m,2H).

[0319] Example 29: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)amino)piperidine-1-carbonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (29) [ka] 1) Step 1: Compound 29a (200 mg, 0.660 mmol, prepared by the method disclosed in the specification of patent application "WO2020 / 113233Al") and compound 29b (150 mg, 0.750 mmol, Bi De) were dissolved in N,N-dimethylcarboxamide (5 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (250 mg, 0.660 mmol) and N,N-diisopropylethylamine (250 mg, 1.93 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 (10 mL x 3). The combined organic phase was washed with saturated saline solution (50 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 using an eluent system (dichloromethane / methanol = 60 / 1 to 10 / 1) to obtain compound 29c. MS m / z (ESI): 508.2 [M+23] + .

[0320] 2) Step 2: Compound 29c (120 mg, 0.250 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 29d. MS m / z (ESI): 386.1 [M+1] + .

[0321] 3) Step 3: Compound 29d (50.0 mg, 0.130 mmol) and compound 1e (65.0 mg, 0.130 mmol) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (75.0 mg, 0.360 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL), and the aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated saline solution (20 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% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 29. MS m / z (ESI): 867.7 [M+1] + .

[0322] Example 30: 3-(4-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperazine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (30) [ka] Compound 30a (30.0 mg, 90.0 μmol, prepared by the method disclosed in intermediate GS on page 550 of the specification in patent application "WO2022236058A1") was dissolved in a solution of dichloroethane (2 mL) and N,N-dimethylcarboxamide (1 mL), and triethylamine (0.1 mL) was added. The reaction mixture was stirred for 0.5 hours. Compound 1e (52.0 mg, 0.100 mmol) and acetic acid (0.2 mL) were added to the reaction mixture and stirred for 0.5 hours. Sodium borohydride acetate (55.0 mg, 0.260 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 30. MS m / z (ESI): 825.6 [M+1] + . 1 HNMR(400MHz,DMSO-d6):δ 11.11(s,1H),8.78(d,J=7.8Hz,1H),8.68(s,1H),8.55(s,1H),8.40(s,1H),7. 22(t,J=53.2Hz,1H),7.04-6.90(m,3H),6.86-6.80(m,1H),5.42-5.32(m,1H),4 .41-4.22(m,1H),3.75(s,8H),3.66(s,3H),3.10-2.83(m,7H),2.75-2.59(m,3 H),2.29-2.07(m,4H),2.04-1.94(m,3H),1.93-1.81(m,2H),1.37-0.91(m,4H).

[0323] Example 31: 7-(1-(3-(difluoromethyl)-1-(1r,4r)-4-(4-(4-(2,6-dioxopyridine-3-yl)carbamoyl)-3-fluorophenylpiperazine-1-yl)methyl)cyclohexyl-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (31) [ka] Compound 28a (40.0 mg, 0.110 mmol, prepared by the method disclosed in step 7 of the intermediate compound on page 867 of the specification in patent application "WO2023 / 017446Al"), compound 19d (49.0 mg, 0.110 mmol), and triethylamine (0.1 mL) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), and the reaction mixture was stirred at 15°C for 10 minutes. Acetic acid (0.1 mL) and sodium triacetoxyborohydride (68.3 mg, 0.320 mmol) were added to the reaction mixture, and the reaction was stirred at 15°C for 30 minutes. Water (10 mL) was added to the reaction mixture, and the organic phase was extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: C18 150×30 mm, mobile phase: Waters (FA-CH3CN, gradient mixing ratio: acetonitrile 16%~56%, flow rate: 30 mL / min) to obtain compound 31. MS m / z (ESI): 773.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 10.85(s,1H),9.01(s,1H),8.78(d,J=2.2Hz,1H),8.75(s,1H),8.66(d,J=2.2Hz,1H),8.19-8.12(m ,1H),8.06(d,J=6.7Hz,1H),7.68-7.54(m,3H),7.38-7.09(m,1H),7.05(d,J=4.6Hz,1H),6.89-6.74 (m,2H),4.81-4.67(m,1H),4.40-4.23(m,1H),3.32-3.28(m,8H),2.85-2.72(m,1H),2.46-2.44(m, 1H),2.26-2.09(m,5H),2.02-1.94(m,3H),1.89-1.78(m,2H),1.72-1.59(m,1H),1.20-1.05(m,2H).

[0324] Example 32: 3-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexylmethyl)-2,7-diazaspiro[4.4]non-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(32) [ka] 1) Step 1: Compound 19e (300 mg, 0.890 mmol, prepared by the method disclosed in Step 3 Product on page 88 of the specification in patent application "WO2022012623A") was dissolved in toluene (10 mL), compound 32a (301 mg, 1.33 mmol, Shanghai Shaoyuan), palladium acetate (39.8 mg, 0.180 mmol), and 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (82.8 mg, 0.180 mmol) were added, and lithium bis(trimethylsilyl)amide (4.4 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution) was added dropwise to the reaction mixture under nitrogen gas protection. The reaction mixture was stirred at 80°C under nitrogen gas protection for 2 hours. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an elution system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 32b. MS m / z (ESI): 484.3 [M+1] + .

[0325] 2) Step 2: Compound 32b (200 mg, 0.410 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at 15°C for 30 minutes. The reaction mixture was concentrated to obtain compound 32c. MS m / z (ESI): 384.0 [M+1] + .

[0326] 3) Step 3: Compound 32c (100 mg, 0.260 mmol), Compound 1e (130 mg, 0.260 mmol), and triethylamine (0.5 mL) were dissolved in tetrahydrofuran (3 mL) and N,N-dimethylcarboxamide (1.5 mL), and the mixture was stirred at 15°C for 10 minutes. Then, acetic acid (0.5 mL) and sodium triacetoxyborohydride (165 mg, 0.780 mmol) were added to the reaction mixture, and the mixture was stirred at 15°C for 30 minutes. Water (15 mL) was added to the reaction mixture, and it was extracted with dichloromethane (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography column: C18 150×30 mm, mobile phase: Waters(FA)-CH3CN, gradient mixing ratio: acetonitrile 13%~53%, flow rate: 30 mL / min) to obtain compound 32. MS m / z(ESI): 865.4[M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.10(s,1H),8.76(d,J=7.9Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),8.18(s,1H),7.33-7.05(m,1H) ,7.00-6.93(m,2H),6.85(dd,J=1.9,6.2Hz,1H),6.81(d,J=7.9Hz,1H),5.34(dd,J=5.4,12.6Hz,1H),4.28(m ,J=3.4,8.3,11.9Hz,1H),3.72(s,8H),3.61-3.60(m,2H),3.11-3.03(m,3H),3.00-2.88(m,2H),2.73-2.57 (m,5H),2.33(d,J=6.8Hz,2H),2.17-2.09(m,2H),2.03-1.77(m,10H),1.59-1.47(m,1H),1.16-1.03(m,2H).

[0327] Example 33: 3-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methylhexahydropyrrolo[3,4-c]pyrroridine-2(1H)-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (33) [ka] 1) Step 1: Compound 33a (314 mg, 1.48 mmol, Bi De) was dissolved in toluene (5 mL). Compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), 2-bicyclohexylphosphine-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 gas protection, lithium bis(trimethylsilyl)amide (3.7 mL, 3.70 mmol, 1.0 M tetrahydrofuran solution) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 33b. MS m / z (ESI): 470.3 [M+1] + .

[0328] 2) Step 2: Compound 33b (50.0 mg, 0.110 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 33c. MS m / z (ESI): 370.2 [M+1] + .

[0329] 3) Step 3: Compound 33c (39.0 mg, 0.110 mmol), compound 1e (57.8 mg, 0.120 mmol), and triethylamine (21.4 mg, 0.210 mmol) were dissolved in methanol (1 mL) and N,N-dimethylcarboxamide (0.5 mL). Sodium cyanoborohydride (5.71 mg, 30.0 μmol) was added. The mixture was reacted at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure, it was purified by high-performance liquid chromatography (Gilson GX-281, chromatography column: Boston Prime C18, 30 × 150 mm, 5 μm, mobile phase: water (containing 0.0500% aqueous ammonia and 10.0 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%~70%, flow rate: 25 mL / min) to obtain compound 33. MS m / z (ESI): 851.4 [M+1] + . 1 1H NMR (400MHz, DMSO-d6):δ 11.10(s,1H),8.76(d,J=4.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H), 7.37-7.04(m,1H),6.98-6.79(m,4H),5.45-5.22(m,1H),4.37-4.20(m,1H),3 .76-3.64(m,11H),3.16(s,2H),2.94-2.60(m,10H),2.25(s,2H),2.13(s,2H) ),1.99(s,3H),1.82(d,J=10.3Hz,2H),1.59-1.45(m,1H),1.28-1.00(m,3H).

[0330] Example 34: 3-(4-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl-methylpiperazine-1-yl)piperazine-1-yl)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperazine-2,6-dione (34) [ka] 1) Step 1: Compound 34a (398 mg, 1.48 mmol, Bi-de) was dissolved in toluene (5 mL), and compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), 2-bicyclohexylphosphine-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 gas protection, lithium bis(trimethylsilyl)amide (3.7 mL, 3.70 mmol, 1.0 M tetrahydrofuran solution) was added dropwise to the reaction mixture. The reaction was carried out at 80°C for 12 hours under a nitrogen gas atmosphere. 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 34b. MS m / z (ESI): 527.3 [M+1] + .

[0331] 2) Step 2: Compound 34b (60.0 mg, 0.110 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 34c.

[0332] 3) Step 3: Compound 34c (48.0 mg, 0.110 mmol), compound 1e (61.6 mg, 0.120 mmol), and triethylamine (22.8 mg, 0.230 mmol) were dissolved in methanol (1 mL) and N,N-dimethylcarboxamide (0.5 mL). Sodium cyanoborohydride (5.71 mg, 30.0 μmol) was added. The reaction mixture was allowed to react at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, it was purified by high-performance liquid chromatography (Gilson GX-281, chromatography column: Boston Prime C18, 30 × 150 mm, 5 μm, mobile phase: water (containing 0.225% formic acid) and acetonitrile, gradient ratio: acetonitrile 11%~41%, flow rate: 25 mL / min) to obtain compound 34. MS m / z (ESI): 908.4 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.23-10.98(m,1H),8.74(d,J=7.9Hz,1H),8.64(s,1H),8.53(s,1H),8.38(s,1H),8.20(s,1H),7. 19(t,J=53.2Hz,1H),7.00-6.94(m,1H),6.92-6.85(m,2H),6.80(d,J=7.9Hz,1H),5.33(m,J=5.3,1 2.6Hz,1H),4.35-4.21(m,1H),3.62(s,3H),3.20-3.07(m,4H),2.95-2.79(m,2H),2.76-2.62(m,6H) ),2.44-2.28(m,6H),2.23-2.06(m,6H),2.04-1.72(m,10H),1.70-1.50(m,4H),1.11-1.02(m,2H).

[0333] Example 35: (1-(3-(difluoromethyl)-1-((1r,4r)-4-((2-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (35) [ka] Compound 35a (100 mg, 0.261 mmol, prepared by the method disclosed in intermediate BIL on page 220 of the specification in patent application "WO2021 / 158634Al") was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL). Triethylamine (52.6 mg, 0.521 mmol) was added until the pH exceeded 7, and the mixture was stirred at 25°C for 10 minutes. Acetic acid (146 mg, 0.781 mmol) was added at -10°C, followed by compound 19d (222 mg, 0.391 mmol). The mixture was stirred at 25°C for 20 minutes, after which sodium borohydride acetate (165 mg, 0.780 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 35. MS m / z (ESI): 822.8 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.10(s,1H),9.01(s,1H),8.79(d,J=2.1Hz,1H),8.75(s,1H),8.66(d,J=2.2Hz,1H),8.17(s,1H),7.68-7.63(m, 1H),7.58(s,1H),7.24(t,J=53.3Hz,1H),7.05(d,J=4.6Hz,1H),6.95(t,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),6.68 (d,J=8.0Hz,1H),5.38-5.27(m,1H),4.41-4.18(m,1H),3.62-3.56(m,7H),2.96-2.81(m,1H),2.73-2.58(m,3H), 2.40-2.29(m,4H),2.20-2.12(m,4H),1.98-1.83(m,4H),1.81-1.77(m,4H),1.65-1.58(m,1H),1.16-1.03(m,2H).

[0334] Example 36: 3-(4-(9-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (36) [ka] 1) Step 1: At room temperature, compound 19e (200 mg, 0.590 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), compound 36a (301 mg, 1.18 mmol, Bi De), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (55.0 mg, 0.120 mmol) and Me Tansulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.0 mg, 30.0 μmol) was dissolved in toluene (3 mL), and lithium bistrimethylsilylamide (3 mL, 3.00 mmol, 1.0 M tetrahydrofuran solution, An Naiji) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15 mL x 3). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 36b. MS m / z (ESI): 510.4 [M-1] - .

[0335] 2) Step 2: At room temperature, compound 36b (120 mg, 0.210 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. The solvent was removed from the reaction mixture under reduced pressure. Compound 36c was obtained without purification. MS m / z (ESI): 412.6 [M+1] + .

[0336] 3) Step 3: At room temperature, dissolve compound 36c (80.0 mg, 0.140 mmol) and triethylamine (14.0 mg, 0.160 mmol) in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (2 mL), and stir for 10 minutes. Add acetic acid (13.0 mg, 0.200 mmol) and compound 1e (61.0 mg, 0.120 mmol), and stir the reaction mixture at 25°C for 0.5 hours. Slowly add sodium borohydride acetate (96.0 mg, 0.460 mmol), and stir the reaction mixture for 1 hour. Remove the solvent by reducing the pressure. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient mixing ratio: acetonitrile 20%~80%, flow rate: 25 mL / min) to obtain compound 36. MS m / z (ESI): 893.8 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),7.2 0(t,J=53.2Hz,1H),6.98-6.93(m,2H),6.88-6.86(m,1H),6.82(d,J=7.9Hz,1H),5.38-5.33(m,1H),4.3 2-4.26(m,1H),3.73(s,8H),3.63(s,3H),2.96-2.78(m,5H),2.71-2.59(m,2H),2.38(s,4H),2.18-2.12 (m,4H),2.00-1.91(m,3H),1.86-1.80(m,2H),1.77-1.68(m,5H),1.52-1.43(m,4H),1.12-1.06(m,2H).

[0337] Example 37: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((8-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-2,8-diazaspiro[4.5]deca-2-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (37) [ka] 1) Step 1: Compound 19e (300 mg, 0.890 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 18b (426 mg, 1.77 mmol, Bi-de), Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2 Palladium(II)-yl (149 mg, 0.180 mmol, Adamas) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (83.0 mg, 0.180 mmol, Bi-de) were dissolved in toluene (3 mL), and lithium bistrimethylsilylamide (4.4 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution, An-Nai-ji) was added dropwise under nitrogen gas protection. The reaction mixture was allowed to react at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 37a. MS m / z (ESI): 498.3 [M+1] + .

[0338] 2) Step 2: Compound 37a (100 mg, 0.200 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 20°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the trifluoroacetate salt of the crude product compound 37b was obtained. MS m / z (ESI): 398.2 [M+1] + .

[0339] 3) Step 3: Dissolve the trifluoroacetate salt of compound 37b (100 mg, 0.250 mmol) in tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL), and add triethylamine (0.04 mL, 0.250 mmol). Stir the reaction mixture for 0.5 hours. Add compound 19d (114 mg, 0.250 mmol) and acetic acid (0.02 mL, 0.380 mmol) to the reaction mixture and stir for 0.5 hours. Add sodium borohydride acetate (105 mg, 0.500 mmol) to the reaction mixture. Stir the reaction mixture at 25°C for 17 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% FA / H2O, B: ACN, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 35%~45%, flow rate: 25 mL / min) to obtain compound 37. MS m / z (ESI): 836.8 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ11.10(s,1H),9.04-8.98(m,1H),8.81-8.77(m,1H),8.75(s,1H),8.70-8.63(m, 1H),8.16(s,1H),7.68-7.64(m,1H),7.58(s,1H),7.32-7.15(m,1H),7.05(d,J=4.6Hz,1H),6.99-6.90(m ,2H),6.89-6.84(m,1H),5.40-5.30(m,1H),4.35-4.24(m,1H),3.64(s,3H),3.04-2.88(m,3H),2.80-2.5 8(m,6H),2.37-2.26(m,3H),2.19-2.10(m,2H),2.03-1.92(m,3H),1.85-1.51(m,10H),1.18-1.04(m,2H).

[0340] Example 38: 3-(4-(9-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (38) [ka] 1) Step 1: Compound 19e (400 mg, 1.18 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 38a (606 mg, 2.36 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (110 mg, 0.240 mmol), and methanes A palladium(II) solution (24.8 mg, 30.0 μmol) of bisphosphonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) was dissolved in toluene (6 mL), and lithium bistrimethylsilylamide (6 mL, 6.00 mmol, 1.0 M tetrahydrofuran solution, Anji) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 38b. MS m / z (ESI): 512.4 [M-1] - .

[0341] 2) Step 2: Compound 38b (230 mg, 0.450 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 obtain compound 38c. MS m / z (ESI): 414.7 [M+1] + .

[0342] 3) Step 3: Compound 38c (100 mg, 0.240 mmol) and triethylamine (25.0 mg, 0.250 mmol) were dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (2 mL), and the mixture was stirred for 10 minutes. Acetic acid (19.0 mg, 0.320 mmol) and compound 1e (99.0 mg, 0.220 mmol) were added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium borohydride acetate (154 mg, 0.730 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The solvent was removed by reducing the pressure. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 2%~98%, flow rate: 25 mL / min) to obtain compound 38. MS m / z (ESI): 896.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ11.12(s,1H),8.77(d,J=7.9Hz,1H),8.65(s,1H),8.54(s,1H),8.38(s,1H),7.20(t, J=53.2Hz,1H),7.03-6.87(m,3H),6.82(d,J=7.9Hz,1H),5.39-5.35(m,1H),4.37-4.18(m,1H),4.04-3.87(m, 1H),3.72(s,8H),3.65(s,3H),3.45-3.29(m,3H),3.07-2.96(m,1H),2.94-2.76(m,3H),2.72-2.58(m,3H),2. 42-2.20(m,3H),2.19-2.08(m,4H),2.02-1.87(m,3H),1.851.72(m,2H),1.70-1.47(m,4H),1.20-0.93(m,2H).

[0343] Example 39: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]deca-8-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (39) [ka] Compound 37b trifluoroacetate (100 mg, 0.250 mmol) was dissolved in tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL), and triethylamine (0.04 mL, 0.250 mmol) was added. The reaction mixture was stirred for 0.5 hours. Compound 1e (125 mg, 0.250 mmol) and acetic acid (0.02 mL, 0.380 mmol) were added to the reaction mixture and stirred for 0.5 hours. Sodium borohydride acetate (105 mg, 0.500 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 17 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% FA / H2O, B: ACN, chromatography column: Waters-CORTECS-C18-2.7μm-4.6×30mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 75%~85%, flow rate: 25 mL / min) to obtain compound 39. MS m / z (ESI): 879.8 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ11.11(s,1H),8.77(d,J=7.6Hz,1H),8.66(s,1H),8.57-8.52(m,1H),8.3 8(s,1H),7.34-7.07(m,1H),7.02-6.90(m,2H),6.90-6.85(m,1H),6.82(d,J=7.6Hz,1H),5.42-5. 31(m,1H),4.35-4.22(m,1H),3.80-3.69(m,8H),3.64(s,3H),3.03-2.85(m,3H),2.77-2.57(m,6H) ),2.41-2.25(m,3H),2.18-2.09(m,2H),2.05-1.92(m,3H),1.89-1.50(m,10H),1.19-1.01(m,2H).

[0344] Example 40: 3-(4-(4-(-4-(1-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1-1,2,3-triazole-1--1,2,3-triazole-1-pyrazole-1-yl)cyclohexylmethyl)piperidine-4-ylpiperazine-1-yl)-piperazine-1-acyl)-3-methyl-3-methyl-2-oxo-2,3-dihydrodihydro-1H-benzo[imidazole-1--1-piperidine-2,6-piperidinedione (40) [ka] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 40a (179 mg, 0.660 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol, Bi-de), and methanesulfur Phosphate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (111 mg, 0.130 mmol, Adamas) was dissolved in toluene (5 mL), and lithium bistrimethylsilylamide (2.6 mL, 2.60 mmol, 1.0 M tetrahydrofuran solution, Annaigi) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C under a nitrogen gas 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 phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then 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 40b. MS m / z (ESI): 527.3 [M+1] + .

[0345] 2) Step 2: Compound 40b (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 40c. MS m / z (ESI): 427.3 [M+1] + .

[0346] 3) Step 3: Compound 40c (90.0 mg, 0.120 mmol) was dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (3 mL), triethylamine (24.0 mg, 0.240 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Compound 1e (58.0 mg, 0.120 mmol) and acetic acid (35.0 mg, 0.580 mmol) were added to the reaction mixture and the mixture was stirred for 30 minutes. Sodium borohydride acetate (124 mg, 0.590 mmol) was added to the reaction mixture and the mixture was stirred for 1 hour. The mixture was concentrated to obtain the residue. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 8%~95%, flow rate: 25 mL / min) to obtain compound 40. MS m / z (ESI): 908.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.08(s,1H),8.76(d,J=8.0Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),7.1 9(t,J=53.2Hz,1H),7.01-6.85(m,3H),6.81(d,J=7.9Hz,1H),5.40-5.32(m,1H) ,4.32-4.25(m,1H),3.72(s,8H),3.62(s,3H),3.18-2.74(m,9H),2.74-2.54(m, 3H), 2.48-2.08(m, 6H), 2.05-1.73(m, 9H), 1.67-1.43(m, 3H), 1.13-1.04(m, 2H).

[0347] Example 41: 3-(4-(4-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-ylcyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (41) [ka] 1) Step 1: Compound 19e (300 mg, 0.890 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 5a (340 mg, 1.33 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (120 mg, 0.260 mmol, Bi-de), and methanesulfonic acid (2-dicyclohexyl Phosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (220 mg, 0.260 mmol, Adamas) was dissolved in toluene (12 mL), and lithium bistrimethylsilylamide (5 mL, 5.0 mmol, 1.0 M tetrahydrofuran solution, Annaigi) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C under a nitrogen gas atmosphere for 2 hours. The mixture was poured into water (20 mL), and the aqueous phase was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1~0 / 1) to obtain compound 41a. MS m / z (ESI): 514.2 [M+1] + .

[0348] 2) Step 2: Compound 41a (110 mg, 0.210 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 41b. MS m / z (ESI): 414.2 [M+1] + .

[0349] 3) Step 3: Compound 41b (62.0 mg, 0.110 mmol) was dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (3 mL), triethylamine (28.0 mg, 0.280 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Compound 1e (67.0 mg, 0.130 mmol) and acetic acid (41.0 mg, 0.680 mmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Sodium borohydride acetate (143 mg, 0.670 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain the residue. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Wetch-Ultimate-XB-C18-10μm-21.2×150mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15%~95%, flow rate: 25 mL / min) to obtain compound 41. MS m / z (ESI): 895.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.08(s,1H),8.76(d,J=8.0Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s,1H),7.19( t,J=53.2Hz,1H),7.01-6.89(m,2H),6.86(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),5 .37-5.32(m,1H),4.38-4.26(m,1H),3.81-3.61(m,13H),3.09-2.89(m,5H),2.74-2 .58(m,2H),2.43-2.03(m,10H),2.02-1.78(m,5H),1.63(s,3H),1.14-1.04(m,2H).

[0350] Example 42: 3-(4-(3-(4-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperazine-1-yl)azetidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (42) [ka] 1) Step 1: Compound 42a (100 mg, 0.300 mmol, Rakken), Compound 19e (107 mg, 0.440 mmol, prepared by the method disclosed in the product of Step 3 on page 88 of the specification in patent application "WO2022012623A"), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (27.6 mg, 60.0 μmol, Bi-de), and methanesulfonic acid (2-Dicyclo Lohexylphosphinol-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (251 mg, 0.300 mmol, Adamas) was dissolved in toluene (2 mL), and under nitrogen gas protection, lithium bistrimethylsilylamide (1.5 mL, 1.48 mmol, 1.0 M tetrahydrofuran solution, Anji) was added dropwise, and the reaction mixture was allowed to react at 80°C for 2 hours. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using an elution system (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 42b. MS m / z (ESI): 499.2 [M+1] + .

[0351] 2) Step 2: Compound 42b (80.0 mg, 0.160 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25°C for 3 hours. The reaction mixture was concentrated to obtain compound 42c. MS m / z (ESI): 399.2 [M+1] + .

[0352] 3) Step 3: Compound 42c (30.0 mg, 80.0 μmol) was dissolved in N,N-dimethylcarboxamide (1.5 mL) and tetrahydrofuran (1 mL), triethylamine (0.03 mL, 0.190 mmol) was added, and the mixture was reacted at 25°C for 10 minutes. Then, compound 1e (41.2 mg, 80.0 μmol) and acetic acid (0.03 mL, 0.450 mmol) were added sequentially, and the mixture was reacted at 25°C for 30 minutes. Finally, sodium borohydride acetate (95.3 mg, 0.450 mmol) was added, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-Xbrid ge-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15%~95%, flow rate: 25 mL / min) to obtain compound 42. MS m / z (ESI): 880.4 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 11.08(s,1H),8.76(d,J=7.9Hz,1H),8.64(s,1H),8.53(s,1H),8.38(s,1H),7.19(t,J=53.2Hz,1H),6.95(t, J=8.0Hz,1H),6.81(d,J=7.9Hz,1H),6.74(d,J=7.8Hz,1H),6.67(d,J=8.2Hz,1H),5.36-5.29(m,1H),4.36-4 .21(m,1H),3.89(s,2H),3.72(s,8H),3.63(t,J=6.0Hz,2H),3.57(s,3H),3.27-3.09(m,2H),2.93-2.81(m,1 H),2.75-2.60(m,2H),2.36(s,7H),2.14(d,J=7.1Hz,4H),2.01-1.76(m,5H),1.59(s,1H),1.11-1.05(m,2H).

[0353] Example 43: 3-(4-(7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (43) [ka] Compound 35a (28.0 mg, 71.0 μmol, prepared by the method disclosed in intermediate BIL on page 220 of the specification of patent application "WO2021 / 158634Al") was dissolved in a solution of 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL). Triethylamine (8.51 mg, 81.0 μmol) was added until the pH exceeded 7, and the reaction mixture was stirred at 25°C for 10 minutes. Acetic acid (26.1 mg, 0.141 mmol) and compound 1e (41.8 mg, 81.0 μmol) were added at -10°C. The reaction mixture was stirred at 25°C for 20 minutes, after which sodium borohydride acetate (29.7 mg, 0.141 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 43. MS m / z (ESI): 865.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),8.77(d,J=7.9Hz,1H),8.70-8.63(m,1H),8.54(s,1H),8.39(s,1H),8.16(s,1H),7.20(t,J=5 3.2Hz,1H),6.96(t,J=8.0Hz,1H),6.82(d,J=7.9Hz,1H),6.73(d,J=8.1Hz,1H),6.68(d,J=8.2Hz,1H),5.38- 5.27(m,1H),4.36-4.23(m,1H),3.73(s,8H),3.62-3.52(m,8H),2.93-2.84(m,1H),2.70-2.61(m,2H),2.41- 2.27(m,4H),2.20-2.09(m,4H),2.03-1.86(m,4H),1.82-1.78(m,4H),1.68-1.56(m,1H),1.15-1.01(m,2H).

[0354] Example 44: 3-(4-(4-(1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-ylcyclohexyl)methyl)azetidine-3-yl)piperazine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (44) [ka] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 44a (160 mg, 0.660 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol), methanes A palladium(II) (111 mg, 0.130 mmol) rufonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) was dissolved in toluene (5 mL), and lithium bistrimethylsilylamide (2.3 mL, 2.30 mmol, 1.0 M tetrahydrofuran solution, An Naiji) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C under a nitrogen gas 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 phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and then concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 44b. MS m / z(ESI):499.2[M+1] + .

[0355] 2) Step 2: Compound 44b (60.0 mg, 0.120 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 44c. MS m / z (ESI): 399.2 [M+1] + .

[0356] 3) Step 3: Compound 44c (68.0 mg, 0.120 mmol) was dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (3 mL), triethylamine (24.0 mg, 0.240 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Compound 1e (59.0 mg, 0.120 mmol) and acetic acid (40.0 mg, 0.670 mmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Sodium borohydride acetate (127 mg, 0.600 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain the residue. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15%~95%, flow rate: 25 mL / min) to obtain compound 44. MS m / z (ESI): 440.9 [M / 2+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.11(s,1H),8.77(d,J=8.0Hz,1H),8.72-8.65(m,1H),8.56-8.53(m,1H),8.38(d, J=1.6Hz,1H),7.36-7.04(m,1H),7.02-6.84(m,3H),6.81(d,J=8.0Hz,1H),5.40-5.3 3(m,1H),4.43-4.19(m,1H),3.72(s,8H),3.61(s,3H),3.48-3.43(m,2H),3.34(s,1H) ),3.08-2.56(m,12H),2.33(d,J=6.0Hz,1H),2.27-1.27(m,11H),1.15-1.03(m,1H).

[0357] Example 45: 3-(4-(8-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (45) [ka] 1) Step 1: Compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 45a (533 mg, 2.22 mmol, Bi-de), Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl Palladium(II)-2-yl (248 mg, 0.300 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (138 mg, 0.300 mmol) were dissolved in toluene (5 mL), and lithium bistrimethylsilylamide (7.4 mL, 7.39 mmol, 1.0 M tetrahydrofuran solution, Annaigi) was added dropwise under nitrogen gas protection. The reaction mixture was allowed to react at 80°C under a nitrogen gas atmosphere for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (20 mL), the aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 45b. MS m / z (ESI): 498.4 [M+1] + .

[0358] 2) Step 2: Compound 45b (80.0 mg, 0.160 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, compound 45c was obtained. MS m / z (ESI): 398.5 [M+1] + .

[0359] 3) Step 3: Compound 45c (50.0 mg, 0.130 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.1 mL) was added, and the mixture was stirred for 0.5 hours. Compound 1e (75.0 mg, 0.150 mmol) and acetic acid (0.2 mL) were added to the reaction mixture and the mixture was stirred for 0.5 hours. Sodium borohydride acetate (80.0 mg, 0.380 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 45. MS m / z (ESI): 877.7 [M-1] - . 1 H NMR(400MHz,DMSO-d6):δ 11.11(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H) ,7.00-6.93(m,2H),6.88-6.79(m,2H),5.40-5.32(m,1H),4.32-4.23(m,1H),3.73(s,8H),3.59(s, 3H),3.07(t,J=6.8Hz,2H),2.93-2.83(m,3H),2.73-2.58(m,2H),2.43-2.24(m,4H),2.18-2.09(m, 4H),2.02-1.89(m,3H),1.86-1.78(m,2H),1.76-1.72(m,2H),1.67-1.55(m,5H),1.15-0.98(m,2H).

[0360] Example 46: 3-(4-((R)-4-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2-methylpiperazine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (46) [ka] 1) Step 1: Compound 46a (400 mg, 1.18 mmol, Bi De), Compound 19e (355 mg, 1.77 mmol, prepared by the method disclosed in the product of Step 3 on page 88 of the specification in patent application "WO2022012623A"), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (110 mg, 0.240 mmol), and methanesulfonic acid (2-dicyclohexyl (198 mg, 0.240 mmol) of palladium(II) (2-amino-1,1'-biphenyl-2-yl) was dissolved in toluene (8 mL). Under nitrogen gas protection, lithium bistrimethylsilylamide (5.9 mL, 5.91 mmol, 1.0 M tetrahydrofuran solution, AN-Naiji) was added dropwise, and the reaction mixture was allowed to proceed at 80°C under a nitrogen gas atmosphere for 3 hours. Water (50 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography using an elution system (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 46b. MS m / z (ESI): 402.1 [M-55] + .

[0361] 2) Step 2: Compound 46b (176 mg, 0.380 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added while stirring. The reaction mixture was allowed to react at 25°C for 3 hours. The reaction mixture was concentrated to obtain compound 46c. MS m / z (ESI): 358.2 [M+1] + .

[0362] 3) Step 3: Compound 46c (70.0 mg, 60.0 μmol) was dissolved in N,N-dimethylcarboxamide (1.5 mL) and tetrahydrofuran (1 mL), triethylamine (0.02 mL, 0.150 mmol) was added, and the reaction mixture was allowed to react at 25°C for 10 minutes. Then, compound 1e (32.5 mg, 70.0 μmol) and acetic acid (0.02 mL, 0.360 mmol) were added sequentially, and the reaction was allowed to proceed at 25°C for 30 minutes. Sodium borohydride acetate (75.2 mg, 0.360 mmol) was added, and the reaction was allowed to proceed at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-Xbrid ge-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15%~95%, flow rate: 25 mL / min) to obtain compound 46. MS m / z (ESI): 839.4 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),8.76(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.21-7.15(m,1H), 7.14-7.07(m,1H),6.98-6.92(m,1H),6.91-6.86(m,1H),6.81(d,J=7.9Hz,1H),5.39-5.33(m,1H ),4.33-4.28(m,1H),3.73(s,8H),3.64(s,3H),3.32-3.30(m,4H),3.06-2.82(m,5H),2.77-2.5 6(m,4H),2.24-2.10(m,3H),2.03-1.95(m,2H),1.91-1.74(m,3H),1.66-1.54(m,1H),1.10-1.02 (m,3H).

[0363] Example 47: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-ylcyclohexyl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (47) [ka] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 14a (151 mg, 0.670 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol, Bi-de), and methanesulfate Phosphate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (111 mg, 0.130 mmol, Adamas) was dissolved in toluene (5 mL), and lithium bistrimethylsilylamide (2.7 mL, 2.70 mmol, 1.0 M tetrahydrofuran solution, Annaigi) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C under a nitrogen gas 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 phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 47a. MS m / z(ESI):484.3[M+1] + .

[0364] 2) Step 2: Compound 47a (86.0 mg, 0.180 mmol) was dissolved in 1,4-dioxane (2 mL), and hydrochloric acid-1,4-dioxane solution (2 mL, 4.0 M) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain compound 47b. MS m / z (ESI): 384.2 [M+1] + .

[0365] 3) Step 3: Compound 47b (60.0 mg, 0.130 mmol) was dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (3 mL), triethylamine (24.0 mg, 0.240 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Compound 1e (60.0 mg, 0.120 mmol) and acetic acid (40.0 mg, 0.670 mmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Sodium borohydride acetate (145 mg, 0.680 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain the residue. The reaction mixture was concentrated under reduced pressure and then purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 17%~95%, flow rate: 25 mL / min) to obtain compound 47. MS m / z (ESI): 865.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.08(s,1H),8.76(d,J=8.0Hz,1H),8.72-8.62(m,1H),8.54(d,J=4.8Hz,1H),8.38(s,1H),7 .36-7.04(m,1H),7.01-6.93(m,1H),6.92-6.84(m,2H),6.81(d,J=8.0Hz,1H),5.37-5.32(m, 1H),4.40-4.20(m,1H),3.72(s,8H),3.62(s,3H),3.32-2.77(m,8H),2.76-2.56(m,4H),2.37 (d,J=6.4Hz,1H),2.20-1.96(m,3H),1.95-1.75(m,7H),1.74-1.26(m,3H),1.10-1.02(m,1H).

[0366] Example 48: 3-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (48) [ka] 1) Step 1: Compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), compound 48a (471 mg, 2.22 mmol, Bi-de), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (138 mg, 30.0 μmol), and methanesulfonic acid (2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (248 mg, 30.0 μmol) were dissolved in toluene (5 mL), and lithium bis(trimethylsilyl)amide (8.9 mL, 8.87 mmol, 1 M tetrahydrofuran solution, An-Nai-ji) was added dropwise under nitrogen gas protection. The reaction was carried out at 80°C for 2 hours under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 48b. MS m / z (ESI): 470.2 [M+1] + .

[0367] 2) Step 2: Compound 48b (300 mg, 30.0 μmol) was dissolved in dioxane hydrochloride (5 mL, 4.0 M) and stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 48c. MS m / z (ESI): 370.0 [M+1] + .

[0368] 3) Step 3: Compound 48c (40.9 mg, 0.100 mmol) and compound 1e (50.0 mg, 0.100 mmol) were dissolved in N,N-dimethylcarboxamide (0.5 mL), triethylamine (22.3 mg, 0.200 mmol) and sodium cyanoborohydride (9.43 mg, 0.150 mmol) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (GILSON: GX-281, chromatography column: Phenomenex Gemini NX 150 × 30 mm, 5 μm, mobile phase: water (containing 0.225% formic acid) and acetonitrile, gradient ratio: acetonitrile 13%~53%, flow rate: 60 mL / min) to obtain compound 48. MS m / z (ESI): 851.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),8.76(d,J=7.8Hz,1H),8.66(s,1H),8.54(s,1H),8.39(s,1H),7.38-7.02(m,1 H),6.95-6.85(m,1H),6.84-6.76(m,2H),6.71(d,J=8.2Hz,1H),5.37-5.31(m,1H),4.34-4. 27(m,1H),3.80-3.68(m,13H),2.96-2.82(m,1H),2.79-2.58(m,4H),2.50-2.40(m,2H),2.2 5-2.12(m,4H),2.05-1.92(m,3H),1.90-1.75(m,6H),1.70-1.50(m,1H),1.16-1.03(m,2H).

[0369] Example 49: 3-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (49) [ka] 1) Step 1: Compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), compound 49a (471 mg, 2.22 mmol, Bi De), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (248 mg, 0.530 mmol), and methanesulfonic acid (2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (17.1 mg, 20.0 μmol) were dissolved in toluene (5.00 mL), and lithium bis(trimethylsilyl)amide (8.4 mL, 8.40 mmol, 1.0 M tetrahydrofuran solution) was added dropwise under nitrogen gas protection. The reaction mixture was reacted at 80°C under a nitrogen gas atmosphere for 2 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 49b. MS m / z (ESI): 470.2 [M+1] + .

[0370] 2) Step 2: Compound 49b (200 mg, 0.430 mmol) was dissolved in hydrochloric acid-1,4-dioxane (0.5 mL, 4.0 M). The reaction mixture was allowed to react at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 49c.

[0371] 3) Step 3: Compound 49c (50.0 mg, 140 μmol), compound 1e (67.3 mg, 140 μmol), and triethylamine (27.4 mg, 270 μmol) were dissolved in N,N-dimethylcarboxamide (1 mL). Sodium cyanoborohydride (12.8 mg, 0.200 mmol) was added. The mixture was reacted at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, it was purified by high-performance liquid chromatography (Gilson GX-281, chromatography column: Boston Prime C18, 30*150 mm, 5 μm, mobile phase: water (containing 0.0500% aqueous ammonia and 10.0 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 47%~77%, flow rate: 25 mL / min) to obtain compound 49. MS m / z (ESI): 851.5 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),8.76(d,J=7.8Hz,1H),8.66(s,1H),8.54(s,1H),8.39(s,1H),7.36-7.05(m,1H), 6.93-6.87(m,1H),6.83-6.76(m,2H),6.73-6.62(m,1H),5.34(m,J=5.1,12.6Hz,1H),4.35-4.2 5(m,1H),3.73(s,9H),3.70(s,3H),2.95-2.82(m,1H),2.78-2.57(m,4H),2.42(d,J=9.8Hz,2H) ,2.26-2.10(m,4H),2.06-1.93(m,3H),1.91-1.75(m,6H),1.65-1.55(m,1H),1.19-1.04(m,3H).

[0372] Example 50: 3-(4-((R)-4-(((1r,4R)-4-)3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl(cyclohexyl)-3-methylpiperazine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione(50) [ka] 1) Step 1: Compound 19e (400 mg, 1.18 mmol, prepared by the method disclosed in the product of Step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 50a (355 mg, 1.77 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (110 mg, 0.240 mmol, Bi-de), and methanesulfonic acid (2-dicyclohexylphosphine-2 ',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (197 mg, 0.240 mmol, Adamas) was dissolved in toluene (12 mL). The reaction mixture was purged three times with nitrogen gas, and then lithium bistrimethylsilylamide (6.5 mL, 6.50 mmol, 1.0 M tetrahydrofuran solution, Annaigi) was added dropwise. The reaction mixture 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 phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1~0 / 1) to obtain compound 50b. MS m / z (ESI): 458.2 [M+1] + .

[0373] 2) Step 2: Compound 50b (150 mg, 0.110 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain compound 50c. MS m / z (ESI): 358.2 [M+1] + .

[0374] 3) Step 3: Compound 50c (170 mg, 0.110 mmol) was dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (3 mL), triethylamine (22.0 mg, 0.220 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Compound 1e (54.0 mg, 0.110 mmol) and acetic acid (33.0 mg, 0.550 mmol) were added to the reaction mixture, and the mixture was stirred for 30 minutes. Then, sodium borohydride acetate (115 mg, 0.540 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 6%~95%, flow rate: 25 mL / min) to obtain compound 50. MS m / z (ESI): 839.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),8.76(d,J=8.0Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.19(t,J=53 .2Hz,1H),7.02-6.84(m,3H),6.81(d,J=8.0Hz,1H),5.43-5.28(m,1H),4.30(t,J=13.2Hz) ,1H),3.73(s,8H),3.64(s,3H),3.08-2.77(m,5H),2.76-2.52(m,4H),2.46-2.28(m,2H), 2.23-2.07(m,3H),2.04-1.93(m,2H),1.92-1.71(m,3H),1.60(s,1H),1.26-0.95(m,5H).

[0375] Example 51: 7-(1-(3-(difluoromethyl)-1-((1R,4r)-4-(((3R)-4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-3-methylpiperazine-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (51) [ka] Compound 46c (70.0 mg, 60.0 μmol) was dissolved in N,N-dimethylcarboxamide (1.5 mL) and tetrahydrofuran (1 mL). Triethylamine (0.02 mL, 0.150 mmol) was added, and the mixture was reacted at 25°C for 10 minutes. Then, compound 19d (29.7 mg, 70.0 μmol) and acetic acid (0.02 mL, 0.360 mmol) were added sequentially, and the mixture was reacted at 25°C for 30 minutes. Sodium borohydride acetate (75.2 mg, 0.360 mmol) was added, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-Xbrid ge-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 10%~95%, flow rate: 25 mL / min) to obtain compound 51. MS m / z (ESI): 796.4 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 11.12(s,1H),9.01(s,1H),8.78(d,J=2.3Hz,1H),8.75(s,1H),8.66(d,J=2.2Hz,1H),7.6 5(d,J=4.6Hz,1H),7.58(s,1H),7.24(t,J=53.3Hz,1H),7.09-6.94(m,5H),5.43-5.30(m,1 H),4.31(s,1H),3.64(s,3H),3.27(s,2H),2.98-2.78(m,4H),2.74-2.54(m,3H),2.25-2. 14(m,4H),2.06-1.79(m,6H),1.69-1.59(m,1H),1.22-1.01(m,3H),0.80(d,J=5.9Hz,2H).

[0376] Example 52: 7-(1-(3-difluoromethyl)-1-(1R,4R)-4-(4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)ethinyl)piperidine-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (52) [ka] 1) Step 1: Compound 19e (200 mg, 0.590 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 52a (355 mg, 1.77 mmol, Bi-de), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (55.0 mg, 0.120 mmol), and methane Sulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (74.0 mg, 90.0 μmol) was dissolved in toluene (3 mL), and lithium bistrimethylsilylamide (4 mL, 4.00 mmol, 1.0 M tetrahydrofuran solution, An Naiji) was added dropwise under nitrogen gas protection. The reaction mixture was stirred at 80°C under a nitrogen gas 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 phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 52b. MS m / z (ESI): 458.3 [M+1] + .

[0377] 2) Step 2: Compound 52b (110 mg, 0.240 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent and obtain compound 52c. MS m / z (ESI): 358.4 [M+1] + .

[0378] 3) Step 3: Compound 52c (50.0 mg, 0.140 mmol) and triethylamine (28.0 mg, 0.280 mmol) were dissolved in N,N-dimethylcarboxamide (2 mL) and tetrahydrofuran (2 mL), and the mixture was stirred for 10 minutes. Acetic acid (21.0 mg, 0.350 mmol) and compound 1e (70.0 mg, 0.140 mmol) were added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium borohydride acetate (89.0 mg, 0.40 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the solvent was removed. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 10%~90%, flow rate: 25 mL / min) to obtain compound 52. MS m / z (ESI): 839.7 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.10(s,1H),8.77(d,J=7.6Hz,1H),8.66(s,1H),8.54(s,1H),8. 38(s,1H),7.20(t,J=53.2Hz,1H),7.01-6.97(m,1H),6.93-6.88(m,2H),6.82(d,J=8.0Hz,1 H),5.38-5.33(m,1H),4.30-4.27(m,1H),3.73(s,8H),3.64(s,3H),2.99-2.84(m,6H),2.7 1-2.59(m,4H),2.18-2.14(m,3H),2.01-1.98(m,2H),1.86-1.83(m,4H),1.18-1.05(m,6H).

[0379] Example 53: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)-2,9-diazaspiro[5.5]undecane-9-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (53) [ka] 1) Step 1: Under nitrogen gas protection, 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, adamas) is mixed with compound 19e (150 mg, 0.440 mmol, step 88 of the specification in patent application "WO2022012623A" Compound 53a (226 mg, 0.890 mmol, Bi-de), prepared by the method disclosed in Product 3, was added to a toluene (3 mL) solution containing lithium bistrimethylsilylamide (2.2 mL, 2.22 mmol, 1.0 M tetrahydrofuran solution, An-Nai-ji) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (41.0 mg, 90.0 μmol, Bi-de). The reaction mixture was purged three times with nitrogen gas and reacted at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), the aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 53b. MS m / z (ESI): 512.5 [M+1] + .

[0380] 2) Step 2: Compound 53b (100 mg, 0.200 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 20°C for 2 hours. After concentrating the reaction mixture under reduced pressure, the trifluoroacetate salt of the crude product compound 53c was obtained. MS m / z (ESI): 412.8 [M+1] + .

[0381] 3) Step 3: Dissolve the trifluoroacetate salt of compound 53c (100 mg, 0.190 mmol) in tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL), add triethylamine (0.03 mL, 0.190 mmol), and stir the reaction mixture for 0.5 hours. Add compound 1e (114 mg, 0.250 mmol) and acetic acid (0.02 mL, 0.290 mmol) to the reaction mixture and stir for 0.5 hours. Add sodium borohydride acetate (80.0 mg, 0.380 mmol) to the reaction mixture. Stir the reaction mixture at 25°C for 17 hours. The residue obtained after concentrating the reaction mixture under reduced pressure was purified by high-performance liquid chromatography (A: 0.1% FA / H2O, B: ACN, chromatography column: Waters-CORTECS-C18-2.7μm-4.6×30mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 90%~70%, flow rate: 25 mL / min) to obtain compound 53. MS m / z (ESI): 893.9 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ11.08(s,1H),8.76(d,J=8.0Hz,1H),8.65(s,1H),8.53(s,1H),8.38(s, 1H),7.19(t,J=53.2Hz,1H),7.02-6.91(m,2H),6.90-6.77(m,2H),5.41-5.29(m,1H),4.34-4.21 (m,1H),3.81-3.67(m,8H),3.63(s,3H),2.96-2.80(m,5H),2.74-2.56(m,3H),2.37-2.27(m,2H) ,2.19-2.03(m,5H),2.01-1.73(m,7H),1.68-1.42(m,6H),1.31-1.21(m,1H),1.12-0.97(m,2H).

[0382] Example 54: 3-(4-(1S,4S)-4-((1r,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl(methyl)amino)cyclohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (54) [ka] 1) Step 1: Compound 54a (1.00 g, 2.45 mmol, prepared by the method disclosed in Compound 3A on page 306 of patent application "WO2023017442A") was dissolved in methanol (10 mL), and wet palladium carbon (0.130 g, 10%) was added. The reaction mixture was purged three times with a hydrogen gas balloon. The reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 54b. MS m / z (ESI): 229.7 [M+1] + .

[0383] 2) Step 2: Methanesulfonic acid (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (294 mg, 0.350 mmol, Bi-de), Compound 19e (593 mg, 1.75 mmol, disclosed as the product of Step 3 on page 88 of the specification in patent application "WO2022012623A" Compound 54b (600 mg, 2.63 mmol) and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (164 mg, 0.350 mmol, Bi-de), prepared by the method described above, were dissolved in toluene (5 mL). Under nitrogen gas protection, lithium bistrimethylsilylamide (8.8 mL, 8.76 mmol, 1.0 M tetrahydrofuran solution, An-Nai-ji) was added dropwise. After substituting the reaction mixture with nitrogen gas three times, the reaction was carried out at 80°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 54c. MS m / z(ESI):486.4[M+1] + .

[0384] 3) Step 3: Compound 54c (300 mg, 0.620 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the crude product compound 54d was obtained. MS m / z (ESI): 386.2 [M+1] + .

[0385] 4) Step 4: Compound 54d (200 mg, 0.520 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylcarboxamide (1 mL), triethylamine (0.1 mL) was added, and the reaction mixture was stirred for 0.5 hours. Compound 1e (310 mg, 0.620 mmol) and acetic acid (0.2 mL) were added to the reaction mixture and stirred for 0.5 hours. Sodium borohydride acetate (80.0 mg, 0.380 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours. The residue obtained after concentrating the reaction mixture under reduced pressure was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~48%, flow rate: 25 mL / min) to obtain compound 54. MS m / z (ESI): 867.7 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.07(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.34-7.02(m,3H),6.88-6.7 9(m,2H),6.54-6.47(m,2H),5.42-5.24(m,2H),4.60-4.50(m,1H),4.33-4.23(m,1H),3.73(s,8H),3.60( s,3H),2.90-2.85(m,1H),2.34-2.23(m,4H),2.22(s,3H),2.16-2.11(m,2H),2.08-2.04(m,2H),1.99-1. 96(m,2H),1.95-1.91(m,2H),1.85-1.79(m,2H),1.77-1.72(m,2H),1.45-1.32(m,3H),1.10-1.00(m,2H).

[0386] Example 55: 3-(4-(((1R,4r)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)amino)3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (55) [ka] 1) Step 1: Compound 19e (518 mg, 1.53 mmol, prepared by the method disclosed in the product of Step 3 on page 88 of the specification in patent application "WO2022012623A"), Compound 55a (698 mg, 3.06 mmol, prepared by the method disclosed in intermediate 4 on page 858 of the specification in patent application "US2019 / 0192668A1"), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (140 mg, 0.300 mmol, BD) and 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) were dissolved in toluene (8 mL), and lithium bistrimethylsilylamide (8.9 mL, 8.87 mmol, 1 M tetrahydrofuran solution, ANNAI) was added dropwise under nitrogen gas protection. The reaction mixture was allowed to react at 80°C under a nitrogen gas atmosphere for 1 hour. Water (10 mL) was added to the reaction mixture, the aqueous phase was extracted with dichloromethane (50 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 55b. MS m / z (ESI): 486.4 [M+1] + .

[0387] 2) Step 2: Compound 55b (350 mg, 0.721 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was allowed to react at 25°C for 2 hours, and after concentrating the reaction mixture under reduced pressure, compound 55c was obtained. MS m / z (ESI): 386.7 [M+1] + .

[0388] 3) Step 3: Dissolve compound 55c (271 mg, 0.701 mmol) in 1,2-dichloroethane (5 mL), tetrahydrofuran (5 mL), and N,N-dimethylcarboxamide (5 mL). Add triethylamine (106 mg, 1.06 mmol) until the pH exceeds 7, and stir the reaction mixture at 25°C for 10 minutes. Add acetic acid (262 mg, 1.41 mmol) and compound 1e (350 mg, 0.701 mmol) at -10°C. Stir the reaction mixture at 25°C for 20 minutes, then add sodium borohydride acetate (298 mg, 1.41 mmol, Bi De). Stir the reaction mixture for a further 1 hour. After concentrating the reaction mixture under reduced pressure, the resulting residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 55. MS m / z (ESI): 867.1 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 11.06(s,1H),8.76(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.43-8.35(m,1H),7.20(t,J=53.2Hz,1 H),6.90-6.78(m,2H),6.55-6.47(m,2H),5.38-5.29(m,1H),4.65-4.44(m,1H),4.36-4.22(m,1H),3.73 (s,8H),3.61(s,3H),2.93-2.83(m,1H),2.72-2.62(m,2H),2.31-2.25(m,3H),2.23(s,3H),2.18-2.06 (m,5H),2.02-1.87(m,4H),1.84-1.73(m,4H),1.44-1.34(m,2H),1.32-1.21(m,2H),1.10-1.00(m,2H).

[0389] Example 56: 3-(4-(1R,4R)-4-(4-(4-(5-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-3-(difluoromethyl)-1H-pyrazole-1-yl)cyclohexyl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl)piperidine-2,6-dione (56) [ka] 1) Step 1: Compound 1c-1 (3.02 g, 19.5 mmol) was dissolved in acetonitrile (30 mL). N,N-diisopropylethylamine (6.89 g, 53.3 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.41 g, 17.8 mmol) were added sequentially. The reaction mixture was stirred at 60°C for 4 hours. Water (50 mL) was added to the reaction mixture, and it was extracted twice with ethyl acetate (50 mL). The mixture was washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 56a. MS m / z (ESI): 217.1 [M+H] + .

[0390] 2) Step 2: Compound 56a (1.02 g, 4.62 mmol) was dissolved in acetonitrile (20 mL). N-iodosuccinimide (1.56 g, 6.94 mmol) was added. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with saturated sodium thiosulfate aqueous solution (20 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 2 / 1) to obtain compound 56b. MS m / z (ESI): 343.0 [M + H] + .

[0391] 3) Step 3: Compound 56b (1.00 g, 2.93 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred. Trimethylsilylacetylene (285 mg, 2.93 mmol), triethylamine (890 mg, 8.77 mmol), cuprous iodide (55.1 mg, 0.29 mmol), and bistriphenylphosphine dichloride palladium (205 mg, 0.29 mmol) were added sequentially. The system was purged with nitrogen gas three times. The reaction mixture was stirred at 25°C for 18 hours. Water (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (30 mL). The mixture was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was dissolved in methanol (10 mL), then potassium carbonate (810 mg, 5.85 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 56c. MS m / z (ESI): 241.1 [M+H] + .

[0392] 4) Step 4: Compound 56d (300 mg, 1.09 mmol, prepared by the method disclosed in the intermediates section on page 402 of the specification in patent application "WO2022125790A1") was dissolved in acetonitrile (8 mL). Isoamyl nitrite (153 mg, 1.31 mmol) was added under ice bath. The reaction mixture was stirred at 0°C for 1 hour. Trimethylsilyl azide (188 mg, 1.64 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain compound 56e. MS m / z (ESI): 300.1 [M + H] + .

[0393] 5) Step 5: To a mixed solution of compound 56e (325 mg, 1.09 mmol) in ethanol (8 mL) and water (5 mL), sodium vitamin C (40 mg, 0.22 mmol), copper sulfate pentahydrate (50 mg, 0.22 mmol), and compound 56c (240 mg, 1.09 mmol) were sequentially added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 15 / 1 to 10 / 1) to obtain compound 56f. MS m / z (ESI): 540.2 [M+H] + .

[0394] 6) Step 6: Add compound 56f (320 mg, 0.59 mmol) to a 50 mL three-necked flask, add tetrahydrofuran (5 mL), stir until dissolved, purge the system three times with nitrogen gas, cool to -50°C, and add lithium aluminum hydride tetrahydrofuran solution (0.60 mL, 0.60 mmol, 1.0 M) to the reaction mixture. Stir the reaction mixture at -50°C for 1 hour. Add water (20 mL) to the reaction mixture and extract with ethyl acetate (20 mL x 3). Wash with saturated brine (50 mL x 1) and dry over anhydrous sodium sulfate. Concentrate under reduced pressure, and purify the residue by column chromatography (methanol / dichloromethane = 15 / 1 to 10 / 1) to obtain compound 56 g. MS m / z (ESI): 512.2 [M + H] + .

[0395] 7) Step 7: 56 g (200 mg, 0.39 mmol) of compound was dissolved in 8 mL of dichloromethane, to which Dess-Martin oxidizing agent (250 mg, 0.59 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was beaten with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 5 mL) to obtain compound 56i. MS m / z (ESI): 510.1 [M + H] + .

[0396] 8) Step 8: Compound 11a (56.2 mg, 0.140 mmol, prepared by the method disclosed for intermediate AZK on page 222 of the specification in patent application "WO2021158634A1") was dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and triethylamine (13.9 mg, 0.140 mmol) was added. After stirring the reaction mixture at 25°C for 10 minutes, acetic acid (8.25 mg, 0.140 mmol) and compound 56i (65.0 mg, 0.130 mmol) were added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 0.5 hours, sodium borohydride acetate (166 mg, 0.780 mmol) was added. After stirring the reaction mixture for 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). After separating the aqueous phase, it was extracted with dichloromethane (3 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 56. MS m / z (ESI): 836.4 [M+1] + . 1 H NMR(400MHz,CDCl3):δ 8.65(s,1H),8.53(s,1H),8.41-8.21(m,2H),8.12(s,1H),7.11-6.68(m,4H),6.14(s,1H), 5.25-5.18(m,1H),4.78(s,1H),4.25-4.15(m,1H),4.03-3.93(m,2H),3.70(s,3H),3.63-3. 60(m,1H),3.29-3.18(m,3H),3.00-2.88(m,1H),2.86-2.62(m,2H),2.45-2.39(m,2H),2.3 4-2.23(m,5H),2.17-2.10(m,4H),2.07-2.01(m,3H),1.92-1.86(m,5H),1.27-1.18(m,2H).

[0397] Example 57: 7-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)piperazine-1-ylmethyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-pyrazole-4-yl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (57) [ka] Compound 30a (37.8 mg, 0.110 mmol, prepared by the method disclosed in intermediate 199 on page 222 of the specification in patent application "WO2021158634A1") was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL), and triethylamine (5.57 mg, 60.0 μmol) was added. After stirring the reaction mixture at 25°C for 10 minutes, acetic acid (3.3 mg, 60.0 μmol) and compound 19d (25 mg, 0.110 mmol) were added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, sodium borohydride acetate (70.0 mg, 0.330 mmol) was added. After stirring the reaction mixture at 25°C under nitrogen gas protection for 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). After separating the aqueous phase, it was extracted with dichloromethane (3 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 57. MS m / z (ESI): 782.6 [M+1] + . 1H NMR(400MHz,DMSO-d6):δ 11.09(s,1H),9.01(s,1H),8.78(d,J=2.2Hz,1H),8.74(s,1H),8.65(d,J=2.2Hz,1H),8.15(s,1H),7.65( d,J=4.6Hz,1H),7.55(s,1H),7.17(t,J=53.3Hz,1H),7.05(d,J=4.6Hz,1H),7.01-6.92(m,2H),6.91-6.86 (m,1H),5.39-5.30(m,1H),4.35-4.26(m,1H),3.63(s,3H),3.04-2.76(m,8H),2.73-2.57(m,3H),2.26-2. 22(m,2H),2.21-2.16(m,2H),2.01-1.94(m,3H),1.87-1.78(m,2H),1.69-1.61(m,1H),1.18-1.07(m,2H).

[0398] Example 58: 3-(4-(9-(((1S,4r)-4-(3-(difluoromethyl)-4-(4-(5-((S)-3-methylmorpholinyl)pyrazole[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl(cyclohexyl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (58) [ka] 1) Step 1: Compound 1c-1 (15.0 g, 97.7 mmol, Shanghai Haohong) was dissolved in N,N-dimethylcarboxamide (200 mL), cesium carbonate (47.7 g, 147 mmol) and compound 58a (10.4 g, 103 mmol, Bi De) were added, and the reaction mixture was allowed to react at 110°C for 12 hours. Water (1 L) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 = 3 / 1 to 1 / 1) to obtain compound 58b. MS m / z (ESI): 219.2 [M+1] + .

[0399] 2) Step 2: Compound 58b (4.00 g, 18.3 mmol) was dissolved in acetonitrile (40 mL), and N-iodosuccinimide (6.19 g, 27.5 mmol) was slowly added little by little. The reaction was allowed to proceed at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 = 3 / 1 to 1 / 1) to obtain compound 58c. MS m / z (ESI): 345.1 [M+1] + .

[0400] 3) Step 3: Compound 58c (6.00 g, 17.4 mmol) was dissolved in tetrahydrofuran (100 mL), triethylamine (2.65 g, 26.2 mmol), trimethylsilylacetylene (3.70 mL, 26.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.22 g, 1.74 mmol), and cuprous iodide (330 mg, 1.74 mmol) were added, the reaction mixture was purged three times with nitrogen gas, and the mixture was reacted at 25°C for 1 hour. Then, water (50 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 = 3 / 1 to 1 / 1) to obtain compound 58d. MS m / z (ESI): 315.1 [M+1] + .

[0401] 4) Step 4: Compound 58d (3.00 g, 9.54 mmol) was dissolved in methanol (30 mL), potassium carbonate (2.64 g, 19.1 mmol) was added, and the mixture was reacted at 25°C for 1 hour. Water (50 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 = 3 / 1 to 1 / 1) to obtain compound 58e. MS m / z (ESI): 243.0 [M+1] + .

[0402] 5) Step 5: Compound 58e (1.80 g, 7.43 mmol) was dissolved in tert-butanol (20 mL), and sodium vitamin C (150 mg, 0.740 mmol, Annaigi), compound 1b (2.02 g, 7.43 mmol), and cuprous oxide (860 mg, 5.94 mmol, Bide) were added. The reaction mixture was allowed to react at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 58f. MS m / z (ESI): 514.2 [M+1]+ . 1 H NMR(400MHz,DMSO-d6):δ 8.77(d,J=7.9Hz,1H),8.67(s,1H),8.52(s,1H),8.38(s,1H),7.21(t,J=53.1Hz,1H),6.7 9(d,J=7.7Hz,1H),4.57-4.49(m,2H),4.32-4.17(m,2H),4.00-3.93(m,1H),3.78-3.72(m, 1H),3.69-3.63(m,1H),3.56-3.46(m,1H),3.43-3.37(m,1H),3.31-3.20(m,4H),2.18-2. 09(m,2H),1.93-1.86(m,2H),1.86-1.74(m,2H),1.55-1.38(m,1H),1.25(d,J=6.8Hz,3H).

[0403] 6) Step 6: Compound 58f (780 mg, 1.52 mmol) was dissolved in dichloromethane (25 mL), and Dessmartin oxidizing agent (980 mg, 2.31 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was beaten with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1.20 mL) to obtain compound 58 g. MS m / z (ESI): 512.3 [M+1] + .

[0404] 7) Step 7: Compound 36c (125 mg, 0.170 mmol) was dissolved in N,N-dimethylcarboxamide (0.5 mL) and tetrahydrofuran (2 mL), triethylamine (51.0 mg, 0.500 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Then, 58 g of compound (87.0 mg, 0.170 mmol) and acetic acid (61.0 mg, 1.02 mmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Sodium borohydride acetate (217 mg, 1.02 mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the resulting residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-SunFire-C18-10μm-19×250mm, mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 19%~95%, flow rate: 25 mL / min) to obtain compound 58. MS m / z (ESI): 907.6 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 11.10(s,1H),8.76(d,J=8.0Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),7.00-6.92(m,2H) ,6.86(d,J=5.2Hz,1H),6.78(d,J=8.0Hz,1H),5.35(dd,J=12.8,5.2Hz,1H),4.54(s,1H),4.33-4.13(m,2H),3.98-3.94 (m,1H),3.78-3.74(m,1H),3.66-3.62(m,4H),3.50(t,J=10.4Hz,1H),3.27-3.19(m,1H),2.87(s,5H),2.73-2.57(m,2H) ),2.36(s,4H),2.23-2.07(m,4H),2.04-1.76(m,5H),1.73-1.37(m,9H),1.24(d,J=6.8Hz,3H),1.07(q,J=11.2Hz,2H).

[0405] Example 59: 3-(4-(4-(-4-(((1S,4r)-4-(3-(difluoromethyl)-4-(4-(5-((S)-3-methylmorpholinyl)pyrazole[1,5-a]pyrimidine-3-yl)-1H-1,2,3-triazole-1-yl)-1H-pyrazole-1-yl(cyclohexyl)methyl)piperazine-1-yl)piperidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)pyridine-2,6-dione (59) [ka] Compound 34c (70.0 mg, 0.130 mmol) was dissolved in N,N-dimethylcarboxamide (1.5 mL) and tetrahydrofuran (1 mL), and triethylamine (0.04 mL, 0.320 mmol) was added. The reaction mixture was allowed to react at 25°C for 10 minutes. Then, 58 g (72.9 mg, 0.140 mmol) and acetic acid (0.04 mL, 0.780 mmol) were added sequentially, and the reaction was allowed to proceed at 25°C for 30 minutes. Finally, sodium borohydride acetate (164 mg, 0.780 mmol) was added, and the reaction was allowed to proceed at 25°C for 2 hours. After concentrating the reaction mixture under reduced pressure, the resulting residue was purified by high-performance liquid chromatography (Gilson 306-1741, chromatography column: Waters-Xbrid ge-C18-10μm-19×250mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 15%~95%, flow rate: 25 mL / min) to obtain compound 59 (18.7 mg). MS m / z (ESI): 922.6 [M+1] + . 1HNMR(400MHz,DMSO-d6):δ 11.11(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.52(s,1H),8.38(s,1H),7.20(t,J=53.2Hz,1H),6.97(t,J=7.9Hz,1H),6.92-6. 83(m,2H),6.78(d,J=8.0Hz,1H),5.35(dd,J=12.6,5.3Hz,1H),4.53(s,1H),4.35-4.14(m,2H),3.96(dd,J=11.7,4.0Hz,1H),3.75( d,J=11.4Hz,2H),3.62(s,3H),3.56-3.45(m,2H),3.28-3.03(m,4H),2.93-2.82(m,1H),2.77-2.62(m,4H),2.56(d,J=15.7Hz,4H), 2.42-2.25(m,4H),2.13(d,J=7.1Hz,4H),1.98-1.78(m,6H),1.60(d,J=10.2Hz,3H),1.24(d,J=6.7Hz,3H),1.07(d,J=13.5Hz,2H).

[0406] Example 60: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((2-((1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-3,3-dihydro-1H-benzo[d]imidazole-4-yl)methyl)-2-azaspiro[3.5]non-7-yl)methyl(amino)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole)pyrrolo[1,2-b]pyridazine-3-carboxamide (60) [ka] 1) Step 1: Compound 60a (50.0 mg, 0.100 mmol, bisulfite) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. After stirring at 25°C for 2 hours, the reaction mixture was directly concentrated under reduced pressure, and the residue was used directly as the starting material for the next step without purification to obtain compound 60b. MS m / z (ESI): 156.1 [M+1] + .

[0407] 2) Step 2: Compound 3a (175 mg, 0.570 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification in patent application "WO2020206424A1") was dissolved in acetonitrile (8 mL), compound 60b (106 mg, 0.680 mmol) and potassium carbonate (393 mg, 2.84 mmol) were added, and the reaction mixture was allowed to react at 80°C for 2 hours. Then, water (10 mL) was added to the reaction mixture, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, 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 60c. MS m / z (ESI): 427.3 [M+1] + .

[0408] 3) Step 3: Compound 60c (120 mg, 0.280 mmol) was dissolved in dichloromethane (5 mL), and Dess Martin oxidizing agent (239 mg, 0.560 mmol) was slowly added to the reaction mixture at 30°C for 2 hours. After that, the reaction mixture was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 60d. MS m / z (ESI): 425.1 [M+1] + .

[0409] 4) Step 4: Compound 60f (3.00 g, 18.4 mmol) and compound 60e (6.00 g, 20.2 mmol, prepared by the method disclosed in intermediate k on page 73 of the specification in patent application "WO2014195919A1") were dissolved in N,N-dimethylcarboxamide (25 mL), and cesium carbonate (18.0 g, 55.2 mmol) was added. After reacting the reaction mixture at 80°C for 12 hours, the reaction mixture was added to water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1~5 / 1) to obtain 60 g of compound. MS m / z (ESI): 383.0 [M+23] + .

[0410] 5) Step 5: 60 g (2.00 g, 5.55 mmol) of compound was dissolved in methanol (10 mL), and wet palladium carbon (300 mg, 10%) was added. After replacing the reaction mixture three times with a hydrogen gas balloon, the reaction mixture was allowed to react at 25°C for 12 hours. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure, and the residue was used directly as the starting material for the next step without purification to obtain compound 60h. MS m / z (ESI): 331.2 [M+1] + .

[0411] 6) Step 6: Compound 60h (2.00 g, 6.05 mmol) was dissolved in acetonitrile (25 mL), and 2-methyl-2-nitrosopropane (0.9 mL, 7.26 mmol) was added at 0°C. After reacting the reaction mixture at 0°C for 30 minutes, trimethylsilyl azide (1.2 mL, 9.08 mmol) was added, the reaction mixture was heated to 25°C, and reacted at this temperature for 1 hour. Then, water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 60i. MS m / z (ESI): 301.0 [M-55] + .

[0412] 7) Step 7: Compound 19b (200 mg, 1.08 mmol) and compound 60i (385 mg, 1.08 mmol) were dissolved in water (4 mL) and ethanol (4 mL). Copper sulfate pentahydrate (27.0 mg, 0.110 mmol, AN-Nai-Gi) and sodium vitamin C (21.0 mg, 0.110 mmol, AN-Nai-Gi) were added. The reaction mixture was allowed to react at 25°C for 12 hours. After that, it was concentrated under reduced pressure to remove the ethanol, water (10 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was used directly as the starting material for the next step without purification to obtain compound 60j. MS m / z (ESI): 542.1 [M+1] + .

[0413] 8) Step 8: Compound 60j (150 mg, 0.280 mmol) was dissolved in hydrochloric acid-1,4-dioxane (9 mL, 4.0 M), and the reaction mixture was reacted at 25°C for 1 hour. After that, the reaction mixture was directly concentrated under reduced pressure, and the residue was used directly as the starting material for the next step without purification to obtain compound 60k. MS m / z (ESI): 442.3 [M+1] + .

[0414] 9) Step 9: Dissolve compound 60k (52.0 mg, 0.120 mmol) in 1,2-dichloroethane (2.5 mL) and tetrahydrofuran (2.5 mL), add triethylamine (0.02 mL, 0.120 mmol), and react the mixture at 25°C for 15 minutes. Then add compound 60d (50.0 mg, 0.150 mmol) and acetic acid (0.01 mL, 0.240 mmol), and stir for 30 minutes. Then add sodium cyanohydride. Thorium (50.0 mg, 0.240 mmol) was added, and the reaction was stirred for 30 minutes. The reaction system was then concentrated directly, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 60. MS m / z (ESI): 850.4 [M+1] +.

[0415] Example 61: 7-(1-(3-(difluoromethyl)-1-((1R,4r)-4-((((1r,4R)-4-((1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)amino)cyclohexyl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (61) [ka] Compound 55c (12.7 mg, 31.0 μmol) was dissolved in 1,2-dichloroethane (1 mL) and tetrahydrofuran (1 mL). Triethylamine (3.34 mg, 31.0 μmol) was added until the pH value exceeded 7, and the reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was cooled to -10°C, and acetic acid (8.01 mg, 41.0 μmol) and compound 19d (15.0 mg, 31.0 μmol) were added. The reaction mixture was heated to 25°C and stirred at this temperature for 20 minutes, after which sodium borohydride acetate (14.1 mg, 71.0 μmol) was added. The reaction mixture was stirred at 25°C for 1 hour. After concentrating the reaction mixture under reduced pressure, the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 compound 61. MS m / z (ESI): 824.4 [M+1] + .

[0416] Example 62: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((2-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-2,8-diazaspiro[4.5]decane-8-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-pyrazole-1,2,3-triazole-4)pyrrolo[1,2-b]pyridazine-3-carboxamide (62) [ka] Compound 45c (31.0 mg, 80 μmol) is dissolved in N,N-dimethylcarboxamide (0.7 mL) and tetrahydrofuran (2 mL), triethylamine (0.01 mL, 80 μmol) is added, and the reaction mixture is allowed to react at 25°C for 15 minutes. Then, compound 19d (35.0 mg, 80 μmol) and acetic acid (0.01 mL, 0.150 mmol) are added, and the reaction is stirred for 30 minutes. Finally, sodium cyanoborohydride (49.0 Compound 62 was obtained by adding (0.230 mmol mg) and stirring for 30 minutes. The reaction system was then concentrated directly, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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). MS m / z (ESI): 836.4 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 11.09(s,1H),9.01(s,1H),8.81-8.77(m,1H),8.74(s,1H),8.69-8.62(m,1H),8.15(s,1H),7.65(d,J=4.7Hz,1H) ,7.61-7.51(m,1H),7.30(t,J=53.4Hz,1H),7.05(d,J=4.6Hz,1H),6.98-6.93(m,2H),6.89-6.82(m,1H),5.41-5. 28(m,1H),4.35-4.22(m,1H),3.59(s,3H),3.31(s,8H),3.09-3.04(m,2H),2.89-2.87(m,2H),2.69-2.64(m,2H), 2.34-2.31(m,2H),2.15-2.12(m,2H),1.97-1.91(m,2H),1.86-1.72(m,4H),1.67-1.60(m,4H),1.10-1.06(m,1H).

[0417] Example 63: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)azetidine-3-yl)piperazine-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (63) [ka] Compound 42c (61.0 mg, 0.150 mmol) is dissolved in N,N-dimethylcarboxamide (1 mL) and tetrahydrofuran (4 mL), triethylamine (0.02 mL, 0.150 mmol) is added, and the reaction mixture is allowed to react at 25°C for 15 minutes. Then, compound 19d (70.0 mg, 0.150 mmol) and acetic acid (0.02 mL, 0.310 mmol) are added, and the reaction is stirred for 30 minutes, after which sodium cyanoborohydride ( 12.0 mg (0.190 mmol) was added, and the reaction was stirred for 30 minutes. The reaction system was then concentrated directly, and the residue was purified by high-performance liquid chromatography (Waters-2545, chromatography 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 63. MS m / z (ESI): 837.3 [M+1] + .

[0418] Example 64: 7-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-2,7-diazaspiro[3.5]nonane-2-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-1H-pyrazole-4-yl)-1H-1,2,3-triazole-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (64) [ka] Compound 47b (80.0 mg, 0.210 mmol, prepared by the method disclosed in intermediate BJR on page 389 of the specification in patent application "WO2021 / 127283A2") and compound 19d (100 mg, 0.220 mmol) were dissolved in tetrahydrofuran (1 mL) and N,N-dimethylcarboxamide (0.5 mL), and acetic acid (0.1 mL) and sodium borohydride acetate (125 mg, 0.590 mmol) were added sequentially. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated saline solution (20 mL), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, chromatography column: Waters-SunFire-C18-10 μm-19 × 250 mm, mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%~70%, flow rate: 25 mL / min) to obtain compound 64. MS m / z (ESI): 822.3 [M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 11.11(s,1H),9.01(s,1H),8.83-8.74(m,2H),8.66(d,J=2.1Hz,1H),8.16(s,1H),7.66(d,J=4.6 Hz,1H),7.58(s,1H),7.24(t,J=53.3Hz,1H),7.05(d,J=4.6Hz,1H),6.99-6.93(m,1H),6.91-6.8 4(m,2H),5.43-5.30(m,1H),4.38-4.18(m,1H),3.62(s,3H),3.11-2.87(m,6H),2.72-2.60(m,4H ),2.36-2.2...

Claims

1. Compound of formula (A), 【Chemistry 1】 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, Here, L Ａ is selected from a bond and a linear or branched C １－４ alkylene group, and the C １－４ alkylene group is optionally substituted with one or more substituents independently selected from the group consisting of a C １－４ alkyl group, a C １－４ haloalkyl group, a halogen, an oxo group (=O), OH, CN, NH ２ , -NH(C １－４ alkyl), -N(C １－４ alkyl) ２ and is substituted with one or more substituents independently selected from the group consisting of: L Ｂ The elements are 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)-Cycle 1-Cycle (O)-Nine Ｌ１ -、 (8)-CyL1-NR Ｌ１ -C(O)-、 (9)-CyL1-CyL2-, (10)-NR Ｌ１ -RL1-L]-、 (11)-NR Ｌ１ -CyL1-Lb-、 (12)-NR Ｌ１ -CyL3-NR Ｌ２ -、 (13)-NR Ｌ１ -[L3-L!-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 -L-, (20)-CyL1-La-CyL3-, and (21)-CyL1-Lc-CyL4-, Here, In the groups (1) to (21) above, the leftmost protruding bond of each group is the L Ａ It is connected to the above, and the rightmost protruding connection is the above 【Chemistry 2】 The portion is connected, or the leftmost protruding bond of each unit is the 【Transformation 3】 The connection is made to the L Ａ It is connected to, Each time CyL1 and CyL2 appear, they are independently selected from a 3- to 12-membered heterocycloalkylene group, where the heterocycloalkylene group preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. CyL3, each time it appears, C ３－１２ A cycloalkylene group and a 3- to 12-membered heterocycloalkylene group are independently selected. Each time CyL4 appears, it is independently selected from a 5- to 12-membered heteroarylene group. Each time La appears, C １－４ Independently selected from alkylene groups, Each time Lb appears, it is a linear C ２－４ A group independently selected from alkylene groups, where the linear C ２－４ It is one or two of the alkylene groups, but not all of them. ２ O, S, NR Ｌ１ , substituted with one or two groups selected from the group consisting of C(O), Each time Lc appears, it is bound or C １－４ Independently selected from alkylene groups, CyL1, CyL2, CyL3, CyL4, La, Lb, and Lc are each optionally C １－４ alkyl group, C １－４ Haloalkyl groups, halogens, OH, CN, NH ２ ,-NH(C １－４ Alkyl), -N(C １－４ Alkyl) ２ Substituted with one or more groups independently selected from the group consisting of methyl, ethyl, F, Cl, Br, OH, CN, and NH ２ It is, more preferably, a methyl group, F, Cl and OH, R Ｌ１ and R Ｌ２ Each time they appear, H and C １－４ Selected independently of alkyl groups, The aforementioned 【Chemistry 4】 The part has the following: (I) Structure of formula (1): 【Transformation 5】 Here, Ring A 【Transformation 6】 The substituent R is selected from a 5-6 member heteroaryl group, and the 5-6 member heteroaryl group is optionally substituted R ｋ Replaced by, R ｋ C １－６ alkyl group, C ３－７ Cycloalkyl group, R ｐ R ｑ N-, C １－６ Haloalkyl group, C １－６ Heteroalkyl groups (e.g., C １－６ Alkoxy group), 4-9 membered heterocyclyl group (e.g., 5-6 membered saturated heterocycloalkyl group), C ６－１０ Selected from the group consisting of aryl groups and 5- to 10-membered heteroaryl groups, R ｐ , R ｑ Each of them is independent of C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Selected from the group consisting of haloalkyl groups, Ring B 【Transformation 7】 The following group (1) to (3) is selected: （１） 【Transformation 8】 Here, R ４ is hydrogen, C １－６ alkyl group, C ４－９ Cycloalkyl groups, C ４－９ Cycloalkyl-C １－６ Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C １－６ Alkyl-, -NR Ｎａ R Ｎｂ Selected from the group consisting of (where R Ｎａ and R Ｎｂ These are H and C, respectively, independently. １－６ alkyl group, C ３－６ Selected from the group consisting of cycloalkyl groups, the C １－６ alkyl group, C ３－６ Cycloalkyl groups can optionally include halogens, hydroxyl groups, and C ３－６ Cycloalkyl groups, C ３－６ The C ４－９ Cycloalkyl groups, C ４－９ Cycloalkyl-C １－６ Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C １－６ Alkyl- is optionally C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, halogen, hydroxyl group, hydroxy-C １－６ Alkylene-, cyano group, oxo, -NH ２ ,-NH(C １－６ Alkyl), -N(C １－６ (Alkyl) (C １－６ Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, R ５ is selected from the group consisting of hydrogen, a cyano group, C １－６ alkyl group, -C(O)NH ２ , -NR ｌ R ｍ and is selected from the group consisting of R ｌ , R ｍ Each of them is independent of C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, （２） 【Chemistry 9】 Here, R ２２ is selected from the group consisting of hydrogen, C ４－９ cycloalkyl group, C ４－９ cycloalkyl-C １－６ alkyl-, 4- to 9-membered saturated heterocycloalkyl group, 4- to 9-membered saturated heterocycloalkyl-C １－６ alkyl-; R ２３ is hydrogen, C １－６ Alkyl group, cyano group, carboxyl group, -C(O)NH ２ , -NR ｌ R ｍ , 【Chemistry 10】 Selected from the group consisting of R ｌ , R ｍ Each of them is independent of C １－６ alkyl group, C ３－６ Selected from cycloalkyl groups, （３） 【Chemistry 11】 Here, R ２５ is hydrogen, C ４－９ Cycloalkyl groups, C ４－９ Cycloalkyl-C １－６ Alkyl-, 4-9 member saturated heterocycloalkyl, 4-9 member saturated heterocycloalkyl-C １－６ Selected from the group consisting of alkyl-, R ２６ is hydrogen, C １－６ Alkyl group, cyano group, carboxyl group, -C(O)NH ２ Selected from the group consisting of, L １ Direct bond, C １－６ Selected from the group consisting of alkyl groups, -NH-, -O-, and -S-, R １３ C １－６ alkyl group, C １－６ Selected from haloalkyl groups, R １４ C ３－６ Selected from the group consisting of a cycloalkylene group, a 5-12 membered spiroheterocycloalkylene group, and a piperidinylene group, the C ３－６ A cycloalkylene group, a 5-12 membered spiroheterocycloalkylene group, and a piperidinylene group can be optionally associated with hydroxyl C １－６ Alkyl group (e.g., hydroxymethyl), formyl group, C １－６ Substituted with one or two substituents selected from the group consisting of alkyl groups, Or, (II) Structure of Equation (2) 【Chemistry 12】 Here, Ring A' 【Chemistry 13】 It is selected from 5- to 10-membered heteroaryl groups, X １ , X ２ , X ３ and X ４ Each is independently N or CH, and X １ , X ２ , X ３ and X ４ At least one of them is not N, Z is CR ４’ And, The letters "a" and "b" refer to the bonds between the ring carbon atom linked to Z and the two adjacent ring carbon atoms, respectively. 【Chemistry 14】 The part is expressed by the structure of the following equation (i) or equation (ii): 【Chemistry 15】 L １’ Direct bonding and NR ７’ Selected from, R １’ is, -L ２’ -R １ａ And, L ２’ is -S(O) ２ NR １ｂ -*, -C(O)-NR １ｂ -*, -NR １ｂ -C(O)-* or -NR １ｂ -S(O) ２ -*, where the bond indicated by * is R １ａ It is connected to, R １ａ C ６－１０ Selected from aryl groups and 5-10 membered heteroaryl groups, where the C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally paired with halogens, OH, SH, and -NR, respectively. １ｅ R １ｆ , CN, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C １－６ Alkylene-OC １－６ Alkyl, -OC １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN and -C １－６ Alkylene-NR １ｅ R １ｆ It is substituted with one or more substituents independently selected from the base, Each R ２’ These are independently H, halogen, OH, SH, -NR ２ａ R ２ｂ , CN, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C １－６ Alkylene-OC １－６ Alkyl, -OC １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN,-C １－６ Alkylene-NR ２ａ R ２ｂ Selected from the group consisting of, m2 is 0, 1, 2, or 3. R ３’ and R ７’ These are H and C, which are independent of each other. １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -C １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN,-C １－６ Alkylene-NR ３ａ R ３ｂ Selected from the group consisting of, R ４’ H, D, halogen, OH, SH, -NR ４ａ R ４ｂ , CN, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -C １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN,-C １－６ Alkylene-NR ４ａ R ４ｂ Selected from the group consisting of, R ５’ C ３－１０ Selected from a cycloalkylene group and a 3- to 10-membered heterocyclene group, where the C ３－１０ The cycloalkylene group and the 3-10 membered heterocyclene group can be optionally each selected as a halogen, OH, SH, or -NR ５ａ R ５ｂ , CN, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C １－６ Alkylene-OC １－６ Alkyl, -OC １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN and -C １－６ Alkylene-NR ５ａ R ５ｂ It is substituted with one or more substituents independently selected from the base, R ６’ H, halogen, OH, SH, -NR ６ａ R ６ｂ , CN, C １－６ alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Haloalkenyl group, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -S-C １－６ Alkyl, -C １－６ Alkylene-OC １－６ Alkyl, -OC １－６ Alkylene-OC １－６ Alkyl, -C １－６ Alkylene-OH, -C １－６ Alkylene-SH, -C １－６ Alkylene-CN,-C １－６ Alkylene-NR ６ａ R ６ｂ Selected from the group consisting of, n2 is 0, 1, 2, 3 or 4, and R １ｂ , R １ｅ , R １ｆ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ Each time it appears, H and C １－６ Selected independently of alkyl groups, The aforementioned 【Chemistry 16】 The part is the ligase binding site, which is the compound.

2. L Ａ is a bond and C １－２ Selected from alkylene groups, the C １－２ The alkylene group can be optionally C １－２ alkyl group, C １－２ Haloalkyl groups, halogens, oxo groups, OH, CN, NH ２ ,-NH(C １－２ Alkyl), -N(C １－２ Alkyl) ２ Substituted with one or more substituents independently selected from the group consisting of, Preferably, L Ａ is a bond and C １－２ Selected from alkylene groups, the C １－２ The alkylene group can be optionally C １－２ Substituting with substituents selected from the group consisting of alkyl groups, halogens, and oxo groups, More preferably, L Ａ The bond is -CH ２ -ien-CH ２ -CH ２ -, -CH(CH ３ Selected from the group consisting of )- and -C(O)-, More preferably, L Ａ is, -CH ２ - or -CH ２ -CH ２ - and more preferably -CH ２ - The compound according to claim 1.

3. The aforementioned 【Chemistry 17】 The compound according to claim 1 or 2, wherein the portion has the structure of formula (1).

4. The ring A is selected from a five-membered heteroaryl group, the five-membered heteroaryl group contains at least one N atom, and the five-membered heteroaryl group optionally has a substituent R ｋ Replaced by, Preferably, the ring A is selected from a five-membered heteroaryl group, the five-membered heteroaryl group contains two to three heteroatoms, at least two of which are nitrogen atoms, and the five-membered heteroaryl group optionally has a substituent R ｋ Replaced by, More preferably, the ring A is selected from the group consisting of a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a pyrazolyl group, an imidazolyl group, a 1,3,4-thiadiazolyl group, and a 1,3,4-oxadiazolyl group. More preferably, the ring A is [Chemistry 18] A group consisting of is selected, where #C is, 【Chemistry 19】 This represents a connecting part that is connected to a section, $L １ is, L １ This represents the connecting part that is connected to, More preferably, the ring A is 【Chemistry 20】 Selected from, where #C is, 【Chemistry 21】 This represents a connecting part that is connected to a section, $L １ is, L １ This represents the connecting part that is connected to, and / or, R ｋ C １－６ alkyl group, C ３－６ Cycloalkyl group, R ｐ R ｑ N-, C １－６ Selected from the group consisting of haloalkyl groups and 4- to 9-membered saturated heterocycloalkyl groups (e.g., 5- to 6-membered saturated heterocycloalkyl groups), Preferably, R ｋ C １－６ alkyl group, C ３－６ Cycloalkyl group, R ｐ R ｑ N-, C １－６ Selected from the group consisting of haloalkyl groups and morpholinyl groups, and / or, R ｐ , R ｑ These are, independently, hydrogen and C １－６ Selected from alkyl groups, and / or, More specifically, R ｋ isopropyl group, cyclopropyl group, dimethylamino group, difluoromethyl group, 【Chemistry 22】 A compound according to any one of claims 1 to 3, selected from the group consisting of the following.

5. L １ It is selected from direct bonding and -NH-, and preferably direct bonding. and / or, R １３ C １－４ Selected from haloalkyl groups, preferably -CHF ２ and a trifluoromethyl group, more preferably -CHF ２ The compound according to any one of claims 1 to 4.

6. The structure of formula (1) is given by the following formulas (1-1) or (1-2): 【Chemistry 23】 A compound according to any one of claims 1 to 5, represented by [the given expression].

7. The ring B is selected from the following groups (1) to (3): （１） 【Chemistry 24】 Here, R ４ This includes hydrogen, 4-7 member saturated monocyclic heterocycloalkyl groups, 6-9 member saturated cross-linked heterocycloalkyl groups, 6-9 member saturated spiroheterocycloalkyl groups, and 4-7 member saturated monocyclic heterocycloalkyl groups - C １－４ Alkyl-, 6-9 member saturated crosslinked heterocycloalkyl-C １－４ Alkyl-, -NR Ｎａ R Ｎｂ Selected from the group consisting of (where R Ｎａ and R Ｎｂ These are H and C, respectively, independently. １－６ alkyl group, C ３－６ Selected from the group consisting of cycloalkyl groups, the C １－６ alkyl group, C ３－６ Cycloalkyl groups can optionally include halogens, hydroxyl groups, and C ３－６ Cycloalkyl groups, C ３－６ Halocycloalkyl groups, which may be substituted with 1 to 3 substituents selected from the group consisting of 4-7 membered heterocyclyl groups, the 4-7 membered saturated monocyclic heterocycloalkyl groups, the 6-9 membered saturated crosslinked heterocycloalkyl groups, the 6-9 membered saturated spiroheterocycloalkyl groups, and the 4-7 membered saturated monocyclic heterocycloalkyl-C １－４ Alkyl-, 6-9 member saturated crosslinked heterocycloalkyl-C １－４ Alkyl- is optionally C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, halogen, hydroxyl group, hydroxy-C １－６ Alkilen-, oxo, -NH ２ ,-NH(C １－６ Alkyl), -N(C １－６ (Alkyl) (C １－６ Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, Preferably, R ４ This includes hydrogen, 4-7 member saturated monocyclic heterocycloalkyl groups, 6-9 member saturated cross-linked heterocycloalkyl groups, 6-9 member saturated spiroheterocycloalkyl groups, and -NR Ｎａ R Ｎｂ Selected from the group consisting of (where R Ｎａ and R Ｎｂ These are H and C, respectively, independently. １－６ alkyl group, C ３－６ Selected from the group consisting of cycloalkyl groups, the C １－６ alkyl group, C ３－６ Cycloalkyl groups can optionally include a hydroxyl group and a C group. ３－６ The 4-7 member saturated monocyclic heterocycloalkyl group, the 6-9 member saturated crosslinked heterocycloalkyl group, and the 6-9 member saturated spiroheterocycloalkyl group may be optionally substituted with one, two, or three substituents selected from cycloalkyl groups. １－６ alkyl group, C １－６ Haloalkyl group, hydroxyl group, hydroxy-C １－６ Alkylene-,-NH ２ ,-NH(C １－６ Alkyl), -N(C １－６ (Alkyl) (C １－６ Substituted with one, two, or three substituents selected from the group consisting of alkyl groups, R ４ is hydrogen, 【Chemistry 25】 Selected from the group consisting of the above, 【Chemistry 26】 C is, optionally, １－６ Alkyl alkyl groups, halogens, hydroxyl groups, hydroxy(C) １－６ Alkyl)-, cyano group, -NH ２ , -N(C １－６ Alkyl), -N(C １－６ (Alkyl) (C １－６ Substituted with 1 to 3 substituents selected from the group consisting of alkyl groups, m1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0, and n1 is selected from the group consisting of 0, 1, 2, and 3, preferably 0 or 1. Preferably, R ４ is hydrogen, 【Chemistry 27】 Selected from the group consisting of the above, 【Chemistry 28】 C is, optionally, １－６ Alkyl group, hydroxyl group, -NH ２ , hydroxy(C １－６ Substituted with one, two, or three substituents selected from the group consisting of alkyl)-, and / or, R ４ is hydrogen, 【Chemistry 29】 Selected from the group consisting of, and / or, R ５ It consists of hydrogen, a cyano group, and -C(O)NH ２ , -NR ｌ R ｍ Selected from the group consisting of, and / or, R ｌ , R ｍ Each of them is independent of C １－６ Selected from alkyl groups, and / or, R ５ It is selected from hydrogen and cyano groups, and / or, 【Transformation 30】 Overall, 【Chemistry 31】 Selected from the group consisting of, Preferably, 【Chemistry 32】 Overall, 【Transformation 33】 Selected from the group consisting of, （２） 【Transformation 34】 Here, R ２２ is hydrogen and 【Chemistry 35】 m4 is selected from the group consisting of 0, 1, 2, and 3, and n4 is selected from the group consisting of 0, 1, 2, and 3. Preferably, R ２２ is hydrogen and 【Transformation 36】 Selected from, More specifically, R ２２ It is selected from hydrogen, and / or, R ２３ is hydrogen, C １－６ Alkyl group, cyano group, carboxyl group, -C(O)NH ２ , -NR ｌ R ｍ Selected from the group consisting of, Preferably, R ２３ It consists of hydrogen, a cyano group, a carboxyl group, and -C(O)NH ２ , -NR ｌ R ｍ Selected from the group consisting of, Preferably, R ２３ It consists of hydrogen, a cyano group, and -C(O)NH ２ , -NR ｌ R ｍ Selected from the group consisting of, More specifically, R ２３ is -C(O)NH ２ Selected from, and / or, R ｌ , R ｍ These are, independently, hydrogen and C １－６ Selected from alkyl groups, and / or, 【Chemistry 37】 Overall, 【Transformation 38】 Selected from the group consisting of, Preferably, 【Chemistry 39】 Overall, 【Chemistry 40】 Selected from, more, 【Chemistry 41】 Overall, 【Chemistry 42】 And, （３） 【Chemistry 43】 Here, R ２５ is hydrogen, 【Chemistry 44】 m6 is selected from the group consisting of 0, 1, 2, 3, and n6 is selected from the group consisting of 0, 1, 2, 3. Preferably, R ２５ is hydrogen, 【Chemistry 45】 Selected from, more preferably R ２５ It is hydrogen, and / or, R ２６ is hydrogen, C １－６ Alkyl group, cyano group, -C(O)NH ２ Selected from the group consisting of R ２６ is hydrogen, C １－６ Alkyl alkyl group, -C(O)NH ２ Selected from the group consisting of R ２６ is -C(O)NH ２ Selected from, and / or, 【Chemistry 46】 Overall, 【Chemistry 47】 Selected from the group consisting of, Preferably, 【Chemistry 48】 Overall, 【Chemistry 49】 The compound according to any one of claims 1 to 6.

8. R １４ C ３－６ Selected from cycloalkylene groups, the C ３－６ The cycloalkylene group can optionally be hydroxy C １－６ Substituted with one or two substituents selected from alkyl groups (e.g., hydroxymethyl groups) and formyl groups, Preferably, R １４ teeth, [Transformation 50] p is selected from the group consisting of 0, 1, and 2, R ｇ is hydrogen, hydroxyl C １－６ Selected from the group consisting of alkyl groups and formyl groups, preferably R ｇ It is selected from hydrogen, Or, R １４ The group is selected from 7-11 member spiroheterocycloalkylene groups, and the 7-11 member spiroheterocycloalkylene group is optionally hydroxy C １－６ Alkyl group (e.g., hydroxymethyl group), formyl group, C １－３ Substituted with one or two substituents selected from the group consisting of alkyl groups, Preferably, R １４ The group is selected from 9-11 membered spiroheterocycloalkylene groups, and the 9-11 membered spiroheterocycloalkylene group has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. Or, R １４ The group is selected from piperidinylene groups, and the piperidinylene group is optionally composed of 1 to 2 carbon atoms. １－３ Substituted with an alkyl group (preferably a methyl group), More specifically, R １４ teeth, 【Chemistry 51】 Selected from the group consisting of, more preferably, 【Chemistry 52】 And moreover, 【Chemistry 53】 Here, the bond indicated by x is linked to the pyrazole ring, and the bond indicated by y is the L Ａ A compound according to any one of claims 1 to 7, which is linked to the compound. 【Request Item 9】 【Chemistry 54】 The part is, 【Transformation 55】 【Transformation 56】 【Chemistry 57】 A compound according to any one of claims 1 to 8, selected from the group consisting of the following.

10. The aforementioned 【Transformation 58】 The compound according to claim 1 or 2, wherein the portion has the structure of formula (2).

11. R ３’ H, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -C １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ３ａ R ３ｂ Selected from the group consisting of H and C １－４ The compound according to any one of claims 1 to 2 and 10, wherein the compound is an alkyl group, preferably H and a methyl group, more preferably H.

12. The structure of the above formula (2) is as follows: 【Chemistry 59】 The compound according to any one of claims 1 to 2 and 10 to 11, as represented by [the above].

13. n2 is either 0 or 1. and / or, R ５’ C ３－１０ Selected from a cycloalkylene group and a 3- to 10-membered heterocyclene group, where the C ３－１０ The cycloalkylene group and the 3-10 membered heterocyclene group can be optionally each selected as a halogen, OH, SH, or -NR ５ａ R ５ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -O-C １－４ Alkyl, -O-C １－４ Haloalkyl, -S-C １－４ Alkyl, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN and -C １－４ Alkylene-NR ５ａ R ５ｂ It is substituted with one or more substituents independently selected from the base, Preferably, R ５’ C ３－６ Selected from a cycloalkylene group and a 5-10 membered heterocycloalkylene group, where the C ３－６ The cycloalkylene group and the 5-10 membered heterocycloalkylene group can be optionally each selected as a halogen, OH, SH, or -NR ５ａ R ５ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -O-C １－４ Alkyl, -O-C １－４ Haloalkyl, -S-C １－４ Alkyl, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN and -C １－４ Alkylene-NR ５ａ R ５ｂ It is substituted with one or more substituents independently selected from the base, More specifically, R ５’ C ３－６ Selected from a cycloalkylene group and a 5-10 membered heterocycloalkylene group, where the C ３－６ The cycloalkylene group and the 5-10 membered heterocycloalkylene group are each optionally C １－４ alkyl group, C １－４ Haloalkyl group, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN and -C １－４ Alkylene-NR ５ａ R ５ｂ It is substituted with one or more substituents independently selected from the base, More specifically, R ５’ teeth, 【Transformation 60】 Selected from the group consisting of, preferably, 【Chemistry 61】 And, moreover, 【Transformation 62】 And here, the bond indicated by "c" is the L Ａ The bond indicated by "d" is connected to the ring A', or preferably, the bond indicated by "c" is connected to the ring A', and the bond indicated by "d" is connected to the L Ａ It is connected to, and / or, The ring A' is selected from a 5-10 member monocyclic or fused bicyclic heteroaryl group. Preferably, the ring A' is selected from a 5-6 member monocyclic heteroaryl group and a 9-10 member condensed bicyclic heteroaryl group. More preferably, the ring A' is selected from a 5-6 member monocyclic heteroaryl group and a benzo 5-6 member monocyclic heteroaryl group, where preferably the ring A' is connected to the L via the 5-6 member monocyclic heteroaryl group. １’ It is connected to, More preferably, the ring A' is selected from a five-membered monocyclic heteroaryl group and a benzo five-membered monocyclic heteroaryl group, where preferably, the ring A' is connected to the L via the five-membered monocyclic heteroaryl group. １ It is connected to, And / or, here preferably, the five-membered monocyclic heteroaryl group is selected from the group consisting of a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, and a tetrazolyl group. More preferably, the ring A' is selected from the group consisting of a pyrazolyl group, a benzofuryl group, a benzothienyl group, and an indolyl group, where preferably the benzofuryl group is connected to the L via a furan ring. １ The benzothienyl group is linked to the L via the thiophene ring. １ The indolyl group is connected to the L via the pyrrole ring. １ It is connected to, More preferably, the ring A' is 【Transformation 63】 Selected from the group consisting of, Preferably, the above 【Chemistry 64】 The part is, 【Transformation 65】 Selected from the group consisting of, more preferably, 【Chemical Formula 66】 And, and / or, X １ , X ２ and X ３ These are CH and X respectively. １ is N and X ２ and X ３ These are CH and X respectively. ２ is N and X １ and X ３ These are CH and X respectively. ３ is N and X １ and X ２ These are CH and X respectively. １ and X ２ Each of these is N, and X ３ is CH, or X １ and X ３ Each of these is N, and X ２ is CH, or X ２ and X ３ Each of these is N, and X １ is CH, or X １ , X ２ and X ３ The compound according to any one of claims 1 to 2 and 10 to 12, wherein each of the elements is N.

14. The structure of formula (2) is, Formula (2-2)-(2-4): 【Transformation 67】 As shown, Preferably, formula (2-5)-(2-8): 【Transformation 68】 The compound according to any one of claims 1 to 2 and 10 to 13, as shown below.

15. R ７’ H, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -C １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ３ａ R ３ｂ Selected from the group consisting of H and C １－４ It is an alkyl group, more preferably H and a methyl group, and even more preferably H. and / or, R ４’ H, D, halogen, OH, SH, -NR ４ａ R ４ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -C １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ４ａ R ４ｂ Selected from the group consisting of H, D, halogen, OH, -NR ４ａ R ４ｂ , CN, C １－４ Alkyl and C １－４ The haloalkyl group is preferably H, D, F, Cl, OH, -NH ２ CN, methyl group, ethyl group, -CHF ２ and -CF ３ It is, more preferably H, D, F, Cl, a methyl group and an ethyl group, and even more preferably H. and / or, R ６’ H, halogen, OH, SH, -NR ６ａ R ６ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -O-C １－４ Alkyl, -O-C １－４ Haloalkyl, -S-C １－４ Alkyl, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ６ａ R ６ｂ Selected from the group consisting of, Preferably, R ６’ H, halogen, OH, SH, -NR ６ａ R ６ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ６ａ R ６ｂ Selected from the group consisting of, More specifically, R ６’ H, F, Cl, OH, -NH ２ , - NHCH ３ , -N(CH ３ ) ２ CN, methyl group, ethyl group, -CHF ２ , -CF ３ Selected from the group consisting of H, more preferably -NH ２ , - NHCH ３ , -N(CH ３ ) ２ methyl group, ethyl group, -CHF ２ and -CF ３ More preferably, H, a methyl group, an ethyl group, and -CHF ２ The compound according to any one of claims 1 to 2 and 10 to 14.

16. The structure of equation (2) is given by equation (2-9)-(2-12): 【Transformation 69】 The compound according to any one of claims 1 to 2 and 10 to 15, as shown below.

17. R １ａ C ６－１０ The aryl group and the 5-10 membered heteroaryl group, where the C ６－１０ The aryl group and the 5-10 membered heteroaryl group can be optionally paired with halogens, OH, SH, and -NR, respectively. １ｅ R １ｆ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -O-C １－４ Alkyl, -O-C １－４ Haloalkyl, -S-C １－４ Alkyl, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN and -C １－４ Alkylene-NR １ｅ R １ｆ It is substituted with one or more substituents independently selected from the base, Preferably, R １ａ is a phenyl group, where the phenyl group can optionally be a halogen, OH, or -NR １ｅ R １ｆ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, -O-C １－４ Alkyl and -O-C １－４ It is substituted with one or more substituents independently selected from the haloalkyl group, preferably F, Cl, OH, -NH ２ , CN, methyl group and ethyl group, More specifically, R １ａ teeth, 【Transformation 70】 Selected from, and / or, L ２’ is -S(O) ２ NR １ｂ -*, -C(O)-NR １ｂ - * or - NR １ｂ -C(O)-*, preferably -S(O) ２ NR １ｂ -*, where the bond indicated by * is R １ａ It is connected to, and / or, Each R ２’ These are independently H, halogen, OH, SH, -NR ２ａ R ２ｂ , CN, C １－４ alkyl group, C １－４ Haloalkyl group, C ２－４ Alkenyl group, C ２－４ Haloalkenyl group, -O-C １－４ Alkyl, -O-C １－４ Haloalkyl, -S-C １－４ Alkyl, -C １－４ Alkylene-OC １－４ Alkyl, -OC １－４ Alkylene-OC １－４ Alkyl, -C １－４ Alkylene-OH, -C １－４ Alkylene-SH, -C １－４ Alkylene-CN,-C １－４ Alkylene-NR ２ａ R ２ｂ Selected from the group consisting of, preferably H, and / or, R １ｂ , R １ｅ , R １ｆ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , R ５ｂ , R ６ａ , R ６ｂ Each time it appears, H and C １－４ A compound according to any one of claims 1 to 2 and 10 to 16, which is independently selected from alkyl groups, preferably H, a methyl group, and an ethyl group. 【Request Item 18】 【Chemistry 71】 The part is, 【Transformation 72】 A compound according to any one of claims 1 to 2 and 10 to 17, selected from the group consisting of the above.

19. Each CyL1 and CyL2 group is independently selected from 4- to 11-membered heterocycloalkylene groups each time it appears, preferably a 4- to 7-membered monocyclic heterocycloalkylene group, a 6- to 10-membered condensed bicyclic heterocycloalkylene group, a 6- to 9-membered bridged heterocycloalkylene group, and a 5- to 12-membered spiroheterocycloalkylene group, more preferably a 4- to 6-membered monocyclic heterocycloalkylene group, an 8- to 10-membered condensed bicyclic heterocycloalkylene group, a 6- to 8-membered bridged heterocycloalkylene group, and a 7- to 11-membered spiroheterocycloalkylene group, where any one of the above heterocycloalkylene groups preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. and / or, Each time the CyL3 group appears, C ４－１１ A cycloalkylene group and a 4- to 11-membered heterocycloalkylene group are independently selected, preferably C ４－６ Monocyclic cycloalkylene group, C ６－１０ Condensed bicyclic cycloalkylene group, C ６－９ Crosslinked cycloalkylene group, C ５－１２ The group is a spirocycloalkylene group, a 4-7 member monocyclic heterocycloalkylene group, a 6-10 member condensed bicyclic heterocycloalkylene group, a 6-9 member bridged heterocycloalkylene group, and a 5-12 member spiroheterocycloalkylene group, more preferably C ５－６ Monocyclic cycloalkylene group, C ８－１０ Condensed bicyclic cycloalkylene group, C ６－８ Crosslinked cycloalkylene group, C ７－１１ The group is a spirocycloalkylene group, a 4-6 member monocyclic heterocycloalkylene group, an 8-10 member condensed bicyclic heterocycloalkylene group, a 6-8 member bridged heterocycloalkylene group, and a 7-11 member spiroheterocycloalkylene group, more preferably C ５－６ Monocyclic cycloalkylene group, C ９－１１ A spirocycloalkylene group, where any one of the above heterocycloalkylene groups preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S. and / or, Each time the CyL4 group appears, it is independently selected from 5- to 10-membered heteroarylene groups, preferably a 5- to 6-membered heteroarylene group, and more preferably a 5- to 6-membered nitrogen-containing heteroarylene group. and / or, Each time La appears, C １－４ Alkylene group, C ２－４ Alkenylene group, C ２－４ Independently selected from the group consisting of alkynylene groups, preferably -CH ２ -, - (CH ２ ) ２ -, - (CH ２ ) ３ -, - (CH ２ ) ４ -, -CH=CH-, -CH ２ -CH=CH-, -CH=CH-CH ２ -, -C≡C-, -CH ２ -C≡C-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ -ien-CH ２ CH ２ -C≡C- and -CH ２ -C≡C-CH ２ - and more preferably -CH ２ -, - (CH ２ ) ２ -, - (CH ２ ) ３ -, -C≡C-, -CH ２ -C≡C-, -C≡C-CH ２ -, -C≡C-CH ２ CH ２ - and -CH ２ CH ２ -C ≡ C-, and / or, Each time Lb appears, it is a linear chain of -O-C １－３ Alkylene, -linear carbon １－３ Alkylene-O-,-O-C ２－３ Alkenylene, -C ２－３ Alkenylene-O-,-O-C ２－３ Alkynylene, -C ２－３ Alkynylene-O-,-NR ８’ - Linear C １－３ Alkylene-,-linear C １－３ Alkylene-NR ８’ -, - Linear C １－２ Alkylene-NR ８’ - Linear C １－２ Alkylene-,-linear C １－２ Alkylene-C(O)-NR ８’ -, -NR ８’ -C(O)- Linear C １－２ Alkylene-,-C(O)- linear chain C １－３ Alkylene-,-linear C １－３ Alkylene-C(O)-, -linear C １－２ Alkylene-NR ８’ -C(O)-, -C(O)-NR ８’ - Linear C １－２ Independently selected from the group consisting of alkylenes, preferably -O-C ２－３ Alkynylene, -NR ８’ - Linear C １－３ Alkylene-,-linear C １－３ Alkylene-NR ８’ -, - Linear C １－２ Alkylene-NR ８’ - Linear C １－２ Alkylene-,-linear C １－２ Alkylene-C(O)-NR ８’ -, -C(O)- Linear C １－３ It is alkylene-, and here, R ８’ Each time it appears, H and C １－４ Selected independently of alkyl groups, and / or, Each time Lc appears, it is bound to a linear C chain. １－３ Independently selected from alkylene groups, preferably a bond, a methylene group, or an ethylene group, more preferably a bond or a methylene group. and / or, R Ｌ１ , R Ｌ２ and R ８’ Each instance of this group is independently selected from the group consisting of H, a methyl group, and an ethyl group, and more preferably H and a methyl group. and / or L Ｂ The elements are selected from the following groups (1) to (21): （１） 【Transformation 73】 （２） 【Chemistry 74】 （３） 【Chemistry 75】 （４） 【Transformation 76】 （５） 【Chemical 77】 （６） 【Transformation 78】 （７） 【Chemistry 79】 （８） 【Chemistry 80】 （９） 【Chemistry 81】 （１０） 【Chemistry 82】 （１１） 【Chemistry 83】 （１２） 【Chemical 84】 （１３） 【Chemical 85】 （１４） 【Chemical 86】 （１５） 【Transformation 87】 （１６） 【Chemical 88】 （１７） 【Chemical 89】 （１８） [Chemical 90] （１９） 【Chemistry 91】 （２０） 【Chemistry 92】 （２１） 【Chemistry 93】 Here, preferably, in any one of the groups (1) to (21) above, the bond indicated by "u" is connected to the LA, and the bond indicated by "v" is 【Chemical 94】 A compound according to any one of claims 1 to 18, which is linked to a portion.

20. The aforementioned 【Chemical 95】 The part is an E3 ubiquitin ligase ligand, Preferably, the above 【Chemistry 96】 The part is, 【Chemistry 97】 Selected from the group consisting of, Here, Ring Aa 【Chem.98】 is a five-membered heterocyclyl group or a five-membered heteroaryl group, preferably a five-membered heterocyclyl group or a five-membered heteroaryl group having 1, 2 or more N heteroatoms, where the five-membered heterocyclyl group and the five-membered heteroaryl group can optionally be H, halogen, OH, NH ２ CN, oxo group, C １－４ Substituted with one or more substituents independently selected from the group consisting of alkyl groups, Preferably, 【Chem.99】 The part is, 【Chemistry 100】 A group consisting of is selected, where the bond denoted by "z" is X ５ It is connected to, each ring 【Chemistry 101】 These are independently a phenyl group or a 5-6 membered heteroaryl group, preferably a phenyl group. X ５ CR Ｌ７ or N, where t is 0 or 1, preferably 1. R Ｌ１ , R Ｌ５ and R Ｌ６ Each time they appear, H and C １－４ Independently selected from alkyl groups, preferably H and a methyl group, R Ｌ２ and R Ｌ３ Each time they appear, H and C １－４ Independently selected from alkyl groups, preferably H and a methyl group, or R Ｌ２ and R Ｌ３ They combine to form an oxo group, R Ｌ４ and R Ｌ７ Each time they appear, H, halogen, OH, NH ２ , CN, C １－４ A group independently selected from the group consisting of alkyl groups, preferably H, F, Cl, Br, and C １－２ It is an alkyl group, more preferably H, F, Cl and a methyl group. m5 is 0, 1, 2, 3 or 4, preferably 1 or 2. Preferably, the above 【Chemical Engineering 102】 The part is, 【Chemistry 103】 A compound according to any one of claims 1 to 19, selected from the group consisting of the following. 【Request Item 21】 【Chemistry 104】 The part is, 【Chemistry 105】 A compound according to any one of claims 1 to 20, selected from the group consisting of the following.

22. The compound is selected from the compounds listed in Table 1 of the specification, and is a compound according to any one of claims 1 to 21.

23. The compound has the structure shown in formula (B), 【Chemistry 106】 Here, L Ｂ The following can be selected: (1) -CyL1-, where the CyL1 group is selected from 7- to 11-membered spiroheterocycloalkylene groups, more preferably a 9- to 11-membered spiroheterocycloalkylene group, where the 7- to 11-membered spiroheterocycloalkylene group and the 9- to 11-membered spiroheterocycloalkylene group each have one or two, preferably two, nitrogen heteroatoms, and optionally C １－４ Substituted with one or more groups independently selected from alkyl groups and halogens, preferably a methyl group, F and Cl, more preferably a methyl group and F, or (2) -CyL1-CyL2-, where CyL1 and CyL2 groups are independently selected from 4- to 7-membered monocyclic heterocycloalkylene groups, more preferably 4- to 6-membered monocyclic heterocycloalkylene groups, where the 4- to 7-membered monocyclic heterocycloalkylene group and the 4- to 6-membered monocyclic heterocycloalkylene group each have one or two nitrogen heteroatoms, and optionally C １－４ Substituted with one or more groups independently selected from alkyl groups and halogens, preferably a methyl group, F and Cl, more preferably a methyl group and F. R ４ These are 4-6 member saturated monocyclic heterocycloalkyl groups and -NR Ｎａ R Ｎｂ Selected from, here, R Ｎａ H and C １－６ Selected from alkyl groups, and R Ｎｂ C ３－６ Selected from cycloalkyl groups, wherein the 4-6 member saturated monocyclic heterocycloalkyl group and the C ３－６ The cycloalkyl group is substituted with one to three substituents selected from halogens and hydroxyl groups, R ５ The compound according to claim 1, wherein is hydrogen.

24. L Ｂ teeth, 【Chemistry 107】 Selected from the group consisting of, more preferably, 【Chemistry 108】 And here, in any one of the above groups, the bond indicated by "u" is, 【Chemistry 109】 A connection that is linked to a part and is indicated by "v" is 【Chemical 110】 Connected to the section, and / or, R ４ This consists of a 4-6 member saturated monocyclic nitrogen-containing heterocycloalkyl group (preferably a piperidinyl group) and -NR Ｎａ R Ｎｂ Selected from, here, R Ｎａ is H and R Ｎｂ C ３－６ Selected from cycloalkyl groups (preferably cyclohexyl groups), wherein the 4-6 member saturated monocyclic nitrogen-containing heterocycloalkyl group and the C ３－６ The cycloalkyl group is substituted with one hydroxyl group. Preferably, R ４ teeth, 【Chemistry 111】 Selected from, more preferably, 【Chemistry 112】 The compound according to claim 23.

25. The aforementioned compound, 【Chemistry 113】 A compound according to claim 23 or 24, selected from the group consisting of the following.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuteride), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

27. Uses of a compound according to any one of claims 1 to 25, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystalline forms, hydrates, solvates, or pharmaceutically acceptable salts, or a pharmaceutical composition according to claim 26, in the manufacture of a drug for treating diseases, disorders, or conditions related to IRAK4 protein kinase.

28. A method for treating a disease, disorder or condition related to IRAK4 protein kinase, the method comprising administering to an individual in need a therapeutically effective amount of a compound according to any one of claims 1 to 25 or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 26.

29. The diseases, disorders, or conditions related to IRAK4 protein kinase are selected from the group consisting of autoimmune diseases, inflammatory diseases, cancer, graft rejection, thromboembolism, atherosclerosis, myocardial infarction, and metabolic syndrome. Preferably, the inflammatory disease 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 allergy, and preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, and chronic nephritis, and / or, Preferably, the autoimmune disease 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, and preferably psoriasis, and / or Preferably, the graft rejection reaction is selected from graft-versus-host disease and allograft rejection, and / or Preferably, the cancers include brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumors, breast cancer, bladder cancer, colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, head and neck tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermal carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminomas, melanoma, acute myeloid leukemia, chronic myeloid leukemia, and diffuse large B cell carcinoma. The use described in claim 27, or the method described in claim 28, selected from the group consisting of lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

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