Protein degradation targeting chimera compound for degrading IRAK4 and application of protein degradation targeting chimera compound

Abstract

The present application relates to an IRAK4-degrading protein degradation targeting chimera compound of formula (A) and a preparation method thereof, a pharmaceutical composition comprising the compound, and use of the pharmaceutical composition in treatment of diseases, disorders or conditions associated with IRAK4 protein kinase.

Description

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

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311018650.4 filed on August 11, 2023, Chinese patent application CN202311038908.7 filed on August 16, 2023, Chinese patent application CN202311618951.0 filed on November 29, 2023, and Chinese patent application CN202410120222.0 filed on January 26, 2024, and incorporates their contents as a whole into this application by reference and for all purposes. Technical Field

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

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

[0005] Research has confirmed that IRAK4 is highly expressed in various tumor cells and inflammatory models. The development of inhibitors targeting IRAK4 is becoming an increasingly important area of ​​research for the treatment of autoimmune diseases and tumors. IRAK4 possesses both kinase and scaffold activities, both of which play a crucial role in regulating downstream signaling. Conventional small-molecule IRAK4 kinase inhibitors, which inhibit kinase activity alone, are ineffective in achieving optimal therapeutic effects and pose potential risks, such as target protein mutations and drug resistance.

[0006] The ubiquitin-proteasome pathway (UPP) is a key pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP plays a central role in multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0007] Protein degradation targeting chimera (PROTAC) technology is a new technology that has emerged in recent years. Since its advent in 2001, this technology has attracted much attention. At present, many drug developments based on this technology have entered the clinical research stage, and some have entered clinical phase 2. PROTAC, as a heterogeneous bifunctional molecule, consists of three parts: a small molecule inhibitor that can recognize the target protein at one end, a linker, and a ligand that can recognize the E3 ubiquitin ligase at the other end. This bifunctional molecule recognizes the target protein in the body and brings the target protein and the E3 ubiquitin ligase together to form a ternary complex. The target protein is then ubiquitinated and marked, thereby initiating a degradation pathway that depends on the ubiquitin-proteasome. Compared with traditional small molecule inhibitors, PROTAC technology achieves simultaneous inhibition of the two functions of IRAK4 by degrading the IRAK4 protein, which can effectively solve the problems of insufficient activity of small molecule inhibitors or target protein mutations.

[0008] It is necessary to develop novel PROTAC compounds that degrade IRAK4 for the treatment of diseases, disorders or conditions associated with IRAK4 protein kinase.

[0009] Summary of the Invention

[0010] The present invention provides PROTAC compounds targeting IRAK4, which are used to recruit IRAK4 kinase to E3 ubiquitin ligase for degradation. In other words, the bifunctional PROTAC compounds of the present invention have the utility of a regulator of targeted ubiquitination of IRAK4 kinase, which is degraded and / or otherwise inhibited by the bifunctional compounds as described herein. The inventors of the present application have shown that the compounds of the present invention can effectively degrade IRAK4 kinase. The compounds of the present invention can be used to treat diseases, disorders or conditions associated with IRAK4 protein kinase. In addition, the compounds of the present invention have better physicochemical properties (such as solubility, physical and / or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiotoxicity) and / or less side effects), less prone to drug resistance and other more excellent properties.

[0011] In one aspect, the present invention provides a compound of formula (A) as defined below:

[0012] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides a method for targeted degradation of IRAK4 protein kinase, comprising contacting the IRAK4 protein kinase with a compound of formula (A) of the present invention in the presence of an E3 ubiquitin ligase.

[0014] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (A) of the present invention or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

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

[0016] In another aspect, the present invention provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) of the present invention, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0017] In another aspect, the present invention provides a process for preparing a compound of formula (A) of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG1 shows the effects of Yangshen in Experimental Example 3 and Example 146 of the present application on the level of IRAK4 protein degradation in the spleen of Balb / c mice;

[0019] FIG2 is a data graph showing the inhibition of LPS-induced hPBMC secretion of multiple cytokines by Yang Shen in Experimental Example 6 and Example 146 of the present application. DETAILED DESCRIPTION

[0020] definition

[0021] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0022] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of and "consisting of").

[0023] As used herein, the term "hydrocarbyl" means a straight or branched saturated or unsaturated aliphatic hydrocarbon group. Hydrocarbyl groups include alkyl, alkenyl, and alkynyl groups. In some embodiments, the hydrocarbyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Hydrocarbon" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2-6 Hydrocarbon", "C 2-5 Hydrocarbon" and "C 1-4 As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from the "hydrocarbon group" as defined above.

[0024] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0025] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group of 1 to 6 carbon atoms, including "C 2-6 Alkyl", "C 2-5 Alkyl" and "C 1-4 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term "C 1-4The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0026] As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from an "alkyl" as defined above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 1-6 Alkylene", "C 2-6 Alkylene", "C 2-5 Alkylene" and "C 1-4 Alkylene". "C 1-6 Examples of "alkylene" include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene and n-hexylene. The term "C 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0027] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above.

[0028] As used herein, the term "heteroalkyl" refers to an alkyl group as defined above wherein one or more, but not all, C atoms in the alkyl chain are replaced by heteroatoms or radicals selected from NR', O, C(O), S, S(O), and S(O), wherein R' is a suitable substituent, such as H, alkyl, or the like. The heteroalkyl group may be attached to the remainder of the molecule via a C atom or such heteroatom or radical. Preferably, the heteroalkyl group is attached to the remainder of the molecule via a C atom.

[0029] As used herein, the term "alkenyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 Alkenyl", such as "C 2-4 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, etc.

[0030] As used herein, the term "alkynyl" means a linear or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C 2-6 Alkynyl", such as "C 2-4 The alkynyl group is, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl and 2-methyl-3-pentynyl. The term "alkynylene" is the corresponding divalent group, including, for example, "C 2-6 Alkynylidene", "C 2-4 Specific examples include, but are not limited to, -C≡C-, -CH2C≡C-, -C≡C-CH2-, -CH2-C≡C-CH2-, pentynylene, hexynylene, and the like.

[0031] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0032] As used herein, the term "bridge" or "bridged" means that two or more ring structures share two non-adjacent atoms with each other.

[0033] As used herein, the term "spiro" or "spiro-connected" means that two or more ring structures share 1 atom with each other.

[0034] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to a saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-12 (suitably having 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. It includes, but is not limited to, cyclopropyl (ring), cyclobutyl (ring), cyclopentyl (ring), cyclohexyl (ring), cycloheptyl (ring), cyclooctyl (ring), cyclononyl (ring), cyclobutenyl (ring), cyclopentenyl (ring), cyclohexenyl (ring), cycloheptenyl (ring), cyclooctenyl (ring), cyclononenyl (ring), etc. In some embodiments, the cycloalkyl group includes an aromatic-fused cycloalkyl group, as long as the entire ring system is non-aromatic.

[0035] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). The cycloalkyl group has 3-15 carbon atoms, suitably 3-12, 3-10, 3-8, 3-7, 3-6, 4-6 or 5-6 carbon atoms. For example, the term "C 3-6 Cycloalkyl" and "C 3-6 "Cycloalkylene" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl).

[0036] The terms "spirocycloalkyl" and "spirocycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share one carbon atom. For example, "C 7-12 Spirocycloalkyl" and "C 7-12 "Spirocycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 5-12 or 7-11) carbon atoms and formed by at least two rings sharing one atom.

[0037] The terms "fused cycloalkyl" and "fused cycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share two adjacent carbon atoms. For example, "C 4-10 Fused cycloalkyl" and "C 4-10 "Fused cycloalkylene" refers to a fused ring containing from 4 to 10 (e.g., 6-10 or 8-10) ring carbon atoms and formed from two or more rings which share two adjacent carbon atoms.

[0038] The terms "bridged cycloalkyl" and "bridged cycloalkylene" refer to polycyclic (such as bicyclic) "cycloalkyl" and "cycloalkylene" as defined above, wherein any two linked rings share two non-adjacent carbon atoms. For example, "C 7-10 Bridged cycloalkyl" and "C 7-10 "Cycloalkylene" refers to a cyclic structure containing 7 to 12 (e.g., 6-10, 6-9, or 6-8) carbon atoms and formed by two rings that share two non-adjacent atoms.

[0039] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds within the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6.

[0040] As used herein, the terms "heterocyclyl," "heterocycle," and "heterocyclylene" refer to saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monocyclic or polycyclic (e.g., bicyclic) ring structures having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and 1 or more (e.g., 1, 2, 3, or 4) heteroatom-containing groups selected from O, S, S(═O), S(═O) 2, and NR', wherein R' is as defined above. The heterocycle may be attached to the remainder of the molecule through any of the carbon atoms or, if present, the nitrogen atom. In particular, a 3-12 membered heterocycle is a group having 3-12 (e.g., 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11, or 8-12) carbon atoms and heteroatoms in the ring. Examples that may be mentioned include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

[0041] As used herein, the heterocycles described above include nitrogen-containing heterocycles, oxygen-containing heterocycles, and sulfur-containing heterocycles. For example, a "nitrogen-containing heterocycle" has at least one nitrogen atom, which may also optionally have one or more (e.g., one, two, three, or four) ring members selected from N, O, C=O, S, S=O, and S(=O). The nitrogen-containing heterocycle may be attached to the rest of the molecule via the nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 12-membered nitrogen-containing heterocycle is a group having 3-12 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0042] As used herein, the heterocycles described above include monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., monocyclic heterocycles, bridged heterocycles, spiro heterocycles, and fused heterocycles. The point of attachment of the bridged heterocycles, spiro heterocycles, and fused heterocycles to other groups can be on any ring in the structure.

[0043] As used herein, fused heterocycle refers to a polycyclic (such as bicyclic) heterocycle as defined above, wherein any two connected rings share two adjacent atoms. Fused heterocycles include, but are not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example, 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (Mono)cycloalkyl. Preferably, the fused heterocycle is 6 to 10-membered, and more preferably 8-10-membered. Examples of fused heterocycles include, but are not limited to, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl, In some embodiments, fused heterocyclyls also include heteroaryl-fused heterocyclyls or cycloalkyls, and aryl-fused heterocyclyls, as long as the entire ring system is non-aromatic. In some embodiments, fused heterocyclyls include 5-6 membered monocyclic heteroaryl-fused C 5-6 Monocyclic cycloalkyl, 5-6 membered monocyclic heteroaryl-fused 5-6 membered monocyclic heterocyclyl, and phenyl-fused 5-6 membered monocyclic heterocyclyl, such as pyrrolotetrahydropyridinyl, pyrazolotetrahydropyridinyl and imidazotetrahydropyridinyl.

[0044] As used herein, spiro heterocycle refers to polycyclic (such as bicyclic) heterocycle defined above, wherein any two connected rings share a carbon atom.Preferably, spiro heterocycle is 5-12 yuan, and more preferably 7-11 yuan.According to the number of shared spiral atoms, spiro heterocycle is divided into single spiral heterocycle, two spiral heterocycles or many spiral heterocycles, and preferably refers to single spiral heterocycle or two spiral heterocycles, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocycles.

[0045] As used herein, bridged heterocycle or bridged heterocycle refers to a polycyclic (such as bicyclic) heterocycle as defined above, wherein any two connected rings share two non-adjacent atoms. One or more rings of the bridged heterocycle may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocycle is 6 to 9 members, and more preferably 6-8 members. Depending on the number of member rings, bridged heterocycles are divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycles, and preferably refer to bicyclic, tricyclic or tetracyclic bridged heterocycles, and more preferably bicyclic or tricyclic bridged heterocycles.

[0046] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

[0047] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and 1, 2, 3, 4, or 5 identical or different heteroatoms independently selected from N, O, S, and S(O)2. One or more of the ring carbon atoms in the heteroaryl group may be replaced by C(O). The heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridonyl, pyrimidinyl, pyrimidonyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolinyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, triazolopyridinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

[0048] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0049] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0050] As used herein, the term "haloalkenyl" refers to an alkenyl group substituted with one or more (such as 1 to 3) the same or different halogen atoms, as defined herein. 2-8 Halogenated alkenyl, "C 2-6 Halogenated alkenyl" and "C 2-4 The term "haloalkenyl" refers to haloalkenyl groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, and 2 to 4 carbon atoms, respectively.

[0051] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0052] If a group is described as "optionally substituted with" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0053] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0054] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0055] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0056] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such substituent may be bonded to any atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown as carrying a substitutable hydrogen atom, such substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is to the available ring member.

[0057] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13N) can be substituted in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6. In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0058] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0059] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0060] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0061] The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0062] The compounds of the present invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0063] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely about double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0064] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0065] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0066] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0067] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0068] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0069] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0070] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0071] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0072] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0073] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0074] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0075] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0076] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0077] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0078] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0079] Compound

[0080] In one aspect, the present invention provides compounds of formula (A):

[0081] or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0082] in:

[0083] described Some are IRAK4 ligands that can bind to IRAK4;

[0084] described The part is the ligase binding part,

[0085] –L A –L B – is to Part and Partially connected to the divalent part.

[0086] In some embodiments, the present invention provides a compound of formula (A), wherein:

[0087] L A Selected from bonds and straight or branched C 1-4 Alkylene, the C 1-4 The alkylene group is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2 is substituted with a substituent;

[0088] L B A group selected from the following groups (1) to (21):

[0089] (1)–CyL1–,

[0090] (2)–CyL1–La–,

[0091] (3)–CyL1–Lb–,

[0092] (4)–CyL1–La–CyL2–La–,

[0093] (5)–CyL1–NR L1 –,

[0094] (6)–CyL1–C(O)–,

[0095] (7)–CyL1–C(O)-NR L1 –,

[0096] (8)–CyL1–NRL1 -C(O)–,

[0097] (9)–CyL1–CyL2–,

[0098] (10)–NR L1 -CyL1-La–,

[0099] (11)–NR L1 -CyL1-Lb–,

[0100] (12)–NR L1 -CyL3-NR L2 –,

[0101] (13)–NR L1 -CyL3-La-NR L2 –,

[0102] (14)–NR L1 -CyL1-C(O)–,

[0103] (15)–NR L1 -La-CyL1-La–,

[0104] (16)–La–CyL1–,

[0105] (17)–O-La–,

[0106] (18)–S-La–,

[0107] (19)–NR L1 -La–,

[0108] (20)–CyL1–La–CyL3-, and

[0109] (21)–CyL1–Lc–CyL4-;

[0110] in:

[0111] In the groups (1) to (21), the leftmost extending bond of each group is connected to the L A and the rightmost key is connected to the part, or the leftmost bond of each group is connected to the part and the rightmost key is connected to the L A ,

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

[0113] CyL3 is independently selected at each occurrence from C 3-12 Cycloalkylene, 3-12 membered heterocycloalkylene,

[0114] CyL4 is independently selected at each occurrence from a 5-12 membered heteroarylene group,

[0115] La is independently selected at each occurrence from C 1-4 alkylene,

[0116] Lb is independently selected at each occurrence from a linear C 2-4 Hydrocarbylene, wherein the straight chain C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O),

[0117] Lc is independently selected at each occurrence from a bond or C 1-4 alkylene,

[0118] CyL1, CyL2, CyL3, CyL4, La, Lb, and Lc are each optionally substituted by one or more groups independently selected from the following: 1-4 Alkyl, C 1-4 Haloalkyl, halogen, OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2, preferably methyl, ethyl, F, Cl, Br, OH, CN and NH 2, more preferably methyl, F, Cl and OH; and

[0119] R L1 and R L2 Each is independently selected at each occurrence from H and C 1-4 alkyl;

[0120] described Some have:

[0121] (I) Structure of formula (1):

[0122] in:

[0123] Ring A is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by R k replaced by;

[0124] R k Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, R p R q N-、C 1-6 Halogenated alkyl, C1-6 Heteroalkyl (e.g. C 1-6 alkoxy), 4-9 membered heterocyclic group (e.g. 5-6 membered saturated heterocyclic alkyl), C 6-10 Aryl, 5-10 membered heteroaryl;

[0125] R p 、R q are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl halide;

[0126] Ring B Selected from the following groups (1)-(3):

[0127] (1) in:

[0128] R 4 Selected from hydrogen, C 1-6 Alkyl, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from halogen, hydroxy, C 3-6 Cycloalkyl, C 3-6 substituted with a halogenated cycloalkyl or a 4-7 membered heterocyclic group), wherein the C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-optionally substituted by 1-3 groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, halogen, hydroxy, hydroxy-C 1-6 Alkylene-, cyano, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0129] R 5Selected from hydrogen, cyano, C 1-6 Alkyl, -C(O)NH2, -NR l R m ;

[0130] R l 、R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0131] (2) in:

[0132] R 22 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 alkyl-;

[0133] R 23 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2, -NR l R m 、 and R l 、R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0134] (3) in:

[0135] R 25 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-; R 26 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2;

[0136] L 1 Selected from direct bond, C 1-6 Alkyl, -NH-, -O-, -S-;

[0137] R 13 Selected from C 1-6 Alkyl, C 1-6 alkyl halide;

[0138] R 14 Selected from C 3-6Cycloalkylene, 5-12 membered spiro heterocycloalkylene and piperidinylene, the C 3-6 Cycloalkylene, 5-12 membered spiroheterocycloalkylene and piperidinylene are optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Alkyl (such as hydroxymethyl), formyl, C 1-6 substituted by an alkyl substituent;

[0139] or

[0140] (II) Structure of formula (2)

[0141] in:

[0142] Ring A' is selected from 5-10 membered heteroaryl;

[0143] X 1 、X 2 、X 3 and X 4 are each independently N or CH; and X 1 、X 2 、X 3 and X 4 At least one of them is not N;

[0144] Z is CR 4’ ;

[0145] The characters "a" and "b" each indicate a bond between a ring carbon atom to which Z is attached and two adjacent ring carbon atoms;

[0146] The moiety is represented by the structure of the following formula (i) or formula (ii):

[0147] L 1’ Selected from direct bond and NR 7’ ; R 1’ -L 2’ -R 1a ;

[0148] L 2’ -S(O)2NR 1b -*、-C(O)-NR 1b -*, -NR 1b -C(O)-*or -NR 1b -S(O)2-*, where the bond indicated by * is connected to R 1a ;

[0149] R 1a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 1e R 1f 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 1e R 1f ;

[0150] Each R 2’ Independently selected from: H, halogen, OH, SH, -NR 2a R 2b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 2a R 2b ;

[0151] m2 is 0, 1, 2, or 3;

[0152] R 3’ and R 7’ Each independently selected from: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C1-6 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 3a R 3b ;

[0153] R 4’ Selected from: H, D, halogen, OH, SH, -NR 4a R 4b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C 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 4a R 4b ;

[0154] R 5’ Selected from C 3-10 Cycloalkylene and 3-10 membered heterocyclylene, wherein the C 3-10 The cycloalkylene and 3-10 membered heterocyclylene are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 5a R 5b ;

[0155] R 6’Selected from: H, halogen, OH, SH, -NR 6a R 6b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 6a R 6b ;

[0156] n2 is 0, 1, 2, 3, or 4; and

[0157] 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 independently selected at each occurrence from H and C 1-6 Alkyl; and

[0158] described The part is the ligase binding part.

[0159] In some embodiments, the compound of formula (A), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof,

[0160] in:

[0161] L A Selected from bonds and straight or branched C 1-4 Alkylene, the C 1-4 The alkylene group is optionally substituted by one or more independently selected from C 1-4 Alkyl, C1-4 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl)2 is substituted with a substituent;

[0162] L B A group selected from the following groups (1) to (19):

[0163] (1)–CyL1–,

[0164] (2)–CyL1–La–,

[0165] (3)–CyL1–Lb–,

[0166] (4)–CyL1–La–CyL2–La–,

[0167] (5)–CyL1–NR L1 –,

[0168] (6)–CyL1–C(O)–,

[0169] (7)–CyL1–C(O)-NR L1 –,

[0170] (8)–CyL1–NR L1 -C(O)–,

[0171] (9)–CyL1–CyL2–,

[0172] (10)–NR L1 -CyL1-La–,

[0173] (11)–NR L1 -CyL1-Lb–,

[0174] (12)–NR L1 -CyL3-NR L2 –,

[0175] (13)–NR L1 -CyL3-La-NR L2 –,

[0176] (14)–NR L1 -CyL1-C(O)–,

[0177] (15)–NR L1 -La-CyL1-La–,

[0178] (16)–La–CyL1–,

[0179] (17)–O-La–,

[0180] (18)–S-La–, and

[0181] (19)–NR L1 -La–,

[0182] in:

[0183] In the groups (1) to (21), the leftmost extending bond of each group is connected to the L A and the rightmost key is connected to the part, or the leftmost bond of each group is connected to the part and the rightmost key is connected to the L A ,

[0184] CyL1 and CyL2 are each independently selected at each occurrence from a 3-12 membered heterocycloalkylene group, wherein the heterocycloalkylene group preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S,

[0185] CyL3 is independently selected at each occurrence from C 3-12 Cycloalkylene,

[0186] CyL4 is independently selected at each occurrence from a 5-12 membered heteroarylene group,

[0187] La is independently selected at each occurrence from C 1-4 alkylene,

[0188] Lb is independently selected at each occurrence from a linear C 2-4 Alkylene, wherein the linear C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O),

[0189] Lc is independently selected at each occurrence from a bond or C 1-4 alkylene,

[0190] CyL1, CyL2, CyL3, CyL4, La, Lb and Lc are each optionally substituted with one or more groups independently selected from the following: 1-4 Alkyl, C 1-4 Haloalkyl, halogen, OH, CN, NH2, -NH(C 1-4 alkyl) and -N(C 1-4 alkyl) 2, preferably methyl, ethyl, F, Cl, Br, OH, CN and NH 2, more preferably methyl, F, Cl and OH; and

[0191] R L1 and RL2 Each is independently selected at each occurrence from H and C 1-4 alkyl;

[0192] described Some have:

[0193] (I) Structure of formula (1):

[0194] in:

[0195] Ring A is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by R k replaced by;

[0196] R k Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, R p R q N-、C 1-6 Halogenated alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 alkoxy), 4-9 membered heterocyclic group (e.g. 5-6 membered saturated heterocyclic alkyl), C 6-10 Aryl, 5-10 membered heteroaryl;

[0197] R p 、R q are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkyl halide;

[0198] Ring B Selected from the following groups (1)-(3):

[0199] (1) in:

[0200] R 4 Selected from hydrogen, C 1-6 Alkyl, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from halogen, hydroxy, C 3-6 Cycloalkyl, C 3-6 substituted with a halogenated cycloalkyl or a 4-7 membered heterocyclic group), wherein the C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-optionally substituted by 1-3 groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, halogen, hydroxy, hydroxy-C 1-6 Alkylene-, cyano, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0201] R 5 Selected from hydrogen, cyano, C 1-6 Alkyl, -C(O)NH2, -NR l R m ;

[0202] R l 、R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0203] (2) in:

[0204] R 22 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 alkyl-;

[0205] R 23 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2, -NR l R m 、 and R l 、R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0206] (3) in:

[0207] R 25 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 Alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-; R 26 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2;

[0208] L 1 Selected from direct bond, C 1-6 Alkyl, -NH-, -O-, -S-;

[0209] R 13 Selected from C 1-6 alkyl halide;

[0210] R 14 Selected from C 3-6 Cycloalkylene, 5-12 membered spiro heterocycloalkylene and piperidinylene, the C 3-6 Cycloalkylene, 5-12 membered spiroheterocycloalkylene and piperidinylene are optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Alkyl (such as hydroxymethyl), formyl, C 1-6 substituted by an alkyl substituent;

[0211] or

[0212] (II) Structure of formula (2)

[0213] in:

[0214] Ring A' is selected from 5-10 membered heteroaryl;

[0215] X 1 、X 2 、X 3 and X 4 are each independently N or CH; and X 1 、X 2 、X 3 and X 4 At least one of them is not N;

[0216] Z is CR 4’ ;

[0217] The characters "a" and "b" each indicate a bond between a ring carbon atom to which Z is attached and two adjacent ring carbon atoms;

[0218] The moiety is represented by the structure of the following formula (i) or formula (ii):

[0219] L 1’ Selected from direct bond and NR 7’ ; R 1’ -L 2’ -R 1a ;

[0220] L 2’ -S(O)2NR 1b -*、-C(O)-NR 1b -*, -NR 1b -C(O)-*or -NR 1b -S(O)2-*, where the bond indicated by * is connected to R 1a ;

[0221] R 1a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 1e R 1f 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 1e R 1f ;

[0222] Each R 2’ Independently selected from: H, halogen, OH, SH, -NR 2a R 2b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6Halogenated alkyl, -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 Alkylene-NR 2a R 2b ;

[0223] m2 is 0, 1, 2, or 3;

[0224] R 3’ and R 7’ Each independently selected from: H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C 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 3a R 3b ;

[0225] R 4’ Selected from: H, D, halogen, OH, SH, -NR 4a R 4b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C 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 4a R 4b ;

[0226] R 5’ Selected from C 3-10 Cycloalkylene and 3-10 membered heterocyclylene, wherein the C 3-10 The cycloalkylene and 3-10 membered heterocyclylene are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR5a R 5b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 5a R 5b ;

[0227] R 6’ Selected from: H, halogen, OH, SH, -NR 6a R 6b 、CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 6a R 6b ;

[0228] n2 is 0, 1, 2, 3, or 4; and

[0229] R 1b 、R 1e 、R 1f 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 4b 、R 5a 、R 5b 、R6a and R 6b independently selected at each occurrence from H and C 1-6 Alkyl; and

[0230] described The part is the ligase binding part.

[0231] Linking group L A

[0232] In some embodiments, the present invention provides compounds of formula (A) according to the present invention, which have L as defined above. A group.

[0233] In some embodiments, L A Selected from bonds and C 1-2 Alkylene, the C 1-2 The alkylene group is optionally substituted by one or more independently selected C 1-2 Alkyl, C 1-2 Haloalkyl, halogen, oxo, OH, CN, NH2, -NH(C 1-2 alkyl) and -N(C 1-2 alkyl)2 is substituted with a substituent.

[0234] In some embodiments, L A Selected from bonds and C 1-2 Alkylene, the C 1-2 Alkylene is optionally selected from C 1-2 Substituents of alkyl, halogen and oxo are substituted.

[0235] In some embodiments, L A is selected from the group consisting of a bond, -CH2-, -CH2-CH2-, -CH(CH3)-, and -C(O)-. In some preferred embodiments, L A It is -CH2- or -CH2-CH2-, more preferably -CH2-.

[0236] IRAK4 ligands

[0237] I) IRAK ligand having the structure of formula (1)

[0238] In some embodiments, the present invention provides a compound of formula (A) according to the present invention, wherein The part has the structure of formula (1).

[0239] 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 replaced.

[0240] In some embodiments, the ring A is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 5-membered heteroaryl group is optionally substituted by R k replaced.

[0241] In some preferred embodiments, the ring A is selected from 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, imidazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0242] More preferably, the ring A is selected from Where #C represents connection Partial connection site, $L 1 Indicates connection L 1 connection site.

[0243] Further preferably, the ring A is selected from Where #C represents connection Partial connection site, $L 1 Indicates connection L 1 connection site.

[0244] In some embodiments, R k Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, R p R q N-、C 1-6 haloalkyl and 4-9 membered saturated heterocycloalkyl (e.g., 5-6 membered saturated heterocycloalkyl).

[0245] Preferably, R k Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, R p R q N-、C 1-6 haloalkyl and morpholinyl.

[0246] In some embodiments, R p 、R q are each independently selected from hydrogen and C 1-6 alkyl.

[0247] In some preferred embodiments, R k Selected from isopropyl, cyclopropyl, dimethylamino, difluoromethyl,

[0248] In some embodiments, L 1 It is selected from a direct bond and -NH-, preferably a direct bond.

[0249] In some embodiments, R 13 Selected from C 1-4 The haloalkyl group is preferably -CHF2 and trifluoromethyl, more preferably -CHF2.

[0250] In some embodiments, the structure of formula (1) is represented by the following formula (1-1) or (1-2):

[0251] In some embodiments, the ring B is selected from the following groups (1) to (3).

[0252] In some embodiments, in group (1) middle,

[0253] R 4 Selected from hydrogen, 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl-C 1-4 Alkyl-, 6-9 membered saturated bridged heterocyclic alkyl-C 1-4 Alkyl-, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from halogen, hydroxy, C 3-6 Cycloalkyl, C 3-6 substituted with a halogenated cycloalkyl or a 4-7 membered heterocyclic group), the 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl-C 1-4 Alkyl-, 6-9 membered saturated bridged heterocyclic alkyl-C 1-4 Alkyl-optionally substituted by 1-3 groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, halogen, hydroxy, hydroxy-C 1-6 Alkylene-, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0254] In some embodiments, R 4 Selected from hydrogen, 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl, -NR Na RNb (where R Na and R Nb Independent H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from hydroxy, C 3-6 The 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, hydroxy-C 1-6 Alkylene-、-NH2、-NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0255] R 4 Selected from hydrogen, described Optionally 1-3 selected from C 1-6 Alkyl, halogen, hydroxy, hydroxy (C 1-6 alkyl)-, cyano, -NH2, -N(C 1-6 alkyl) and -N(C 1-6 Alkyl)(C 1-6 alkyl), m1 is selected from 0, 1, 2 and 3, preferably 0, and n1 is selected from 0, 1, 2 and 3, preferably 0 or 1.

[0256] In some embodiments, R 4 Selected from hydrogen, described Optionally 1-3 selected from C 1-6 Alkyl, halogen, hydroxy, hydroxy (C 1-6 alkyl)-, cyano, -NH2, -N(C 1-6 alkyl) and -N(C 1-6 Alkyl)(C 1-6 alkyl), m1 is selected from 0, 1, 2 and 3, preferably 0, and n1 is selected from 0, 1, 2 and 3, preferably 0 or 1.

[0257] In some embodiments, R 4 Selected from hydrogen, described Optionally 1, 2 or 3 selected from C 1-6 Alkyl, hydroxy, -NH2, hydroxy (C 1-6 alkyl)-substituents.

[0258] In some embodiments, R 4 Selected from hydrogen, (include ), (include ), (include ), (include ), (include ), (include Preferred ), (include Preferred ), (include ).

[0259] In some embodiments, R 4 Selected from hydrogen, (include ), (include ), (include ), (include ), (include ), (,include Preferred ), (including including Preferred ), (include ).

[0260] In some embodiments, R 5 Selected from hydrogen, cyano, -C(O)NH2, -NR l R m .

[0261] In some embodiments, Rl 、R m are each independently selected from hydrogen, C 1-6 alkyl.

[0262] In some embodiments, R 5 Selected from hydrogen and cyano.

[0263] In some embodiments, As a whole, selected (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred )and

[0264] In some preferred embodiments, As a whole, selected (Preferred ), (Preferred ), ( ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred )and In some embodiments, As a whole, selected (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred )and

[0265] In some embodiments, As a whole, selected (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ), (Preferred ).

[0266] In some embodiments, in group (2) middle,

[0267] R 22 Selected from hydrogen and m4 is selected from 0, 1, 2, 3, and n4 is selected from 0, 1, 2, 3.

[0268] Preferably, R 22 Selected from hydrogen and

[0269] More preferably, R 22 Selected from hydrogen.

[0270] In some embodiments, R 23 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2 and -NR l R m .

[0271] Preferably, R 23 Selected from hydrogen, cyano, carboxyl, -C(O)NH2 and -NRl R m .

[0272] More preferably, R 23 Selected from hydrogen, cyano, -C(O)NH2 and -NR l R m .

[0273] More preferably, R 23 Selected from -C(O)NH2.

[0274] In some embodiments, R l 、R m are each independently selected from hydrogen and C 1-6 alkyl.

[0275] In some preferred embodiments, As a whole, selected

[0276] More preferably, As a whole, selected

[0277] More preferably, As a whole,

[0278] In some embodiments, in group (3) middle,

[0279] R 25 Selected from hydrogen, m6 is selected from 0, 1, 2 and 3, and n6 is selected from 0, 1, 2 and 3.

[0280] Preferably, R 25 Selected from hydrogen,

[0281] More preferably, R 25 For hydrogen.

[0282] In some embodiments, R 26 Selected from hydrogen, C 1-6 Alkyl, cyano and -C(O)NH2.

[0283] Preferably, R 26 Selected from hydrogen, C 1-6 Alkyl and -C(O)NH2.

[0284] More preferably, R 26 Selected from -C(O)NH2.

[0285] In some preferred embodiments, As a whole, selected

[0286] In some more preferred embodiments, As a whole,

[0287] In some embodiments, R 14 Selected from C 3-6 Cycloalkylene, the C 3-6 Cycloalkylene is optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Preferably, R 14 Selected from p is selected from 0, 1, 2; R g Selected from hydrogen, hydroxyl C 1-6 Preferably, R g Selected from hydrogen.

[0288] In other embodiments, R 14 is selected from 7-11 membered spiroheterocycloalkylene, wherein the 7-11 membered spiroheterocycloalkylene is optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Alkyl (such as hydroxymethyl), formyl and C 1-3 Preferably, R 14 is selected from 9-11 membered spiroheterocycloalkylene groups having 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0289] In other embodiments, R 14 is selected from piperidinyl, said piperidinyl being optionally substituted with 1-2 C 1-3 Alkyl (preferably methyl) substituted.

[0290] In some preferred embodiments, R 14 Selected from Further more preferably Even more preferred wherein the bond identified by x is connected to the pyrazole ring, and the bond identified by y is connected to the L A .

[0291] In some embodiments, the Some selected from:

[0292] In some preferred embodiments, the Some selected from:

[0293] In some preferred embodiments, the Some selected from:

[0294] II) IRAK4 ligand having the structure of formula (2)

[0295] In some embodiments, the present invention provides a compound of formula (A) according to the present invention, wherein The part has the structure of formula (2).

[0296] In some embodiments, R 3’ Selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 3a R 3b Preferably, R 3’ Selected from H and C 1-4 Alkyl, more preferably H and methyl. Further preferably H.

[0297] In some embodiments, the structure of formula (2) is represented by formula (2-1):

[0298] In some embodiments, n2 is 0 or 1.

[0299] In some embodiments, R 5’ Selected from: C 3-10 Cycloalkylene and 3-10 membered heterocyclylene, wherein the C 3-10 The cycloalkylene and 3-10 membered heterocyclylene are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 5a R 5b .

[0300] Preferably, R 5’ Selected from: C 3-6 Cycloalkylene and 5-10 membered heterocycloalkylene, wherein the C 3-6 The cycloalkylene and 5-10 membered heterocycloalkylene are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 5a R 5b .

[0301] More preferably, R 5’ Selected from: C 3-6 Cycloalkylene and 5-10 membered heterocycloalkylene, wherein the C 3-6 The cycloalkylene and 5-10 membered heterocycloalkylene are each optionally substituted with one or more substituents independently selected from the following groups: 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OC 1-4 Alkyl, -OC 1-4Alkylene-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 .

[0302] In some further more preferred embodiments, R 5’ Selected from:

[0303] Preferred

[0304] More preferred

[0305] wherein the bond designated by "c" is connected to the L A and the bond identified by "d" is connected to the ring A'; or preferably, the bond identified by "c" is connected to the ring A' and the bond identified by "d" is connected to the L A .

[0306] In some embodiments, the ring A' is selected from a 5-10 membered monocyclic or fused bicyclic heteroaryl.

[0307] Preferably, the ring A' is selected from a 5-6 membered monocyclic heteroaryl group and a 9-10 membered fused bicyclic heteroaryl group.

[0308] More preferably, the ring A' is selected from: 5-6 membered monocyclic heteroaryl and benzo 5-6 membered monocyclic heteroaryl, wherein preferably, the ring A' is connected to the L through the 5-6 membered monocyclic heteroaryl ring. 1’ connect.

[0309] More preferably, the ring A' is selected from: 5-membered monocyclic heteroaryl and benzo 5-membered monocyclic heteroaryl, wherein preferably, the ring A' is connected to the L through the 5-membered monocyclic heteroaryl ring. 1 connect.

[0310] In some preferred embodiments, any of the above 5-membered monocyclic heteroaryl groups is selected from furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, and tetrazolyl.

[0311] In some more preferred embodiments, the ring A' is selected from pyrazolyl, benzofuranyl, benzothienyl and indolyl. Preferably, the benzofuranyl is connected to the L through the furan ring. 1 The benzothiophene group is connected to the L through the thiophene ring 1Connected, and the indolyl group is connected to the L through the pyrrole ring 1 connect.

[0312] In some more preferred embodiments, the ring A' is selected from

[0313] In some more preferred embodiments, the Partially selected More preferred

[0314] In some more preferred embodiments, the Partially selected

[0315] In some embodiments, X 1 、X 2 and X 3 Each is CH; or X 1 is N, and X 2 and X 3 Each is CH; or X 2 is N, and X 1 and X 3 Each is CH; or X 3 is N, and X 1 and X 2 Each is CH; or X 1 and X 2 Each is N, and X 3 is CH; or X 1 and X 3 Each is N, and X 2 is CH; or X 2 and X 3 Each is N, and X 1 is CH; or X 1 、X 2 and X 3 Each is N.

[0316] In some preferred embodiments, the structure of formula (2) is represented by formula (2-2)-(2-4):

[0317] More preferably, as shown in formula (2-5)-(2-8):

[0318] In some embodiments, R 4’ Selected from: H, D, halogen, OH, SH, -NR 4a R4b 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 4a R 4b .

[0319] Preferably, R 4’ Selected from H, D, halogen, OH, -NR 4a R 4b 、CN、C 1-4 Alkyl and C 1-4 Halogenated alkyl.

[0320] More preferably, R 4’ Selected from H, D, F, Cl, OH, -NH2, CN, methyl, ethyl, -CHF2 and -CF3.

[0321] More preferably, R 4’ It is selected from H, D, F, Cl, methyl and ethyl, and more preferably H.

[0322] In some embodiments, R 6’ Selected from: H, halogen, OH, SH, -NR 6a R 6b 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 6a R 6b .

[0323] Preferably, R 6’Selected from: H, halogen, OH, SH, -NR 6a R 6b 、CN、C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene-OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN and -C 1-4 Alkylene-NR 6a R 6b .

[0324] More preferably, R 6’ Selected from: H, F, Cl, OH, -NH2, -NHCH3, -N(CH3)2, CN, methyl, ethyl, -CHF2 and -CF3.

[0325] More preferably, R 6’ Selected from: H, -NH2, -NHCH3, -N(CH3)2, methyl, ethyl, -CHF2 and -CF3, further more preferably H, methyl, ethyl and -CHF2.

[0326] In some embodiments, R 7’ Selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 3a R 3b .

[0327] Preferably, R 7’ Selected from H and C 1-4 Alkyl, more preferably H and methyl, further more preferably H.

[0328] In some embodiments, the structure of formula (2) is represented by formula (2-9)-(2-12):

[0329] In some embodiments, R 1a C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 1e R1f 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 1e R 1f ;

[0330] Preferably, R 1a is phenyl, wherein the phenyl group is optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, -NR 1e R 1f 、CN、C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl and -OC 1-4 Halogenated alkyl, preferably F, Cl, OH, -NH2, CN, methyl and ethyl.

[0331] More preferably, R 1a Selected from

[0332] In some embodiments, L 2’ -S(O)2NR 1b -*、-C(O)-NR 1b -* or -NR 1b -C(O)-*, preferably -S(O)2NR 1b -*, where the bond indicated by * is connected to R 1a .

[0333] In some embodiments, each R 2’ Independently selected from: H, halogen, OH, SH, -NR 2a R 2b 、CN、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC1-4 Halogenated alkyl, -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, -C 1-4 Alkylene-NR 2a R 2b . Preferably, each R 2’ is independently H.

[0334] 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 independently selected at each occurrence from H and C 1-4 Alkyl, preferably H, methyl and ethyl.

[0335] In some preferred embodiments, Some selected from:

[0336] Linking group L B

[0337] In some embodiments, the present invention provides compounds of formula (A) according to the present invention, which have L as defined above. B group.

[0338] In some embodiments, the CyL1 and CyL2 groups are each independently selected at each occurrence from 4-11 membered heterocycloalkylene, preferably 4-7 membered monocyclic heterocycloalkylene, 6-10 membered fused bicyclic heterocycloalkylene, 6-9 membered bridged heterocycloalkylene, and 5-12 membered spiro heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, 8-10 membered fused bicyclic heterocycloalkylene, 6-8 membered bridged heterocycloalkylene, and 7-11 membered spiro heterocycloalkylene. In some preferred embodiments, any of the above heterocycloalkylene groups has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0339] In some embodiments, the CyL3 group is independently selected at each occurrence from C 4-11 Cycloalkylene, 4-11 membered heterocycloalkylene, preferably C 4-6 Monocyclic cycloalkylene, C 6-10 Fused bicyclic cycloalkylene, C 6-9 Cycloalkylene, C 5-12 Spirocycloalkylene, 4-7 membered monocyclic heterocycloalkylene, 6-10 membered fused bicyclic heterocycloalkylene, 6-9 membered bridged heterocycloalkylene and 5-12 membered spiro heterocycloalkylene, more preferably C 5-6 Monocyclic cycloalkylene, C 8-10 Fused bicyclic cycloalkylene, C 6-8 Cycloalkylene C 7-11 Spirocycloalkylene, 4-6 membered monocyclic heterocycloalkylene, 8-10 membered fused bicyclic heterocycloalkylene, 6-8 membered bridged heterocycloalkylene and 7-11 membered spiroheterocycloalkylene, any of which preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S.

[0340] In some embodiments, the CyL3 group is independently selected at each occurrence from C 4-11 Cycloalkylene, preferably C 4-6 Monocyclic cycloalkylene, C 6-10 Fused bicyclic cycloalkylene, C 6-9 Cycloalkylene and C 5-12 Spirocycloalkylene, more preferably C 5-6 Monocyclic cycloalkylene, C 8-10 Fused bicyclic cycloalkylene, C 6-8 Cycloalkylene and C 7-11 Spirocycloalkylene.

[0341] In some embodiments, the CyL3 group is independently selected at each occurrence from C 5-6 Monocyclic cycloalkylene, C 9-11 Spirocycloalkylene.

[0342] In some embodiments, the CyL4 group is independently selected at each occurrence from a 5-10 membered heteroarylene group, preferably a 5-6 membered heteroarylene group, more preferably a 5-6 membered nitrogen-containing heteroarylene group;

[0343] In some embodiments, La at each occurrence is independently selected from C 1-4 Alkylene, C 2-4 Alkenylene and C 2-4 Alkynylidene.

[0344] Preferably, La at each occurrence is independently selected from -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-.

[0345] More preferably, La at each occurrence is independently selected from -CH2-, -(CH2)2-, -(CH2)3-, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -C≡C-CH2CH2- and -CH2CH2-C≡C-.

[0346] In some embodiments, Lb is independently selected at each occurrence from -O- linear C 1-3 Alkylene, - straight chain C 1-3 Alkylene-O-, -OC 2-3 Alkenylene, -C 2-3 Alkenylene-O-, -OC 2-3 Alkynylidene, -C 2-3 Alkynylidene-O-, -NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -、-NR 8’ -C(O)-straight chain C 1-2 Alkylene-, -C(O)- straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-C(O)-, -straight chain C 1-2 Alkylene-NR 8’ -C(O)- and -C(O)-NR 8’ -Straight chain C 1-2 Alkylene-.

[0347] In some embodiments, Lb is independently selected at each occurrence from -O- linear C 1-3 Alkylene, - straight chain C 1-3 Alkylene-O-, -OC 2-3 Alkenylene, -C 2-3 Alkenylene-O-, -OC 2-3 Alkynylidene, -C 2-3Alkynylidene-O-, -NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -、-NR 8’ -C(O)-straight chain C 1-2 Alkylene-, -C(O)- straight chain C 1-3 Alkylene- and - straight-chain C 1-3 Alkylene-C(O)-, where R 8’ independently selected at each occurrence from H and C 1-4 alkyl.

[0348] In some embodiments, Lb is independently selected at each occurrence from -OC 2-3 Alkynylidene, -NR 8’ -Straight chain C 1-3 Alkylene-, -straight chain C 1-3 Alkylene-NR 8’ -,-straight chain C 1-2 Alkylene-NR 8’ -Straight chain C 1-2 Alkylene-, -straight chain C 1-2 Alkylene-C(O)-NR 8’ -、-C(O)-straight chain C 1-3 Alkylene-.

[0349] In some embodiments, Lc is independently selected at each occurrence from a bond or a linear C 1-3 Alkylene, preferably a bond, methylene or ethylene, more preferably a bond or methylene;

[0350] In some embodiments, R L1 、R L2 and R 8’ Each at each occurrence is independently selected from H, methyl and ethyl, more preferably H and methyl.

[0351] In some preferred embodiments, L B A group selected from the following groups (1) to (21):

[0352] (1) (Preferred ), (Preferred (Preferred ),

[0353] (2)

[0354] (3) (Preferred ),

[0355] (4)

[0356] (5)

[0357] (6)

[0358] (7)

[0359] (8)

[0360] (9) (Preferred ), (Preferred ), (Preferred ),

[0361] (10)

[0362] (11)

[0363] (12) (Preferred )

[0364] (13)

[0365] (14)

[0366] (15)

[0367] (16)

[0368] (17)

[0369] (18)

[0370] (19)

[0371] (20) Preferred as well as

[0372] (twenty one)

[0373] Preferably, in any of the groups (1) to (21) above, the bond identified by "u" is connected to the LA, and the bond identified by "v" is connected to the part.

[0374] In some preferred embodiments, L B A group selected from the following groups (1) to (21):

[0375] (1) (Preferred ), (Preferred ), (Preferred ),

[0376] (2)

[0377] (3) (Preferred ),

[0378] (4)

[0379] (5)

[0380] (6)

[0381] (7)

[0382] (8)

[0383] (9) (Preferred ), (Preferred ), (Preferred ),

[0384] (10)

[0385] (11)

[0386] (12) (Preferred )

[0387] (13)

[0388] (14)

[0389] (15)

[0390] (16)

[0391] (17)

[0392] (18)

[0393] (19)

[0394] (20) Preferred ( )and as well as

[0395] (twenty one)

[0396] Preferably, in any of the groups (1) to (21) above, the bond identified by "u" is connected to the LA, and the bond identified by "v" is connected to the part.

[0397] In some preferred embodiments, L B A group selected from the following groups (1) to (19):

[0398] (1) (Preferred ), (Preferred ), (Preferred ),

[0399] (2)

[0400] (3) (Preferred ),

[0401] (4)

[0402] (5)

[0403] (6)

[0404] (7)

[0405] (8)

[0406] (9) (Preferred ), (Preferred ), (Preferred ),

[0407] (10)

[0408] (11)

[0409] (12) (Preferred )

[0410] (13)

[0411] (14)

[0412] (15)

[0413] (16)

[0414] (17)

[0415] (18) as well as

[0416] (19)

[0417] Preferably, in any of the groups (1) to (19) above, the bond identified by "u" is connected to the LA, and the bond identified by "v" is connected to the part.

[0418] Ligase binding part

[0419] In some embodiments, the present invention provides a compound of formula (A) according to the present invention, wherein Some are E3 ubiquitin ligase ligands.

[0420] In some preferred embodiments, the Some selected from:

[0421] in:

[0422] Ring Aa is a 5-membered heterocyclic group or a 5-membered heteroaryl group, preferably a 5-membered heterocyclic group or a 5-membered heteroaryl group having 1, 2 or more N heteroatoms, wherein the 5-membered heterocyclic group and the 5-membered heteroaryl group are optionally substituted by one or more independently selected from H, halogen, OH, NH2, CN, oxo and C 1-4 Alkyl substituents are substituted,

[0423] Preferably, Partially selected The bond marked with "z" is connected to X 5 ;

[0424] Each ring are independently phenyl or 5-6 membered heteroaryl, preferably phenyl;

[0425] X 5 CR L7 or N;

[0426] t is 0 or 1, preferably 1;

[0427] R L1 、R L5 and R L6 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl;

[0428] R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together they form an oxo group;

[0429] R L4 and R L7 Each is independently selected at each occurrence from H, halogen, OH, NH2, CN and C 1-4 Alkyl, preferably H, F, Cl, Br and C 1-2 Alkyl, more preferably H, F, Cl and methyl;

[0430] m5 is 0, 1, 2, 3 or 4, preferably 1 or 2.

[0431] In some more preferred embodiments, the Some selected from:

[0432] In some more preferred embodiments, Some selected from:

[0433] In some more preferred embodiments, Some selected from:

[0434] In some preferred embodiments, the present invention provides a compound of formula (A), wherein the compound has a structure shown in formula (B):

[0435] in:

[0436] L B Selected from:

[0437] (1) -CyL1-, wherein the CyL1 group is selected from 7-11 membered spiroheterocycloalkylene, more preferably 9-11 membered spiroheterocycloalkylene, wherein the 7-11 membered spiroheterocycloalkylene and the 9-11 membered spiroheterocycloalkylene each have 1 or 2, preferably 2, nitrogen heteroatoms, and are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; or

[0438] (2) –CyL1–CyL2–, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, wherein the 4-7 membered monocyclic heterocycloalkylene and the 4-6 membered monocyclic heterocycloalkylene each have 1 or 2 nitrogen heteroatoms, and are optionally substituted by one or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F;

[0439] R 4Selected from 4-6 membered saturated monocyclic heterocycloalkyl and -NR Na R Nb , where R Na Selected from H and C 1-6 Alkyl and R Nb Selected from C 3-6 cycloalkyl, and wherein the 4-6 membered saturated monocyclic heterocycloalkyl and the C 3-6 The cycloalkyl group is substituted with 1 to 3 substituents selected from halogen and hydroxy; and R 5 For hydrogen.

[0440] In some embodiments, L B Selected from: (Preferred ), (Preferred ), (Preferred (Preferred ), More preferred wherein in any of the above groups, the bond identified by "u" is connected to part, and the key marked with "v" is connected to part.

[0441] In some preferred embodiments, L B Selected from:

[0442] (Preferred ), (Preferred ), (Preferred ), (Preferred ), More preferred wherein in any of the above groups, the bond identified by "u" is connected to part, and the key marked with "v" is connected to part.

[0443] In some preferred embodiments, R 4 Selected from 4-6 membered saturated monocyclic nitrogen-containing heterocyclic alkyl (preferably piperidinyl) and -NR Na R Nb , where R Na H and R NbSelected from C 3-6 Cycloalkyl (preferably cyclohexyl), wherein the 4-6 membered saturated monocyclic nitrogen-containing heterocycloalkyl and the C 3-6 The cycloalkyl group is substituted with one hydroxy group.

[0444] In some more preferred embodiments, R 4 Selected from More preferred

[0445] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0446] In some embodiments, the present invention provides a compound of formula (A), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following Table 1:

[0447] Table 1:

[0448] In some embodiments, the present invention provides a compound of formula (A), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein the compound is selected from Compound 1 to Compound 282.

[0449] In some preferred embodiments, the compound is selected from:

[0450] Pharmaceutical compositions and uses

[0451] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.

[0452] In another aspect, the present invention provides a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or the use of a pharmaceutical composition of the present invention for the preparation of a medicament.

[0453] In some embodiments, the compound of the invention, the pharmaceutical composition of the invention, or the medicament is used to treat a disease, disorder, or condition associated with IRAK4 protein kinase.

[0454] In another aspect, the present invention also provides a method for treating a disease, disorder or condition associated with IRAK4 protein kinase, alleviating its symptoms, delaying its development or onset, which comprises administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0455] In another aspect, the present invention provides a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention, for use in treating a disease, disorder or condition associated with IRAK4 protein kinase.

[0456] In another aspect, the present invention also provides the use of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention for the preparation of a medicament as an IRAK4 inhibitor.

[0457] In another aspect, the present invention provides a method of inhibiting IRAK4 activity in a subject, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or a pharmaceutical composition of the present invention.

[0458] In another aspect, the present invention provides a method for targeted degradation of IRAK4 protein kinase, comprising contacting the IRAK4 protein kinase with a compound of formula (A) according to the present invention as described above, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof in the presence of an E3 ubiquitin ligase. In some embodiments, the method is performed in vitro or ex vivo. In other embodiments, the method is performed in vivo.

[0459] In some embodiments, the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: an autoimmune disorder, an inflammatory disorder, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction, and metabolic syndrome.

[0460] In some embodiments, the inflammatory disorder is selected from the group consisting of osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fever, atopic dermatitis, hidradenitis suppurativa, chronic nephritis, allergic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma, and allergies, preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, and chronic nephritis.

[0461] In some embodiments, the autoimmune disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis, and systemic juvenile idiopathic arthritis, preferably psoriasis.

[0462] In some embodiments, the transplant rejection is selected from graft-versus-host disease and allograft rejection.

[0463] In some embodiments, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma Myeloma, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

[0464] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0465] As used herein, unless otherwise indicated, the terms "treat," ...

[0466] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0467] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.

[0468] Example

[0469] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all commercially available conventional products.

[0470] NMR was measured using a Bruker Avance III 400 NMR spectrometer, and the chemical shift (δ) was measured at 10 -6 The unit is ppm. The solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0471] MS was measured using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B).

[0472] High-performance liquid chromatography (HPLC) assay conditions: Gilson GX-281, C18 column (10 μM, 19 mm x 250 mm), UV detection at 220 and 254 nm, elution with a gradient of 5–95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate) over 15 min.

[0473] Reverse phase purification was performed using the Biotage Isolera Rapid Purification System.

[0474] Thin layer chromatography separation and purification were performed using thin layer chromatography silica gel plates (aluminum plates (20 cm x 20 cm x 1 mm) produced by Meck, or GF 254 produced in Yantai).

[0475] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0476] Reaction monitoring is usually performed by TLC or LCMS. Common developing solvent systems include: dichloromethane / methanol, n-hexane / ethyl acetate, petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0477] The silica gel used in column chromatography is generally 100-200 mesh. Common eluent systems include dichloromethane / methanol and petroleum ether / ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0478] The reagents and solvents of the present invention were purchased from Aldrich Chemical Company, Anage, J&K Technology, Shanghai Bid Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

[0479] Synthesis Example

[0480] Example 1: 3-(4-((R)-3-((1-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)but-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1)

[0481] 1) Step 1: At room temperature, compound 1c-1 (5.00 g, 32.56 mmol) and acetonitrile (50 mL) were added sequentially 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 added sequentially. The atmosphere was purged with nitrogen three times, and the reaction mixture was 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] + .

[0482] 2) Step 2: Compound 1c-2 (2.00 g, 9.79 mmol) and acetonitrile (25 mL) were added to a 100 mL single-necked flask at room temperature and stirred until dissolved. N-iodosuccinimide (3.30 g, 14.7 mmol) was added, and the atmosphere was purged with nitrogen three times. 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] + .

[0483] 3) Step 3: At room temperature, compound 1c-3 (500 mg, 1.51 mmol) and tetrahydrofuran (10 mL) were added sequentially to a 100 mL single-necked flask and stirred until dissolved. Trimethylethynylsilane (1.07 mL, 7.57 mmol), cuprous iodide (28.8 mg, 0.150 mmol), triethylamine (460 mg, 4.54 mmol), and bistriphenylphosphine palladium dichloride (106.31 mg, 0.15 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction mixture was 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] + .

[0484] 4) Step 4: At room temperature, compound 1c-4 (300 mg, 1.00 mmol) and anhydrous methanol (10 mL) were added sequentially to a 50 mL single-necked flask and stirred until dissolved. Potassium carbonate (276 mg, 2.00 mmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was added with water (10 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a product containing compound 1c, which was directly used for subsequent reactions. MS m / z (ESI): 228.9 [M+H] + .

[0485] 5) Step 5: Compound 1a (3.00 g, 12.2 mmol, prepared by the method disclosed in the intermediate step 6 compound on page 137 of the specification of the patent application "WO2022161414 A1") was dissolved in acetonitrile (35 mL) and isoamyl nitrite (2.10 g, 17.9 mmol, Bid) was added at 0 ° C. After stirring the reaction solution for 30 minutes, azidotrimethylsilane (2.00 g, 17.4 mmol) was added. The reaction solution was stirred at 25 ° C for 18 hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was 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] + .

[0486] 6) Step 6: Compound 1b (2.20 g, 8.11 mmol) was dissolved in ethanol (30 mL) and water (10 mL). Vitamin C sodium (0.33 g, 1.67 mmol, Anaiji), copper sulfate pentahydrate (0.41 g, 1.64 mmol, Anaiji) and compound 1c (1.86 g, 8.15 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 25 ° C for 18 hours. The reaction solution was filtered, the solid was collected and slurried with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 30 mL) to give compound 1d. 1 H NMR (400MHz, DMSO-d6): δ8.76(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).

[0487] 7) Step 7: Compound 1d (3.20 g, 6.41 mmol) was dissolved in dichloromethane (50 mL) and Dess-Martin periodinane (4.10 g, 9.67 mmol) was added. The reaction solution was stirred at 25°C for two hours. The reaction solution was poured into water (80 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was slurried with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 30 mL) to obtain compound 1e. 1 H NMR (400MHz, DMSO-d6): δ9.63(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).

[0488] 8) Step 8: Compound 1f (50.0 mg, 0.12 mmol, prepared by the method disclosed for intermediate AVF on page 1148 of the specification of patent application "CN113423427") was dissolved in a mixed solution of tetrahydrofuran (1 mL) and N,N-dimethylformamide (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 1f (60.6 mg After stirring for 2 hours, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30 x 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 H NMR (400MHz, CDCl3): δ8.61 (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).

[0489] Example 2: 3-(4-(3-((S)-2-((((4-(-3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methyl)amino)methyl)morpholinyl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (2)

[0490] Compound 2a (80.0 mg, 0.190 mmol, prepared using the method disclosed for intermediate SR on page 934 of the specification of patent application "US20190192668 A1") 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. The reaction solution was stirred at 25°C for 10 minutes, and sodium cyanoborohydride (48.4 mg, 0.770 mmol) was added. The reaction solution was stirred for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 2. MS m / z(ESI):897.6[M+1] + .

[0491] Example 3: 3-(4-((((1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)methyl)(methyl)amino)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (3)

[0492] 1) The first step: Compound 3a (100 mg, 0.320 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") was dissolved in acetonitrile (5 mL), and compound 3b (74.0 mg, 0.320 mmol, Bid), potassium carbonate (135 mg, 0.970 mmol) were added. The reaction solution was stirred at 80 ° C. for 2 hours, and water (10 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 3c.

[0493] 2) Step 2: Compound 3c (50 mg, 0.100 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction solution 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 3d. MS m / z (ESI): 400.2 [M+1] + .

[0494] 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-dimethylformamide (1 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (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 phases were washed with saturated brine (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, 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. MS m / z (ESI): 441.6 [M / 2+1] + .

[0495] Example 4: 3-(4-(2-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)amino)-7-azaspiro[3.5]nonan-7-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (4)

[0496] 1) The first step: Compound 3a (160 mg, 0.520 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and 4a (162 mg, 0.680 mmol, Bid) were dissolved in acetonitrile (6 mL) and potassium carbonate (138 mg, 1.04 mmol) was added. The reaction solution was heated to 80 ° C under a nitrogen atmosphere and reacted for 2 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL×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 with an eluent system (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 4b. MS m / z (ESI): 512.2 [M+1] + .

[0497] 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] + .

[0498] 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-dimethylformamide (1 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (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 phases were 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 high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] + .

[0499] Example 5: 3-(4-(4-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (5)

[0500] 1) The first step: Compound 3a (100 mg, 0.320 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and 6a (100 mg, 0.390 mmol, Bid) were dissolved in acetonitrile (5 mL) and potassium carbonate (150 mg, 1.09 mmol) was added. The reaction solution was heated to 80 ° C under a nitrogen atmosphere for 18 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL×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 with an eluent system (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 5b. MS m / z (ESI): 528.7 [M+1] + .

[0501] 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] + .

[0502] 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-dimethylformamide (1 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (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 brine (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, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] + .

[0503] Example 6: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)amino)piperidine-1-carbonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (6)

[0504] Compound 6a (80.0 mg, 0.190 mmol, prepared by the method disclosed in intermediate CA on page 411 of the specification of patent application "WO2022236058 A1") and compound 1e (100 mg, 0.200 mmol) were dissolved in tetrahydrofuran (3 mL) and N, N-dimethylformamide (1 mL), and acetic acid (0.2 mL) and sodium acetate borohydride (120 mg, 0.570 mmol) were added sequentially. The reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL × 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 high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] + .

[0505] Example 7: 3-(4-(3-(1-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)propyl-1-ynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (7)

[0506] Compound 7a (50.0 mg, 0.130 mmol, prepared using the method disclosed for intermediate APT on page 91 of the specification of patent application "WO2021247899 A1") and compound 1e (65.0 mg, 0.130 mmol) were dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (75.0 mg, 0.360 mmol) were added sequentially. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, 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]. + .

[0507] Example 8: 3-(4-(1-(((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexylmethyl)piperidin-4-yl)methyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (8)

[0508] 1) Step 1: Compound 8a (240 mg, 0.670 mmol, prepared using the method disclosed for the intermediate step AVW compound on page 639 of the specification of patent application "WO 2020 / 264499 Al") was dissolved in dichloromethane (10 mL), and triethylamine (0.20 mL, 1.35 mmol), 8b (144 mg, 0.670 mmol, Bid), acetic acid (0.08 mL, 1.35 mmol), and sodium acetate borohydride (428 mg, 2.02 mmol) were added. The reaction solution was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC (GILSON-215, column: Boston-Prime C18, 30×150 mm, 5 μm; mobile phase: water (containing 0.05% ammonium hydroxide) and acetonitrile, gradient: 45% to 65% acetonitrile, flow rate: 35 mL / min) to obtain compound 8c. MS m / z (ESI): 554.3 [M+1] + .

[0509] 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 incubated 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] + .

[0510] 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 reacted at room temperature for 1 hour. Sodium triacetylborohydride (22.4 mg, 110 μmol) was then added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a 20 / 1 dichloromethane / methanol system to yield compound 8. MS m / z (ESI): 935.5 [M+1].

[0511] Example 9: 3-(4-(7-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-7-azaspiro[3.5]nonan-2-ylmethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (9)

[0512] Compound 9a (40.0 mg, 0.100 mmol, prepared using the method disclosed for intermediate BAQ on page 786 of the specification of patent application "WO2020264499") was dissolved in 1,2-dichloroethane (2 mL) and N,N-dimethylformamide (1 mL). Triethylamine (0.1 mL) was added and stirred for 0.5 hours. Compound 1e (59.0 mg, 90.0 μmol) and acetic acid (0.1 mL) were added to the reaction solution and stirred for 0.5 hours. Sodium cyanoboride (19.0 mg, 0.300 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] +. 1 H NMR(400MHz,DMSO-d6)δ11.06(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).

[0513] Example 10: 3-(4-(((7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl(cyclohexyl)methyl)-7-azaspiro[3.5]nonan-2-yl)amino)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (10)

[0514] 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, Bid) and acetic acid (14.4 mg, 0.240 mmol) were added. The reaction solution was stirred at 25°C for 10 minutes, and sodium triacetoxyborohydride (306 mg, 1.45 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction solution was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain compound 10a. MS m / z (ESI): 722.4 [M+1] + .

[0515] 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] + .

[0516] 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 intermediate on page 171 of the specification of the patent application "WO2022140472 A1") and tetraethyl titanate (0.050 mL, 0.26 mmol) were added. The reaction solution 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 solution was poured into water (5 mL), and the aqueous phase was extracted with dichloromethane (5 mL × 3). The combined organic phase was washed with saturated brine (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, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] + .

[0517] Example 11: 3-(4-(1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (11)

[0518] Compound 11a (165 mg, 0.480 mmol, prepared by the method disclosed in Intermediate 199 on page 222 of the specification of patent application "WO2021158634 A1") was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL), and triethylamine (40.7 mg, 0.400 mmol) was added. The reaction solution was stirred at 25 ° C for 10 minutes, and then acetic acid (24.1 mg, 0.400 mmol) and compound 1e (200 mg, 0.400 mmol) were added. After the reaction solution was stirred at 25 ° C under nitrogen protection for 1 hour, sodium acetate borohydride (511 mg, 2.41 mmol) was added. After the reaction solution was stirred at 25 ° C under nitrogen protection for 1 hour, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (8 mL) and dichloromethane (10 mL). After the aqueous phase was separated, it was extracted with dichloromethane (5 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 11. MS m / z (ESI): 824.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.10(s,1H),8.76(d,J=4.0Hz,1H),8.65(s,1H),8.54(s,1H),8.38(s,1H),7.2 0(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).

[0519] Example 12: 3-(4-((6-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (12)

[0520] 1) Step 1: Compound 3a (120 mg, 0.390 mmol, prepared using the method disclosed for intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and compound 12a (92.8 mg, 0.470 mmol, Bid) were dissolved in acetonitrile (8 mL), potassium carbonate (55.0 mg, 0.390 mmol) was added, and the reaction was stirred at 80°C for 1.5 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 12b. MS m / z (ESI): 470.6 [M+1] + .

[0521] 2) Step 2: Compound 12b (120 mg, 0.260 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.8 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 12c. MS m / z (ESI): 370 [M+1] + .

[0522] 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 was greater than 8, and the mixture was stirred at 25°C for 10 minutes. The reaction solution 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 solution was warmed to 25°C and stirred at this temperature for 20 minutes. Then, sodium acetate borohydride (76.7 mg, 0.361 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, 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): δ11.10(s,1H),8.76(d,J=7.9Hz,1H),8.64(s,1H),8.53(d,J=3.9Hz,1H),8.20(s,1H),7.34–7.0 2(m,2H),7.00–6.88(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,10 H),3.63(s,3H),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).

[0523] Example 13: 3-(4-((7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (13)

[0524] 1) Step 1: Compound 3a (100 mg, 0.321 mmol, prepared using the method disclosed for intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and compound 13a (73.5 mg, 0.321 mmol, Bi) were dissolved in acetonitrile (8 mL), and potassium carbonate (112 mg, 0.810 mmol) was added. The reaction solution was stirred at 80°C for 1.5 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 13b. MS m / z (ESI): 498.6 [M+1] + .

[0525] 2) Step 2: Compound 13b (25.0 mg, 51.0 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (0.8 mL) was added. The reaction mixture was incubated at 25°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain compound 13c. MS m / z (ESI): 398 [M+1] + .

[0526] 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 was greater than 8, and the reaction solution was stirred at 25°C for 10 minutes. The reaction solution was cooled to -10°C, and acetic acid (186 mg, 91.0 μmol) and 1e (30.0 mg, 61.0 μmol) were added. The reaction solution was warmed to 25°C and stirred at this temperature for 20 minutes before sodium acetate borohydride (25.7 mg, 0.121 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, 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] + .

[0527] Example 14: 3-(4-(2-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (14)

[0528] 1) The first step: 3a (100 mg, 0.321 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and compound 14a (100 mg, 0.440 mmol, Bid) were dissolved in acetonitrile (2 mL) and potassium carbonate (122 mg, 0.880 mmol) was added. The reaction solution was replaced with nitrogen three times and reacted at 80 ° C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (20 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 14-b. MS m / z (ESI): 498 [M+1] + .

[0529] 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. The reaction mixture was concentrated under reduced pressure to obtain compound 14c. MS m / z (ESI): 398.2 [M+1] + .

[0530] 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-dimethylformamide (1 mL). Triethylamine (0.05 mL) was added, and the reaction mixture was stirred for 0.5 hours. Compound 1a (54.0 mg, 0.110 mmol) and acetic acid (0.1 mL) were then added to the reaction mixture and stirred for 0.5 hours. Sodium acetate borohydride (17.0 mg, 0.270 mmol, Anaiji) was then added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to obtain 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).

[0531] Example 15: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)piperidin-1-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (15)

[0532] 1) The first step: Compound 3a (80.0 mg, 0.260 mmol, prepared by the method disclosed in intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") and compound 15a (67.0 mg, 0.310 mmol, Bid) were dissolved in acetonitrile (5 mL) and potassium carbonate (71.0 mg, 0.520 mmol) was added. The reaction solution was replaced with nitrogen three times and reacted at 80 ° C for 2 hours. The reaction solution was diluted with aqueous ammonium chloride (20 mL), extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 15b. MS m / z (ESI): 486.7 [M+1] + .

[0533] 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. The reaction solution was concentrated under reduced pressure to obtain crude compound 15c. MS m / z (ESI): 368.2 [M+1] + .

[0534] 3) Step 3: Compound 15c (30.0 mg, 80.0 μmol) was dissolved in 1,2-dichloroethane (2 mL) and N,N-dimethylformamide (1 mL). Triethylamine (0.1 mL) was added and stirred for 0.5 h. Compound 1e (47.0 mg, 90.0 μmol) and glacial acetic acid (0.1 mL) were added to the reaction solution and stirred for 0.5 h. Finally, sodium acetate borohydride (15.0 mg, 0.230 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, 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): δ11.13(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).

[0535] Example 16: 3-(4-(3-(2-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-oxopropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (16)

[0536] 1) Step 1: Compound 16a (100 mg, 0.300 mmol, prepared using the method disclosed for Intermediate B-116 on page 171 of the specification of patent application "WO2023019166 A1") and N,N-diisopropylethylamine (0.2 mL, 1.21 mmol) were dissolved in N,N-dimethylformamide (2.5 mL). Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.360 mmol) was added. The reaction mixture was incubated at 25°C for 10 minutes, followed by the addition of compound 16b (88.8 mg, 0.390 mmol). The reaction mixture was stirred for 1 hour, diluted with ethyl acetate (2 mL), and quenched with water (4 mL). The aqueous phase was separated and extracted with ethyl acetate (2 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 10 / 1) to obtain compound 16c. MS m / z (ESI): 540.7 [M+1] + .

[0537] 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 incubated at 25°C for 30 minutes, and then concentrated under reduced pressure to yield compound 16d. MS m / z (ESI): 440.6 [M+1] + .

[0538] 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. The reaction mixture was stirred at 25°C for 10 minutes, and then acetic acid (4.47 mg, 70.0 μmol) and compound 1e (37.0 mg, 70.0 μmol) were added. The reaction mixture was stirred at 25°C under nitrogen for 1 hour, and then sodium acetate borohydride (94.6 mg, 0.780 mmol) was added. The reaction mixture was stirred at 25°C under nitrogen for 1 hour, and then quenched with saturated aqueous sodium bicarbonate (5 mL) and dichloromethane (5 mL). The aqueous phase was separated and extracted with dichloromethane (3 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 16 (23.5 mg). MS m / z (ESI): 921.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(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,3 H),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).

[0539] Example 17: 3-(4-(1-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (17)

[0540] Compound 17a (50.0 mg, 0.140 mmol, prepared using the method disclosed for intermediate YL on page 858 of the specification of patent application "WO 2020113233") and triethylamine (14.0 mg, 0.140 mmol) were dissolved in N,N-dimethylformamide (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 solution was stirred at 25°C for 0.5 hours. Sodium acetate borohydride (87.0 mg, 0.410 mmol) was slowly added, and the reaction solution 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, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 46% to 95%, flow rate: 25 mL / min) to obtain compound 17. MS m / z (ESI): 848.6 [M+1] + . 1 H 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).

[0541] Example 18: 2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-N-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxamide (18)

[0542] 1) Step 1: Compound 18a (171 mg, 0.620 mmol, prepared by the method disclosed in Intermediate 495 on page 172 of the specification of patent application "WO2022068933 A1") 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 solution was stirred at 50°C for 0.5 hours. After the reaction solution was cooled to 25°C, compound 18b (150 mg, 0.620 mmol, Bid) was added to the reaction solution. After the reaction solution was reacted at 25°C for 0.5 hours, the reaction solution was added dropwise to a mixed solution of saturated sodium bicarbonate aqueous solution (10 mL) and dichloromethane (20 mL) to quench the reaction. After the aqueous phase was separated, it was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 15 / 1) to obtain compound 18c. MS m / z (ESI): 541.4 [M+1] + . 1 H NMR (400MHz, CDCl3): δ8.69–8.41(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).

[0543] 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 and then concentrated under reduced pressure to afford crude compound 18d. MS m / z (ESI): 441.6 [M+1]+ . 1 H NMR (400MHz, MeOD): δ7.09–7.01(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).

[0544] 3) Step 3: Compound 18d (58.4 mg, 0.130 mmol) was dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL), and triethylamine (12.2 mg, 0.120 mmol) was added. The reaction solution was stirred at 25°C for 5 minutes, and then acetic acid (7.24 mg, 0.120 mmol) and compound 1e (60.0 mg, 0.120 mmol) were added. The reaction solution was stirred at 25°C for 0.5 hours, and then sodium acetate borohydride (127 mg, 0.600 mmol) was added. The reaction solution was stirred at 25°C for 0.5 hours, and then quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (10 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 18 (34.6 mg). MS m / z (ESI): 922.7 [M+1] + .

[0545] Example 19: 3-(4-((R)-3-((1-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)but-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (19)

[0546] 1) Step 1: Compound 19a-1 (300 mg, 2.10 mmol, prepared using the method disclosed for the intermediate pyrrolo[1,2-b]pyndazine-3-carbonitrile on page 75 of the specification of patent application "WO2015117563 A1") and N-iodosuccinimide (707 mg, 3.14 mmol) were added to acetonitrile (10 mL) at room temperature. The reaction solution was stirred at 60°C for 1 hour. TLC monitored the reaction completion, and saturated sodium sulfite solution (10 mL) was carefully added to the reaction solution. The mixture was then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 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).

[0547] 2) Step 2: Compound 19a-2 (1.16 g, 4.31 mmol) was added to tetrahydrofuran (10 mL), followed by the addition of cuprous iodide (80 mg, 0.43 mmol), bistriphenylphosphine palladium dichloride (300 mg, 0.43 mmol), and triethylamine (1.20 mL, 8.62 mmol). The atmosphere was then purged with nitrogen, and trimethylethynylsilane (6.14 mL, 43.1 mmol) was added. The mixture was stirred at room temperature overnight. The reaction system was added to water, and then extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 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): δ8.75(d,J=2.2Hz,1H),8.63(d,J=2.2Hz,1H),7.38(d,J=4.7Hz,1H),6.96(d,J=4.8Hz,1H),0.27(s,9H).

[0548] 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. Water was added to the reaction system, followed by extraction with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 20) to yield product 19a. 1 H NMR (400MHz, CDCl3) δ8.28(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).

[0549] 4) Step 4: Compound 19a (300 mg, 1.79 mmol) was dissolved in dimethyl sulfoxide (0.6 mL) and ethanol (3 mL). Sodium hydroxide (86.0 mg, 2.15 mmol) and hydrogen peroxide (0.2 mL, 30% aqueous solution) were added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Water (15 mL) was then added and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to provide compound 19b. MS m / z (ESI): 186.1 [M+1] + .

[0550] 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), and copper sulfate pentahydrate (27.0 mg, 0.110 mmol, Anaiji) and sodium ascorbyl palmitate (21.0 mg, 0.11 mmol, Anaiji) were added. The reaction solution was stirred at 25°C for 12 hours, and then concentrated under reduced pressure to remove ethanol. Water (15 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 19c. MS m / z (ESI): 457.2 [M+1] + .

[0551] 6) Step 6: Compound 19c (33.0 mg, 70.0 μmol) was dissolved in dichloromethane (2 mL). Dess-Martin periodinane (61.0 mg, 0.140 mmol) was slowly added to the reaction mixture at 30°C. The reaction mixture was stirred at 30°C for 30 minutes. The reaction system was then quenched by adding saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, 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]. + .

[0552] 7) Step 7: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A") was dissolved in N, N-dimethylformamide (2 mL), and compound 19f (104 mg, 0.530 mmol, Bid), bistriphenylphosphine palladium dichloride (31.1 mg, 40.0 μmol, Bid), triethylamine (0.3 mL, 1.77 mmol) were added. After reacting for 0.5 hours, the temperature was raised to 50 ° C and reacted at this temperature for 3 hours. After the reaction solution returned to 25 ° C, water (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 19g. MS m / z(ESI):453.3[M-1] - .

[0553] 8) Step 8: Dissolve compound 19g (60.0 mg, 0.130 mmol) in dichloromethane (2 mL) and add trifluoroacetic acid (1 mL). Stir the reaction mixture at 25°C for 2 hours. Concentrate under reduced pressure to obtain compound 19h. MS m / z (ESI): 355.2 [M+1] + .

[0554] 9) Step 9: Compound 19h (60.0 mg, 0.170 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL) and N,N-dimethylformamide (1 mL), and triethylamine (0.02 mL, 0.170 mmol) was added. The mixture was reacted at 25°C for 10 minutes. Compound 19d (92.3 mg, 0.200 mmol) and acetic acid (0.02 mL, 0.340 mmol) were then added. After reacting for 2 hours, sodium triacetoxyborohydride (214 mg, 1.02 mmol) was added, and the reaction solution 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, 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): δ11.13(s,1H),9.04–8.99(m,1H),8.80–8.72(m,2H),8.67–8.65(m,1H),8.15(s,1H),7.6 7–7.64(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).

[0555] Example 20: 3-(4-((4-((((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (20)

[0556] 1) The first step: Compound 18a (100 mg, 0.361 mol, prepared by the method disclosed in the intermediate CD on page 394 of the specification of the patent application "WO 2021 / 188948 A1") and compound 20a (106 mg, 0.471 mmol, Bid) were dissolved in dioxane (8 mL) and tetraethyl titanate (0.5 mL, 0.721 mmol) was added. The reaction solution was stirred at 80 ° C under nitrogen protection for 18 hours. The reaction solution was cooled to 25 ° C and sodium cyanoborate (45.3 mg, 0.721 mmol) was added. The reaction solution was stirred at 25 ° C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtering to remove the desiccant, 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]. + .

[0557] 2) Step 2: Compound 20b (30.0 mg, 0.0610 mmol) was dissolved in a hydrochloric acid / dioxane solution (3 mL, 4.0 M). The reaction mixture was incubated at 25°C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain compound 20c. MS m / z (ESI): 386.5 [M+1] + .

[0558] 3) Step 3: Compound 20c (25.0 mg, 0.0610 mmol) was dissolved in ethanol (3 mL). Triethylamine (8.12 mg, 0.0810 mmol) was added until the pH was greater than 8. The reaction solution was stirred at 25°C for 10 minutes. The reaction solution 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 solution was warmed to 25°C and stirred at this temperature for 20 minutes. Then, sodium cyanoborohydride (10.1 mg, 0.161 mmol, Bid) was added. The reaction solution was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, 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] + .

[0559] Example 21: 3-(4-((((1S,4s)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)methyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (21)

[0560] 1) Step 1: Compound 18a (100 mg, 0.360 mmol, prepared using the method disclosed in step 4, product on page 171 of patent application "WO2022068933 A1") was dissolved in 1,4-dioxane (5 mL). Compound 21a (88.0 mg, 0.360 mmol, Bid) and tetraethyl titanate (166 mg, 0.730 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to 25°C, and sodium cyanoborohydride (69.0 mg, 1.09 mmol) was added to the reaction mixture. 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, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 21b. MS m / z (ESI): 522.2 [M+23] + .

[0561] 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] + .

[0562] 3) Step 3: Compound 21c (75.0 mg, 0.190 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (0.03 mL, 0.190 mmol) was added. The reaction solution was stirred at 25°C for 15 minutes, and then compound 1e (93.0 mg, 0.190 mmol) and glacial acetic acid (0.01 mL, 0.19 mmol) were added. After stirring at 25°C for 1 hour, sodium cyanoborohydride (35.0 mg, 0.560 mmol) was added. After stirring for 1 hour, the reaction system was directly concentrated under reduced pressure. The residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 21. MS m / z(ESI):881.6[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.07(s,1H),8.76(d,J=7.9Hz,1H),8.74–8.55(m,2H),8.54(s,1H),8.39(s,1H),7.3 3–7.07(m,1H),6.90–6.78(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. 17–2.11(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).

[0563] Example 22: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-{[4-(2-{[(3Z)-5-[(4-fluorophenyl)sulfamoyl]-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-3-methyl-1H-indol-6-yl)piperazin-1-yl]methyl}piperidin-1-yl)benzamide (22)

[0564] 1) Step 1: Compound 22h-1 (2.00 g, 7.20 mmol) and dimethyl sulfoxide (15 mL) were added sequentially to a single-necked flask and stirred until dissolved. Ethyl isocyanoacetate (895 mg, 7.92 mmol), cuprous iodide (137 mg, 0.72 mmol), and cesium carbonate (4.69 g, 14.4 mmol) were added sequentially. The reaction mixture was stirred at 50°C under nitrogen for 16 hours. 150 mL of water was added to the reaction mixture, and the mixture was 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 yield compound 22h-8. MS m / z (ESI): 284.0 [M+1]+.

[0565] 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), tris(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 then added sequentially. The reaction mixture was stirred at 65°C under nitrogen for 16 hours. Water (80 mL) was added to the reaction mixture, and the mixture was 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 yield compound 22h-4. MS m / z(ESI):388.1[M+1] + .

[0566] 3) Step 3: Add lithium aluminum tetrahydride (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. Slowly add the tetrahydrofuran solution of compound 22h-4 dropwise to the tetrahydrofuran solution of lithium aluminum tetrahydride at 0°C. Stir the reaction solution at 0°C for 5 minutes and at 25°C for 20 minutes. Add saturated ammonium chloride (50 mL) to the reaction solution and extract with ethyl acetate (30 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 22h-5. MS m / z (ESI): 346.1 [M+1] + .

[0567] 4) Step 4: Compound 22h-5 (600 mg, 1.74 mmol) and chloroform (15 mL) were added sequentially 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] + .

[0568] 5) Step 5: Compound 22h-7 (1.00 g, 4.32 mmol), pyridine (0.68 g, 8.64 mmol), 22h-8 (0.96 g, 8.64 mmol), and tetrahydrofuran (10 mL) were added to a single-necked flask and stirred at 25°C for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was slurried with petroleum ether / ethyl acetate (5 / 1) to obtain compound 22h-9. MS m / z (ESI): 307.0 [M+1] + .

[0569] 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. Compound 22h-9 (117.1 mg, 0.38 mmol) and piperidine (29.8 mg, 0.35 mmol) were then added sequentially. The reaction mixture was stirred at 70°C for 2 hours. The temperature was then lowered to 25°C, the reaction mixture was filtered, the solid collected, and dried to yield compound 22h-10. MS m / z (ESI): 632.1 [M+1] + .

[0570] 7) Step 7: Compound 22h-10 (180 mg, 0.28 mmol) and tetrahydrofuran (2 mL) were added to a single-necked flask in sequence, stirred until dissolved, and then dioxane hydrochloride (4M, 15 mL) was added. The reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated, the residue was dissolved in tetrahydrofuran (40 mL) and ammonia water (6 mL) was added, and the solution was stirred at room temperature for 1 hour. After concentration, water (30 mL) was added and stirred at room temperature for 1 hour. Filter and collect the solid. The solid was dissolved in tetrahydrofuran (15 mL) and petroleum ether (40 mL) was slowly added under stirring. The solid precipitated and the suspension was stirred for 30 minutes. Filter, collect the solid and dry to obtain compound 22h. MS m / z (ESI): 532.1[M+1] + .

[0571] 8) Step 8: Compound 22a (1.50 g, 6.44 mmol, Bidler) and 1,4-dioxane (15 mL) were added sequentially to a three-necked flask, followed by 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 with nitrogen three times and stirred at 100°C under a nitrogen atmosphere for 2 hours. After the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 5 / 10) to afford compound 22c. MS m / z (ESI): 268.1 [M+1] + .

[0572] 9) Step 9: Compound 22c (1.00 g, 3.74 mmol) and tetrahydrofuran (10 mL) were added to a single-necked flask, followed by lithium hydroxide (780 mg, 18.7 mmol) and water (3 mL). The reaction solution was stirred at 80°C for 5 hours. After the reaction was completed, 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 was 3, and solids 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): δ12.75–12.01(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).

[0573] 10) Step 10: Compound 22d (200 mg, 0.730 mmol) and N,N-dimethylformamide (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, 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 desiccant, and the filtrate was concentrated under reduced pressure to obtain an oily residue. To the residue were added 3 to 5 drops of dichloromethane, and after standing for 30 minutes, a solid precipitated, which was collected to obtain a crude compound 22f.

[0574] 11) Step 11: Compound 22f (100 mg, 0.280 mmol) was dissolved in dichloromethane (1 mL) and Dess-Martin reagent (175 mg, 0.410 mmol) was slowly added in batches. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined and washed with saturated brine (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 30 / 1 to 20 / 1) to obtain compound 22g. MS m / z (ESI): 364.1 [M+1] + .

[0575] 12) Step 12: Compound 22g (50.0 mg, 0.100 mmol) and N,N-dimethylformamide (0.5 mL) were added sequentially to a single-necked flask, followed by compound 22h (51.5 mg, 0.100 mmol) and a drop of glacial acetic acid. The reaction mixture was stirred at 25°C for 1 hour, and then sodium acetate borohydride (40.9 mg, 0.190 mmol) was added and stirred at 25°C for 1 hour. The reaction mixture was filtered, and the residue was purified by HPLC (ACSSH-CH, 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): δ12.74(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).

[0576] Example 23: 3-(4-((7-((((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)spiro[3.5]nonan-2-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (23)

[0577] 1) The first step: Compound 18a (200 mg, 0.731 mol, prepared by the method disclosed in the intermediate CD on page 394 of the specification of the patent application "WO 2021 / 188948 A1") and compound 23a (307 mg, 1.02 mmol, prepared by the method disclosed in the intermediate 00967 on page 374 of the specification of the patent application "WO 2021 / 188948 Al") were dissolved in dioxane (8 mL) and tetraethyl titanate (0.5 mL, 1.46 mmol) was added. The reaction solution was stirred at 80 ° C under nitrogen protection for 18 hours. The reaction solution was cooled to room temperature and sodium cyanoborate (91.6 mg, 1.46 mmol) was added. The reaction solution was stirred at 25 ° C for 1 hour. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 x 150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 23b. MS m / z (ESI): 560.0 [M+1]. + .

[0578] 2) Step 2: Compound 23b (40.0 mg, 0.0710 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). Wet palladium on carbon (10.0 mg, 10%) was added. The reaction solution was replaced with hydrogen three times and stirred at 25°C for 18 hours. The reaction solution was filtered and concentrated to obtain compound 23c. MS m / z (ESI): 426.6 [M+1] + .

[0579] 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 acetate borohydride (38.2 mg, 0.181 mmol) was added. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure and purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 23. MS m / z (ESI): 907.7 [M+1]+ .

[0580] Example 24: 3-(4-((((1R,4r)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)methyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (24)

[0581] 1) Step 1: Compound 18a (54.0 mg, 0.200 mmol, prepared by the method disclosed in step 4 product on page 171 of the specification of patent application "WO2022068933 A1") was dissolved in 1,4-dioxane (5 mL), and compound 24a (95.0 mg, 0.390 mmol, Bid) and tetraethyl titanate (90.0 mg, 0.390 mmol) were added. The reaction solution was stirred at 80 ° C for 12 hours. The reaction solution was cooled to 25 ° C, and sodium cyanoborohydride (37.0 mg, 0.590 mmol) was added to the reaction solution. After stirring at room temperature for 1 hour, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 24b. MS m / z(ESI):444.2[M-55] + .

[0582] 2) Step 2: Compound 24b (150 mg, 0.360 mmol) was dissolved in dichloromethane (4 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 24c. MS m / z (ESI): 400.2 [M+1] + .

[0583] 3) Step 3: Compound 21c (25.0 mg, 60.0 μmol) was dissolved in a mixture of N,N-dimethylformamide (0.5 mL) and tetrahydrofuran (2 mL). Triethylamine (0.01 mL, 60.0 μmol) was added, and the reaction mixture was stirred at 25°C for 15 minutes. Compound 1e (31.0 mg, 60.0 μmol) and acetic acid (0.01 mL, 0.190 mmol) were then added. After reacting for 1 hour, sodium cyanoborohydride (12.0 mg, 0.190 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction system was concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 24. MS m / z(ESI):881.3[M+1] + .

[0584] Example 25: 3-(4-(4-(4-[(4-)(1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl(cyclohexyl)methyl)(methyl)amino)methyl)piperidin-1-yl)but-1-ynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25)

[0585] 1) Step 1: Compound 25a (1.00 g, 4.38 mmol, Bid) and compound 25b (0.6 mL, 6.57 mmol, Bid) were dissolved in acetonitrile (20 mL). Potassium carbonate (1.81 g, 13.1 mmol) was added. The reaction mixture was stirred at 80°C for 18 hours. Water (20 mL) was then added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 25c. MS m / z (ESI): 281.0 [M+1] + .

[0586] 2) Step 2: Compound 25c (200 mg, 0.710 mmol) and compound 19e (241 mg, 0.710 mmol, prepared using the method disclosed in step 3 on page 88 of patent application "WO2022012623 A") were dissolved in N,N-dimethylformamide (7 mL). Bistriphenylphosphine palladium dichloride (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. Under nitrogen protection, the reaction was carried out at 80°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 40 / 1 to 20 / 1) to obtain compound 25e. MS m / z (ESI): 538.0 [M+1] + .

[0587] 3) Step 3: Compound 25e (80.0 mg, 0.145 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 25f. MS m / z (ESI): 438.0 [M+1] + .

[0588] 4) Step 4: To a solution of 25f (61.5 mg, 0.141 mmol) in 1,2-dichloroethane (3 mL) and tetrahydrofuran (5 mL) was added triethylamine (14.2 mg, 0.141 mmol) until the pH was greater than 8, and the mixture was stirred at 25°C for 10 minutes. Acetic acid (12.6 mg, 0.212 mmol) was added at -10°C, and 1e (70.0 mg, 0.141 mmol) was added. The mixture was then stirred at 25°C for 20 minutes, and sodium acetate borohydride (59.6 mg, 0.282 mmol, Bidler) was added. The mixture was stirred at 25°C for an additional hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 25. MS m / z (ESI): 919.5 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.12(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.54(s,1H),8.3 8(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).

[0589] Example 26: 3-(4-((2-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-azaspiro[3.3]hept-6-yl)ethyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (26)

[0590] 1) Step 1: Compound 26a (310 mg, 1.28 mmol, Bid) was dissolved in dichloromethane (10 mL). Dess-Martin periodinane (1.09 g, 2.57 mmol) was added portionwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified with neutral alumina using an eluent system (petroleum ether / ethyl acetate = 100 / 1 to 3 / 1) to obtain compound 26b. 1 H NMR (400MHz, CDCl3): δ9.83–9.60(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).

[0591] 2) Step 2: Compound 18a (220 mg, 0.800 mmol, prepared by the method disclosed in intermediate 495 on page 172 of the specification of patent application "WO2022068933 A1"), compound 26b (230 mg, 0.960 mmol) and ethyl titanate (0.3 mL, 1.60 mmol) were dissolved in dioxane (10 mL). The reaction solution was stirred at 100 ° C under nitrogen protection for 12 hours, and then the reaction solution was cooled to 25 ° C. Sodium cyanoborohydride (252 mg, 4.01 mmol) was added, the reaction was stirred at 25 ° C for 1 hour, and the reaction solution was quenched with water (20 mL) and ethyl acetate (20 mL). The reaction solution was filtered using diatomaceous earth, and after the aqueous phase was separated, it was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 100 / 1 to 20 / 1) to obtain compound 26c. MS m / z (ESI): 520.2 [M+23] + . 1 H NMR (400MHz, CDCl3): δ8.14(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),3.75(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).

[0592] 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. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure to obtain compound 26d. MS m / z (ESI): 398.2 [M+1] + .

[0593] 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. The reaction mixture was stirred at 25°C for 10 minutes, and then acetic acid (7.85 mg, 0.130 mmol) and compound 1e (65.0 mg, 0.130 mmol) were added. The reaction mixture was stirred at 25°C under nitrogen for 1 hour, and then sodium acetate borohydride (166 mg, 0.780 mmol) was added. The reaction mixture was stirred at 25°C under nitrogen for 12 hours, and then quenched with saturated aqueous sodium bicarbonate (5 mL) and dichloromethane (10 mL). The aqueous phase was separated and extracted with dichloromethane (3 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 26. MS m / z (ESI): 879.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.05(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).

[0594] Example 27: 3-(4-(1-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)azetidin-3-ylethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (27)

[0595] 1) Step 1: Compound 19e (120 mg, 0.661 mmol, prepared using the method disclosed in step 3, product on page 88 of patent application "WO2022012623 A") and compound 27a (172 mg, 0.508 mmol, Bid) were dissolved in N,N-dimethylformamide (2 mL). 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 and stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, and 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to afford compound 16b. MS m / z (ESI): 461.1 [M+23]. + .

[0596] 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 solution was concentrated under reduced pressure to obtain a crude product, which was purified on a reverse phase column (water / acetonitrile = 25 / 75 to 80 / 20) to obtain compound 16c. MS m / z (ESI): 339.1 [M+1] + .

[0597] 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-dimethylformamide (1 mL). Triethylamine (8.97 mg, 88.7 μmol) was added and stirred for 5 minutes. Glacial acetic acid (7.95 mg, 133 μmol) was then added and the reaction mixture was stirred at 40°C for 2 hours. Sodium acetate borohydride (37.4 mg, 177 μmol) was then added and stirred at 40°C for 2 hours. The reaction mixture was filtered and purified by HPLC (ACSSH-CP, column: C18 150 × 30 mm; mobile phase: water (formic acid)-acetonitrile, gradient: acetonitrile 3% to 43%, flow rate: 30 mL / min) to obtain compound 16. MS m / z (ESI): 820.4 [M+1] + .

[0598] Example 28: 4-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-acylinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexylmethyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (28)

[0599] Compound 28a (80.0 mg, 220 μmol, prepared by the method disclosed in the intermediate step 7 compound on page 867 of the specification of the patent application "WO 2023 / 017446 Al"), compound 1e (107 mg, 220 μmol) and triethylamine (0.05 mL) were dissolved in tetrahydrofuran (3 mL) and N, N-dimethylformamide (1.5 mL). The reaction solution was stirred at 15 ° C for 10 minutes, and then acetic acid (0.05 mL) and sodium triacetoxyborohydride (136 mg, 0.65 mmol) were added. The reaction solution was stirred at 15 ° C for half an hour. Water (15 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (15 mL × 3), dried, and concentrated. The residue was purified by high performance liquid chromatography (Waters-2545, column: Boston Green ODS 150×30 mm, 5 μm; mobile phase: Waters (FA-CH3CN, gradient ratio: acetonitrile 16%-56%, flow rate: 30 mL / min) to obtain compound 28. MS m / z (ESI): 816.5 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.85(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).

[0600] Example 29: 3-(4-(4-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)amino)piperidine-1-carbonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (29)

[0601] 1) The first step: Compound 29a (200 mg, 0.660 mmol, prepared by the method disclosed in the specification of patent application "WO 2020 / 113233 Al") and 29b (150 mg, 0.750 mmol, Bid) were dissolved in N, N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-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 solution was stirred at 25 ° C for 2 hours. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 60 / 1 to 10 / 1) to give compound 29c. MS m / z (ESI): 508.2 [M+23] + .

[0602] 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] + .

[0603] 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-dimethylformamide (1 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (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 phases were 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 high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] + .

[0604] Example 30: 3-(4-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (30)

[0605] Compound 30a (30.0 mg, 90.0 μmol, prepared using the method disclosed for intermediate GS on page 550 of the specification of patent application "WO2022236058 A1") was dissolved in dichloroethane (2 mL) and N,N-dimethylformamide (1 mL) solution, and triethylamine (0.1 mL) was added. The reaction solution 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 solution and stirred for 0.5 hours. Sodium acetate borohydride (55.0 mg, 0.260 mmol) was added to the reaction solution. The reaction solution was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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): δ11.11(s,1H),8.78(d,J=7.8Hz,1H),8.68(s,1H),8.55(s,1 H),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),2.75–2.5 9(m,3H),2.29–2.07(m,4H),2.04–1.94(m,3H),1.93–1.81(m,2H),1.37–0.91(m,4H).

[0606] Example 31: 7-(1-(3-(difluoromethyl)-1-(1r,4r)-4-(4-(4-(2,6-dioxopyridin-3-yl)carbamoyl)-3-fluorophenylpiperazin-1-yl)methyl)cyclohexyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (31)

[0607] Compound 28a (40.0 mg, 0.110 mmol, prepared using the method disclosed in the intermediate step 7 compound on page 867 of the specification of the patent application "WO 2023 / 017446 Al"), compound 19d (49.0 mg, 0.110 mmol) and triethylamine (0.1 mL) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL), and the reaction solution 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 solution, and the reaction was stirred at 15 ° C for half an hour. Water (10 mL) was added to the reaction solution, and the organic phase was extracted with dichloromethane (10 mL × 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, column: C18 150×30 mm; mobile phase: Waters (FA-CH3CN, gradient ratio: acetonitrile 16%-56%, flow rate: 30 mL / min) to give compound 31. MS m / z (ESI): 773.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.85(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).

[0608] Example 32: 3-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-acylinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexylmethyl)-2,7-diazaspiro[4.4]nonyl-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (32)

[0609] 1) Step 1: Compound 19e (300 mg, 0.890 mmol, prepared using the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A") 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-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (82.8 mg, 0.180 mmol) were added. Under nitrogen protection, lithium bis(trimethylsilyl)amide (4.4 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution) was added dropwise to the reaction solution. The reaction solution was stirred at 80°C under nitrogen protection for 2 hours. Water (30 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (30 mL × 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 eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 32b. MS m / z (ESI): 484.3 [M+1] + .

[0610] 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 solution was concentrated to obtain compound 32c. MS m / z (ESI): 384.0 [M+1] + .

[0611] 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-dimethylformamide (1.5 mL) and stirred at 15°C for 10 minutes. Acetic acid (0.5 mL) and sodium triacetoxyborohydride (165 mg, 0.780 mmol) were then added to the reaction mixture, and the mixture was stirred at 15°C for half an hour. Water (15 mL) was added to the reaction mixture, and the mixture 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, column: C18 150×30 mm; mobile phase: Waters (FA)-CH3CN, gradient ratio: acetonitrile 13%-53%, flow rate: 30 mL / min) to obtain compound 32. MS m / z (ESI): 865.4 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.10(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).

[0612] Example 33: 3-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-acylinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (33)

[0613] 1) Step 1: Compound 33a (314 mg, 1.48 mmol, Bid) was dissolved in toluene (5 mL). Compound 19e (500 mg, 1.48 mmol, prepared using the method disclosed in step 3 on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (138 mg, 0.300 mmol), and (2-amino-[1,1-biphenyl]-2-yl)(dicyclohexyl(2,6-diisopropoxy-[1,1-biphenyl]-2-yl)phosphoryl)palladium chloride (230 mg, 0.300 mmol) were added. Under nitrogen protection, lithium bis(trimethylsilyl)amide (3.7 mL, 3.70 mmol, 1.0 M solution in tetrahydrofuran) was added dropwise to the reaction solution. The reaction solution was reacted 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] + .

[0614] 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 incubated 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] + .

[0615] 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-dimethylformamide (0.5 mL). Sodium cyanoborohydride (5.71 mg, 30.0 μmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson GX-281, column: Boston Prime C18, 30×150 mm, 5 μm; mobile phase: water (containing 0.0500% 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 H NMR (400MHz, DMSO-d6): δ11.10(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).

[0616] Example 34: 3-(4-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-acylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl-methylpiperazin-1-yl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione (34)

[0617] 1) Step 1: Compound 34a (398 mg, 1.48 mmol, Bid) was dissolved in toluene (5 mL), and compound 19e (500 mg, 1.48 mmol, prepared using the method disclosed in step 3 on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (138 mg, 0.300 mmol), and (2-amino-[1,1-biphenyl]-2-yl)(dicyclohexyl(2,6-diisopropoxy-[1,1-biphenyl]-2-yl)phosphoryl)palladium chloride (230 mg, 0.300 mmol) were added. Under nitrogen protection, lithium bis(trimethylsilyl)amide (3.7 mL, 3.70 mmol, 1.0 M tetrahydrofuran solution) was added dropwise. The reaction mixture was reacted at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 34c. MS m / z (ESI): 527.3 [M+1] + .

[0618] 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 mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 34c.

[0619] 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-dimethylformamide (0.5 mL). Sodium cyanoborohydride (5.71 mg, 30.0 μmol) was added. The reaction mixture was incubated at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by HPLC (Gilson GX-281, 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] + . 1H NMR (400MHz, DMSO-d6): δ11.23–10.98(m,1H),8.74(d,J=7.9Hz,1H),8.64(s,1H),8.53(s,1H),8.38(s,1 H),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),5.3 3(m,J=5.3,12.6Hz,1H),4.35–4.21(m,1H),3.62(s,3H),3.20–3.07(m,4H),2.95–2.79(m,2H),2.76–2.6 2(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).

[0620] Example 35: (1-(3-(Difluoromethyl)-1-((1r,4r)-4-((2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (35)

[0621] Compound 35a (100 mg, 0.261 mmol, prepared by the method disclosed in intermediate BIL on page 220 of the specification of patent application "WO 2021 / 158634 Al") was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL), and triethylamine (52.6 mg, 0.521 mmol) was added until the pH value was greater than 7, and the mixture was stirred at 25 ° C for 10 minutes. Acetic acid (146 mg, 0.781 mmol) was added at -10 ° C, and compound 19d (222 mg, 0.391 mmol) was added. After the mixture was stirred at 25 ° C for 20 minutes, sodium acetate borohydride (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 purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 35. MS m / z (ESI): 822.8 [M+1]+ . 1 H NMR (400MHz, DMSO-d6): δ11.10(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=8.0 Hz,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).

[0622] Example 36: 3-(4-(9-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (36)

[0623] 1) Step 1: At room temperature, compound 19e (200 mg, 0.590 mmol, prepared using the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 36a (301 mg, 1.18 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (55.0 mg, 0.120 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (25.0 mg, 30.0 μmol) were dissolved in toluene (3 mL). Under nitrogen protection, lithium bistrimethylsilylamide (3 mL, 3.00 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15 mL x 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 36b. MS m / z (ESI): 510.4 [M-1]. - .

[0624] 2) Step 2: 36b (120 mg, 0.210 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. The solvent was removed under reduced pressure. Compound 36c was obtained without purification. MS m / z (ESI): 412.6 [M+1] + .

[0625] 3) Step 3: Compound 36c (80.0 mg, 0.140 mmol) and triethylamine (14.0 mg, 0.160 mmol) were dissolved in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) at room temperature and stirred for 10 minutes. Acetic acid (13.0 mg, 0.200 mmol) and compound 1e (61.0 mg, 0.120 mmol) were added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium acetate borohydride (96.0 mg, 0.460 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 20%-80%, flow rate: 25 mL / min) to give 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).

[0626] Example 37: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((8-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,8-diazaspiro[4.5]dec-2-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (37)

[0627] 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 of patent application "WO2022012623 A"), compound 18b (426 mg, 1.77 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (149 mg, 0.180 mmol, adamas) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (83.0 mg, 0.180 mmol, Bid) were dissolved in toluene (3 mL). Under nitrogen protection, lithium bistrimethylsilylamide (4.4 mL, 4.44 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction mixture was incubated at 80°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 37a. MS m / z (ESI): 498.3 [M+1] + .

[0628] 1) 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. The reaction mixture was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 37b. MS m / z (ESI): 398.2 [M+1] + .

[0629] 2) 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). The reaction mixture is stirred for 0.5 hours. Compound 19d (114 mg, 0.250 mmol) and acetic acid (0.02 mL, 0.380 mmol) are added to the reaction mixture, and stirred for 0.5 hours. Sodium acetate borohydride (105 mg, 0.500 mmol) is added to the reaction mixture. The reaction mixture is stirred at 25°C for 17 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (A: 0.1% FA / H2O B: ACN, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 35%-45%, flow rate: 25 mL / min) to obtain compound 37. MS m / z (ESI): 836.8 [M+1]+ . 1 H 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,2 H),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),2.80–2.58 (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).

[0630] Example 38: 3-(4-(9-(1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (38)

[0631] 1) Step 1: Compound 19e (400 mg, 1.18 mmol, prepared using the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 38a (606 mg, 2.36 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (110 mg, 0.240 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (24.8 mg, 30.0 μmol) were dissolved in toluene (6 mL). Under nitrogen protection, lithium bistrimethylsilylamide (6 mL, 6.00 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, water (40 mL) was added, and the 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 desiccant, and 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] - .

[0632] 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] + .

[0633] 3) Step 3: Compound 38c (100 mg, 0.240 mmol) and triethylamine (25.0 mg, 0.250 mmol) were dissolved in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) and 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 acetate borohydride (154 mg, 0.730 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 2%-98%, flow rate: 25 mL / min) to give compound 38. MS m / z (ESI): 896.0 [M+1] + . 1H 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).

[0634] Example 39: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]dec-8-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (39)

[0635] The trifluoroacetic acid salt of compound 37b (100 mg, 0.250 mmol) was dissolved in tetrahydrofuran (1 mL) and 1,2-dichloroethane (1 mL). Triethylamine (0.04 mL, 0.250 mmol) was added, and 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 the mixture was stirred for 0.5 hours. Sodium acetate borohydride (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 purified by high-performance liquid chromatography (HPLC: 0.1% FA / H2OB:ACN, column: Waters-CORTECS-C18-2.7 μm-4.6×30 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 75%-85%, flow rate: 25 mL / min) to afford 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).

[0636] Example 40: 3-(4-(4-(-4-(1-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyranazolo[1,5-a]pyrimidin-3-yl)-1-1,2,3-triazol-1-yl-1,2,3-triazol-1-pyrazol-1-yl)cyclohexylmethyl)piperidin-4-ylpiperazin-1-yl)-piperazine-1-yl)-3-methyl-3-methyl-2-oxo-2,3-dihydrodihydro-1H-benzo[imidazol-1-yl]-1-piperidin-2,6-piperidin-1-yl)-piperidin-2,6-piperidin-1-yl)-piperidin-3-one (40)

[0637] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 40a (179 mg, 0.660 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (111 mg, 0.130 mmol, adamas) were dissolved in toluene (5 mL). Under nitrogen protection, lithium bistrimethylsilylamide (2.6 mL, 2.60 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give compound 40b. MS m / z (ESI): 527.3 [M+1] + .

[0638] 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] + .

[0639] 3) Step 3: Compound 40c (90.0 mg, 0.120 mmol) was dissolved in N,N-dimethylformamide (2 mL) and tetrahydrofuran (3 mL). Triethylamine (24.0 mg, 0.240 mmol) was added and 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 solution and stirred for 30 minutes. Sodium acetate borohydride (124 mg, 0.590 mmol) was added to the reaction solution and stirred for 1 hour. The mixture was concentrated to obtain a residue. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; 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): 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),7.01–6.85(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).

[0640] Example 41: 3-(4-(4-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-3-methyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (41)

[0641] 1) Step 1: Compound 19e (300 mg, 0.890 mmol, using patent application "WO2022012623 A" prepared by the method disclosed in step 3 product on page 88 of the specification), compound 5a (340 mg, 1.33 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (120 mg, 0.260 mmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (220 mg, 0.260 mmol, adamas) were dissolved in toluene (12 mL) and lithium bis(trimethylsilyl)amide (5 mL, 5.0 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction solution was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL) and the aqueous phase was extracted 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 desiccant, 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 41a. MS m / z (ESI): 514.2 [M+1] + .

[0642] 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] + .

[0643] 3) Step 3: Compound 41b (62.0 mg, 0.110 mmol) was dissolved in N,N-dimethylformamide (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 solution, and the mixture was stirred at 25°C for 30 minutes. Sodium acetate borohydride (143 mg, 0.670 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain a residue. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson 306-1741, column: Wetch-Ultimate-XB-C18-10 μm-21.2×150 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15% to 95%, flow rate: 25 mL / min) to obtain compound 41. MS m / z (ESI): 895.6 [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),7.01–6.89(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).

[0644] Example 42: 3-(4-(3-(4-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazin-1-yl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (42)

[0645] 1) Step 1: Compound 42a (100 mg, 0.300 mmol, Leyan), compound 19e (107 mg, 0.440 mmol, patent application "WO2022012623 A” in the specification of step 3 on page 88 of the product prepared by the method disclosed), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (27.6 mg, 60.0 μmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (251 mg, 0.300 mmol, adamas) were dissolved in toluene (2 mL), and under nitrogen protection, lithium bistrimethylsilylamine (1.5 mL, 1.48 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise, and the reaction solution was reacted at 80 ° C for 2 hours. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 42b. MS m / z (ESI): 499.2 [M+1] + .

[0646] 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 solution was concentrated to obtain compound 42c. MS m / z (ESI): 399.2 [M+1] + .

[0647] 3) Step 3: Compound 42c (30.0 mg, 80.0 μmol) was dissolved in N,N-dimethylformamide (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. Compound 1e (41.2 mg, 80.0 μmol) and acetic acid (0.03 mL, 0.450 mmol) were then added sequentially. The mixture was reacted at 25°C for 30 minutes. Sodium acetate borohydride (95.3 mg, 0.450 mmol) was then added and the mixture was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-Xbrid ge-C18-10 μm-19×250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient: acetonitrile 15%-95%, flow rate: 25 mL / min) to obtain compound 42. MS m / z (ESI): 880.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.08(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),2.93–2.8 1(m,1H),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).

[0648] Example 43: 3-(4-(7-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (43)

[0649] Compound 35a (28.0 mg, 71.0 μmol, prepared by the method disclosed in the intermediate BIL on page 220 of the specification of the patent application "WO 2021 / 158634 Al") was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL). Triethylamine (8.51 mg, 81.0 μmol) was added to a solution until the pH value was greater than 7, and the reaction solution 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. After stirring the reaction solution at 25 ° C for 20 minutes, sodium acetate borohydride (29.7 mg, 0.141 mmol) was added. The reaction solution was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 43. MS m / z (ESI): 865.5 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(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=53.2Hz,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).

[0650] Example 44: 3-(4-(4-(1-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methyl)azetidin-3-yl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (44)

[0651] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 40a (160 mg, 0.660 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (111 mg, 0.130 mmol) were dissolved in toluene (5 mL), and under nitrogen protection, lithium bistrimethylsilylamide (2.3 mL, 2.30 mmol, 1.0 M tetrahydrofuran solution, Anaiji) 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 × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 44b. MS m / z (ESI): 499.2 [M+1] + .

[0652] 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] + .

[0653] 3) Step 3: Compound 44c (68.0 mg, 0.120 mmol) was dissolved in N,N-dimethylformamide (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 solution, and the mixture was stirred at 25°C for 30 minutes. Sodium acetate borohydride (127 mg, 0.600 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain a residue. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19*250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 15% to 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): δ11.11(s,1H),8.77(d,J=8.0Hz,1H),8.72–8.65(m,1H),8.56–8.5 3(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 ),5.40–5.33(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).

[0654] Example 45: 3-(4-(8-((1R,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (45)

[0655] 1) The first step: Compound 19e (500 mg, 1.48 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification of patent application "WO2022012623 A"), compound 45a (533 mg, 2.22 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl) palladium (II) (248 mg, 0.300 mmol, Bid) and 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl (138 mg, 0.300 mmol, Bid) were dissolved in toluene (5 mL). Under nitrogen protection, lithium bistrimethylsilylamide (7.4 mL, 7.39 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with saturated ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 45b. MS m / z (ESI): 498.4 [M+1] + .

[0656] 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. The reaction solution was concentrated under reduced pressure to obtain compound 45c. MS m / z (ESI): 398.5 [M+1] + .

[0657] 3) Step 3: Compound 45c (50.0 mg, 0.130 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL), triethylamine (0.1 mL) was added, and the mixture was stirred for 0.5 h. Compound 1a (75.0 mg, 0.150 mmol) and acetic acid (0.2 mL) were added to the reaction solution and stirred for 0.5 h. Sodium acetate borohydride (80.0 mg, 0.380 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 h. The reaction solution was concentrated under reduced pressure and purified by HPLC (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; 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] - . 1H 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),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,8 H),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).

[0658] Example 46: 3-(4-((R)-4-(((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2-methylpiperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (46)

[0659] 1) The first step: Compound 46a (400 mg, 1.18 mmol, Bid), compound 19e (355 mg, 1.77 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification of patent application "WO2022012623 A"), 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl (110 mg, 0.240 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl) palladium (II) (198 mg, 0.240 mmol) were dissolved in toluene (8 mL). Under nitrogen protection, lithium bistrimethylsilylamide (5.9 mL, 5.91 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise, and the reaction solution was reacted at 80 ° C. under a nitrogen atmosphere for 3 hours. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 46b. MS m / z (ESI): 402.1 [M-55] + .

[0660] 2) Step 2: Compound 46b (176 mg, 0.380 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added with stirring. The reaction mixture was incubated at 25°C for 3 hours. The reaction mixture was concentrated to yield compound 46c. MS m / z (ESI): 358.2 [M+1] + .

[0661] 3) Step 3: Compound 46c (70.0 mg, 60.0 μmol) was dissolved in N,N-dimethylformamide (1.5 mL) and tetrahydrofuran (1 mL). Triethylamine (0.02 mL, 0.150 mmol) was added, and the reaction mixture was reacted at 25°C for 10 minutes. Compound 1e (32.5 mg, 70.0 μmol) and acetic acid (0.02 mL, 0.360 mmol) were then added sequentially. The reaction mixture was reacted at 25°C for 30 minutes. Sodium acetate borohydride (75.2 mg, 0.360 mmol) was then added, and the mixture was reacted at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-Xbrid ge-C18-10 μm-19×250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient: acetonitrile 15%-95%, flow rate: 25 mL / min) to obtain compound 46. MS m / z (ESI): 839.4 [M+1]+ . 1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.76(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.2 1–7.15(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).

[0662] Example 47: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-ylcyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (47)

[0663] 1) Step 1: Compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 14a (151 mg, 0.670 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (62.0 mg, 0.130 mmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (111 mg, 0.130 mmol, adamas) were dissolved in toluene (5 mL). Under nitrogen protection, lithium bistrimethylsilylamide (2.7 mL, 2.70 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 47a. MS m / z (ESI): 484.3 [M+1] + .

[0664] 2) Step 2: Compound 47a (86.0 mg, 0.180 mmol) was dissolved in 1,4-dioxane (2 mL), and a 4.0 M hydrochloric acid / 1,4-dioxane solution (2 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to afford compound 47b. MS m / z (ESI): 384.2 [M+1] + .

[0665] 3) Step 3: Compound 47b (60.0 mg, 0.130 mmol) was dissolved in N,N-dimethylformamide (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 solution, and the mixture was stirred at 25°C for 30 minutes. Sodium acetate borohydride (145 mg, 0.680 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain a residue. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19*250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 17% to 95%, flow rate: 25 mL / min) to obtain compound 47. MS m / z (ESI): 865.6 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.08(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).

[0666] Example 48: 3-(4-((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-acylinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (48)

[0667] 1) Step 1: Compound 19e (500 mg, 1.48 mmol, prepared using the method disclosed in step 3 on page 88 of the specification of patent application "WO2022012623 A"), compound 48a (471 mg, 2.22 mmol, Bid), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (138 mg, 30.0 μmol), and methanesulfonic acid (2-dicyclohexylphosphino-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). Under nitrogen protection, lithium bis(trimethylsilyl)amide (8.9 mL, 8.87 mmol, 1 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction was carried out at 80°C under a nitrogen atmosphere 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 (dichloromethane / methanol = 40 / 1 to 15 / 1) to obtain compound 48b. MS m / z (ESI): 470.2 [M+1] + .

[0668] 2) Step 2: Compound 48c (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 solution was concentrated under reduced pressure to obtain compound 48c. MS m / z (ESI): 370.0 [M+1] + .

[0669] 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-dimethylformamide (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 solution was filtered, and the filtrate was purified by HPLC (GILSON: GX-281, 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 4. MS m / z (ESI): 851.5 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.09(s,1H),8.76(d,J=7.8Hz,1H),8.66(s,1H),8.54(s,1H),8.39(s,1 H),7.38–7.02(m,1H),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,2 H),2.25–2.12(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).

[0670] Example 49: 3-(4-((1R,4R)-4-(3-(difluoromethyl)-4-(4-(5-acylinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (49)

[0671] 1) Step 1: Compound 19e (500 mg, 1.48 mmol, prepared using the method disclosed in step 3 on page 88 of the specification of patent application "WO2022012623 A"), compound 49a (471 mg, 2.22 mmol, obtained), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (248 mg, 0.530 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-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). Under nitrogen protection, lithium bis(trimethylsilyl)amide (8.4 mL, 8.40 mmol, 1.0 M tetrahydrofuran solution) was added dropwise. The reaction solution was reacted at 80°C under a nitrogen 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] + .

[0672] 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 incubated at 25°C for 1 hour. The reaction mixture was then concentrated under reduced pressure to yield compound 49c.

[0673] 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-dimethylformamide (1 mL). Sodium cyanoborohydride (12.8 mg, 0.200 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by HPLC (Gilson GX-281, column: Boston Prime C18, 30*150 mm, 5 μm; mobile phase: water (containing 0.0500% 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): δ11.09(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 ),4.35–4.25(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=9.8H z,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).

[0674] Example 50: 3-(4-((R)-4-(((1r,4R)-4-)3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl(cyclohexyl)-3-methylpiperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (50)

[0675] 1) Step 1: Compound 19e (400 mg, 1.18 mmol, prepared by the method of patent application "WO2022012623 A" in the specification of step 3 on page 88 of the product disclosed in the method prepared), compound 50a (355 mg, 1.77 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (110 mg, 0.240 mmol, Bid) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (197 mg, 0.240 mmol, adamas) were dissolved in toluene (12 mL), and the reaction solution was replaced with nitrogen three times, and then lithium bistrimethylsilylamide (6.5 mL, 6.50 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction solution was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to obtain compound 50b. MS m / z (ESI): 458.2 [M+1] + .

[0676] 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] + .

[0677] 3) Step 3: Compound 50c (170 mg, 0.110 mmol) was dissolved in N,N-dimethylformamide (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 solution, and after stirring for 30 minutes, sodium acetate borohydride (115 mg, 0.540 mmol) was added to the reaction solution, 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, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 6% to 95%, flow rate: 25 mL / min) to obtain compound 50. MS m / z (ESI): 839.6 [M+1]+ . 1 H NMR (400MHz, DMSO-d6): δ11.09(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).

[0678] Example 51: 7-(1-(3-(difluoromethyl)-1-((1R,4r)-4-(((3R)-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3-methylpiperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (51)

[0679] Compound 46c (70.0 mg, 60.0 μmol) was dissolved in N,N-dimethylformamide (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. Compound 19d (29.7 mg, 70.0 μmol) and acetic acid (0.02 mL, 0.360 mmol) were then added in sequence. The mixture was reacted at 25°C for 30 minutes. Sodium acetate borohydride (75.2 mg, 0.360 mmol) was then added and the mixture was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-Xbrid ge-C18-10 μm-19×250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient: 10% to 95% acetonitrile, flow rate: 25 mL / min) to obtain compound 51. MS m / z (ESI): 796.4 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.12(s,1H),9.01(s,1H),8.78(d,J=2.3Hz,1H),8.75(s,1H),8.66(d ,J=2.2Hz,1H),7.65(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,1H),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).

[0680] Example 52: 7-(1-(3-difluoromethyl)-1-(1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethynyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (52)

[0681] 1) Step 1: Compound 19e (200 mg, 0.590 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 52a (355 mg, 1.77 mmol, Bid), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (55.0 mg, 0.120 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.0 mg, 90.0 μmol) were dissolved in toluene (3 mL) and lithium bistrimethylsilylamide (4 mL, 4.00 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water (10 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane / methanol (15 / 1, 15 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 52b. MS m / z (ESI): 458.3 [M+1] + .

[0682] 2) Step 2: Compound 52b (110 mg, 0.240 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain compound 52c. MS m / z (ESI): 358.4 [M+1] + .

[0683] 3) Step 3: Compound 52c (50.0 mg, 0.140 mmol) and triethylamine (28.0 mg, 0.280 mmol) were dissolved in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) and stirred for 10 minutes. Acetic acid (21.0 mg, 0.350 mmol) and 1e (70.0 mg, 0.140 mmol) were added, and the reaction mixture was stirred at 25°C for 0.5 hours. Sodium acetate borohydride (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 to remove the solvent. The residue was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 10%-90%, flow rate: 25 mL / min) to give 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).

[0684] Example 53: 3-(4-(2-(((1r,4r)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)-2,9-diazaspiro[5.5]undec-9-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (53)

[0685] 1) Step 1: Under nitrogen 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) was added to a toluene (3 mL) solution containing compound 19e (150 mg, 0.440 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 53a (226 mg, 0.890 mmol, Bid), lithium bis(trimethylsilylamide) (2.2 mL, 2.22 mmol, 1.0 M tetrahydrofuran solution, Anaiji) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (41.0 mg, 90.0 μmol, Bid). The reaction solution was purged with nitrogen three times and reacted at 80°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 53b. MS m / z (ESI): 512.5 [M+1] + .

[0686] 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. The reaction mixture was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 53c. MS m / z (ESI): 412.8 [M+1] + .

[0687] 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 for 0.5 hour. 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 hour. Add sodium acetate borohydride (80.0 mg, 0.380 mmol) to the reaction mixture. Stir the reaction at 25°C for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by high-performance liquid chromatography (A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6×30 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 90% to 70%, flow rate: 25 mL / min) to afford 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).

[0688] Example 54: 3-(4-(1S,4S)-4-((1r,4R)-4-(3-difluoromethyl)-4-(4-(5-morpholinylpyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl(methyl)amino)cyclohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (54)

[0689] 1) Step 1: Compound 54a (1.00 g, 2.45 mmol, prepared using the method disclosed for compound 3A on page 306 of patent application "WO2023017442 A") was dissolved in methanol (10 mL) and wet palladium on carbon (0.130 g, 10%) was added. The reaction solution was purged with a hydrogen balloon three times. The reaction solution was reacted at 25°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 54b. MS m / z (ESI): 229.7 [M+1] + .

[0690] 2) The second step: methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl) (2-amino-1, 1'-biphenyl-2-yl) palladium (II) (294 mg, 0.350 mmol, Bid), compound 19e (593 mg, 1.75 mmol, prepared by the method disclosed in the product of step 3 on page 88 of the specification of patent application "WO2022012623A"), compound 54b (600 mg, 2.63 mmol) and 2-dicyclohexylphosphino-2', 6'-diisopropoxy-1, 1'-biphenyl (164 mg, 0.350 mmol, Bid) were dissolved in toluene (5 mL), and under nitrogen protection, lithium bistrimethylsilylamide (8.8 mL, 8.76 mmol, 1.0 M tetrahydrofuran solution, Anaiji) was added dropwise. The reaction mixture was purged with nitrogen three times and then reacted at 80°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to obtain compound 54c. MS m / z (ESI): 486.4 [M+1] + .

[0691] 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. The reaction mixture was concentrated under reduced pressure to obtain crude compound 54d. MS m / z (ESI): 386.2 [M+1] + .

[0692] 4) Step 4: Compound 54d (200 mg, 0.520 mmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL). Triethylamine (0.1 mL) was added, and the reaction mixture was stirred for 0.5 h. Compound 1e (310 mg, 0.620 mmol) and acetic acid (0.2 mL) were added to the reaction mixture and stirred for 0.5 h. Sodium acetate borohydride (80.0 mg, 0.380 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue which was purified by high performance liquid chromatography (HPLC) (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to afford compound 54. MS m / z (ESI): 867.7 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.07(s,1H),8.77(d,J=7.9Hz,1H),8.66(s,1H),8.53(s,1H),8.38(s,1H),7.34–7.0 2(m,3H),6.88–6.79(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).

[0693] Example 55: 3-(4-(((1R,4r)-4-((((1r,4R)-4-(3-(difluoromethyl)-4-(4-(5-morpholinopyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)(methyl)amino)cyclohexyl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (55)

[0694] 1) Step 1: Compound 19e (518 mg, 1.53 mmol, prepared by the method disclosed in step 3 product on page 88 of the specification of patent application "WO2022012623 A"), compound 55a (698 mg, 3.06 mmol, prepared by the method disclosed in patent application "US 2019 / 0192668 A1 "prepared by the method disclosed in the intermediate 4 on page 858 of the specification), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (140 mg, 0.300 mmol, Bid), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II) (74.2 mg, 90.0 μmol, adamas) was dissolved in toluene (8 mL), and lithium bistrimethylsilylamine (8.9 mL, 8.87 mmol, 1 M tetrahydrofuran solution, Anaiji) was added dropwise under nitrogen protection. The reaction solution was reacted at 80 ° C. under a nitrogen atmosphere for 1 hour. Water (10 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 20 / 1) to obtain compound 55b. MS m / z (ESI): 486.4 [M+1]. + .

[0695] 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 incubated at 25°C for 2 hours and then concentrated under reduced pressure to obtain compound 55c. MS m / z (ESI): 386.7 [M+1] + .

[0696] 3) Step 3: Compound 55c (271 mg, 0.701 mmol) was dissolved in 1,2-dichloroethane (5 mL), tetrahydrofuran (5 mL), and N,N-dimethylformamide (5 mL). Triethylamine (106 mg, 1.06 mmol) was added until the pH was greater than 7. The reaction solution was stirred at 25°C for 10 minutes. Acetic acid (262 mg, 1.41 mmol) and compound 19d (350 mg, 0.701 mmol) were added at -10°C. The reaction solution was stirred at 25°C for 20 minutes, and then sodium acetate borohydride (298 mg, 1.41 mmol, Bidler) was added. The reaction solution was stirred for an additional hour. The reaction mixture was concentrated under reduced pressure to obtain a residue which was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to afford compound 55. MS m / z (ESI): 867.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.06(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,1H),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).

[0697] Example 56: 3-(4-(1R,4R)-4-(4-(4-(5-(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (56)

[0698] 1) Step 1: Dissolve compound 1c-1 (3.02 g, 19.5 mmol) in acetonitrile (30 mL). Add 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) in sequence. Stir the reaction solution at 60°C for 4 hours. Add water (50 mL) to the reaction solution, extract twice with ethyl acetate (50 mL), wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is 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] + .

[0699] 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 solution was stirred at 25°C for 18 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution (20 ml), extracted with ethyl acetate (30 mL*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] + .

[0700] 3) Step 3: Compound 56b (1.00 g, 2.93 mmol) was dissolved in tetrahydrofuran (10 mL) with stirring. Trimethylethynylsilane (285 mg, 2.93 mmol), triethylamine (890 mg, 8.77 mmol), cuprous iodide (55.1 mg, 0.29 mmol), and bistriphenylphosphine palladium dichloride (205 mg, 0.29 mmol) were added sequentially. The system was purged with nitrogen three times. The reaction solution was stirred at 25°C for 18 hours. Water (50 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (30 mL). The solution 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), and potassium carbonate (810 mg, 5.85 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was 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] + .

[0701] 4) Step 4: Compound 56d (300 mg, 1.09 mmol, prepared by the method disclosed in the intermediate on page 402 of the specification of the patent application "WO2022125790 A1") was dissolved in acetonitrile (8 mL). Isoamyl nitrite (153 mg, 1.31 mmol) was added under ice bath. The reaction solution was stirred at 0 ° C for 1 hour. Azidotrimethylsilane (188 mg, 1.64 mmol) was added to the reaction solution. The reaction solution was stirred at 25 ° C for 16 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure to give compound 56e. MS m / z (ESI): 300.1 [M+H] + .

[0702] 5) Step 5: To a mixed solution of compound 56e (325 mg, 1.09 mmol) in ethanol (8 mL) and water (5 mL) were added sodium ascorbyl palmitate (40 mg, 0.22 mmol), copper sulfate pentahydrate (50 mg, 0.22 mmol) and compound 56c (240 mg, 1.09 mmol) in sequence. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL × 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] + .

[0703] 6) Step 6: Compound 56f (320 mg, 0.59 mmol) was added to a 50 mL three-necked flask, tetrahydrofuran (5 mL) was added and stirred until dissolved, the system was replaced with nitrogen 3 times, cooled to -50 ° C, and lithium aluminum hydride tetrahydrofuran solution (0.60 mL, 0.60 mmol, 1.0 M) was added to the reaction solution. The reaction solution was stirred at -50 ° C for 1 hour. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL × 3). Washed with saturated brine (50 mL × 1) and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the residue was purified by column chromatography (methanol / dichloromethane = 15 / 1 to 10 / 1) to obtain compound 56g. MS m / z (ESI): 512.2 [M+H] + .

[0704] 7) Step 7: Dess-Martin periodinane (250 mg, 0.59 mmol) was added to a solution of compound 56g (200 mg, 0.39 mmol) in dichloromethane (8 mL). The reaction solution was stirred at room temperature for 30 minutes. Water (15 mL) was added to the reaction solution, extracted with dichloromethane (15 mL × 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 slurried with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 5 mL) to obtain compound 56i. MS m / z (ESI): 510.1 [M+H] + .

[0705] 8) Step 8: Compound 11a (56.2 mg, 0.140 mmol, prepared using the method disclosed for intermediate AZK on page 222 of the specification of patent application "WO2021158634 A1") was dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and triethylamine (13.9 mg, 0.140 mmol) was added. The reaction solution was stirred at 25°C for 10 minutes, and then acetic acid (8.25 mg, 0.140 mmol) and compound 56i (65.0 mg, 0.130 mmol) were added. The reaction solution was stirred at 25°C under nitrogen for 0.5 hours, and then sodium acetate borohydride (166 mg, 0.780 mmol) was added. After stirring the reaction solution for 1 hour, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). After the aqueous phase was separated, it was extracted with dichloromethane (3 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 56. MS m / z (ESI): 836.4 [M+1] + . 1H NMR (400MHz, CDCl3): δ8.65(s,1H),8.53(s,1H),8.41–8.21(m,2H),8.12(s,1H),7.11–6.68(m,4 H),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,3 H),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 ),2.34–2.23(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).

[0706] Example 57: 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)piperazin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (57)

[0707] Compound 30a (37.8 mg, 0.110 mmol, prepared using the method disclosed for intermediate 199 on page 222 of the specification of patent application "WO2021158634 A1") was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (3 mL), and triethylamine (5.57 mg, 60.0 μmol) was added. The reaction solution was stirred at 25°C for 10 minutes, and then acetic acid (3.3 mg, 60.0 μmol) and compound 19d (25 mg, 0.110 mmol) were added. The reaction solution was stirred at 25°C under nitrogen for 1 hour, and then sodium acetate borohydride (70.0 mg, 0.330 mmol) was added. The reaction solution was stirred at 25°C under nitrogen for 1 hour, and then the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). After the aqueous phase was separated, it was extracted with dichloromethane (3 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 57. MS m / z (ESI): 782.6 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(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).

[0708] Example 58: 3-(4-(9-(((1S,4r)-4-(3-(difluoromethyl)-4-(4-(5-((S)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl(cyclohexyl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (58)

[0709] 1) Step 1: Compound 1c-1 (15.0 g, 97.7 mmol, Shanghai Haohong) was dissolved in N,N-dimethylformamide (200 mL). Cesium carbonate (47.7 g, 147 mmol) and compound 58a (10.4 g, 103 mmol, Bidex) were added. The reaction mixture was reacted at 110°C for 12 hours. Water (1 L) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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] + .

[0710] 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 in portions. The reaction was allowed to react at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford compound 58c. MS m / z (ESI): 345.1 [M+1] + .

[0711] 3) Step 3: Compound 58c (6.00 g, 17.4 mmol) was dissolved in tetrahydrofuran (100 mL), and 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 solution was purged with nitrogen three times and reacted at 25°C for 1 hour. Water (50 mL) was then added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 58d. MS m / z (ESI): 315.1 [M+1]. + .

[0712] 4) Step 4: Compound 58d (3.00 g, 9.54 mmol) was dissolved in methanol (30 mL), and potassium carbonate (2.64 g, 19.1 mmol) was added. The mixture was reacted at 25°C for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to provide compound 58e. MS m / z (ESI): 243.0 [M+1] + .

[0713] 5) Step 5: Compound 58e (1.80 g, 7.43 mmol) was dissolved in tert-butanol (20 mL), and sodium ascorbyl palmitate (150 mg, 0.740 mmol, Anaiji), compound 1b (2.02 g, 7.43 mmol), and cuprous oxide (860 mg, 5.94 mmol, Bidler) were added. The reaction mixture was reacted at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain compound 58f. MS m / z (ESI): 514.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ8.77(d,J=7.9Hz,1H),8.67(s,1H),8.52(s,1H),8.38(s,1H),7.21(t, J=53.1Hz,1H),6.79(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).

[0714] 6) Step 6: Compound 58f (780 mg, 1.52 mmol) was dissolved in dichloromethane (25 mL) and Dess-Martin periodinane (980 mg, 2.31 mmol) was added. The reaction solution was stirred at 25°C for two hours. The reaction solution was poured into water (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was slurried with a mixed solvent (petroleum ether / ethyl acetate = 1 / 1, 20 mL) to obtain compound 58g. MS m / z (ESI): 512.3 [M+1] + .

[0715] 7) Step 7: Compound 36c (125 mg, 0.170 mmol) was dissolved in N,N-dimethylformamide (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. Compound 58g (87.0 mg, 0.170 mmol) and acetic acid (61.0 mg, 1.02 mmol) were then added to the reaction mixture, and the mixture was stirred at 25°C for 30 minutes. Sodium acetate borohydride (217 mg, 1.02 mmol) was then added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 26.5 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 19% to 95%, flow rate: 25 mL / min) to obtain compound 58. MS m / z (ESI): 907.6 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.10(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).

[0716] Example 59: 3-(4-(4-(-4-(((1S,4r)-4-(3-(difluoromethyl)-4-(4-(5-((S)-3-methylmorpholinyl)pyrazolo[1,5-a]pyrimidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl(cyclohexyl)methyl)piperazin-1-yl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyridine-2,6-dione (59)

[0717] Compound 34c (70.0 mg, 0.130 mmol) was dissolved in N,N-dimethylformamide (1.5 mL) and tetrahydrofuran (1 mL), and triethylamine (0.04 mL, 0.320 mmol) was added. The reaction solution was reacted at 25°C for 10 minutes, and then 58 g (72.9 mg, 0.140 mmol) and acetic acid (0.04 mL, 0.780 mmol) were added in sequence. After reacting at 25°C for 30 minutes, sodium acetate borohydride (164 mg, 0.780 mmol) was added, and the reaction was continued at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by high-performance liquid chromatography (Gilson 306-1741, column: Waters-Xbrid ge-C18-10 μm-19×250 mm; mobile phase: water (0.1% formic acid) and acetonitrile, gradient: acetonitrile 15% to 95%; flow rate: 25 mL / min) to afford compound 59 (18.7 mg). MS m / z (ESI): 922.6 [M+1]. + . 1 HNMR (400MHz, DMSO-d6): δ11.11(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=11.7,4.0H z,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=15.7H z,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).

[0718] Example 60: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-3,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-2-azaspiro[3.5]nonan-7-yl)methyl(amino)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazole)pyrrolo[1,2-b]pyridazine-3-carboxamide (60)

[0719] 1) Step 1: Compound 60a (50.0 mg, 0.100 mmol, Bid) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added. After stirring at 25°C for 2 hours, the reaction solution was directly concentrated under reduced pressure. 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] + .

[0720] 2) Step 2: Compound 3a (175 mg, 0.570 mmol, prepared using the method disclosed for intermediate B32-2 on page 574 of the specification of patent application "WO2020206424A1") was dissolved in acetonitrile (8 mL), and compound 60b (106 mg, 0.680 mmol) and potassium carbonate (393 mg, 2.84 mmol) were added. The reaction solution was stirred at 80°C for 2 hours. Water (10 mL) was then added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to obtain compound 60c. MS m / z (ESI): 427.3 [M+1] + .

[0721] 3) Step 3: Compound 60c (120 mg, 0.280 mmol) was dissolved in dichloromethane (5 mL). Dess-Martin periodinane (239 mg, 0.560 mmol) was slowly added to the reaction solution at 30°C. The reaction solution was stirred at 30°C for 2 hours. The reaction solution was then quenched by adding saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, 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] + .

[0722] 4) Step 4: Compound 60f (3.00 g, 18.4 mmol) and compound 60e (6.00 g, 20.2 mmol, prepared using the method disclosed for intermediate k on page 73 of the specification of patent application "WO2014195919 A1") were dissolved in N,N-dimethylformamide (25 mL) and cesium carbonate (18.0 g, 55.2 mmol) was added. The reaction solution was stirred at 80 ° C for 12 hours, and then water (200 mL) was added to the reaction solution and extracted with ethyl acetate (150 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain compound 60g. MS m / z (ESI): 383.0 [M+23] + .

[0723] 5) Step 5: Compound 60g (2.00g, 5.55mmol) was dissolved in methanol (10mL) and wet palladium on carbon (300mg, 10%) was added. The reaction solution was purged with a hydrogen balloon three times and stirred at 25°C for 12 hours. The reaction solution was filtered 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 60h. MS m / z (ESI): 331.2 [M+1] + .

[0724] 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 the reaction solution was reacted at 0°C for 30 minutes, trimethylsilyl azide (1.2 mL, 9.08 mmol) was added. The reaction solution was warmed to 25°C and stirred at this temperature for 1 hour. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was directly used as the raw material for the next step without purification to obtain compound 60i. MS m / z (ESI): 301.0 [M-55] + .

[0725] 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), and copper sulfate pentahydrate (27.0 mg, 0.110 mmol, Anaiji) and sodium ascorbyl palmitate (21.0 mg, 0.110 mmol, Anaiji) were added. The reaction solution was stirred at 25 ° C for 12 hours, and then concentrated under reduced pressure to remove ethanol. Water (10 mL) was added to the reaction solution, and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was directly used as the next raw material without purification to obtain compound 60j. MS m / z (ESI): 542.1 [M+1] + .

[0726] 8) Step 8: Compound 60j (150 mg, 0.280 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (9 mL, 4.0 M). The reaction mixture was incubated at 25°C for 1 hour. The reaction mixture was then 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] + .

[0727] 9) Step 9: Compound 60k (52.0 mg, 0.120 mmol) was dissolved in 1,2-dichloroethane (2.5 mL) and tetrahydrofuran (2.5 mL), and triethylamine (0.02 mL, 0.120 mmol) was added. The reaction solution was stirred at 25°C for 15 minutes, and then 60d (50.0 mg, 0.150 mmol) and acetic acid (0.01 mL, 0.240 mmol) were added. After stirring for 30 minutes, the mixture was stirred for 2 minutes. Sodium cyanoborohydride (50.0 mg, 0.240 mmol) was added, and the reaction was stirred for 30 minutes. The reaction system was then concentrated, and the residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 60. MS m / z (ESI): 850.4 [M+1] + .

[0728] Example 61: 7-(1-(3-(difluoromethyl)-1-((1R,4r)-4-((((1r,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)cyclohexyl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (61)

[0729] 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 was greater than 7. The reaction solution was stirred at 25°C for 10 minutes. The reaction solution 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 solution was warmed to 25°C and stirred at this temperature for 20 minutes. Then, sodium acetate borohydride (14.1 mg, 71.0 μmol, Bid) was added. The reaction solution was stirred 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, 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] + .

[0730] Example 62: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-pyrazol-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (62)

[0731] Compound 45c (31.0 mg, 80 μmol) was dissolved in N,N-dimethylformamide (0.7 mL) and tetrahydrofuran (2 mL), and triethylamine (0.01 mL, 80 μmol) was added. The reaction solution was stirred at 25°C for 15 minutes, and then 19d (35.0 mg, 80 μmol) and acetic acid (0.01 mL, 0.150 mmol) were added. After stirring for 30 minutes, sodium cyanoborohydride (49.0 mg, 0.230 mmol) was added. After stirring for 30 minutes, the reaction system was directly concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to give compound 62. MS m / z(ESI):836.4[M+1] + . 1 H NMR(400MHz,DMSO-d6)δ11.09(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),7.6 5(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,1 H),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).

[0732] Example 63: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidin-3-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (63)

[0733] Compound 42c (61.0 mg, 0.150 mmol) was dissolved in N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL), and triethylamine (0.02 mL, 0.150 mmol) was added. The reaction solution was stirred at 25°C for 15 minutes, and then 19d (70.0 mg, 0.150 mmol) and acetic acid (0.02 mL, 0.310 mmol) were added. After stirring for 30 minutes, sodium cyanoborohydride (12.0 mg, 0.190 mmol) was added. After stirring for 30 minutes, the reaction system was directly concentrated, and the residue was purified by HPLC (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to give compound 63. MS m / z(ESI):837.3[M+1] + .

[0734] Example 64: 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (64)

[0735] Compound 47b (80.0 mg, 0.210 mmol, prepared by the method disclosed in intermediate BJR on page 389 of the specification of patent application "WO 2021 / 127283 A2") and compound 19d (100 mg, 0.220 mmol) were dissolved in tetrahydrofuran (1 mL) and N, N-dimethylformamide (0.5 mL), and acetic acid (0.1 mL) and sodium acetate borohydride (125 mg, 0.590 mmol) were added sequentially. The reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), the desiccant was removed by filtration, 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, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-70%, flow rate: 25 mL / min) to obtain compound 65. MS m / z (ESI): 822.3 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ11.11(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=4.6Hz,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 ),6.91–6.84(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),2.36–2.29(m,2H),2.22–2.12(m,2H),1.98–1.75(m,9H),1.63–1.37(m,2H),1.24–1.03(m,2H).

[0736] Example 65: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propan-2-n-1-yl)oxy)piperidin-1-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (65)

[0737] Compound 19d (70.0 mg, 0.150 mmol) and compound 7a (91.6 mg, 0.230 mmol, prepared by the method disclosed in intermediate 3692 on page 1233 of the specification of patent application "WO2020 / 113233A1") were dissolved in N, N-dimethylformamide (1 mL), and triethylamine (46.8 mg, 0.460 mmol) was added. The reaction solution was stirred at 20 ° C for 5 minutes, and then acetic acid (28.7 mg, 0.150 mmol) was added. The reaction solution was warmed to 40 ° C and stirred at this temperature for 2 hours. After that, the reaction solution was cooled to 20 ° C and sodium acetate borohydride (65.0 mg, 0.310 mmol) was added. The reaction solution was stirred at 20 ° C for 2 hours. Water (2 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration to remove the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (GILSON: GX-281, column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: water (containing 0.0500% ammonia) and acetonitrile, gradient ratio: acetonitrile 37%-77%, flow rate: 60 mL / min) to obtain compound 65. MS m / z (ESI): 835.3 [M+1]. + . 1 H NMR (400MHz, DMSO-d6): δ11.13(s,1H),9.05–8.98(m,1H),8.85–8.77(m,1H),8.74(s,1H),8.66(d,J=2.1Hz ,1H),8.16(s,1H),7.66(d,J=4.6Hz,1H),7.58(s,1H),7.41–7.22(m,1H),7.18(d,J=7.6Hz,1H),7.15–7.09( m,1H),7.08–6.97(m,2H),5.41(dd,J=5.1,12.8Hz,1H),4.48(s,2H),4.35–4.23(m,1H),3.65(s,3H),2.96– 2.80(m,1H),2.76–2.61(m,4H),2.28–1.98(m,8H),1.96–1.75(m,5H),1.65–1.43(m,4H),1.14–0.98(m,2H).

[0738] Example 66: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)amino)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (66)

[0739] 1) Step 1: Compound 18a (100 mg, 0.361 mmol, prepared by the method disclosed in Intermediate CD on page 394 of the specification of patent application "WO 2021 / 188948 A1") and compound 66a (142 mg, 0.721 mmol, Bid) were dissolved in 1,4-dioxane (8 mL) and tetraethyl titanate (0.3 mL, 0.731 mmol) was added. The reaction solution was stirred at 80 ° C under nitrogen protection for 18 hours. The reaction solution was cooled to room temperature and sodium cyanoborate (45.8 mg, 0.731 mmol) was added. The reaction solution was stirred at 25 ° C for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent system (dichloromethane / methanol = 40 / 1 to 5 / 1) to obtain compound 66b. MS m / z (ESI): 456 [M-1] - .

[0740] 2) Step 2: Compound 66b (70.0 mg, 0.151 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was incubated at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to yield 66c. MS m / z (ESI): 358.1 [M+1] + .

[0741] 3) Step 3: Compound 66c (32.2 mg, 91.0 μmol) was dissolved in 1,2-dichloroethane (1 mL) and tetrahydrofuran (1 mL). Triethylamine (8.91 mg, 91.0 μmol) was added until the pH was greater than 7. The reaction mixture was stirred at 25°C for 10 minutes. The reaction mixture was cooled to -10°C, and acetic acid (21.4 mg, 0.112 mmol) and compound 19d (40.0 mg, 91.0 μmol) were added. The reaction mixture was warmed to 25°C and stirred at this temperature for 20 minutes. Sodium acetate borohydride (37.3 mg, 0.182 mmol, Bid) was then added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 66. MS m / z (ESI): 796.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.00(s,1H),8.78(d,J=2.1Hz,1H),8.74(s,1H),8.66(d,J=2.1Hz,1H),8.18(s, 1H),7.65(d,J=4.6Hz,1H),7.56(s,1H),7.23(t,J=53.3Hz,1H),7.05(d,J=4.6Hz,1H),6.86(t,J=8.0Hz,1H),6.51(t, J=8.1Hz,2H),5.33–5.22(m,1H),4.72–4.50(m,1H),4.38–4.23(m,1H),3.62(s,3H),3.25–3.19(m,2H),2.94–2.75(m, 3H),2.72–2.57(m,2H),2.22–2.04(m,6H),2.01–1.89(m,5H),1.89–1.76(m,2H),1.60–1.52(m,2H),1.17–1.02(m,2H).

[0742] Example 67: 7-(1-(3-difluoromethyl)-1-(1R,4R)-4-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)piperazin-1-yl)azepine)-1H-pyrazol-4-yl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (67)

[0743] Compound 44c (20.0 mg, 50.0 μmol) was dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (1 mL), and triethylamine (0.1 mL) was added. The reaction mixture was stirred for 0.5 hours. Compound 19d (28.0 mg, 60.0 μmol) and acetic acid (0.2 mL) were added to the reaction mixture, and the mixture was stirred for 0.5 hours. Sodium acetate borohydride (32.0 mg, 0.150 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 to obtain a residue which was purified by high performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 32%-48%, flow rate: 25 mL / min) to afford compound 67 (5.00 mg). MS m / z (ESI): 837 [M+1] + .

[0744] Example 68: 7-(1-(2,6-difluoromethyl)-1-(1R,4R)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-ylmethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (68)

[0745] Compound 19d (45.0 mg, 0.100 mmol) and compound 68a (37.2 mg, 0.100 mmol, prepared by the method disclosed in the intermediate ARK on page 697 of the specification of the patent application "WO2020264499 A1") were dissolved in 1,2-dichloroethane (1 mL), N,N-dimethylformamide (1 mL) and tetrahydrofuran (1 mL), and triethylamine (10.0 mg, 0.100 mmol) was added. The reaction solution was stirred at 25 ° C for 5 minutes, and then acetic acid (5.95 mg, 0.100 mmol) was added. After the reaction solution was stirred at 25 ° C for 1 hour, sodium acetate borohydride (70.0 mg, 0.330 mmol) was added. The reaction solution was stirred at 25 ° C for 0.5 hours, and the reaction solution was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (10 mL). After separation of the aqueous phase, the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30 x 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 68. MS m / z (ESI): 796.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.00(s,1H),8.78(d,J=1.7Hz,1H),8.73(s,1H),8.65(d,J=1.8Hz,1H),8.16 (s,1H),7.65(d,J=4.5Hz,1H),7.58–7.35(m,1H),7.28–7.04(m,3H),6.96(t,J=7.7Hz,1H),6.88(d,J=7.5Hz,1H),5. 42–5.30(m,1H),4.32–4.23(m,1H),3.67(s,3H),3.64(s,2H),2.92–2.85(m,1H),2.75–2.56(m,4H),2.45–2.29(m,6H ),2.18–2.10(m,4H),2.04–1.99(m,1H),1.96–1.90(m,2H),1.85–1.75(m,2H),1.61–1.52(m,1H),1.14–1.01(m,2H).

[0746] Example 69: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)carbamoyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (69)

[0747] 1) The first step: 18a (100 mg, 0.361 mmol, prepared by the method disclosed in the intermediate CD on page 394 of the specification of the patent application "WO 2021 / 188948 Al") and 69a (174 mg, 0.621 mmol, Bid) were dissolved in dichloromethane (2 mL) and triethylamine (0.2 mL, 1.09 mmol) was added. The reaction solution was stirred at 25 ° C. under nitrogen protection for 1 hour. Water (10 mL) was added to the reaction solution, and ethyl acetate (15 mL × 3) was extracted. The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtering to remove the desiccant. The residue was purified by silica gel column chromatography with an eluent system (dichloromethane / methanol = 40 / 1 to 20 / 1) to obtain compound 69b. MS m / z (ESI): 542 [M+23] + .

[0748] 2) Step 2: Compound 69b (120 mg, 0.231 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran solution (3 mL), and wet palladium on carbon (24 mg, 10%) was added. The reaction solution was purged with a hydrogen balloon three times and reacted at 25°C under a hydrogen atmosphere for 18 hours. The reaction solution was filtered and concentrated to obtain compound 69c. MS m / z (ESI): 386.1 [M+1] + .

[0749] 3) Step 3: Compound 69c (67.8 mg, 0.181 mmol) and compound 19d (80.1 mg, 0.181 mmol) were dissolved in 1,2-dichloroethane (2 mL) and tetrahydrofuran (2 mL), and acetic acid (39.4 mg, 0.211 mmol) was added. The reaction solution was stirred at 25°C for 20 minutes, and then sodium acetate borohydride (74.6 mg, 0.351 mmol, Bidler) was added. The reaction solution was stirred at 25°C for another hour. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by HPLC (Waters-2545, column: SharpSil-T C18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38% to 45%, flow rate: 30 mL / min) to obtain compound 69. MS m / z(ESI):824.2[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.11(s,1H),9.63(s,1H),9.01(s,1H),8.79(d,J=2.1Hz,1H),8.74(s,1H),8.66 (d,J=2.1Hz,1H),8.20(s,1H),7.67–7.62(m,1H),7.59–7.53(m,1H),7.23(t,1H),7.06–6.91(m,3H),6.79( d,J=6.9Hz,1H),5.48–5.28(m,1H),4.34–4.24(m,1H),3.47(s,1H),3.39(s,3H),2.96–2.90(m,2H),2.78–2 .61(m,2H),2.23–2.11(m,5H),2.00–1.89(m,5H),1.87–1.75(m,5H),1.73–1.64(m,2H),1.14–1.02(m,2H).

[0750] Example 70: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (70)

[0751] Compound 70a (80.0 mg, 0.210 mmol, prepared using the intermediate method described on page 568 of the specification of patent application CN112010858, 2020, A) and triethylamine (21.4 mg, 0.210 mmol) were dissolved in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL). The reaction solution was stirred at 0°C for 10 minutes. Acetic acid (25.4 mg, 0.420 mmol) and compound 19d (106 mg, 0.230 mmol) were added, and the reaction solution was stirred at 0°C for 30 minutes. Sodium triacetoxyborohydride (66.8 mg, 0.320 mmol) was added to the reaction solution, and the reaction solution was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding water (1 mL). The reaction mixture was concentrated, and the resulting residue was purified by high-performance liquid chromatography (Waters-2545, column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: Waters (HCl)-CH3CN, gradient ratio: acetonitrile 16% to 56%, flow rate: 30 mL / min) to obtain compound 70. MS m / z (ESI): 781.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),10.64(s,1H),9.01(s,1H),8.79(d,J=2.2Hz,1H),8.75(s,1H),8.67(d,J=2.2Hz,1H ),8.17(s,1H),7.76(d,J=8.4Hz,1H),7.65(d,J=4.5Hz,1H),7.55(s,1H),7.49(d,J=1.8Hz,1H),7.39–7.35(m,1H),7.35–7. 10(m,1H),7.05(d,J=4.5Hz,1H),5.13–5.07(m,1H),4.42–4.30(m,1H),4.20(d,J=13.0Hz,2H),3.60–3.44(m,4H),3.22–3.0 4(m,4H),2.96–2.82(m,1H),2.63–2.52(m,2H),2.24–2.14(m,2H),2.13–1.96(m,4H),1.94–1.84(m,2H),1.35–1.16(m,2H).

[0752] Example 71: 7-(1-(3-difluoromethyl)-1-(1R,4R)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (71)

[0753] Compound 40c (50.0 mg, 0.120 mmol) and compound 19d (50.0 mg, 0.110 mmol) were dissolved in tetrahydrofuran (1 mL) and N,N-dimethylformamide (0.5 mL). Acetic acid (0.1 mL) and sodium acetate borohydride (75.0 mg, 0.350 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 brine (10 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (A: 0.1% formic acid / water, B: acetonitrile, column: Waters-SunFire-C18-10 μm-19×250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient ratio: acetonitrile 32%-75%, flow rate: 25 mL / min) to obtain compound 71. MS m / z (ESI): 865.4 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ11.09(s,1H),9.01(s,1H),8.79(d,J=2.2Hz,1H),8.74(s,1H),8.6 6(d,J=2.1Hz,1H),8.15(s,1H),7.65(d,J=4.6Hz,1H),7.56(s,1H),7.23(t,J=53.3Hz,1H), 7.05(d,J=4.6Hz,1H),7.01–6.86(m,3H),5.41–5.28(m,1H),4.36–4.22(m,1H),3.62(s,3H) ,3.00–2.78(m,8H),2.75–2.62(m,2H),2.27–2.10(m,5H),2.00–1.73(m,9H),1.69–1.33(m, 4H),1.19–0.91(m,2H).

[0754] Example 72: 7-(1-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (72)

[0755] Compound 72a (33.0 mg, 0.100 mmol, prepared by the method of patent application "WO2023023537 A1 (prepared by the method disclosed in step 3 on page 222 of the specification) was dissolved in N,N-dimethylformamide (1 mL) and tetrahydrofuran (4 mL), and triethylamine (0.01 mL, 0.100 mmol) was added. The reaction solution was stirred at 25° C. for 15 minutes, and then 19d (45.0 mg, 0.100 mmol) and acetic acid (0.01 mL, 0.200 mmol) were added. After stirring for 30 minutes, sodium cyanoborohydride (105 mg, 0.500 mmol) was added. After stirring for 30 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-TC18, 30×150 mm, 5 μm; mobile phase: water (containing 10 mmol / L formic acid) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain compound 72. MS m / z(ESI):767.2[...

Claims

1. A compound of formula (A): or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably a deuterated compound), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein: L A Selected from bonds and straight or branched C 1-4 Alkylene, the C 1-4 The alkylene group is optionally substituted by one or more independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, oxo (=O), OH, CN, NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 Alkyl)2 is substituted by a substituent; L B A group selected from the following groups (1) to (21): (1)–CyL1–, (2)–CyL1–La–, (3)–CyL1–Lb–, (4)–CyL1–La–CyL2–La–, (5)–CyL1–NR L1 –, (6)–CyL1–C(O)–, (7)–CyL1–C(O)-NR L1 –, (8)–CyL1–NR L1 -C(O)–, (9)–CyL1–CyL2–, (10)–NR L1 -CyL1-La–, (11)–NR L1 -CyL1-Lb–, (12)–NR L1 -CyL3-NR L2 –, (13)–NR L1 -CyL3-La-NR L2 –, (14)–NR L1 -CyL1-C(O)–, (15)–NR L1 -La-CyL1-La–, (16)–La–CyL1–, (17)–O-La–, (18)–S-La–, (19)–NR L1 -To–, (20)–CyL1–La–CyL3-, and (21)–CyL1–Lc–CyL4-; in: In the groups (1) to (21), the leftmost extending bond of each group is connected to the L A and the rightmost extended key is connected to the part, or the leftmost bond of each group is connected to the The rightmost key is connected to the L A , CyL1 and CyL2 are each independently selected at each occurrence from 3-12 membered heterocycloalkylene, wherein the heterocycloalkylene preferably has 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S, CyL3 is independently selected from C at each occurrence 3-12 Cycloalkylene, 3-12 membered heterocycloalkylene, CyL4 is independently selected at each occurrence from a 5-12 membered heteroarylene group, La is independently selected at each occurrence from C 1-4 Hydrocarbylene, Lb is independently selected at each occurrence from a linear C 2-4 Hydrocarbylene, wherein the straight chain C 2-4 One or two but not all CH2 in the alkylene group are selected from O, S, NR L1 and 1 or 2 groups of C(O), Lc is independently selected at each occurrence from a bond or C 1-4 Hydrocarbylene, CyL1, CyL2, CyL3, CyL4, La, Lb and Lc are each optionally substituted by one or more groups independently selected from the following: 1-4 Alkyl, C 1-4 Haloalkyl, halogen, OH, CN, NH2, -NH(C 1-4 Alkyl) and -N(C 1-4 alkyl) 2, preferably methyl, ethyl, F, Cl, Br, OH, CN and NH 2, more preferably methyl, F, Cl and OH; and R L1 and R L2 Each is independently selected at each occurrence from H and C 1-4 alkyl; Said Some have: (I) Structure of formula (1): in: Ring A is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by R k replaced by; R k Selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, R p R q N-、C 1-6 Haloalkyl, C 1-6 Heteroalkyl (e.g. C 1-6 alkoxy), 4-9 membered heterocyclic group (e.g. 5-6 membered saturated heterocyclic alkyl), C 6-10 Aryl, 5-10 membered heteroaryl; R p , R q are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl; Ring B Selected from the following groups (1)-(3): (1) in: R 4 Selected from hydrogen, C 1-6 Alkyl, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from halogen, hydroxy, C 3-6 Cycloalkyl, C 3-6 substituted with a halogenated cycloalkyl or a 4-7 membered heterocyclic group), wherein the C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl - optionally substituted by 1-3 groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Halogen, Hydroxyl, Hydroxy-C 1-6 Alkylene-, cyano, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent; R 5 Selected from hydrogen, cyano, C 1-6 Alkyl, -C(O)NH2, -NR l R m ; R l , R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; (2) in: R 22 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 alkyl-; R 23 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2, -NR l R m , and R l , R m are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl; (3) in: R 25 Selected from hydrogen, C 4-9 Cycloalkyl, C 4-9 Cycloalkyl-C 1-6 alkyl-, 4-9 membered saturated heterocycloalkyl, 4-9 membered saturated heterocycloalkyl-C 1-6 Alkyl-; R 26 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2; L 1 Selected from direct bond, C 1-6 Alkyl, -NH-, -O-, -S-; R 13 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl; R 14 Selected from C 3-6 Cycloalkylene, 5-12 membered spiroheterocycloalkylene and piperidinylene, the C 3-6 Cycloalkylene, 5-12 membered spiroheterocycloalkylene and piperidinylene are optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Alkyl (e.g. hydroxymethyl), formyl, C 1-6 substituted by an alkyl substituent; or (II) Structure of formula (2) in: Ring A' is selected from 5-10 membered heteroaryl; X 1 , X 2 , X 3 and X 4 are each 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’ ; The characters "a" and "b" each indicate a bond between a ring carbon atom to which Z is attached and two adjacent ring carbon atoms; The part is represented by the structure of the following formula (i) or formula (ii): L 1’ Selected from direct bond and NR 7’ ; R 1’ For -L 2’ -R 1a ; L 2’ -S(O)2NR 1b -*、-C(O)-NR 1b -*, -NR 1b -C(O)-*or-NR 1b -S(O)2-*, where the bond indicated by * is connected to R 1a ; R 1a Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 1e R 1f , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 1e R 1f ; Each R 2’ Independently selected from: H, halogen, OH, SH, -NR 2a R 2b , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 2a R 2b ; m2 is 0, 1, 2 or 3; R 3’ and R 7’ Each independently selected from: H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C 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 3a R 3b ; R 4’ Selected from: H, D, halogen, OH, SH, -NR 4a R 4b , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -C 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 4a R 4b ; R 5’ Selected from C 3-10 Cycloalkylene and 3-10 membered heterocyclylene, wherein the C 3-10 The cycloalkylene and 3-10 membered heterocyclylene are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 5a R 5b ; R 6’ Selected from: H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Halogenated alkenyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl, -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 Alkylene-NR 6a R 6b ; 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 and R 5b , R 6a , R 6b is independently selected at each occurrence from H and C 1-6 Alkyl; and Said The part is the ligase binding part.

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

3. The compound according to claim 1 or 2, wherein The part has the structure of the formula (1).

4. A compound according to any one of claims 1 to 3, wherein: 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 by a group R k replaced by; Preferably, the ring A is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group contains 2-3 heteroatoms, and at least 2 heteroatoms are N atoms; the 5-membered heteroaryl group is optionally substituted by R k replaced by; More preferably, the ring A is selected from 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, imidazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl; Further preferably, the ring A is selected from Where #C indicates connection Partial connection site, $L 1 Indicates connection L 1 The attachment site of Further preferably, the ring A is selected from Where #C indicates connection Partial connection site, $L 1 Indicates connection L 1 The attachment site of and / or R k Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, R p R q N-、C 1-6 Haloalkyl and 4-9-membered saturated heterocycloalkyl (e.g. 5-6-membered saturated heterocycloalkyl); Preferably, R k Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, R p R q N-、C 1-6 Haloalkyl and morpholinyl; and / or R p , R q are each independently selected from hydrogen and C 1-6 alkyl; and / or More preferably, R k isopropyl, cyclopropyl, dimethylamino, difluoromethyl, 5. A compound according to any one of claims 1 to 4, wherein: L 1 is selected from a direct bond and -NH-, preferably a direct bond; and / or R 13 Selected from C 1-4 The haloalkyl group is preferably -CHF2 and trifluoromethyl, and more preferably -CHF2.

6. The compound according to any one of claims 1 to 5, wherein the structure of the formula (1) is represented by the following formula (1-1) or (1-2):

7. The compound according to any one of claims 1 to 6, wherein the ring B is selected from the following groups (1) to (3): (1) in: R 4 is selected from hydrogen, 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl, 4-7 membered saturated monocyclic heterocycloalkyl-C 1-4 Alkyl-, 6-9 membered saturated heterocyclic alkyl-C 1-4 Alkyl-, -NR Na R Nb (where R Na and R Nb Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1 to 3 groups selected from halogen, hydroxy, C 3-6 Cycloalkyl, C 3-6 The 4-7-membered saturated monocyclic heterocycloalkyl, 6-9-membered saturated bridged heterocycloalkyl, 6-9-membered saturated spiro heterocycloalkyl, 4-7-membered saturated monocyclic heterocycloalkyl-C 1-4 Alkyl-, 6-9 membered saturated heterocyclic alkyl-C 1-4 Alkyl - optionally substituted by 1-3 groups selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Halogen, Hydroxyl, Hydroxy-C 1-6 Alkylene-, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent; Preferably, R 4 is selected from hydrogen, 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl, -NR Na R Nb (where R Na and R Nb Independent H, C 1-6 Alkyl, C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be optionally substituted by 1, 2 or 3 groups selected from hydroxy, C 3-6 The 4-7 membered saturated monocyclic heterocycloalkyl, 6-9 membered saturated bridged heterocycloalkyl, 6-9 membered saturated spiro heterocycloalkyl are optionally substituted by 1, 2 or 3 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, hydroxy-C 1-6 Alkylene-, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent; R 4 Selected from hydrogen, Said Optionally 1-3 selected from C 1-6 Alkyl, halogen, hydroxyl, hydroxyl (C 1-6 alkyl)-, cyano, -NH2, -N(C 1-6 Alkyl) and -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent, m1 is selected from 0, 1, 2 and 3, preferably 0, and n1 is selected from 0, 1, 2 and 3, preferably 0 or 1; Preferably, R 4 Selected from hydrogen, Said Optionally 1, 2 or 3 selected from C 1-6 Alkyl, hydroxy, -NH2, hydroxy (C 1-6 alkyl)-substituted; and / or R 4 Selected from hydrogen, (include )、 (include )、 (include )、 (include )、 (include )、 (include Best )、 (include Best )、 (include )； and / or R 5 Selected from hydrogen, cyano, -C(O)NH2, -NR l R m ; and / or R l , R m are each independently selected from hydrogen, C 1-6 alkyl; and / or R 5 is selected from hydrogen, cyano; and / or As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )and Preferably, As a whole, selected (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )、 (Preferred )； (2) in: R 22 Selected from hydrogen and m4 is selected from 0, 1, 2, 3, and n4 is selected from 0, 1, 2, 3; Preferably, R 22 Selected from hydrogen and More preferably, R 22 Selected from hydrogen; and / or R 23 Selected from hydrogen, C 1-6 Alkyl, cyano, carboxyl, -C(O)NH2 and -NR l R m ; Preferably, R 23 Selected from hydrogen, cyano, carboxyl, -C(O)NH2 and -NR l R m ; Preferably, R 23 Selected from hydrogen, cyano, -C(O)NH2 and -NR l R m ; More preferably, R 23 Selected from -C(O)NH2; and / or R l , R m are each independently selected from hydrogen and C 1-6 alkyl; and / or As a whole, selected Preferably, As a whole, selected More preferably, As a whole, (3) in: R 25 Selected from hydrogen, m6 is selected from 0, 1, 2 and 3, and n6 is selected from 0, 1, 2 and 3; Preferably, R 25 Selected from hydrogen, More preferably, R 25 is hydrogen; and / or R 26 Selected from hydrogen, C 1-6 alkyl, cyano and -C(O)NH2; preferably, R 26 Selected from hydrogen, C 1-6 Alkyl and -C(O)NH2; more preferably Ground, R 26 Selected from -C(O)NH2; and / or As a whole, selected Preferably, As a whole, 8. A compound according to any one of claims 1 to 7, wherein: R 14 Selected from C 3-6 Cycloalkylene, the C 3-6 The cycloalkylene group is optionally substituted by 1-2 groups selected from hydroxyl C 1-6 Alkyl (e.g., hydroxymethyl) and formyl substituents; Preferably, R 14 Selected from p is selected from 0, 1, 2; R g Selected from hydrogen, hydroxyl C 1-6 Alkyl, formyl; preferably, R g Selected from hydrogen; Or, R 14 is selected from 7-11 membered spiroheterocycloalkylene, the 7-11 membered spiroheterocycloalkylene is optionally substituted by 1-2 selected from hydroxyl C 1-6 Alkyl (e.g. hydroxymethyl), formyl and C 1-3 substituted by an alkyl substituent, Preferably, R 14 is selected from 9-11 membered spiroheterocycloalkylene groups having 1, 2 or more nitrogen heteroatoms and 0, 1 or 2 heteroatoms selected from O and S; Or, R 14 is selected from piperidinyl, the piperidinyl being optionally substituted with 1-2 C 1-3 Alkyl (preferably methyl) substitution; More preferably, R 14 Selected from Further more preferably Even more preferred wherein the bond identified by x is connected to the pyrazole ring, and the bond identified by y is connected to the L A .

9. A compound according to any one of claims 1 to 8, wherein Some selected from:

10. The compound according to claim 1 or 2, wherein The part has the structure of formula (2).

11. A compound according to any one of claims 1-2 and 10, wherein R 3’ Selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 3a R 3b ; H and C are preferred 1-4 Alkyl, preferably H and methyl, more preferably H.

12. The compound according to any one of claims 1-2 and 10-11, wherein the structure of formula (2) is represented by formula (2-1):

13. A compound according to any one of claims 1-2 and 10-12, wherein: n2 is 0 or 1; and / or R 5’ Selected from: C 3-10 Cycloalkylene and 3-10 membered heterocyclylene, wherein the C 3-10 The cycloalkylene and 3-10 membered heterocyclylene are each optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 5a R 5b ; Preferably, R 5’ Selected from: C 3-6 Cycloalkylene and 5-10 membered heterocycloalkylene, wherein the C 3-6 The cycloalkylene and 5-10 membered heterocycloalkylene are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 5a R 5b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 5a R 5b ; More preferably, R 5’ Selected from: C 3-6 Cycloalkylene and 5-10 membered heterocycloalkylene, wherein the C 3-6 The cycloalkylene and 5-10 membered heterocycloalkylene are each optionally substituted by 1 or more substituents independently selected from the following groups: 1-4 Alkyl, C 1-4 Haloalkyl, -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 ; More preferably, R 5’ Selected from Best More preferred The bond marked with "c" is connected to the L A and the bond marked with "d" is connected to the ring A'; or preferably, the bond marked with "c" is connected to the ring A' and the bond marked with "d" is connected to the L A ; and / or The ring A' is selected from a 5-10 membered monocyclic or fused bicyclic heteroaryl group; Preferably, the ring A' is selected from a 5-6 membered monocyclic heteroaryl and a 9-10 membered fused bicyclic heteroaryl; More preferably, the ring A' is selected from: 5-6 membered monocyclic heteroaryl and benzo 5-6 membered monocyclic heteroaryl, wherein preferably, the ring A' is connected to the L through the 5-6 membered monocyclic heteroaryl ring. 1’ connect; More preferably, the ring A' is selected from: a 5-membered monocyclic heteroaryl and a benzo 5-membered monocyclic heteroaryl, wherein preferably, the ring A' is connected to the L through the 5-membered monocyclic heteroaryl ring. 1 connect; and / or, wherein preferably, the 5-membered monocyclic heteroaryl is selected from furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl; More preferably, the ring A' is selected from pyrazolyl, benzofuranyl, benzothienyl and indolyl; wherein preferably, the benzofuranyl is connected to the L through the furan ring. 1 The benzothienyl group is connected to the L 1 The indolyl group is connected to the L through the pyrrole ring. 1 connect; More preferably, the ring A' is selected from Preferably, the Partially selected More preferred and / or X 1 , X 2 and X 3 Each is CH; or X 1 is N, and X 2 and X 3 Each is CH; or X 2 is N, and X 1 and X 3 Each is CH; or X 3 is N, and X 1 and X 2 Each is CH; or X 1 and X 2 Each is N, and X 3 is CH; or X 1 and X 3 Each is N, and X 2 is CH; or X 2 and X 3 Each is N, and X 1 is CH; or X 1 , X 2 and X 3 Each is N.

14. The compound according to any one of claims 1-2 and 10-13, wherein the structure of formula (2) is: As shown in formula (2-2)-(2-4): Preferably, as shown in formula (2-5)-(2-8):

15. A compound according to any one of claims 1-2 and 10-14, wherein: R 7’ Selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 3a R 3b ; H and C are preferred 1-4 Alkyl, more preferably H and methyl, further more preferably H; and / or R 4’ Selected from: H, D, halogen, OH, SH, -NR 4a R 4b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -C 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 4a R 4b ; preferably H, D, halogen, OH, -NR 4a R 4b , CN, C 1-4 Alkyl and C 1-4 Haloalkyl; preferably H, D, F, Cl, OH, -NH2, CN, methyl, ethyl, -CHF2 and -CF3; more preferably H, D, F, Cl methyl and ethyl, further more preferably H; and / or R 6’ Selected from: H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 6a R 6b ; Preferably, R 6’ Selected from: H, halogen, OH, SH, -NR 6a R 6b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -C 1-4 Alkylene -OH, -C 1-4 Alkylene -SH, -C 1-4 Alkylene -CN and -C 1-4 Alkylene-NR 6a R 6b ; More preferably, R 6’ Selected from: H, F, Cl, OH, -NH2, -NHCH3, -N(CH3)2, CN, methyl, ethyl, -CHF2 and -CF3; more preferably H, -NH2, -NHCH3, -N(CH3)2, methyl, ethyl, -CHF2 and -CF3, and further more preferably H, methyl, ethyl and -CHF2.

16. The compound according to any one of claims 1-2 and 10-15, wherein the structure of formula (2) is represented by formula (2-9)-(2-12):

17. A compound according to any one of claims 1-2 and 10-16, wherein: R 1a C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, SH, -NR 1e R 1f , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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 Alkylene-NR 1e R 1f ; Preferably, R 1a is phenyl, wherein the phenyl is optionally substituted by one or more substituents independently selected from the following groups: halogen, OH, -NR 1e R 1f , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Alkyl and -OC 1-4 Haloalkyl, preferably F, Cl, OH, -NH2, CN, methyl and ethyl; More preferably, R 1a Selected from and / or L 2’ -S(O)2NR 1b -*、-C(O)-NR 1b -* or -NR 1b -C(O)-*, preferably -S(O)2NR 1b -*, where the bond indicated by * is connected to R 1a ; and / or Each R 2’ Independently selected from: H, halogen, OH, SH, -NR 2a R 2b , CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, -OC 1-4 Alkyl, -OC 1-4 Halogenated alkyl, -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, -C 1-4 Alkylene-NR 2a R 2b ; 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 is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H, methyl and ethyl.

18. A compound according to any one of claims 1-2 and 10-17, wherein: Some selected from:

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

20. A compound according to any one of claims 1 to 19, wherein: Said Some are E3 ubiquitin ligase ligands, Preferably, the Some selected from: in: Ring Aa is a 5-membered heterocyclic group or a 5-membered heteroaryl group, preferably a 5-membered heterocyclic group or a 5-membered heteroaryl group having 1, 2 or more N heteroatoms, wherein the 5-membered heterocyclic group and the 5-membered heteroaryl group are optionally substituted by one or more independently selected from H, halogen, OH, NH2, CN, oxo and C 1-4 Alkyl substituents are substituted, Preferably, Partially selected The bond marked with "z" is connected to X 5 ; Each ring are independently phenyl or 5-6 membered heteroaryl, preferably phenyl; X 5 CR L7 or N; t is 0 or 1, preferably 1; R L1 , R L5 and R L6 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; R L2 and R L3 Each is independently selected at each occurrence from H and C 1-4 Alkyl, preferably H and methyl; or R L2 and R L3 Together they form an oxo group; R L4 and R L7 Each is independently selected at each occurrence from H, halogen, OH, NH2, CN and C 1-4 Alkyl, preferably H, F, Cl, Br and C 1-2 Alkyl, more preferably H, F, Cl and methyl; m5 is 0, 1, 2, 3 or 4, preferably 1 or 2; Preferably, the Partially selected 21. A compound according to any one of claims 1 to 20, wherein Some selected from:

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

23. The compound according to claim 1, wherein the compound has a structure shown in formula (B): in: L B Selected from: (1) -CyL1-, wherein the CyL1 group is selected from 7-11-membered spiroheterocycloalkylene, more preferably 9-11-membered spiroheterocycloalkylene, wherein the 7-11-membered spiroheterocycloalkylene and the 9-11-membered spiroheterocycloalkylene each have 1 or 2, preferably 2, nitrogen heteroatoms, and are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; or (2) -CyL1-CyL2-, wherein the CyL1 and CyL2 groups are each independently selected from 4-7 membered monocyclic heterocycloalkylene, more preferably 4-6 membered monocyclic heterocycloalkylene, wherein the 4-7 membered monocyclic heterocycloalkylene and the 4-6 membered monocyclic heterocycloalkylene each have 1 or 2 nitrogen heteroatoms, and are optionally substituted by 1 or more groups independently selected from the following: C 1-4 Alkyl and halogen, preferably methyl, F and Cl, more preferably methyl and F; R 4 Selected from 4-6 membered saturated monocyclic heterocycloalkyl and -NR Na R Nb , where R Na Selected from H and C 1-6 Alkyl and R Nb Selected from C 3-6 cycloalkyl, and wherein the 4-6 membered saturated monocyclic heterocycloalkyl and the C 3-6 The cycloalkyl group is substituted with 1 to 3 substituents selected from halogen and hydroxy; and R 5 For hydrogen.

24. The compound according to claim 23, wherein L B Selected from: (Preferred ), (Preferred ), (Preferred ), (Preferred ), More preferred Wherein in any of the above groups, the bond marked with "u" is connected to part, and the key marked with "v" is connected to part; and / or R 4 Selected from 4-6 membered saturated monocyclic nitrogen-containing heterocyclic alkyl (preferably piperidinyl) and -NR Na R Nb , where R Na H and R Nb Selected from C 3-6 Cycloalkyl (preferably cyclohexyl), wherein the 4-6 membered saturated monocyclic nitrogen-containing heterocycloalkyl and the C 3-6 The cycloalkyl group is substituted with one hydroxyl group. Preferably, R 4 Selected from More preferred 25. The compound according to claim 23 or 24, wherein the compound is selected from:

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 deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

27. Use of a compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystalline form, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 in the preparation of a medicament for treating a disease, disorder or condition associated with IRAK4 protein kinase.

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

29. The use according to claim 27, or the method according to claim 28, wherein the disease, disorder or condition associated with IRAK4 protein kinase is selected from the group consisting of: autoimmune disorders, inflammatory disorders, cancer, transplant rejection, thromboembolism, atherosclerosis, myocardial infarction and metabolic syndrome; Preferably, the inflammatory disorder is selected from the group consisting of osteoarthritis, gout, gouty arthritis, chronic obstructive pulmonary disease, periodic fever, atopic dermatitis, hidradenitis suppurativa, chronic nephritis, allergic eczema, lymphadenopathy, sepsis, irritable bowel syndrome (IBD), ulcerative colitis, asthma and allergies, preferably osteoarthritis, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa and chronic nephritis; and / or Preferably, the autoimmune disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, multiple sclerosis, neuropathic pain, ankylosing spondylitis, reactive arthritis and systemic juvenile idiopathic arthritis, preferably psoriasis; and / or Preferably, the transplant rejection is selected from graft-versus-host disease and allogeneic transplant rejection; and / or Preferably, the cancer is selected from the group consisting of brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumors, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma tumors, melanoma, acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

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