Synthesis and use of novel proteolysis chimera compound targeting interleukin-1 receptor-associated kinase 4 (IRAK4)

Abstract

The present invention relates to the technical field of chemical pharmacy, and in particular to a compound for degradation of a targeted interleukin-1 receptor-associated kinase 4 (IRAK4), and a pharmaceutically acceptable salt of the compound. The compound can be used for treating or preventing IRAK4-mediated immune diseases, inflammatory diseases, and cancers.

Description

Synthesis and application of a novel protein degradation chimeric compound targeting interleukin-1 receptor-associated kinase 4 (IRAK4) Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound and a pharmaceutically acceptable salt thereof for targeting the degradation of interleukin-1 receptor-associated kinase 4 (IRAK4), which can be used as a drug for treating or preventing immune diseases and inflammatory diseases mediated by IRAK4. Background Art

[0002] The concept of protein degradation targeting chimeras (PROTACs) was proposed in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). Early PROTACs recruited E3 ligases through peptides, but the molecules had poor membrane permeability and limited activity. In 2008, small molecule PROTACs based on the MDM2 E3 ligase appeared, but the activity of these molecules was not good. It was not until 2010 to 2012 that the currently commonly used ligands based on the cereblon (CRBN) and VHL (von Hippel-Lindau) E3 ligases appeared, which enabled the binding level of small molecule ligands to E3 ligases to reach the micromolar level, laying the foundation for the subsequent development of PROTACs. PROTACs molecules are bifunctional molecules, one end of which contains a ligand that binds to the E3 ubiquitin ligase and the other end contains a ligand that binds to the target protein, and the two parts are connected by a linker unit. By bringing the linker unit closer together, PROTACs bring the E3 ligase and target protein into close proximity, leading to polyubiquitination and proteasomal degradation of the target protein. PROTACs employ a completely different mechanism of action from small molecule inhibitors. First, the E3 ubiquitin ligase ligase's ligand recruits the E3 ubiquitin ligase to the vicinity of the target protein, bringing it into close proximity and labeling it for ubiquitination. The labeled target protein is then degraded by the proteasome system in the body, thereby inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared to traditional small molecule drugs, due to their altered binding mechanism, PROTACs only require transient binding to the target protein to complete the ubiquitin transfer process before irreversible degradation of the target protein is achieved. Therefore, PROTACs offer the following advantages: 1) stronger degradation and longer-lasting efficacy; 2) higher selectivity for the target protein; and 3) the ability to overcome the resistance to traditional small molecule inhibitors caused by target protein mutations (Cell Chem. Biol. 2018, 25, 67-77).

[0003] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine / threonine protein kinase and a member of the IRAK family. IRAK4 is a key signaling node that switches between the transmembrane recognition receptor protein IL-1R and TLR responses, acting upstream of the signaling cascade. When viral, bacterial, or cytokine molecules bind to TLRs / IL-1R receptors, their shared TIR domain recruits the scaffolding protein MyD88 (myeloid differentiation primary response gene 88). MyD88 utilizes its death domain to recruit and bind to IRAK4, leading to its trans-autophosphorylation and activation of its kinase function, which in turn phosphorylates IRAK1, IRAK2, or IRAKM (IRAK3). The MyD88:IRAK4:IRAK1 / 2 complex forms the myddosome, which in turn recruits and activates IRAK1 / 2. Phosphorylation of IRAK1 / 2 recruits TRAF6 (TNF receptor associated factor 6), which in turn activates TAK1, a member of the MAPK kinase family. TAK1 activates IKKβ within the IKK complex, phosphorylating NF-κB. This ultimately promotes the expression of a series of proinflammatory cytokines and chemokines, stimulating inflammation and activating a series of transcription factors downstream (NF-κB, CREB, AP-1, IRF, etc.), promoting the secretion of proinflammatory cytokines and the proliferation and differentiation of immune cells. Therefore, the TLR signaling pathway prompts immune cells to initiate a series of immune responses, thereby activating the body's innate immune system. IRAK4 is central to all MyD88-dependent signaling, playing a connecting role in the TLR / IL-1 signaling pathway. Overactivation or abnormal activity due to mutations leads to sustained activation of downstream signaling molecules, which in turn stably induces the expression of cytokines and chemokines, triggering related inflammatory and immune responses, contributing to the development of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, and gout. IRAK4 with kinase domain mutations has been shown to protect mice in various inflammatory disease models, including septic shock, systemic lupus erythematosus, acute liver injury, cardiovascular disease, and Alzheimer's disease. Therefore, inhibiting IRAK4 has become a highly sought-after therapeutic target for suppressing autoimmune and inflammatory diseases.

[0004] CRBN is a protein encoded by the CRBN gene in humans. Homologs of CRBN are highly conserved from plants to humans. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullin regulator 1 (ROC1). This complex ubiquitinates many other proteins. Through a mechanism that has not yet been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates many developmental processes, such as limb and auditory bulla formation. Therefore, this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of CRBN, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0005] The discovery of CRBN-type E3 ligase ligands was closely related to the study of thalidomide's mechanism of action. In 2010, while investigating thalidomide toxicity, scientists discovered cereblon as a thalidomide-binding protein (Science 2010, 327, 1345). Cerebellum is part of the E3 ubiquitin ligase protein complex, acting as a substrate receptor to selectively target ubiquitinated proteins. This study suggested that thalidomide-cereblon binding in vivo may contribute to thalidomide's teratogenicity. Subsequent studies have shown that this compound and related structures may be useful as anti-inflammatory, anti-angiogenic, and anti-cancer agents. Further structural modifications of thalidomide have resulted in lenalidomide and pomalidomide, which have significantly improved safety and reduced teratogenicity. Lenalidomide was approved by the FDA in 2006. Two groundbreaking papers published in Science in 2014 demonstrated that lenalidomide exerts its effects by degrading two specific B-cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3). This further revealed that thalidomide may further degrade target proteins by binding to the E3 ubiquitin ligase complex of cerebellum (Science, 2014, 343, 301; Science, 2014, 343, 305). Based on this, CRBN ligands have been widely used in protein degradation, and a series of CRBN ligand-based PROTACs have been developed. Because CRBN ligands themselves affect their targets and may also degrade zinc finger domain proteins, the design and synthesis of new, highly selective CRBN ligands is particularly important in the synthesis of PROTACs. Summary of the Invention

[0006] The present invention provides a novel chimeric PROTAC compound molecule targeting interleukin-1 receptor-associated kinase 4 (IRAK4) protein degradation. These molecules show significant activity as IRAK4 degraders in the treatment of IRAK4-mediated or dependent diseases.

[0007] The present invention adopts the following technical solutions:

[0008] The first aspect of the present invention provides a compound, which is a compound represented by formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof:

[0009] Formula (I): PTM-L-CLM;

[0010] Wherein L is a bond or linker moiety connecting CLM and PTM, having the structure -(A L ) q -, A L Each occurrence is the same or different and each occurrence is independently selected from the group consisting of: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、S(O)、S(O)2、NR L3 、C(O)、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 substituted arylene group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 spirocyclylene, and optionally 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene; preferably, A L Each occurrence is the same or different and each occurrence is independently selected from: a covalent bond, a CR L1 R L2 、O、NRL3 , C(O), optionally substituted with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 a heteroarylene group substituted with a group, and optionally substituted with 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene;

[0011] R L1 、R L2 and R L3 Each occurrence is independently selected from H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, -SR L4 、-NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、S(O)2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、C(O)R L6 、CN、NO2、SF5、S(O)2NR L4 R L5 、C(O)NR L4 R L5 、N(R L4 )C(O)NR L5 R L4 and N(R L4 )S(O)2NR L4 R L5 ; preferably R L1 、R L2 and R L3 Each occurrence is independently selected from H, halogen, alkyl, alkoxy, and CN;

[0012] R L4 、R L5 and R L6Each occurrence is independently selected from H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl; preferably R L4 、R L5 and R L6 each occurrence of is independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl;

[0013] q is an integer greater than or equal to 1; preferably q is an integer greater than or equal to 1 and less than or equal to 20; preferably q is an integer greater than or equal to 1 and less than or equal to 15;

[0014] The CLM is selected from the following structures:

[0015] Among them, W n O、C(R N )2、NR N , C(O) or C(O)NR N ; preferably W n O, NR N or C(O); more preferably W n O or NR N ;

[0016] n1 and n2 are each independently 0, 1, 2 or 3; preferably n1 and n2 are each independently 1 or 2;

[0017] n3 and n4 are each independently 1, 2 or 3 when they occur; preferably n3 and n4 are each independently 1 or 2 when they occur;

[0018] R nn Each occurrence is independently selected from H, deuterium, cyano, F, Cl, Br, I, OH, NH2, NO2, C 1- C6 alkyl, C 1- C6 alkoxy, C1-C6 haloalkyl and C2-C6 unsaturated hydrocarbon; preferably R nn Each occurrence is independently selected from H, deuterium, cyano, F, Cl, Br, I, OH, NH2, NO2, C 1- C6 alkyl, C 1- C6 alkoxy, and C1-C6 haloalkyl; preferably R nn Each occurrence is independently selected from H, F, Cl, Br, I, OH, NH2, C 1-C6 alkyl, C 1- C6 alkoxy, and C1-C6 haloalkyl;

[0019] Cy1 is independently selected at each occurrence from 6-10 membered arylene and 5-10 membered heteroarylene containing 1-3 heteroatoms independently selected from N, O and S, wherein said 6-10 membered arylene and 5-10 membered heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro and cycloalkyl;

[0020] Cy2 is independently selected at each occurrence from 5-10 membered heterocycloalkylene containing 1-3 heteroatoms independently selected from N, O, and S and 5-10 membered heteroarylene containing 1-3 heteroatoms independently selected from N, O, and S;

[0021] R n0 Selected from CR a R b NR a , O and S;

[0022] R n1 CR a or N;

[0023] R n2 CR a R b or C(=O);

[0024] R n3 Selected from CR a R b NR a , O and S; preferably R n3 CR a R b or O;

[0025] W1 and W2 are CR independently each time they appear a R b 、C(=O)、NR a or SO2, and at least one of W1 and W2 is C(=O); preferably W1 and W2 are each independently CR a R b or C(=O)2, and at least one of W1 and W2 is C(=O);

[0026] G and Z are each independently selected from O, S and Se at each occurrence; preferably G and Z are each independently selected from O at each occurrence;

[0027] R 3a 、R 3b 、R3c and R 3d Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0028] R 3a0 、R 3b0 、R 3c0 , and R 3d0 Each occurrence is independently selected from a single bond, O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, imino, cycloalkylene, heterocyclylene, alkyleneamino, arylene and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl; 3a0 、R 3b0 、R 3c0 , and R 3d0 Each occurrence is independently a single bond or O;

[0029] W 5 , and W 6 Each occurrence is independently C(R m )2、NR m , O or S; preferably W 5 , and W 6 Each occurrence is independently C(R m )2;

[0030] W 11 CR a R b 、C(=O)、NR a or S(O)2; preferably W 11 is C(=O);

[0031] R 1 、R 2 、R a 、R N and R bEach occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0032] R 22 Selected from single bond, C(O), O, S, S(O)2, NR m NR m A combination of one or more of C(O)-, alkylene, alkenylene, alkynylene, haloalkylene and heteroalkylene; preferably R 22 Selected from single bond, NR m and NR m C(O);

[0033] Each occurrence of n is independently 0, 1, 2 or 3; preferably each occurrence of n is independently 1;

[0034] R 32 and R 42 The carbon atom connected to it forms And R 52 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, 42 and R 52 The carbon atom connected to it forms And R 32 、R 62 and R 72each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, 52 and R 62 The carbon atom connected to it forms And R 32 、R 42 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, 62 and R 72 The carbon atom connected to it forms And R 32 、R 42 and R 52 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, 32 and R 82The atoms to which it is attached form a heterocyclic group, and R 42 、R 52 、R 62 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0035] R d 、R e 、R f 、R g 、R D 、R E 、R F 、R G 、R f1 、R g1 、R F1 and R G1 Each occurrence is independently C(R m )2、NR m , O, C(O) or S, and R d 、R e 、R D and R E at Each occurrence independently represents the site of attachment to a carbon atom on the benzene ring that is attached to R 32 、R 42 、R 52 or R 62 connected carbon atoms;

[0036] W3 and W4 are CR independently each time they appear m or N;

[0037] R t 、R T 、R t1 , and R T1 Each time it appears, it is independently CR m or N, R t 、R T 、R t1 , and R T1 at represents the attachment site to CLM or L;

[0038] R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a hydroxyl, a nitro, a cyano, an amino, a cycloalkyl, a heterocyclyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl are each independently optionally selected from F, Cl, Br, I, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 alkoxy, a hydroxyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a cyano, an amino, nitro, a C3-C6 cycloalkyl, a C3-C6 heterocyclyl, a C1-C6 alkylamino, a C6-C 15 Aryl and C5-C 15 is substituted by one or more substituents in a heteroaryl group;

[0039] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1+m2≤6;

[0040] m3 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7 each time it appears, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8 each time it appears, and m3+m4≤8;

[0041] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7;

[0042] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7+m8≤7;

[0043] m31 and m41 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m31 and m41 are not 0 at the same time, and m31+m41≤7;

[0044] m51 and m61 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m51 and m61 are not 0 at the same time, and m51+m61≤7;

[0045] The PTM is selected from the following structures:

[0046] Among them, L P is a single bond, C1-C6 alkylene, NR m , O, C(O) or -NR m C(O)-; preferably L Pis a single bond or -NR m C(O)-;

[0047] Ring A is a 6-10 membered arylene group, a 5-10 membered cycloalkylene group containing 0-3 heteroatoms each independently selected from N, O, and S, a 7-12 membered bicycloalkylene group, a 5-10 membered heterocycloalkylene group, or a 7-12 membered biheterocycloalkylene group, or a 5-10 membered heteroarylene group or a 7-12 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, Ring A is a 5-6 membered heteroarylene group or a 9-10 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S;

[0048] Ring B is a 6-10 membered arylene group, a 5-10 membered cycloalkylene group containing 0-3 heteroatoms each independently selected from N, O, and S, a 7-12 membered bicycloalkylene group, a 5-10 membered heterocycloalkylene group, or a 7-12 membered biheterocycloalkylene group, or a 5-10 membered heteroarylene group or a 7-12 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, Ring B is a 5-6 membered heteroarylene group or a 9-10 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S;

[0049] The C ring is absent or is a 6-10 membered arylene group, a 3-10 membered cycloalkylene group, a 7-12 membered bicycloalkylene group, a 3-10 membered heterocycloalkylene group or a 7-12 membered biheterocycloalkylene group containing 1-3 heteroatoms each independently selected from N, O, and S, or a 5-10 membered heteroarylene group or a 7-12 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, the C ring is absent or is a 6-10 membered arylene group, a 4-6 membered cycloalkylene group, a 7-12 membered bicycloalkylene group, a 4-6 membered heterocycloalkylene group or a 7-12 membered biheterocycloalkylene group containing 1-3 heteroatoms each independently selected from N, O, and S, or a 5-6 membered heteroarylene group or a 9-10 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S;

[0050] R P Each occurrence is independently selected from halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, -O-cycloalkyl, -O-heterocyclyl, aryl and heteroaryl, said alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, heterobridged ring group, aryl and heteroaryl being optionally substituted by one or more selected from R S3 substituted by a substituent;

[0051] R QEach occurrence is independently selected from halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, heterobridged cyclyl, aryl, and heteroaryl, said heterocyclyl and heterobridged cyclyl being optionally substituted with one or more substituents selected from hydroxy, halogen, and alkyl;

[0052] R S1 Selected from single bond, C(O), O, S, S(O)2, -NR m -、-NR m a combination of one or more of C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0053] R S2 Selected from single bond, C(O), O, S, S(O)2, -NR m -、-NR m a combination of one or more of C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0054] R S3 Each occurrence is independently selected from hydroxy, halogen, alkyl, deuterated alkyl, heteroalkyl, cyano, amino, cycloalkyl, and heterocyclyl;

[0055] m' is 0, 1, 2, or 3; and

[0056] n' is 1, 2 or 3; preferably n' is 1.

[0057] In one embodiment, wherein

[0058] R 32 and R 42 The carbon atom connected to it forms And R 52 、R 62 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 is substituted by one or more substituents of heterocyclic, aryl and heteroaryl; preferably, R 52 、R 62 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably, R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 42 and R 52 The carbon atom connected to it forms And R 32 、R 62 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 is substituted by one or more substituents among heterocyclic, aryl and heteroaryl; preferably, R 32 、R 62 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably, R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 52 and R 62 The carbon atom connected to it forms And R 32 、R 42 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 is substituted by one or more substituents of heterocyclic, aryl and heteroaryl; preferably, R 32 、R 42 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably, R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 62 and R 72 The carbon atom connected to it forms And R 32 、R 42 and R 52 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 42 and R 52 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or, R 32 and R 82 The atoms connected to it form C4-C 10 Heterocyclic group, and R 42 、R 52 , and R 62 Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group or a C1-C6 haloalkyl group; and / or

[0059] R L1 、RL2 and R L3 Each occurrence is independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 NR L4 R L5 , C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH、S(O)2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、C(O)R L6 、CN、NO2、SF5、S(O)2NR L4 R L5 、C(O)NR L4 R L5 、N(R L4 )C(O)NR L5 R L4 or N(R L4 )S(O)2NR L4 R L5 , preferably R L1 、R L2 and R L3 Each occurrence is independently F, Cl, Br, , CN, OH, C1-C6 alkyl or C1-C6 alkoxy, more preferably R L1 、R L2 and R L3 is independently at each occurrence F, CN, OH, methyl or methoxy; and / or

[0060] R L4 and R L5 Each occurrence is independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C5-C 15 Heteroaryl or C5-C 15 halogenated heteroaryl; and / or

[0061] RL6 Each occurrence is independently H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C5-C 15 Heteroaryl or C5-C 15 halogenated heteroaryl; and / or

[0062] W1 and W2 are each independently CH2, N(C1-C6 alkyl) or C(=O), preferably CH2 or C(=O), and at least one of W1 and W2 is C(=O); and / or

[0063] G is O; and / or

[0064] Z is O; and / or

[0065] R d 、R e 、R D and R E Each occurrence is independently NR m 、C(R m )2 or O, and R d 、R e 、R D and R E at Each occurrence independently represents the site of attachment to a carbon atom on the benzene ring that is attached to R 32 、R 42 、R 52 or R 62 The carbon atom connected to the d 、R e 、R D and R E Each time it appears, it is C(R m )2 or 0; and / or

[0066] R f 、R g 、R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or

[0067] m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3; preferably, m1+m2=1 or m1+m2=3; and / or

[0068] m3 is independently an integer of 0, 1, 2, 3, 4, or 5 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5 at each occurrence, and m3+m4≤5; preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0069] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0070] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4, preferably m7+m8=2 or m7+m8=3; and / or

[0071] m31 and m41 are each independently an integer of 0, 1, 2, 3 or 4, m31 and m41 are not 0 at the same time, and m31+m41≤4; preferably m31+m41=2 or m31+m41=3; and / or

[0072] m51 and m61 are each independently an integer of 0, 1, 2, 3 or 4, m51 and m61 are not 0 at the same time, and m51+m61≤4; preferably m51+m61=2 or m51+m61=3; and / or

[0073] W 3 and W 4 is CH or N; and / or

[0074] W5 and W6 are C(R m )2 or N(R m ), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or

[0075] R 3a 、R 3b 、R 3c and R 3d Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and C6-C 15Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C5-C 15 Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C6-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R 3a 、R 3b 、R 3c , and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group and a C1-C3 alkoxy group; and / or

[0076] R 3a0 、R 3b0 、R 3c0 , and R 3d0 Each occurrence is independently selected from a single bond, O, C(O), NH, N(C1-C6 alkyl) and C1-C6 alkylene; preferably, R 3a0 、R 3b0 、R 3c0 , and R 3d0 Each occurrence is independently selected from a single bond, O, C(O) and C1-C3 alkylene; and / or

[0077] R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C 15 Aryl and C5-C 15 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C5-C 15Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C5-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R m is independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or

[0078] R 1 、R 2 、R a , and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; and / or

[0079] R N selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0080] R 22 Selected from single bond, -NR 2A -、-NR 2A C(O)-, C1-C6 alkylene, C1-C6 haloalkylene, R 2Aselected from H and C1-C6 alkyl; and / or

[0081] R P Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, an -O-C3-C8 heterocyclyl group, an -O-C3-C6 cycloalkyl group, an -NH(C1-C6 alkyl group), an -NH(C1-C6 alkyl group)-CN, an -NH-C3-C8 heterocyclyl group, a C6-C 15 Aryl and C5-C 15 Heteroaryl, preferably, R P Each occurrence is independently selected from hydrogen, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C3 deuterated alkyl, C1-C3 heteroalkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, -O-C3-C6 heterocyclyl, -O-C3-C6 cycloalkyl, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)-CN, -NH-C3-C6 heterocyclyl, C6-C 15 Aryl and C5-C 15 Heteroaryl, said heterocyclyl and heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; and / or

[0082] R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C3-C6 10 Heterocyclic group, C5-C 10 Heterobridged ring group, C6-C 15 Aryl and C5-C 15 Heteroaryl, the heterocyclic group and heterobridged ring group are optionally substituted by one or more substituents selected from hydroxyl, halogen and C1-C6 alkyl; preferably, R QEach occurrence is independently selected from hydrogen, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, C1-C3 deuterated alkyl, C1-C3 heteroalkyl, C2-C6 alkenyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, hydroxy, C1-C3 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C7 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C6 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S 10 Heterobridged ring group, C6-C 15 Aryl and C5-C 15 Heteroaryl, the C3-C7 heterocyclic group and C5-C 10 The heterobridged ring group is optionally substituted with one or more substituents selected from hydroxy, halogen and C1-C3 alkyl; and / or

[0083] R S1 Selected from single bond, C(O), O, S, C 1-3 Alkylene, C 2-4 Alkenylene, and C 2-4 A combination of one or more alkynylene groups; preferably, R S1 is selected from a single bond, C1-C3 alkylene, C2-C4 alkenylene and C2-C4 alkynylene; and / or

[0084] R S2 Selected from single bond, C(O), O, -NR m -、-NR m A combination of one or more of C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene, wherein R m Selected from H or C 1-3 Alkylene; preferably, R S2 Selected from single bond, C 1-3 Alkylene, C(O), NH, C(O) and C 1-3 A combination of alkylene, a combination of C(O) and NH; preferably, R S2 is selected from a single bond, C=O, CH2C=O, CH2, CH2CH2, NH, and NHC=O; preferably, R S2 selected from a covalent bond, a C1-C3 alkyl group, an amino group and a carbonyl group; and / or

[0085] L P is a covalent bond or -NHC(O)-; and / or Cy1 is selected from indazolylene, thienylene, furanylene, phenylene and pyridinylene, indazolylene, thienylene, furanylene, phenylene and pyridinylene, which are optionally substituted with one or more substituents selected from C1-C6 alkyl; preferably wherein Optionally substituted with one or more substituents selected from C1-C6 alkyl; and / or

[0086] Cy2 is selected from piperidinyl, piperidinyl, pyrazolyl, pyridinyl and pyrimidinyl, preferably

[0087] In one embodiment, the CLM is selected from:

[0088] R 3a0 、R 3b0 、R 3a 、R 3b 、R 3c 、R 3d 、W 1 、W 2 、R 1 、R 2 、R 32 、R 42 、R 52 、R 62 、R 1D 、R 1E 、R F 、R G 、R T 、R 1d 、R 1e 、R f 、R g 、R f 、R g 、R t 、m1、m3、m4、m5、m6、R N 、W 11 、W 3 、W 4 、R F1 、R G1 、R T1 、m31、m41、m7、m8、R 22 , W7, B1, B2, B3, B4, B5, B6, C1, C2, C3, n2, n3, n4, n5, n6, R 72 、W n 、n1、R nn 、R n1 、R n2 、R n3 、R n0 , Cyn, Z, G, W 5 、W 6 As defined in any one of claims 1 or 2;

[0089] m9 and m10 are each independently an integer of 0, 1, 2, 3, 4, or 5, and m1+m9+m10≤5; preferably, m1, m9, and m10 are each independently an integer of 0, 1, or 2, and m1+m9+m10≤2, preferably m1+m9+m10=1 or m1+m9+m10=0;

[0090] m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1;

[0091] R 1 、R 2 、R a 、R N and R b Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, and a hydroxyalkyl group; preferably, R 1 、R 2 、R a 、R N and R b Each is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group;

[0092] n is 0, 1, 2, or 3;

[0093] R 1d 、R 1e 、R 1D and R 1E Each occurrence is independently O, or C(R m )2;

[0094] W 11 is C(=O);

[0095] R 22 Selected from single bond, -NR 2A -、-NR 2A C(O)-, alkylene and haloalkylene, R 2A Each occurrence is independently selected from H and C1-C6 alkyl; preferably, R 22 Selected from single bond, -NR 2A -、-NR 2A C(O)-, C1-C6 alkylene, C1-C6 haloalkylene, R2A is selected from H and C1-C6 alkyl; preferably, R 22 is a single bond, NH, NHC(O) or N(CH3)C(O);

[0096] W 7 are each independently CH or N;

[0097] Each occurrence of B1 and B3 is independently selected from C(R m )2 and C(O); preferably, each occurrence of B1 and B3 is independently C(R m )2 or O;

[0098] B2 is selected from C(R m )2、NR m , O and S; preferably, B2 is C(R m )2 or O;

[0099] B4 and B5 are each independently selected from CR m and N; preferably, B4 and B5 are each independently selected from CH and N;

[0100] Each time B6 appears, select C(R m )2、NR m , O and S;

[0101] n2, n3, n4, n5 and n6 are each independently 0, 1, 2 or 3;

[0102] Each time C1 and C2 appear, they are independently C(R m )2;

[0103] C3 is selected from CR m and N; C3 side connected Represents the connection site with CLM or L;

[0104] R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro, cyano and amino; preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy.

[0105] In one embodiment, the CLM is selected from the following structures:

[0106] in,

[0107] W 1 、W2 、R T 、R 1d 、R 1e 、R f , Rg, R 1D 、R 1E 、R F 、R G 、R T 、R 1d 、R 1e 、R f 、R g 、R D 、R E 、R d 、R e 、R t , m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, R N 、W 11 、W 3 、W 4 、R T1 、n2、n3、n4、n5、n6、R 22 、W n 、n1、R n1 、R n2 、R n3 、R n0 、Cyn、W 5 、W 6 , as defined in any one of claims 1 to 3;

[0108] R 3a 、R 3b 、R 3c 、R 3d 、R 3a1 、R 3b1 、R 3c1 , and R 3d1 Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group;

[0109] R F0 、R G0 、R d1 、R e1 、R f1 、R g1 、R D1 、R E1 、R F1 , and R G1 Each occurrence is independently C(R m )2 or O;

[0110] R H1 , and Rh1 Each occurrence is independently selected from N and CR m ;

[0111] R nn Each occurrence is independently selected from H, F, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl.

[0112] In one embodiment, the CLM is selected from the following structures:

[0113] W 1 、W 2 、R 3a 、R 3b 、R 3c 、R 3d 、R T 、R T1 、R t 、R D 、R E 、R F 、R G ,m3,m4,m31,m41,m5,m6,m7,m8,R 1D 、R 1E 、R F0 、R G0 、R 1d 、R 1e 、R f 、R g 、R F1 、R G1 、R m As defined in any one of claims 1 to 4;

[0114] Among them, R 3a1 、R 3b1 、R 3c1 , and R 3d1 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group;

[0115] R 1d1 、R 1e1 、R 1D1 and R 1E1 Each occurrence is independently O or C(R m )2;

[0116] W 31 and W 41 Each occurrence is independently N, or CR m ;

[0117] Rh1 and R H1 N, CR m .

[0118] In one embodiment, the CLM is selected from the following structures:

[0119] R f1 、R g1 、R F1 、R G1 、R N 、m3、m4、m5、m6、W 11 , as defined in any one of claims 1 to 4;

[0120] Among them, R 1d1 、R 1e1 、R 1D1 , and R 1E1 Each occurrence is independently O or C(R m )2;

[0121] R h1 and R H1 Each independently selected from N or CR m and / or

[0122] R 3a1 、R 3b1 、R 3c1 , and R 3d1 Each independently represents H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group.

[0123] In one embodiment, the CLM is selected from the following structures:

[0124] Preferably, the CLM is selected from

[0125] In one embodiment, wherein

[0126] A L Each occurrence is the same or different and is independently selected from: a covalent bond, a CR L1 R L2 、O、S、SO、SO2、NR L3 , C(O), cycloalkylene, heterocyclylene, spirocyclylene, heterospirocyclylene, arylene, and heteroarylene, wherein the cycloalkylene, heterocyclylene, spirocyclylene, heterospirocyclylene, arylene, and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 group substitution; and / or

[0127] R L1 、R L2 and R L3 Each occurrence is independently selected from H, F, Cl, Br, I, C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, C 1-8 Alkoxy, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group) (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, C(O)-C 1-8 Alkyl, C(O)OH, CN, CF3, CHF2, CH2F, NO2, C(O)NH-C 1-8 Alkyl, C(O)N(C 1-8 alkyl)2, N(C 1-8 alkyl)C(O)NH(C 1-8 alkyl), N(C 1-8 alkyl)C(O)N(C 1-8 alkyl)2、NHC(O)NH(C 1-8 alkyl), NHC(O)N(C1-8 alkyl) 2, and NHC(O)NH 2, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl, and heteroaryl; and / or

[0128] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0129] In one embodiment, wherein A L One or more selected from the following structures, and the two connection sites of the following structures are interchangeable: covalent bond, -O-, -(CH2) k -, -C(O)-, -NH-, -N(CH3)-, and / or

[0130] k is an integer selected from 1-13, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0131] In one embodiment, L is selected from the following structures:

[0132] Covalent bond, -(CH2) j -、-NH-(CH2) j -、-(CH2) j -NH-, -NH-(CH2) j -NH-,

[0133] j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

[0134] p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0135] k is an integer selected from 1-13, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0136] Preferably, L is selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 10 -、-(CH2) 11-、-NH-CH2-、-NH-(CH2)2-、-NH-(CH2)3-、-NH-(CH2)4-、-NH-(CH2)5-、-NH-(CH2)6-、-NH-(CH2)7-、-NH-(CH2)8-、-C(O)-、-C(O)-CH2-、-C(O)-NH-C H2-、-C(O)-NH-(CH2)2-、-C(O)-NH-(CH2)3-、-C(O)-NH-(CH2)4-、-C(O)-NH-(CH2)5-、-C(O)-NH-(CH2)6-、-C(O)-NH-(CH2)7-、-C(O)-NH-(CH2)8-、 -CH2-NH-、-(CH2)2-NH-、-(CH2)3-NH-、-(CH2)4-NH-、-(CH2)5-NH-、-(CH2)6-NH-、-(CH2)7-NH-、-(CH2)8-NH-、-NH-CH2-NH-、-NH-(CH2)2-NH-、-NH-(CH2)3-NH-、-NH-(CH2)4-NH-、-NH-(CH2)5-NH-、-NH-(CH2)6-NH-、-NH-(CH2)7-NH-、-NH-(CH2)8-NH-、-C(O)-NH-CH2-NH-、-C(O)-NH-(CH2)2-NH- 、-C(O)-NH-(CH2)3-NH-、-C(O)-NH-(CH2)4-NH-、-C(O)-NH-(CH2)5-NH-、-C(O)-NH-(CH2)6-NH-、-C(O)-NH-(CH2)7-NH-、-C(O)-NH-(CH2)8-NH-、-(CH2-CH2-O)-CH2-CH2-、-(CH2-CH2-O)2-CH2-CH2-、-(CH2-CH2-O)3-CH2-CH2-、-NH-(CH2-CH2-O)-CH2-CH2-、-NH-(CH2-CH2-O)2-CH2-CH2-、-NH-(CH2-CH2-O)2-CH2-CH2-、-NH-(C H2-CH2-O)3-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-、-(CH2-CH2-O)-CH2-CH2-NH-、-(CH2-CH2-O)2-CH2-CH2-NH-、-(CH2-CH2-O)3-CH2-CH2-NH-、-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2- CH2-NH-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, - CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O- CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2 -(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3- NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH -, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-NH-, -C(O)-NH-CH2-CH2-(O -CH2-CH2)3-NH-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2), 10 -O-, -(CH2) 11 -O-,

[0137] In one embodiment, the L-CLM is selected from the following structures:

[0138] In one embodiment, the PTM is:

[0139] in,

[0140] Ring A is a 6-10 membered arylene group, a 5-10 membered cycloalkylene group containing 0-3 heteroatoms each independently selected from N, O, and S, a 7-12 membered bicycloalkylene group, a 5-10 membered heterocycloalkylene group or a 7-12 membered biheterocycloalkylene group, or a 5-10 membered heteroarylene group or a 7-12 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, Ring A is a 6 membered arylene group, a 5-6 membered heteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S, or a 9-10 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; more preferably, Ring A is a 6 membered heteroarylene group containing 1 N atom, or a 9 membered biheteroarylene group containing 2 or 3 N atoms; preferably, for in, Indicates that L P The attachment site;

[0141] R Q Definitions are the same as those in any one of claims 1 to 3, wherein n' is independently 1, 2 or 3 at each occurrence; preferably, R Q Each occurrence is independently selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C7 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C6 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S 10 Heterobridged ring group, the C3-C7 heterocyclic group and C5-C 10 The heterobridged ring group is optionally substituted with one or more substituents selected from hydroxy, halogen and C1-C3 alkyl; and / or

[0142] Ring B is a 6-10 membered arylene group, a 5-10 membered cycloalkylene group containing 0-3 heteroatoms each independently selected from N, O, and S, a 7-12 membered bicycloalkylene group, a 5-10 membered heterocycloalkylene group or a 7-12 membered biheterocycloalkylene group, or a 5-10 membered heteroarylene group or a 7-12 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; preferably, Ring B is a 6 membered arylene group, a 5-6 membered heteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S, or a 9-10 membered biheteroarylene group containing 1-3 heteroatoms each independently selected from N, O, and S; more preferably, Ring B is a 5 membered heteroarylene group containing 1-3 N atoms or a 9 membered biheteroarylene group containing 2-3 N atoms; preferably, for Preferably, for

[0143] Preferably, for Among them, *Lp Indicates the binding site with Lp, *R S1 at Represents R S1 The attachment site of R P and Lp are as defined in any one of claims 1 to 3, and m' is independently 0, 1, 2 or 3 each time it occurs; preferably L P is a single bond or -NHC(O)-; and / or

[0144] The C ring is absent or is a 6-10 membered arylene group, a 3-10 membered cycloalkylene group, a 7-12 membered bicycloalkylene group, a 3-10 membered heterocycloalkylene group or a 7-12 membered bicycloalkylene group containing 1-3 heteroatoms independently selected from N, O, and S, or a 5-10 membered heteroarylene group or a 7-12 membered bicycloarylene group containing 1-3 heteroatoms independently selected from N, O, and S; preferably, the C ring is a 5-6 membered cycloalkylene group or a 4-6 membered heterocycloalkylene group containing 1-3 heteroatoms independently selected from N, O, and S; more preferably, the C ring is a cyclohexylene group, an azetidinyl group, a piperidinyl group, or a thiadiazolyl group; more preferably, the C ring is More preferably Among them, *R S1 at Represents R S1 The attachment site, *R S2 at Represents R S2 and / or

[0145] R P Each occurrence is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxy, C 1-6 Hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8 membered heterocyclic group, -NHC 1-6 Alkyl, -NHC 1-6 Alkyl, -CN or -NH-3-8 membered heterocyclic group; preferably, R P Selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, hydroxy, C 1-3 Hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8 membered oxygen-containing heterocycloalkyl, -NHC 1-3 Alkyl, NHC 1-3Alkyl-CN or -NH-3-8 membered heterocyclic group; preferably, R P Each occurrence is independently C(CH3)2OH, OCH3, CH3, OCH(CH3) 2、 NHCH3, NHCH(CH3)2, NHCH2CN, CF3 or CHF 2； and / or

[0146] R Q Each occurrence is independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 haloalkyl, 4-8 membered cycloalkyl, 5-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S, 5-10 membered heterobridged ring group containing 1-3 heteroatoms independently selected from N, O, and S, and 5-10 membered aryl, wherein the heterocyclic group and heterobridged ring group are optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl and C 1-6 The alkyl group is substituted with a substituent; preferably, R Q Selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 haloalkyl, 5-8 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms independently selected from N and O, and 7 membered heterobridged ring groups containing 1-3 heteroatoms independently selected from N and O, the 5-8 membered monocyclic heterocycloalkyl and heterobridged ring groups are optionally substituted by 1, 2 or 3 groups selected from hydroxyl and C 1-3 The alkyl group is substituted with a substituent; preferably, R Q Each occurrence is independently CF3, F, CH3, CN, CHF2, OCH3, and / or

[0147] R S1 Selected from single bond, C(O), O, S, C 1-3 Alkylene, C 2-3 Alkenylene, and C 2-3 A combination of one or more alkynylene groups; preferably, R S1 is a single bond; and / or

[0148] R S2 Selected from single bond, C(O), O, -NR m -、-NR m C(O)-、C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Haloalkylene, and C1-6 A combination of one or more heteroalkylene groups, wherein the R m Each occurrence is independently H or C 1-3 Alkylene; preferably, R S2 Selected from single bond, C 1-3 Alkylene, C(O), NH, C(O) and C 1-3 A combination of alkylene, a combination of C(O) and NH; preferably, R S2 Selected from a single bond, C=O, CH2C=O, CH2, CH2CH2, NH, and NHC=O.

[0149] In one embodiment, the PTM is selected from compounds having the following structural formula:

[0150] Wherein, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8 are each independently selected from CH and N; Q9 is O or NR P1 or S;

[0151] and / or

[0152] X is selected from the following structures, and the two connection sites of the following structures are interchangeable:

[0153] Among them, R P1 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably C1-C4 alkyl, C1-C4 hydroxyalkyl or C1-C4 haloalkyl; and / or

[0154] R P2Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably a hydrogen atom, a C1-C4 alkyl group or a C1-C4 haloalkyl group; and / or

[0155] R P3 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably a hydrogen atom, a C1-C4 alkyl group or a C1-C4 haloalkyl group; and / or

[0156] R P4 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, heterobridged ring, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, 4-8 membered heterocyclic containing 1-3 selected from O, N, S, 4-8 membered heterobridged ring containing 1-3 selected from O, N, S, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably a 4-8 membered hetero-bridged ring group containing 1-3 selected from O, N, S; preferably a 7 membered hetero-bridged ring group containing N, O;

[0157] Preferably, the PTM is selected from More preferably, selected from

[0158] Preferably, R P2 、R P4 Each occurrence is independently selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-8 membered cycloalkyl, 5-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O, S, 5-10 membered heterobridged ring group containing 1-3 heteroatoms selected from N, O, S, 5-10 membered aryl; preferably, selected from C 1-3 Alkyl, C 1-3 Halogenated alkyl, 5-8 membered heterocyclic group containing N, O heteroatoms, 7 membered heterobridged ring group containing N, O heteroatoms, said heterocyclic group and heterobridged ring group are optionally substituted by 1 or 2 selected from C 1-3 More preferably, R P2 、R P4 Each independently is CF3,

[0159] Preferably, R P1 、R P3 Each occurrence is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, C 1-6 Hydroxyalkyl; preferably, R P1 、R P3 Each independently selected from a hydrogen atom, C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy, C 1-3 Hydroxyalkyl; preferably, R P1 、R P3 Each independently is H, -C(CH3)2OH, or CHF2;

[0160] Preferably, X is selected from the following structures:

[0161] In one embodiment, the PTM is selected from the following structures:

[0162] Preferably, the PTM is selected from the following structures:

[0163] In one embodiment, the compound comprises a compound represented by the following formula (IA), formula (IB), formula (IC) or formula (ID):

[0164] L and CLM are each as defined in any one of claims 1 to 11;

[0165] X1 is CH or N; X2 is a single bond or C(O);

[0166] n7 is 0 or 1; n8 is 0 or 1;

[0167] R P1 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably C1-C4 alkyl, C1-C4 hydroxyalkyl or C1-C4 haloalkyl;

[0168] R P2 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably a hydrogen atom, a C1-C4 alkyl group or a C1-C4 haloalkyl group;

[0169] R P3Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 heteroaryl;

[0170] R P4 Each occurrence is independently selected from hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, heterobridged ring, aryl and heteroaryl; preferably hydrogen, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C1-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, 4-8 membered heterocyclic containing 1-3 selected from O, N, S, 4-8 membered heterobridged ring containing 1-3 selected from O, N, S, C6-C 15 Aryl and C6-C 15 Heteroaryl; preferably a 4-8 membered hetero-bridged ring group containing 1-3 selected from O, N, S; preferably a 7 membered hetero-bridged ring group containing N, O;

[0171] Preferably, R P1 is C1-C4 alkyl, C1-C4 hydroxyalkyl or C1-C4 haloalkyl;

[0172] R P2 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0173] R P3 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0174] R P4 It is a 5-8 membered heterocyclic group containing N, O heteroatoms or a 7 membered heterobridged ring group containing N, O, preferably CF3,

[0175] R P5 Hydrogen, NHC 1-6 Alkyl, NHC 1-6Alkyl-CN or -NH-3-8 membered heterocyclic group, preferably NHCH3, NHCH(CH3)2, NHCH2CN or

[0176] R P6 is hydrogen or cyano; and / or

[0177] L is selected from the following structures: Preferably, L is p is 0, 1 or 2, y is 0, 1 or 2; and / or

[0178] The CLM is selected from

[0179] Among them, W 7 is CH or N, preferably N;

[0180] R 22 is a single bond, NH, NHC(O) or N(CH3)C(O); preferably a single bond;

[0181] R 32 、R 62 and R 72 are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy and cyano; preferably H, fluorine, chlorine, methyl, methoxy or cyano; and / or

[0182] B2 is O, NH or N(C1-C6 alkyl), preferably O or N(CH3);

[0183] B1 is a single bond or a C1-C3 alkylene group, preferably a single bond or a methylene group;

[0184] B6 is a single bond or a methylene group, preferably a single bond;

[0185] Preferably, R 32 and R 62 H, R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, and a cyano group, R 72 Preferably H, fluorine, chlorine, methyl, methoxy or cyano;

[0186] Preferably, the CLM is

[0187] In one embodiment, the compound is a compound represented by the following formula (IA1), formula (IB1), formula (IC1) or formula (ID1):

[0188] Among them, R P1 、R P2 、R P3 、R P4 、R P5 、R P6 , L, X2, and CLM each define claim 15.

[0189] The present invention provides compounds, which are compounds represented by formula (II), formula (III) or formula (IV), or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:

[0190] Formula (II): PTM-L-CLM;

[0191] Wherein L is a bond or linker moiety connecting the CLM and PTM, having the structure -(A L ) q -, A L Each occurrence is the same or different and each occurrence is independently selected from the group consisting of: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、SO、SO2、NR L3 、CO、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 substituted arylene group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 Spirocyclyl, optionally substituted by 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene;

[0192] R L1 、R L2 and R L3are each independently H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, -SR L4 、-NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、COR L6 、CN、NO2、SF5、SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ;

[0193] R L4 each independently represents halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0194] R L5 each independently represents H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0195] R L6 each independently represents H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0196] q is an integer greater than or equal to 1;

[0197] The CLM is selected from the following structures:

[0198] Among them, W n O, NR N or C(O)NR N, n1, n2, n3, n4 are each independently 0, 1, 2 or 3; R nn Each occurrence is independently selected from H, deuterium, cyano, F, Cl, Br, I, -OH, -NH2, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 2-6 unsaturated hydrocarbon group;

[0199] Cyn is selected from 6-10 membered aryl and 5-10 membered heteroaryl containing 1-3 heteroatoms each independently selected from N, O and S;

[0200] R n0 Selected from CR a R b NR a , O and S; R n1 CR a or N, R n2 CR a R b Or C=O;R n3 Selected from CR a R b , O and S;

[0201] W 1 and W 2 Each independently CR a R b 、C(=O)、NR a or SO2, and W 1 and W 2 At least one of them is C(=O);

[0202] G and Z are each independently selected from O, S and Se;

[0203] R 3a 、R 3b 、R 3c and R 3d each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0204] R 3a0 、R 3b0 、R3c0 、R 3d0 Each independently selected from a single bond, O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, imino, cycloalkylene, heterocyclylene, alkyleneamino, arylene and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl;

[0205] W 5 、W 6 Each occurrence is independently C(R m )2、NR m , O or S;

[0206] W 11 CR a R b 、C(=O)、NR a or SO2,

[0207] R 1 、R 2 、R a 、R m 、R N and R b Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0208] R 22 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0209] n is 0, 1, 2, or 3;

[0210] R 32 and R 42The carbon atoms connected to it can form And R 52 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0211] R 42 and R 52 The carbon atoms connected to it can form And R 32 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0212] R 52 and R 62 The carbon atoms connected to it can form And R 32 、R 42 and R 72each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0213] R 62 and R 72 The carbon atoms connected to it can form And R 32 、R 42 and R 52 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0214] or R 32 and R N The atoms to which it is attached optionally form a heterocyclic group, and R 42 、R 52 、R 62 、R 72each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0215] R d 、R e 、R f 、R g 、R D 、R E 、R F 、R G 、R f1 、R g1 、R F1 and R G1 Each occurrence is independently C(R m )2、NR m , O, CO or S;

[0216] W 3 and W 4 Each independently CR m or N;

[0217] R t 、R T 、R t1 、R T1 Each independently CR m or N, R t 、R T 、R t1 、R T1 Side connection Represents the connection site with CLM or L;

[0218] R mEach occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a hydroxyl, a nitro, a cyano, an amino, a cycloalkyl, a heterocyclyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl are each independently optionally selected from F, Cl, Br, I, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 alkoxy, a hydroxyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a cyano, an amino, nitro, a C3-C6 cycloalkyl, a C3-C6 heterocyclyl, a C1-C6 alkylamino, a C6-C 15 Aryl and C3-C 15 is substituted by one or more substituents in a heteroaryl group;

[0219] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1+m2≤6;

[0220] m3 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7 each time it appears, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8 each time it appears, and m3+m4≤8;

[0221] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7;

[0222] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7+m8≤7;

[0223] m31 and m41 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m31+m41≤7;

[0224] m51 and m61 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m51+m61≤7;

[0225] The PTM is selected from the following structures:

[0226] wherein Ring A is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 7-12 membered biheterocycloalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered biheteroaryl group containing 1-3 heteroatoms selected from N, O, and S;

[0227] Ring B is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 7-12 membered biheterocycloalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered biheteroaryl group containing 1-3 heteroatoms selected from N, O, and S;

[0228] The C ring is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group, or a 7-12 membered biheterocycloalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered biheteroaryl group containing 1-3 heteroatoms selected from N, O, and S;

[0229] R P each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0230] R Q each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, heterobridged cyclyl, aryl, and heteroaryl;

[0231] R S1 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0232] R S2 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0233] m' is 1, 2 or 3;

[0234] n' is 1, 2, or 3;

[0235] Alternatively, the compound is a compound represented by formula (III), or its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:

[0236] Formula (III): PTM-L-CLM;

[0237] Wherein L is a bond or linker portion connecting the CLM and PTM, having the structure -(A L) q -, A L Each occurrence is the same or different and each occurrence is independently selected from the group consisting of: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、SO、SO2、NR L3 、CO、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 substituted arylene group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 Spirocyclyl, optionally substituted by 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene;

[0238] R L1 、R L2 , and R L3 are each independently H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SR L4 NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、COR L6 、CN、NO2、SF5、SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONRL5 R L4 or N(R L4 )SO2NR L4 R L5 ;

[0239] R L4 , and R L5 each independently represents H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0240] R L6 each independently represents H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0241] q is an integer greater than or equal to 1;

[0242] The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures:

[0243] Among them, W 1 and W 2 Each independently CR a R b 、C(=O)、NR a or SO2, and W 1 and W 2 At least one of them is C(=O); G and Z are each independently selected from O, S and Se;

[0244] R 3a 、R 3b 、R 3c , and R 3d each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0245] R 3a0 、R 3b0 、R 3c0 、R 3d0Each independently selected from O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, imino, cycloalkylene, heterocyclylene, alkyleneamino, arylene and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl;

[0246] W 5 、W 6 Each occurrence is independently C(R m )2、NR m , O or S;

[0247] W 11 CR a R b 、C(=O)、NR a or SO2,

[0248] R 1 、R 2 、R a 、R m 、R N , and R b Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0249] R 22 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0250] n is 0, 1, 2, or 3;

[0251] R 32 and R 42 The carbon atoms connected to it can form And R 52 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0252] R 42 and R 52 The carbon atoms connected to it can form And R 32 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0253] R 52 and R 62 The carbon atoms connected to it can form And R 32 、R 42 and R 72each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0254] R 62 and R 72 The carbon atoms connected to it can form And R 32 、R 42 and R 52 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0255] R d 、R e 、R f 、R g 、R D 、R E 、R F 、R G 、R f1 、R g1 、R F1 and R G1 Each occurrence is independently C(R m )2、NR m , O, CO or S;

[0256] W 3 and W 4 Each independently CR m or N;

[0257] Rt 、R T 、R t1 、R T1 Each independently CR m or N, R t 、R T R t1 、R T1 Side connection represents the connection site between CLM and L;

[0258] R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a hydroxyl, a nitro, a cyano, an amino, a cycloalkyl, a heterocyclyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl are each independently optionally selected from F, Cl, Br, I, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a C1-C6 alkoxy, a hydroxyl, a C1-C6 haloalkyl, a C1-C6 hydroxyalkyl, a cyano, an amino, nitro, a C3-C6 cycloalkyl, a C3-C6 heterocyclyl, a C1-C6 alkylamino, a C6-C 15 Aryl and C6-C 15 is substituted by one or more substituents in a heteroaryl group;

[0259] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1+m2≤6;

[0260] m3 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7 each time it appears, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8 each time it appears, and m3+m4≤8;

[0261] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7;

[0262] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7+m8≤7;

[0263] m31 and m41 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m31+m41≤7;

[0264] m51 and m61 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m51+m61≤7;

[0265] The PTM is an IRAK4 protein targeting moiety selected from the following structures:

[0266] wherein Ring A is a 5-10 membered aromatic ring, a 5-10 membered cycloalkyl containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl, a 5-10 membered heterocycloalkyl, or a 7-12 membered biheterocycloalkyl, or a 5-10 membered heteroaromatic ring or a 7-12 membered biheteroaromatic ring containing 1-3 heteroatoms selected from N, O, and S;

[0267] Ring B is a 5-10 membered aromatic ring, a 5-10 membered cycloalkyl containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl, a 5-10 membered heterocycloalkyl, or a 7-12 membered biheterocycloalkyl, or a 5-10 membered heteroaromatic ring or a 7-12 membered biheteroaromatic ring containing 1-3 heteroatoms selected from N, O, and S;

[0268] Ring C is a 5-10 membered aromatic ring, a 5-10 membered cycloalkyl containing 0-3 heteroatoms selected from N, O, and S, a 7-12 membered bicycloalkyl, a 5-10 membered heterocycloalkyl, or a 7-12 membered biheterocycloalkyl, or a 5-10 membered heteroaromatic ring or a 7-12 membered biheteroaromatic ring containing 1-3 heteroatoms selected from N, O, and S;

[0269] R P each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0270] R Q each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, heterobridged cyclyl, aryl, and heteroaryl;

[0271] R S1 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0272] R S2 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0273] m' is 1, 2 or 3;

[0274] n' is 1, 2, or 3;

[0275] Alternatively, the compound is a compound represented by formula (III), or its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates:

[0276] Formula (IV): PTM-L-CLM;

[0277] Wherein L is a bond or linker portion connecting the CLM and PTM, having the structure -(A L ) q -, A L Each occurrence is the same or different and each occurrence is independently selected from the group consisting of: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、SO、SO2、NR L3 、CO、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 substituted arylene group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 Spirocyclyl, optionally substituted by 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene;

[0278] R L1 、R L2 , and R L3 are each independently H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SR L4 NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、SO2-R L4 、P(O)RL4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、COR L6 、CN、NO2、SF5、SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ;

[0279] R L4 , and R L5 each independently represents H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0280] R L6 each independently represents H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0281] q is an integer greater than or equal to 1;

[0282] The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety selected from the following structures:

[0283] Among them, W 1 and W 2 Each independently CR a R b 、C(=O)、NR a or SO2, and W 1 and W 2 At least one of them is C(=O); G and Z are each independently selected from O, S and Se;

[0284] R 3a 、R 3b 、R 3c , and R 3deach occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0285] R 3a0 、R 3b0 、R 3c0 、R 3d0 Each independently selected from O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, imino, cycloalkylene, heterocyclylene, alkyleneamino, arylene and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkyleneoxy, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl;

[0286] W 5 、W 6 Each occurrence is independently C(R m )2、NR m , O or S;

[0287] W 11 CR a R b 、C(=O)、NR a or SO2,

[0288] R 1 、R 2 、R a 、R m 、R N , and R bEach occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkylamino group, an aryl group, and a heteroaryl group;

[0289] R 22 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0290] n is 0, 1, 2, or 3;

[0291] R 32 and R 42 The carbon atoms connected to it can form And R 52 、R 62 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0292] R 42 and R 52 The carbon atoms connected to it can form And R 32 、R 62 and R 72each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0293] R 52 and R 62 The carbon atoms connected to it can form And R 32 、R 42 and R 72 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0294] R 62 and R 72 The carbon atoms connected to it can form And R 32 、R 42 and R 52 each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0295] R d 、R e 、R f 、R g 、R D 、R E 、R F and R G Each occurrence is independently C(R m )2、NR m , O, CO or S;

[0296] W 3 and W 4 Each independently CR m or N;

[0297] R t 、R T Each independently CR m or N, R t 、R T Side connection represents the connection site between CLM and L;

[0298] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1+m2≤6;

[0299] m3 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7 each time it appears, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8 each time it appears, and m3+m4≤8;

[0300] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7;

[0301] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7+m8≤7;

[0302] The PTM is an IRAK4 protein targeting moiety selected from the following structures;

[0303] Wherein ring A is a 5-10 membered aromatic ring or a 5-10 membered monocyclic or bicyclic ring containing 0-3 heteroatoms selected from N, O, and S;

[0304] Ring B is a 5-10 membered aromatic ring or a 5-10 membered monocyclic or bicyclic ring containing 0-3 heteroatoms selected from N, O, and S;

[0305] Ring C is a 5-10 membered aromatic ring or a 5-10 membered monocyclic or bicyclic ring containing 0-3 heteroatoms selected from N, O, and S.

[0306] RP each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0307] R Q each occurrence is independently selected from the group consisting of hydrogen, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, heterobridged cyclyl, aryl, and heteroaryl;

[0308] R S1 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0309] R S2 Selected from single bond, CO, O, S, SO2, -NR m -、-NR m a combination of one or more of CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene;

[0310] m' is 1, 2 or 3;

[0311] n' is 1, 2 or 3.

[0312] In one embodiment, wherein

[0313] R 32 and R 42 The carbon atom connected to it forms And R 52 、R 62 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 52 、R 62 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0314] R 42 and R 52 The carbon atom connected to it forms And R 32 、R 62 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 62 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0315] R 52 and R 62 The carbon atom connected to it forms And R 32 、R 42 and R 72Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 42 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0316] R 62 and R 72 The carbon atom connected to it forms And R 32 、R42 and R 52 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 42 and R 52 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0317] R L1 、R L2 , and R L3are independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 NR L4 R L5 , C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、COR L6 、CN、NO2、SF5、SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 and / or

[0318] R L4 , and R L5 are independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C6-C 15 Heteroaryl or C6-C 15 halogenated heteroaryl; and / or

[0319] R L6 are each independently H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C6-C 15Heteroaryl or C6-C 15 halogenated heteroaryl; and / or

[0320] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0321] G is O; and / or

[0322] Z is O; and / or

[0323] R d 、R e 、R D and R E Each occurrence is independently C(R m )2 or 0; and / or

[0324] R f 、R g 、R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or

[0325] m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3; preferably, m1+m2=1 or m1+m2=3; and / or

[0326] m3 and m4 are each independently an integer of 0, 1, 2, 3, 4, or 5, and m3+m4≤5, and m3 and m4 are not both 0; preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0327] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0328] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4, preferably m7+m8=2 or m7+m8=3; and / or

[0329] m31 and m41 are each independently an integer of 0, 1, 2, 3 or 4, and m31+m41≤4; preferably m31+m41=2 or m31+m41=3; and / or

[0330] m51 and m61 are each independently an integer of 0, 1, 2, 3 or 4, and m51+m61≤4; preferably m51+m61=2 or m51+m61=3; and / or

[0331] W 3 and W 4 is CH or N; and / or

[0332] W 5 and W 6 C(R m )2 or N(R m ), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or

[0333] R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and C6-C 15 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C6-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R 3a 、R 3b 、R 3c , and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group and a C1-C3 alkoxy group; and / or

[0334] R mEach occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C 15 Aryl and C6-C 15 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C6-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R m is independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or

[0335] R 1 、R 2 、R a , and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group; and / or

[0336] R N independently selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0337] R 22 Selected from single bond, -NR 2A -、-NR 2A CO-, C1-C6 alkyl, C1-C6 haloalkyl; and / or

[0338] R P Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, a C6-C 15 Aryl and C6-C 15 heteroaryl; and / or

[0339] R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, a C3-C6 heterobridged ring group, a C6-C6 15 Aryl and C6-C 15 heteroaryl; and / or

[0340] R S1 selected from a covalent bond, a C1-C3 alkyl group, a C2-C4 alkenyl group, and a C2-C4 alkynyl group; and / or

[0341] R S2 Selected from a covalent bond, a C1-C3 alkyl group, an amino group and a carbonyl group.

[0342] 1 In one embodiment, the compound wherein

[0343] R 32 and R 42 The carbon atom connected to it forms And R 52 、R 62 and R72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 52 、R 62 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0344] R 42 and R 52 The carbon atom connected to it forms And R 32 、R62 and R 72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 The present invention is substituted by one or more substituents of heterocyclic, aryl and heteroaryl, preferably R3, R6 and R7 are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0345] R 52 and R 62 The carbon atom connected to it forms And R 32 、R 42 and R72 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 42 and R 72 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0346] R 62 and R 72 The carbon atom connected to it forms And R 32 、R42 and R 52 Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Substituted by one or more substituents in heterocyclic, aryl and heteroaryl, preferably R 32 、R 42 and R 52 Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0347] R L1 、R L2 , and R L3are independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 NR L4 R L5 , C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、COR L6 、CN、NO2、SF5、SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 and / or

[0348] R L4 , and R L5 are independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C6-C 15 Heteroaryl or C6-C 15 halogenated heteroaryl; and / or

[0349] R L6 are each independently H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclyl, C3-C6 haloheterocyclyl, C6-C 15 Aryl, C6-C 15 Halogenated aryl, C6-C 15Heteroaryl or C6-C 15 halogenated heteroaryl; and / or

[0350] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0351] G is O; and / or

[0352] Z is O; and / or

[0353] R d 、R e 、R D and R E Each occurrence is independently C(R m )2 or 0; and / or

[0354] R f 、R g 、R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or

[0355] m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3; preferably, m1+m2=1 or m1+m2=3; and / or

[0356] m3 and m4 are each independently an integer of 0, 1, 2, 3, 4, or 5, and m3+m4≤5, and m3 and m4 are not both 0; preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0357] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0358] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4, preferably m7+m8=2 or m7+m8=3; and / or

[0359] W 3 and W 4 is CH or N; and / or

[0360] W 5 and W 6 C(R m )2 or N(R m), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or

[0361] R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C 15 Aryl and C6-C 15 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C 15 Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C6-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R 3a 、R 3b 、R 3c , and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group and a C1-C3 alkoxy group; and / or

[0362] R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl, C6-C 15 Aryl and C6-C 15 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 15 Aryl and C6-C15 Heteroaryl is each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C1-C6 alkylamino, C6-C6 15 Aryl and C6-C 15 is substituted by one or more substituents in the heteroaryl group; preferably, R m is independently selected at each occurrence from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or

[0363] R 1 、R 2 、R a , and R b are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group; and / or

[0364] R N independently selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0365] R 22 Selected from single bond, -NR 2A -、-NR 2A CO-, C1-C6 alkyl, C1-C6 haloalkyl; and / or

[0366] R P Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, a C6-C 15 Aryl and C6-C 15 heteroaryl; and / or

[0367] R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclyl group, a C3-C6 heterobridged ring group, a C6-C6 15 Aryl and C6-C 15 heteroaryl; and / or

[0368] R S1 selected from a covalent bond, a C1-C3 alkyl group, a C2-C4 alkenyl group, and a C2-C4 alkynyl group; and / or

[0369] R S2 Selected from a covalent bond, a C1-C3 alkyl group, an amino group and a carbonyl group.

[0370] In one embodiment, it is selected from the following compounds:

[0371] Preferably, the compound is a compound of Table A.

[0372] 20. A compound represented by formula (V) or formula (VI), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof:

[0373] L z1 Each occurrence is independently selected from a single bond, C(O), O, -NR m -、-NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; preferably, L z1 Each occurrence is independently selected from a single bond, C(O), O, -NH-, -NHC(O)-, C 1-6 Alkylene, C 1-6 preferably, L z1 Each occurrence is independently selected from a single bond, C(O), O, -NH-, -NHC(O)-, C 1-3 Alkylene, C 1-3 halogenated alkylene;

[0374] Among them, R 1 、R 2 、W 5 、W 6 、W7、R 32 、R 52 、R 62 、R 72 、R 1D 、R 1E 、R F 、R G 、R T ,B1,B2,B3,B4,B5,B6,C1,C2,m3,m4,m7,m8,W 1 、W 2、n2、n3、n4、n5、n6、R m as defined in claim 1 or 2;

[0375] Each occurrence of Cys is independently selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocyclyl, heterospirocyclyl, fused cyclyl, and heterofused cyclyl, each of which is independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, carboxyl, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl;

[0376] Preferably, each occurrence of Cys is independently selected from C3-C6 cycloalkyl, C5-C 13 Spirocyclyl, C3-C7 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C7 heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O or S 13 Heterospirocyclic group, the C3-C6 cycloalkyl, C5-C 13 Spirocyclyl, C3-C7 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C7 heterocyclyl containing 1, 2 or 3 heteroatoms each independently selected from N, O or S 13 The heterospirocyclic group is each independently optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, carboxyl, and amino; preferably substituted by one or more substituents selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, carboxyl, and amino;

[0377] Preferably, the compound is selected from the following compounds:

[0378] 21. The following compound, or its isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate, wherein the compound is selected from the following structures:

[0379] wherein E is hydrogen or a leaving group; preferably, the leaving group is selected from halogen, hydroxyl, carbonyl, -Ots and -ONO2;

[0380] Preferably, the compound is an interleukin-1 receptor-associated kinase 4 (IRAK4) protein inhibitor;

[0381] Preferably, the compound is selected from:

[0382] The third aspect of the present invention provides a pharmaceutical composition comprising a compound according to the first or second aspect of the present invention, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

[0383] The fourth aspect of the present invention provides a use of the compound of the first or second aspect of the present invention or the pharmaceutical composition of the third aspect for preparing a medicament for preventing or treating a disease or condition mediated by IRAK4, wherein the disease or condition mediated by IRAK4 includes immune diseases, inflammatory diseases and cancer.

[0384] The fifth aspect of the present invention provides a method for treating a disease or condition mediated by IRAK4, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first or second aspect or the pharmaceutical composition of the third aspect of the present invention.

[0385] In some embodiments, the subject expresses IRAK4.

[0386] In some embodiments, the IRAK4-mediated disease is leukemia, preferably acute monocytic leukemia.

[0387] The sixth aspect of the present invention provides use of the pharmaceutical composition according to the third aspect of the present invention for preparing an IRAK4 inhibitor.

[0388] The seventh aspect of the present invention provides a method for degrading IRAK4 protein in a biological sample, comprising contacting the biological sample with the compound of the first or second aspect of the present invention or the pharmaceutical composition of the third aspect.

[0389] An eighth aspect of the present invention provides intermediates for synthesizing the compounds disclosed herein.

[0390] In one embodiment, the intermediate comprises intermediate 1, intermediate 2, intermediate 3, intermediate 4, intermediate 5, intermediate 6, intermediate 7, intermediate 8, intermediate 9, intermediate 10, intermediate 11, intermediate 12, intermediate 13, intermediate 14, intermediate 15, intermediate 16, intermediate 17, intermediate 18, intermediate 19, intermediate 20 and intermediate 21 in a specific embodiment of the present invention.

[0391] In one embodiment, the intermediate comprises CLM2, CLM5, CLM7, CLM8, CLM9, CLM10, CLM11, CLM16, CLM20, CLM27, CLM28, or intermediates D1 to D99 according to a specific embodiment of the invention.

[0392] Definition and detailed description

[0393] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0394] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0395] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0396] As used in this specification and the claims reported herein, the phrase "and / or" is to be interpreted as meaning "either or both" of the elements, ie, the elements may be present in conjunction in some cases or the elements may be present in other cases, separately.

[0397] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0398] The term "heteroatom" is selected from nitrogen, oxygen or sulfur. The nitrogen may be optionally substituted; the sulfur may also be optionally substituted, for example, oxo, i.e., forming S(O) t3 (where t3 is an integer from 0 to 2).

[0399] The term "alkyl" as contemplated herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0400] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by heteroatoms selected from N, O and S or one or more -CH- are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0401] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined herein. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0402] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl is preferably a "C" having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. 2-8 More preferably, C 2-6 Alkenyl (ie, alkenyl having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferably C 2-4 Alkenyl (i.e., an alkenyl having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like. Alkenyl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0403] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkyl is preferably a "C" having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. 2-8 Alkynyl". Preferably C 2-6 Alkynyl (i.e., an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferably, C 2-4Alkynyl (i.e., an alkynyl having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0404] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0405] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0406] The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0407] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0408] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0409] The term "spirocyclylene" refers to a free radical obtained by losing a hydrogen atom from a "spiroalkyl" group. "Spiroalkyl" refers to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a carbon atom (called a spiro atom). Spiroalkyl groups are divided into monospiroalkyl, dispiroalkyl and polyspiroalkyl groups according to the number of spiro atoms shared between the rings. The term "5- to 20-membered spiroalkyl" or "C 5-20 Spiroalkyl refers to a polycyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a 3 to 8-membered monocyclic cycloalkyl ring. Preferably, the 6 to 14-membered (C 6-14 ) spirocycloalkyl, more preferably 6 to 14-membered monospirocycloalkyl, more preferably 7 to 11-membered (C 7-11 ) spirocycloalkyl, more preferably 7 to 11-membered monospirocycloalkyl, most preferably 7-membered (4-membered monocyclic cycloalkyl ring / 4-membered monocyclic cycloalkyl ring), 8-membered (4-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 9-membered (4-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring, 5-membered monocyclic cycloalkyl ring / 5-membered monocyclic cycloalkyl ring), 10-membered (5-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) or 11-membered (6-membered monocyclic cycloalkyl ring / 6-membered monocyclic cycloalkyl ring) monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to:

[0410] The term "heterospirocyclylene" refers to a free radical obtained by losing a hydrogen atom from a "heterospirocycloalkyl" group. "Heterospirocycloalkyl" refers to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(=O). m' (wherein m' is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. When the heteroatom is a nitrogen atom, the nitrogen atom can be substituted or unsubstituted (i.e. N or NR, R is hydrogen or other substituents defined herein). Each monocycle can contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are divided into monospiro heterocyclic groups, dispiro heterocyclic groups or polyspiro heterocyclic groups according to the number of shared spiro atoms between rings. Preferably, "5 to 20 yuan heterospiro cyclic groups" have 5 to 20 ring atoms, wherein one monocycle in the monocycle of the shared spiro atom is a 3 to 8 yuan monocyclic heterocyclic ring, and the other monocycle is a 3 to 8 yuan monocyclic heterocyclic ring or a 3 to 8 yuan monocyclic cycloalkyl ring. Preferably, there are 6 to 14 ring atoms, wherein 1 or 2 ring atoms are 6 to 14 yuan spiro heterocyclic groups of heteroatoms. More preferably, it is a 7- to 11-membered spiro heterocyclic group having 7 to 11 ring atoms, of which 1 or 2 ring atoms are heteroatoms. Most preferably, it is a 7-, 8-, 9-, 10-, or 11-membered monospiro heterocyclic group. Specific examples of spiro heterocyclic groups include, but are not limited to:

[0411] These spiro heterocyclic groups may be attached to the rest of the molecule via any suitable ring atom, preferably a nitrogen atom.

[0412] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0413] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0414] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0415] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0416] The term "amino" refers to -NH2.

[0417] The term "cyano" refers to -CN.

[0418] The term "nitro" refers to -NO2.

[0419] When appearing alone or as part of a substituent, "SO" refers to S(=O), CO refers to C(=O), and SO2 refers to S(=O)2. "O" means -O-.

[0420] The term "covalent bond" includes single bonds, double bonds, and triple bonds, with single bonds being preferred. As used herein, a wavy line on a group, regardless of its appearance, indicates that this is where the group is bonded to the rest of the molecule. If no wavy line is marked on a group, this indicates that any position within the group may be bonded to any other position within the molecule.

[0421] Unless otherwise defined, when a group described in the present invention is substituted by a substituent, it means that all the same groups appearing in the present invention can be substituted by a substituent, that is, the group can be substituted when it exists alone, and it also means that the group can be substituted when it exists in combination with other groups. For example, R is -C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl, -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl or -S(O)2-C 3-6 Monocyclic cycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl groups are optionally substituted; this description also includes -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl and -S(O)2-C 3-6 C in monocyclic cycloalkyl 1-6 Alkyl, C 6-10 Aryl and C 3-6 Monocyclic cycloalkyl groups are optionally substituted.

[0422] Unless otherwise defined, the term "same or different" used in the present invention means that when there are more than one identical substituent group in a general formula, the substituent groups may be the same or different.

[0423] Unless otherwise defined, the "substituents independently selected from..." described in the present invention means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.

[0424] In this paper, C 1-10It can be preferably C 1-6 More preferably C 1-4 More preferably C 1-3 For example, C 1-10 The alkyl group may preferably be C 1-6 Alkyl; more preferably C 1-4 Alkyl; more preferably C 1-3 alkyl.

[0425] The compounds of formula (I) mentioned in the present invention also include their tautomers, stereoisomers, mixtures of stereoisomers, solvates or derivatives.

[0426] The "compounds" of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond accompanied by the migration of a proton. The term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and can rapidly convert into each other. It refers to one of two or more structural isomers that exist in equilibrium and readily convert from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom and is accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomeric groups in solution. In solutions where tautomerism is possible, chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH conditions. The concept of tautomers that can convert into each other through tautomerization is called tautomerism.

[0427] When this specification describes a compound that is susceptible to tautomerization, but only one of the tautomers is described, it should be understood that all tautomers are included as part of the chemical meaning described. It should be understood that the compounds disclosed herein can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compound does not exclude any tautomeric form.

[0428] The term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or as a mixture of two or more isomers. Optically pure forms can be resolved from a mixture of two or more isomers or synthesized using chiral starting materials or reagents.

[0429] Depending on their structure, the compounds of the present invention may exist in different stereoisomeric forms. These forms include configurational isomers or optical conformers (enantiomers and / or diastereomers, including those of atropisomers). Therefore, the present invention includes enantiomers, diastereomers and mixtures thereof. Pure stereoisomeric forms can be isolated from those mixtures of enantiomers and / or diastereomers by methods known in the art, preferably chromatography, in particular high performance liquid chromatography (HPLC) using an achiral or chiral phase. The present invention further includes all mixtures of the above-mentioned stereoisomers, regardless of the ratio, including racemates.

[0430] Depending on their structure, the compounds of the present invention may exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms have been replaced by deuterium atoms, those in which one or more nitrogen atoms have been replaced by 15N atoms, or those in which one or more carbon, fluorine, chlorine, bromine, sulfur or oxygen have been replaced by stable isotopes of the respective original atoms.

[0431] Some of the compounds and salts according to the present invention may exist in different crystalline forms (polymorphs), which are within the scope of the present invention.

[0432] In the present invention, “ (or )"and" (or )" indicates the absolute configuration of a stereocenter. in Refers to the chemical bond connection. Including possible " (or )"and" (or )” configuration, as long as chemically permitted.

[0433] When the ring appears When the connection position is uncertain, it means that the connection site is located at Any atom in the monocyclic ring, as long as the valence permits.

[0434] As used herein, "solvates" refer to complexes formed between a compound of the present invention and a solvent. These complexes are formed by reacting in the solvent or by precipitating or crystallizing from the solvent. For example, a complex formed with water is referred to as a "hydrate." Solvates of the compound of formula (I) of the present invention are also encompassed within the scope of the present invention.

[0435] The present invention includes prodrugs of the above-mentioned compounds. The prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to yield the parent compound. Specific methods for preparing the prodrugs can be found in (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0436] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation via the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation via the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead alter their cellular location or function, for example, through binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by the E3 for chain preparation. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0437] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Such proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, among many others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms that are targets for testing antibiotics and other antimicrobials, plants, and even viruses, among many others.

[0438] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may but need not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0439] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without undue effort.

[0440] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are safe and effective when used in mammals and have the desired biological activity.

[0441] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0442] "Pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of excipient that is compatible with the patient, preferably a mammal, more preferably a human, and is suitable for delivering the active agent to the target site without terminating the activity of the agent.

[0443] As used herein, "patient" or "subject" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.

[0444] As used herein, the term "disease" is a health condition in an animal in which the animal cannot maintain homeostasis and the animal's health continues to deteriorate without improvement of the disease.

[0445] As used herein, "treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of a disease or condition to a certain extent. As used herein, the terms "treatment" or "treating" are defined as administering or administering a therapeutic agent, i.e., a compound of the present disclosure (alone or in combination with another agent), to a patient, or administering or administering a therapeutic agent to a tissue or cell isolated from a patient (e.g., for diagnosis or ex vivo application), wherein the patient suffers from a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or has the potential to develop a disease or condition considered herein, with the purpose of curing, rehabilitating, alleviating, alleviating, changing, remedying, improving, improving, or affecting a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or the possibility of developing a disease or condition considered herein. Based on the knowledge obtained from the field of pharmacogenomics, such treatments can be specifically customized or modified. The term "treating" disease used herein refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject. DETAILED DESCRIPTION

[0446] The following examples are directed to the intermediate compounds and final products identified in the specification and synthesis schemes. The following examples are used to describe the preparation of the compounds of the present invention in detail, but the chemical reactions described are disclosed based on their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to each compound within the scope of the present invention as described. Those skilled in the art will readily recognize compounds for which this will occur. In these cases, the reactions can be successfully carried out by conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0447] The starting materials, chemical reagents, and solvents used in the present invention are all commercially available and were purchased from companies such as Anage Chemical, Shanghai Bid Pharmaceutical, Beijing Inocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0448] The structures of the compounds synthesized in this application were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0449] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker AVANCE-400 / 600 NMR spectrometer. Deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0450] Mass spectrometry (MS) was performed by Waters Acquity Plus device implementation.

[0451] High performance liquid chromatography (HPLC) was performed using a Waters 2489 instrument.

[0452] The medium-pressure flash preparative chromatograph was COMBIFLASH NEXTGEN 300+.

[0453] As the thin layer chromatography silica gel plate, Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence) was used.

[0454] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin layer chromatography was purchased from Inokai.

[0455] The reaction progress in the examples was detected by thin layer chromatography (TLC), and the developing solvent used for monitoring the reaction and the eluent used for purifying the compound by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0456] 1. Synthesis of PTM

[0457] 1) Synthesis of Intermediate 1

[0458] a) tert-butyl 4-aminopiperidine-1-carboxylate, Bu3P, PrOH, 80℃; b) conc.HNO3, conc.H2SO4, 0℃; c) Boc2O, TEA, rt;

[0459] d)NiCl2·6H2O,NaBH4,MeOH,DCM;

[0460] e) 6-(trifluoromethyl)picolinic acid, DIPEA, HATU, THF, rt; f) MeMgBr, THF, 0℃-rt; g) HCl in dioxane, RT.

[0461] Step 1: Methyl 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate (Intermediate 1a)

[0462] In a two-necked flask, methyl 4-formyl-3-nitrobenzoate (393 mg, 1.88 mmol) was dissolved in 30 mL of isopropanol. 4-aminopiperidine-1-carboxylic acid tert-butyl ester (414 mg, 2.07 mmol) was then added. After reacting in an 80°C oil bath for 4 hours, tributylphosphine (1.14 g, 5.64 mmol) was added and the reaction continued in an 80°C oil bath overnight. After completion of the reaction, the solvent was evaporated and column chromatography (PE:EA = 0-40%) was performed to obtain intermediate 1a (554.0 mg, 82%) as a yellow solid.

[0463] LC-MS(ESI):[M-tBu+H] + =304.18

[0464] 1H NMR (400MHz, DMSO-d6) δ8.59(d,J=0.8Hz,1H),8.29(d,J=1.0Hz,1H),7.81(dd,J=8.8,0.8Hz,1H),7.56(dd,J=8.8,1.4Hz,1H ),4.83–4.71(m,1H),4.20–4.00(m,2H),3.87(s,3H),3.10–2.80(s,2H),2.19–2.07(m,2H),2.04–1.88(m,2H),1.43(s,9H).

[0465] Step 2: 5-nitro-2-(piperidin-4-yl)-2H-indazole-6-carboxylic acid methyl ester (Intermediate 1b)

[0466] In a single-necked flask, dissolve methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate (1 g, 2.78 mmol) in 5 mL of concentrated sulfuric acid. Slowly add 1 mL of concentrated nitric acid dropwise and allow to react for half an hour in an ice bath. Pour the mixture into ice to quench the reaction. Extract the mixture with 50 mL of ethyl acetate (3 times ethyl acetate). The combined organic phases are washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield intermediate 1b (484 mg, 56.7%) as a yellow solid, which is used directly in the next step.

[0467] LC-MS(ESI):[M+H] + =305.07.

[0468] Step 3: 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylic acid methyl ester (Intermediate 1c)

[0469] Methyl 5-nitro-2-(piperidin-4-yl)-2H-indazole-6-carboxylate (484 mg, 1.58 mmol) was dissolved in 10 mL of dichloromethane at room temperature. Di-tert-butyl dicarbonate (1.03 g, 4.73 mmol) and triethylamine (2 mL) were then added and allowed to react at room temperature for half an hour. The solvent was concentrated and the mixture was separated by column chromatography (PE:EA = 0-50%) to afford intermediate 1c (354 mg, 55%) as a yellow oil.

[0470] 1 H NMR(600MHz,DMSO-d6)δ8.91(s,1H),8.69(s,1H),8.08(s,1H),4.86–4.82(m,1H),4.18–4.0 4(m,2H),3.84(s,3H),3.10–2.80(m,2H),2.18–2.11(m,2H),2.01–1.92(m,2H),1.43(s,9H).

[0471] LC-MS(ESI):[M-Boc+H] + =305.28.

[0472] Step 4: 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylic acid methyl ester (Intermediate 1d)

[0473] Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate (2.24 g, 5.54 mmol) was dissolved in 20 mL of a 2 / 1 methanol / dichloromethane mixture on an ice bath. Nickel chloride hexahydrate (2.63 g, 11.08 mmol) was then added, followed by sodium borohydride (838.2 mg, 22.16 mmol) added slowly in portions. The mixture was allowed to react at this temperature for 20 minutes. The solvent was concentrated, and column chromatography was performed to obtain 1d (2.98 g, 123%) as a yellow oil, which was used directly in the next step without further purification.

[0474] LC-MS(ESI):[M+H] + =375.09

[0475] Step 5: Methyl 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylate (Intermediate 1e)

[0476] At room temperature, methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate (2.90 g, 5.54 mmol) and 6-(trifluoromethyl)picolinic acid (1.27 g, 6.63 mmol) were dissolved in 60 mL of tetrahydrofuran solution, followed by the addition of HATU (3.15 g, 8.29 mmol) and DIPEA (1.21 g, 9.40 mmol). After 2 hours of reaction, the solvent was evaporated and the product was separated by column chromatography (PE:EA = 0-50%) to give intermediate 1e (1.13 g, 37%) as a yellow oily liquid.

[0477] 1 H NMR(600MHz,DMSO-d6)δ12.56(s,1H),9.07(s,1H),8.63(s,1H),8.48–8.44(m,2H),8.41–8.36(m,1H),8.23–8.18(m,1H), 4.82–4.74(m,1H),4.20–4.05(m,2H),3.95(s,3H),3.10–2.81(m,2H),2.18–2.11(m,2H),2.01–1.92(m,2H),1.43(s,9H).

[0478] LC-MS(ESI):[M-tBu+H] + =492.10.

[0479] Step 6: tert-Butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)pyridinylamino)-2H-indazol-2-yl)piperidine-1-carboxylate (Intermediate 1f)

[0480] Under an ice bath and nitrogen atmosphere, methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylate (1.13 g, 2.06 mmol) was dissolved in 6 mL of tetrahydrofuran. Methylmagnesium bromide (2.8 mL, 8.26 mmol) was then slowly added and the mixture was allowed to react at room temperature for two hours. The reaction was quenched by the slow addition of water and extracted with 100 mL × 3 of ethyl acetate. The combined organic phases were washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated by filtration and the residue was separated by column chromatography (PE:EA = 0-50%). The residue was then concentrated and purified by reverse phase column chromatography to afford intermediate 1e (1.13 g, 99%) as a yellow oily solid.

[0481] 1 H NMR (600MHz, DMSO-d6) δ12.38(s,1H),8.72(s,1H),8.45(d,J=7.8Hz,1H),8.42(s,1H),8.38–8.34(m,1H),8.16(d,J=7.8Hz,1H),7.58(s,1 H),6.00(br,1H),4.72–4.63(m,1H),4.15–4.05(m,2H),3.10–2.82(m,2H),2.14–2.07(m,2H),1.99–1.90(m,2H),1.61(s,6H),1.43(s,9H).

[0482] LC-MS(ESI):[M+H] + =548.45.

[0483] Step 7: N-(6-(2-hydroxypropane-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (Intermediate 1)

[0484] At room temperature, tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)pyridinylamino)-2H-indazol-2-yl)piperidine-1-carboxylate (1.13 g, 2.05 mmol) was dissolved in 10 mL of dichloromethane solution, and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react overnight. After completion of the reaction, the reaction was quenched with aqueous sodium bicarbonate solution and extracted with 100 mL × 3 ethyl acetate. The combined organic phases were washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was filtered and concentrated to give intermediate 7 (828.5 mg, 90%) as a yellow solid.

[0485] LC-MS(ESI):[M+H] + =448.29.

[0486] 1 H NMR (600MHz, DMSO-d6) δ12.37(s,1H),8.71(s,1H),8.45(d,J=7.9Hz,1H),8.40–8.32(m,2H),8.16(d,J=7.7Hz,1H),7.58(s,1H),5.96(s,1 H),4.56-4.44(m,1H),3.07(d,J=12.3Hz,2H),2.63(t,J=11.5Hz,2H),2.02(d,J=10.3Hz,2H),1.98–1.88(m,2H),1.74(s,1H),1.62(s,6H).

[0487] 2) Synthesis of Intermediate 2

[0488] Step 1: (E)-4-Ethoxy-1,1-difluorobut-3-en-2-one (Intermediate 2a)

[0489] To a solution of vinyl ethyl ether (24.86 g, 344.73 mmol) in tert-butyl methyl ether (200 mL) at 0°C was added pyridine (23.86 g, 301.64 mmol), followed by the slow dropwise addition of 2,2-difluoroacetic anhydride (50 g, 287.27 mmol). After reacting at 0°C for half an hour, the reaction mixture was left to react overnight at room temperature. After completion of the reaction, the mixture was slowly diluted with water and extracted with DCM (200 mL x 3). The mixture was washed with saturated sodium bicarbonate (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford intermediate 2a (33.22 g, 77.03%) as a yellow oily liquid.

[0490] 1H NMR (600MHz, DMSO-d6) δ7.93(d,J=12.5Hz,1H),6.35(t,J=53.6Hz,1H),5.88(d,J=12.5Hz,1H),4.14(q,J=7.0Hz,2H),1.29(d,J=7.2Hz,3H).

[0491] LC-MS(ESI):[M+H] + =151.22.

[0492] Step 2: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (Intermediate 2b)

[0493] To a solution of ethyl 5-chloropyrazolo[1,5-A]pyrimidine-3-carboxylate (10 g, 44.3 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (9.01 g, 66.48 mmol) in acetonitrile (200 mL) was added N,N-diisopropylethylamine (25.7 g, 199.4 mmol). The mixture was refluxed at 60°C for two hours. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-100%) to afford intermediate 2b (12.68 g, 99%) as a white solid.

[0494] 1 H NMR(600MHz, CDCl3)δ4.03(q,J=7.1Hz,2H),3.63(s,3H),2.80–2.71(m,1H),2.15(tt,J=12.1,3.4Hz,1H),1 .90(dd,J=34.6,11.8Hz,4H),1.37(qd,J=13.3,3.1Hz,2H),1.22–1.13(m,3H),1.05(td,J=13.4,2.9Hz,2H).

[0495] LC-MS(ESI):[M+H] + =289.28.

[0496] Step 3: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 2c)

[0497] To a solution of ethyl 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (12.68 g, 43.98 mmol) in THF / H₂O (220 mL, 1:10) was added NaOH (3.52 g, 87.9 mmol) and allowed to react overnight at 60°C. After completion of the reaction, dilute hydrochloric acid was slowly added to adjust the pH to neutral, and the mixture was concentrated to afford intermediate 2c (17.57 g, 153%) as a white solid.

[0498] 1 H NMR(400MHz,DMSO-d6)δ11.46(br,1H),8.70(d,J=7.7Hz,1H),8.17(s,1H),6.90–6.25(m,1H), 5.29–4.87(m,1H),4.80–4.62(m,1H),3.90–3.60(m,2H),3.60–3.50(m,2H),2.05–1.80(m,2H).

[0499] LC-MS(ESI):[M+H] + =261.25.

[0500] Step 4: Methyl 2-(4-(ethoxycarbonyl)cyclohexyl)hydrazine-1-carboxylate (Intermediate 2d)

[0501] To a solution of ethyl 4-oxocyclohexane-1-carboxylate (25 g, 146.88 mmol) and methyl hydrazinecarboxylate (13.23 g, 146.88 mmol) in DCM (150 mL) was added acetic acid (17.64 g, 293.76 mmol) under ice-cooling conditions. After stirring at room temperature for 2 h, sodium triacetoxyborohydride (62.26 g, 293.76 mmol) was added and allowed to react overnight at room temperature. After completion of the reaction, the mixture was diluted with DCM (100 mL) and quenched with saturated sodium bicarbonate (500 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford Intermediate 2d (35.55 g, 99.08%) as a yellow oily liquid.

[0502] 1 H NMR (600MHz, CDCl3) δ7.67 (br, 1H), 4.14 (tt, J = 14.2, 7.1Hz, 2H), 3.80 (s, 3H), 2.76–2. 50(m,3H),2.49–2.14(m,2H),2.11–1.97(m,3H),1.86–1.68(m,2H),1.29–1.20(m,3H).

[0503] LC-MS(ESI):[M+H]+ =245.57.

[0504] Step 5: Ethyl 4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 2e)

[0505] To a solution of intermediate 2d (35.55 g, 145.52 mmol) in toluene (200 mL) was slowly added dropwise intermediate 2a (25.78 g, 171.72 mmol) and trifluoroacetic acid (19.97 g, 203.73 mmol) at 0°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was washed with water (1 L), saturated sodium bicarbonate solution (1 L), and saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford intermediate 2e (34.63 g, 87.39%) as a colorless oil.

[0506] LC-MS(ESI):[M+H] + =273.57.

[0507] Step 6: Ethyl 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 2f)

[0508] To a solution of intermediate 2e (34.63 g, 127.18 mmol) in trifluoroacetic acid (150 mL) at -10°C was added trifluoroacetic anhydride (53.42 g, 254.36 mmol) and sodium nitrate (21.62 g, 254.36 mmol). The mixture was allowed to react overnight at -10°C. After completion of the reaction, the reaction solution was slowly added to ice water (500 mL) and extracted with PE / EA = 2 / 1 (300 mL x 3). The mixture was washed with brine (1 L) and then with saturated sodium bicarbonate to pH = 7. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (PE:EA = 0-25%) afforded intermediate 2f (38.13 g, 89.54%) as a yellow oil.

[0509] 1 H NMR(400MHz, CDCl3)δ8.24(s,1H),7.12(td,J=53.4,3.2Hz,1H),4.34–4.09(m,3H),2.46– 2.19(m,5H),1.90–1.77(m,2H),1.71–1.60(m,2H),1.32–1.24(m,3H).LC-MS(ESI):[M+H] + =318.08.

[0510] Step 7: Ethyl (1r, 4r)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 2g)

[0511] To a solution of intermediate 2f (38.13 g, 113.87 mmol) in anhydrous ethanol (200 mL) was added DBU (52.01 g, 341.61 mmol) and stirred overnight in an 85°C oil bath. After completion of the reaction, the mixture was concentrated in vacuo, diluted with ethyl acetate, and the pH was adjusted to 6 with hydrochloric acid (1N). The mixture was washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (PE:EA = 0-25%) afforded a yellow oil. The mixture was then slurried with ethyl acetate / n-heptane, and the filter cake was collected by filtration to afford intermediate 2f (15.7 g, 43.6%) as a white solid.

[0512] 1 H NMR (600MHz, CDCl3) δ8.23(s,1H),7.29(s,1H),7.13(t,J=53.4Hz,1H),4.27–4.16(m,1H),3.73(s,3H),2.42(td,J= 12.2,6.1Hz,1H),2.38–2.29(m,2H),2.29–2.20(m,2H),1.85(qd,J=12.9,3.5Hz,2H),1.68(qd,J=13.6,3.3Hz,2H).

[0513] LC-MS(ESI):[M+H] + =318.08.

[0514] Step 8: Ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 2h)

[0515] To a THF solution of intermediate 2g (2g, 7.3mmol) was added Pd / C (400mg, 20% wt). The mixture was purged three times under a hydrogen atmosphere and allowed to react overnight. After completion of the reaction, the mixture was filtered through celite and concentrated to afford intermediate 2h (1.62g, 90%) as a colorless oil.

[0516] 1H NMR (600MHz, DMSO-d6) δ7.83(s,1H),7.05(t,J=53.9Hz,1H),4.23(dd,J=16.2,7.6Hz,1H),4.07(q,J=7.1Hz,2H),2 .38(ddd,J=12.1,7.7,3.2Hz,1H),2.08–1.99(m,4H),1.83–1.72(m,2H),1.58–1.45(m,2H),1.19(t,J=7.1Hz,3H).

[0517] LC-MS(ESI):[M+H] + =288.28.

[0518] Step 9: (1R,4R)-4-(4-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid ethyl ester (Intermediate 2i)

[0519] To a 20 mL solution of intermediate 2c (1.01 g, 3.90 mmol) in acetonitrile were added 1-methylimidazole (1.13 g, 13.81 mmol) and tetramethylchlorouronium hexafluorophosphate (1.33 g, 4.74 mmol) at room temperature. The mixture was allowed to react for half an hour at room temperature. Intermediate 2h (1.13 g, 3.95 mmol) was then added and the reaction continued for three hours. After completion of the reaction, the product was purified by column chromatography (PE:EA = 0-100%) to afford 2i (1.82 g, 89.54%) as a white solid.

[0520] 1H NMR(600MHz, CDCl3)δ9.74(s,1H),8.52–8.36(m,3H),6.81(dd,J=56.8,51.5Hz,1H),6.38–6.16(m,1H),5.5 0–4.60(m,2H),4.21–4.15(m,2H),4.15–4.10(m,1H),4.00(s,1H),3.99–3.72(m,1H),3.57(dd,J=46.5,9.3H z,2H),2.40(tt,J=12.2,3.5Hz,1H),2.27(dd,J=9.0,3.7Hz,2H),2.21(d,J=12.5Hz,2H),2.13(d,J=9.8Hz,1 H), 2.02 (d, J = 9.2Hz, 1H), 1.85 (qd, J = 12.9, 3.1Hz, 2H), 1.65 (qd, J = 13.5, 2.9Hz, 2H), 1.29 (t, J = 7.1Hz, 3H).

[0521] LC-MS(ESI):[M+H] + =530.49.

[0522] Step 10: (1R,4R)-4-(4-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 2)

[0523] To a solution of intermediate 2i (1.82 g, 3.53 mmol) in a mixture of water and tetrahydrofuran (50 mL, 5 / 1) was added lithium hydroxide (169.1 mg, 7.06 mmol) and the mixture was allowed to react overnight in an oil bath at 60°C. After the reaction, a solution of hydrogen chloride in ethyl acetate (4 mol / L, 2 mL) was added to adjust the pH to a slightly acidic state. The solution was then concentrated to yield intermediate 2 (2.10 g, 118%) as a white solid.

[0524] 1H NMR (400MHz, DMSO-d6) δ12.17(s,1H),9.50(d,J=6.3Hz,1H),8.78(d,J=7.7Hz,1H) ,8.39(d,J=4.5Hz,1H),8.26(d,J=5.5Hz,1H),7.30–6.94(m,1H),6.90–6.42(m,1H ),5.30–5.05(m,1H),4.77(d,J=16.4Hz,1H),4.24(t,J=10.4Hz,1H),3.86–3.42(m ,5H),2.35–2.24(m,1H),2.09–1.91(m,5H),1.87–1.70(m,2H),1.59–1.44(m,2H).

[0525] LC-MS(ESI):[M+H] + =502.39.

[0526] 3) Synthesis of Intermediate 3

[0527] Step 1: ((1R,4R)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexyl)methanol (Intermediate 3a)

[0528] To a solution of the intermediate 2g (10g, 31.52mmol) in THF / MeOH (10 / 1, 70mL) was added lithium borohydride (1.37g, 63.03mmol) portionwise at 0°C, followed by reaction in a 60°C oil bath for 1 hour. After completion of the reaction, the mixture was brought to room temperature, quenched with water, and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 0-100%) to afford 3a (2.045g, 23.57%) as a colorless oil.

[0529] 1 H NMR (600MHz, CDCl3) δ8.24(s,1H),7.14(t,J=53.4Hz,1H),4.20(tt,J=12.1,3.9Hz,1H),3.56(d,J=6.2Hz,2H),2.38–2.27(m ,2H),2.11–2.01(m,2H),1.80(qd,J=12.7,3.5Hz,2H),1.70–1.58(m,1H),1.50(br,1H),1.24(ddd,J=25.8,13.4,3.2Hz,2H).

[0530] Step 2: ((1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (Intermediate 3b)

[0531] To a solution of intermediate 3a (2.04 g, 7.43 mmol) in tetrahydrofuran (50 mL) was added Pd / C (352.0 mg, 17% wt). The mixture was purged three times under a hydrogen atmosphere and allowed to react overnight. After completion of the reaction, the mixture was filtered through celite and concentrated to afford intermediate 3b (2.068 g, 113.49%) as a colorless oil.

[0532] LC-MS(ESI):[M+H] + =246.37.

[0533] Step 3: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 3c)

[0534] To a 50 mL solution of intermediate 2c (1.32 g, 5.06 mmol) in acetonitrile were added 1-methylimidazole (1.45 g, 17.71 mmol) and tetramethylchlorouronium hexafluorophosphate (1.70 g, 6.07 mmol) at room temperature. After a half-hour reaction at room temperature, intermediate 3b (2.07 g, 5.06 mmol) was added and the reaction continued for three hours. After completion of the reaction, intermediate 3c was purified by column chromatography (PE:EA = 0-100%) to yield a white solid (1.82 g, 89.54%).

[0535] 1H NMR (600MHz, DMSO-d6) δ9.50(d,J=9.0Hz,1H),8.79(d,J=7.7Hz,1H),8.39(d,J=6.7Hz,1H),8.26(d,J=8.6H z,1H),7.12(td,J=53.7,5.5Hz,2H),6.90–6.42(m,3H),5.30–4.71(m,1H),4.77(d,J=25.6Hz,1H),4.22–4.1 4(m,1H),3.84–3.73(m,2H),3.65–3.58(m,2H),3.26(d,J=6.2Hz,2H),2.05(d,J=10.2Hz,2H),2.02–1.92(m ,2H),1.86(d,J=11.7Hz,2H),1.74(dt,J=24.8,6.3Hz,2H),1.48–1.40(m,1H),1.10(qd,J=13.3,3.1Hz,2H).

[0536] LC-MS(ESI):[M+H] + =488.49.

[0537] Step 4: 5-((1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-((1r, 4R)-4-formylcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 3)

[0538] To a solution of intermediate 3c (2 g, 4.10 mmol) in acetonitrile (20 mL) was added IBX (1.72 g, 6.15 mmol) and the mixture was reacted at 80°C for 2 hours. After the reaction, the mixture was purified by column chromatography (PE:EA = 0-100%) to give a white solid intermediate 3 (1.339 g, 67.23%).

[0539] LC-MS(ESI):[M+H] + =486.39.

[0540] 4) Synthesis of Intermediate 4

[0541] Step 1: Methyl (1s, 3s)-3-(toluenesulfonyloxy)cyclobutane-1-carboxylate (Intermediate 4a)

[0542] Under nitrogen, to a solution of (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid methyl ester (2 g, 15.37 mmol) in dichloromethane (20 mL) were added 4-toluenesulfonyl chloride (8.79 g, 46.10 mmol), 4-dimethylaminopyridine (187.75 mg, 1.54 mmol), and triethylamine (6.22 g, 61.47 mmol). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford intermediate 4a (2.8 g, 64.08%) as a yellow oil.

[0543] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8.3Hz,2H),7.30(d,J=8.2Hz,2H),4.77–4.61(m,1H),3.60(s,3H),2.65–2.54(m,1H),2.47–2.28(m,7H).

[0544] Step 2: 1-(4-methoxybenzyl)-1H-pyrazole-3-carbaldehyde (Intermediate 4b)

[0545] To a solution of 1H-pyrazole-3-carboxaldehyde (2.0 g, 20.8 mmol) in N,N-dimethylformamide were added p-methoxybenzyl chloride (3.42 g, 21.84 mmol) and cesium carbonate (16.95 g, 52.04 mmol) and allowed to react at room temperature for 2 hours. After completion of the reaction, the solution was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography afforded intermediate 4b (4.04 g, 90%) as a yellow solid.

[0546] 1 H NMR (600MHz, DMSO-d6)) δ9.87(s,1H),8.00(d,J=2.1Hz,1H),7.29(d,J=8.4Hz,2H),6.92(d,J=8.4Hz,2H),5.39(s,2H),3.73(s,3H).

[0547] LC-MS(ESI):[M+H] + =217.25.

[0548] Step 3: 3-(Difluoromethyl)-1-(4-methoxybenzyl)-1H-pyrazole (Intermediate 4c)

[0549] To a dichloromethane solution (5 mL) of intermediate 4b (1.0 g, 4.62 mmol) was added diethylaminosulfur trifluoride (5 mL) under ice conditions and allowed to react overnight at room temperature. After completion of the reaction, the mixture was slowly added to an aqueous sodium bicarbonate solution to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford intermediate 4c (788.4 mg, 71.6%) as a colorless oil.

[0550] LC-MS(ESI):[M+H] + =239.30.

[0551] Step 4: 3-(Difluoromethyl)-1H-pyrazole (Intermediate 4d)

[0552] Trifluoroacetic acid (15 mL) was added to intermediate 4c (6 g, 25.2 mmol) in an ice bath, and the temperature was raised to 85°C and allowed to react overnight. After the reaction was complete, the mixture was concentrated to afford intermediate 4d as a black oil without further treatment.

[0553] Step 5: 3-(Difluoromethyl)-4-nitro-1H-pyrazole (Intermediate 4e)

[0554] Concentrated sulfuric acid (20 mL) and concentrated nitric acid (6 mL) were slowly added to Intermediate 4d under ice conditions, and the temperature was then raised to 85°C and allowed to react overnight. After completion of the reaction, the mixture was slowly poured onto ice and extracted three times with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford Intermediate 4e (2.46 g, 65%) as a yellow oil.

[0555] 1 H NMR (600MHz, DMSO-d6) δ14.40 (s, 1H), 9.03 (s, 1H), 7.32 (t, J = 53.0Hz, 1H).

[0556] Step 6: (1r,3r)-3-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester (Intermediate 4f)

[0557] To a solution of intermediate 4e (1.3 g, 7.97 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (4.96 g, 35.87 mmol) and intermediate 4a (2.72 g, 9.57 mmol), respectively. The reaction was allowed to proceed in an oil bath at 85°C overnight. After completion of the reaction, the reaction mixture was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 0-30%) to afford intermediate 4f (2.1 g, 95.72%) as a yellow oil.

[0558] 1 H NMR (600MHz, CDCl3) δ8.20(s,1H),7.53(t,J=52.3Hz,1H),5.49–5.39(m,1H),3.80(s,3H),3.31–3.27(m,1H),3.11–2.99(m,2H),2.86–2.78(m,2H).

[0559] Step 7: (1r,3r)-3-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid methyl ester (Intermediate 4g)

[0560] Under a hydrogen atmosphere, palladium on carbon (200 mg, 20 wt%) was slowly added portionwise to a solution of intermediate 4f (1 g, 3.63 mmol) in tetrahydrofuran (10 mL). The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the palladium on carbon was filtered through celite and the solvent was dried to afford intermediate 4h (209.19 mg, 23.48%) as a yellow oily liquid.

[0561] 1 H NMR (400MHz, CDCl3) δ8.23(s,1H),7.15(t,J=53.3Hz,1H),5.18–5.06(m,1H),3.79(s,3H),3.34–3.23(m,1H),3.03–2.91(m,2H),2.88–2.76(m,2H).

[0562] Step 8: Methyl (1R,3r)-3-(4-(5-(((1r,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (Intermediate 4h)

[0563] To a solution of Intermediate 2c (212.25 mg, 0.97 mmol) in acetonitrile (7 mL) were added 1-methylimidazole (234.37 mg, 2.85 mmol) and tetramethylchlorouronium hexafluorophosphate (274.6 mg, 0.97 mmol) at room temperature. After half an hour at room temperature, Intermediate 4g (200 mg, 0.81 mmol) was added and the reaction continued for three hours. After completion of the reaction, purification by column chromatography (PE:EA = 0-100%) afforded Intermediate 4h (201.1 mg, 50.58%) as a white solid.

[0564] LC-MS(ESI):[M+H] + =488.49.

[0565] Step 9: (1R, 3r)-3-(4-(5-(((1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (Intermediate 4)

[0566] To a solution of intermediate 4h (165 mg, 0.36 mmol) in water / tetrahydrofuran (10 mL, 5 / 1) was added lithium hydroxide (17.13 mg, 0.31 mmol) and allowed to react overnight in an oil bath at 60°C. After the reaction was complete, a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added to adjust the pH to a slightly acidic state. The solution was then concentrated to yield intermediate 4 (2.10 g, 118%) as a white solid.

[0567] 1 H NMR (400MHz, DMSO-d6) δ9.50 (d, J=4.6Hz, 1H), 8.79 (dd, J=7.8, 1.5Hz, 1H), 8. 45(d,J=4.7Hz,1H),8.30–8.20(m,1H),7.31–7.00(m,1H),6.90–6.42(m,1H),5 .30–4.99(m,2H),4.77(d,J=14.9Hz,1H),3.85–3.72(m,2H),3.67–3.41(m,2H ),3.11–3.02(m,1H),2.78–2.58(m,4H),2.09–2.00(m,1H),1.99–1.91(m,1H).

[0568] LC-MS(ESI):[M+H] + =474.29.

[0569] 5) Synthesis of Intermediate 5

[0570] Step 1: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 5a)

[0571] To a solution of intermediate 4 (200 mg, 0.422 mmol) in tetrahydrofuran (10 mL) at -10°C was added isobutyl chloroformate (69.23 mg, 0.506 mmol) and 4-methylmorpholine (128.19 mg, 1.27 mmol). After stirring at this temperature for 10 minutes, sodium borohydride (19.5 mg, 0.515 mmol) was added. The mixture was then warmed to 0°C and 2 mL of methanol was added dropwise. The reaction was continued for 30 minutes. After completion of the reaction, water (10 mL) was slowly added to quench the reaction. The reaction solution was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (MeOH:DCM = 0-10%) to afford intermediate 5a (112.35 mg, 57.88%) as a yellow oil.

[0572] LC-MS(ESI):[M+H] + =460.39.

[0573] Step 2: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-((1R,3R)-3-formylcyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 5)

[0574] Under nitrogen atmosphere, 2-iodobenzoic acid (60.95 mg, 0.217 mmol) was added to a solution of intermediate 5a (50 mg, 0.108 mmol) in acetonitrile (10 mL), and the mixture was reacted at 80°C for 2 hours. The mixture was filtered and the solvent was dried to give intermediate 5 (73.7 mg, 148.05%) as a yellow oil.

[0575] LC-MS(ESI):[M+H] + =458.39.

[0576] 6) Synthesis of Intermediate 6

[0577] Step 1: Methyl (1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexane-1-carboxylate (Intermediate 6a)

[0578] Under a nitrogen atmosphere, to a solution of 4-bromo-2-nitrobenzaldehyde (10 g, 43.48 mmol) in isopropanol (500 mL) were added methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (10.10 g, 52.17 mmol) and DIEA (6.74 g, 52.17 mmol). The mixture was reacted at 80°C for 4 hours. The reaction mixture was then cooled to room temperature, and tributylphosphine (26.39 g, 130.43 mmol) was added. The reaction mixture was then allowed to react at 80°C overnight. The reaction mixture was purified by column chromatography to afford intermediate 6a (25.69 g, 175.23%) as a pale yellow solid.

[0579] 1 H NMR (400MHz, CDCl3) δ7.93(d,J=0.6Hz,1H),7.91–7.85(m,1H),7.52(dd,J=8.8,0.6Hz,1H),7.16(dd,J=8.8,1.6Hz,1H),4.51–4.27(m, 1H),3.71(s,3H),2.55–2.39(m,1H),2.40–2.30(m,2H),2.30–2.16(m,2H),2.00(qd,J=13.0,3.3Hz,2H),1.69(qd,J=13.5,3.3Hz,2H).

[0580] LC-MS(ESI):[M+H] + =337.29 / 339.29.

[0581] Step 2: ((1r,4r)-4-(6-bromo-2H-indazol-2-yl)cyclohexyl)methanol (Intermediate 6b)

[0582] To a solution of intermediate 6a (25.69 g, 76.18 mmol) in THF / MeOH (10 / 1, 250 mL) was added lithium borohydride (2.057 g, 94.53 mmol) at 0°C under air. The reaction mixture was then transferred to a 60°C oil bath and reacted under nitrogen for 1.5 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford intermediate 6b (9.283 g, 104.5%) as a pale yellow solid.

[0583] 1H NMR (400MHz, CDCl3) δ7.93(s,1H),7.89(s,1H),7.52(d,J=8.8Hz,1H),7.15(dd,J=8.8,1.6Hz,1H),4.38(tt,J=11 .9,3.8Hz,1H),3.55(d,J=6.2Hz,2H),2.43–2.27(m,2H),2.14–1.86(m,4H),1.73–1.60(m,2H),1.31–1.19(m,2H).

[0584] LC-MS(ESI):[M+H] + =309.18 / 311.28.

[0585] Step 3: Ethyl 2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-2H-indazole-6-carboxylate (Intermediate 6c)

[0586] To a solution of intermediate 6b (2 g, 6.47 mmol) in ethanol was added Pd(PPh3)2Cl2 (454.00 mg, 0.647 mmol) and TEA (3.27 g, 32.34 mmol) at room temperature and allowed to react overnight at 80°C. After completion of the reaction, the reaction mixture was purified by column chromatography to afford intermediate 6c (483.2 mg, 24.71%) as a colorless oil.

[0587] 1 H NMR (600MHz, DMSO-d6) δ8.54(d,J=0.7Hz,1H),8.30(d,J=1.0Hz,1H),7.80(dd,J=8.7,0.8Hz,1H),7.56(dd,J=8.7,1.4Hz,1H),4.52(t,J=5.4Hz,1H ),4.34(q,J=7.1Hz,2H),3.30(t,J=5.7Hz,2H),2.20–2.12(m,2H),1.95– 1.87(m,4H),1.55–1.45(m,1H),1.35(t,J=7.1Hz,3H),1.21–1.11(m,2H).

[0588] LC-MS(ESI):[M+H] + =303.38.

[0589] Step 4: Ethyl 5-nitro-2-((1r,4r)-4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-2H-indazole-6-carboxylate (Intermediate 6d)

[0590] Under air, trifluoroacetic anhydride (12.20 g, 58.07 mmol) was added to a dichloromethane solution (10 mL) of intermediate 6c (4.39 g, 14.52 mmol) and allowed to react at room temperature for half an hour. After the reaction, the solution was concentrated, and a sulfuric acid solution (10 mL) of potassium nitrate (2.94 g, 29.04 mmol) was added to the reaction system under ice-salt conditions. The reaction was stirred at this temperature for another half an hour. After the reaction, intermediate 6d (2.91 g, 45.21%) was obtained as a colorless oily liquid after column purification.

[0591] 1 H NMR(600MHz, CDCl3)δ8.43(s,1H),8.23(s,1H),8.06(s,1H),4.55–4.48(m,1H),4.43(q,J= 7.1Hz,2H),4.30(d,J=6.3Hz,2H),2.44–2.38(m,2H),2.14–1.96(m,5H),1.42–1.35(m,5H).

[0592] LC-MS(ESI):[M+H] + =444.29.

[0593] Step 5: Ethyl 5-amino-2-((1r,4r)-4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-2H-indazole-6-carboxylate (Intermediate 6e)

[0594] To a THF solution (50 mL) of intermediate 6d (3.67 g, 8.28 mmol) was added wet Pd / C (623.90 mg, 5.27 mmol) at room temperature. The mixture was allowed to react overnight. After completion of the reaction, the reaction mixture was filtered through celite and dried to afford intermediate 6e (3.49 g, 101.88%) as a colorless oil, which was used directly in the next step without further purification.

[0595] LC-MS(ESI):[M+H] + =414.49.

[0596] Step 6: Ethyl 2-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylate (Intermediate 6f)

[0597] To a THF solution of Intermediate 6e (3.49 g, 8.43 mmol) was added 6-(trifluoromethyl)picolinic acid (1.93 g, 10.12 mmol), HATU (4.81 g, 12.65 mmol), and DIEA (1.85 g, 14.34 mmol) under air. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was purified by column chromatography to yield Intermediate 6f (5.021 g, 101.57%).

[0598] 1 H NMR(600MHz,DMSO-d6)δ12.57(s,1H),9.04(s,1H),8.56(s,1H),8.50–8.43( m,2H),8.38(t,J=7.8Hz,1H),8.19(d,J=7.8Hz,1H),4.55–4.47(m,1H),4.41 (q,J=7.1Hz,2H),3.30(d,J=6.2Hz,2H),3.17(br,1H),2.22–2.14(m,2H),1. 95–1.88(m,4H),1.55–1.45(m,1H),1.38(t,J=7.1Hz,3H),1.21–1.13(m,2H).

[0599] LC-MS(ESI):[M+H] + =491.49.

[0600] Step 7: N-(2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (Intermediate 6g)

[0601] To a solution of intermediate 6f (1.66 g, 3.38 mmol) in THF (40 mL) was added methylmagnesium bromide (3 M in THF, 5.6 mL, 16.92 mmol) dropwise under nitrogen at 0°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, water (10 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford intermediate 6f (582.90 mg, 36.14%) as a yellow solid.

[0602] 1H NMR (600MHz, DMSO-d6) δ12.36(s,1H),8.71(s,1H),8.45(d,J=7.8Hz,1H),8.41–8.32(m,2H),8.16(d,J=7.8Hz,1H),7.58(s,1H),5.96(br,1H),4.56 (t,J=5.3Hz,1H),4.46–4.37(m,1H),3.29(t,J=5.7Hz,3H),2.16–2.10(m, 2H),1.93–1.87(m,4H),1.62(s,6H),1.51–1.45(m,1H),1.20–1.14(m,2H).

[0603] LC-MS(ESI):[M+H] + =477.39.

[0604] Step 8: N-(2-((1r,4r)-4-formylcyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (Intermediate 6)

[0605] Under nitrogen atmosphere, IBX (685.09 mg, 2.45 mmol) was added to a solution of intermediate 6g (582.90 mg, 1.22 mmol) in acetonitrile, and the mixture was allowed to react at 60°C for 2 hours. After completion of the reaction, the reaction mixture was purified by column chromatography to obtain intermediate 6 (553.90 mg, 95.43%) as a yellow solid.

[0606] LC-MS(ESI):[M+H] + =475.39.

[0607] 7) Synthesis of Intermediate 7

[0608] The intermediate was dissolved in acetonitrile (10 mL), and NaH2PO4 (560.1 mg, 5 equiv) was added. H2O2 (30% aqueous solution) (211.7 mg, 2 equiv) was slowly added dropwise in an ice bath, followed by a solution of NaClO2 (591.1 mg, 7 equiv). The mixture was allowed to react at room temperature for one hour. After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to yield intermediate 7 (421 mg, 91%) as a yellow solid.

[0609] LC-MS(ESI):[M+H] + =491.39.

[0610] 8) Synthesis of Intermediate 8

[0611] Step 1: Ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 8a)

[0612] To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL) were added morpholine (1.61 g, 13.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.73 g, 44.32 mmol) at room temperature and the reaction was allowed to proceed at 60°C for 2 hours. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford intermediate 8a (2.51 g, 102.49%) as a white solid.

[0613] 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.9Hz,1H),8.22(s,1H),6.85(d,J=7.9Hz,1H),4.19(q,J=7.1Hz,2H),3.79–3.67(m,8H),1.27(t,J=7.1Hz,3H).

[0614] LC-MS(ESI):[M+H] + =277.37.

[0615] Step 2: 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 8b)

[0616] To a solution of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (2.51 g, 9.08 mmol) in methanol and water (10 V / 1 V) (22 mL) was added sodium hydroxide (2.18 g, 54.51 mmol) at room temperature and allowed to react at 60°C for 2 hours. After the reaction, the methanol was evaporated, and hydrochloric acid was added to the reaction mixture to adjust the pH to 2. Filtration afforded intermediate 8b (1.45 g, 64.30%) as a white solid.

[0617] 1 H NMR (600MHz, DMSO-d6) δ8.74(d,J=7.9Hz,1H),8.20(s,1H),6.84(d,J=7.9Hz,1H),3.77–3.68(m,8H).

[0618] LC-MS(ESI):[M+H] + =249.17.

[0619] Step 3: (1r,4r)-4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid ethyl ester (Intermediate 8c)

[0620] To a solution of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (250 mg, 1.01 mmol) in acetonitrile (5 mL) were added N-(chloro(dimethylamino)methylene)-N-methylmethanamine hexafluorophosphate (V) (339.08 mg, 1.21 mmol) and 1-methyl-1H-imidazole (289.41 mg, 3.52 mmol) at room temperature. The mixture was reacted for 0.5 h at room temperature. Ethyl (1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (318.28 mg, 1.11 mmol) was then added to the reaction mixture, and the reaction was continued at room temperature for 2 h. After the reaction, the solvent was evaporated and the product was purified by column chromatography (DCM:MeOH = 0-20%) to afford intermediate 8c (580 mg, 111.28%) as a white solid.

[0621] 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 8.83 (d, J = 7.9Hz, 1H), 8.39 (s, 1H), 8 .29(s,1H),7.25–6.95(m,1H),6.91(d,J=8.0Hz,1H),4.31–4.20(m,1H),4. 10–3.98(m,3H),3.84–3.76(m,4H),3.76–3.68(m,4H),2.44–2.33(m,1H),2 .08–1.98(m,4H),1.86–1.72(m,2H),1.58–1.49(m,2H),1.21–1.18(m,3H).

[0622] LC-MS(ESI):[M+H] + =518.39.

[0623] Step 4: (1r,4r)-4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 8)

[0624] To a solution of ethyl (1r,4r)-4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (580 mg, 1.12 mmol) in methanol and water (10V / 1V) (5 mL) was added sodium hydroxide (268.94 mg, 6.72 mmol) at room temperature and allowed to react at 60°C for 2 hours. After completion of the reaction, the methanol was evaporated, and hydrochloric acid was added to the reaction mixture to adjust the pH to 2. Filtration afforded Intermediate 8 (370 mg, 67.45%) as a white solid.

[0625] 1 H NMR(600MHz,DMSO-d6)δ9.40(s,1H),8.82(d,J=7.8Hz,1H),8.39(s,1H),8.29(s,1H),7.20–7.01(m,1H),6.91(d,J=7.9Hz,1H),4. 28–4.21(m,1H),3.82–3.70(m,8H),2.34–2.26(m,1H),2.07–2.00(m,4H),1.82–1.74(m,2H),1.55–1.47(m,2H),1.32–1.18(m,1H).

[0626] LC-MS(ESI):[M+H] + =490.399)

[0627] 9) Synthesis of Intermediate 9

[0628] Step 1: 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 9a)

[0629] Under nitrogen, to a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL) were added 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride (1.50 g, 13.30 mmol) and N,N-diisopropylethylamine (5.73 g, 44.32 mmol). The mixture was allowed to react at 60°C for 2 hours. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 70-100%) to afford intermediate 9a (2.60 g, 97.39%) as a white solid.

[0630] 1H NMR (400MHz, DMSO-d6) δ8.74(d,J=7.8Hz,1H),8.21(s,1H),6.77(d,J=7.9Hz,1H),4.46(dq,J=4.4,2.1Hz,2H),4.19(q,J=7.1 Hz,2H),3.38–3.30(m,2H),3.15(d,J=11.3Hz,2H),1.84(dt,J=7.2,2.8Hz,2H),1.69(t,J=6.6Hz,2H),1.27(t,J=7.1Hz,3H).

[0631] LC-MS(ESI):[M+H] + =303.38.

[0632] Step 2: 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 9b)

[0633] To a solution of intermediate 9a (2.61 g, 8.63 mmol) in methanol and water (5:1) was added sodium hydroxide (2.07 g, 51.80 mmol) and allowed to react at 60°C for 1 hour. After the reaction, the solvent was evaporated and the pH was adjusted to 2-3 with 1N HCl. A white solid precipitated and was filtered to yield intermediate 9b (2.45 g, 100%).

[0634] 1 H NMR (400MHz, DMSO-d6) δ11.73(s,1H),8.73(d,J=7.9Hz,1H),8.19(s,1H),6.76(d,J=7.9Hz,1H),4 .46(dt,J=5.1,2.4Hz,2H),3.51–2.99(m,4H),1.83(dd,J=8.5,4.3Hz,2H),1.69(t,J=6.5Hz,2H).

[0635] LC-MS(ESI):[M+H] + =275.27.

[0636] Step 3: Ethyl (1R, 4R)-4-(4-(5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 9c)

[0637] Under a nitrogen atmosphere, to a solution of intermediate 9b (500 mg, 1.82 mmol) in acetonitrile (5 mL) were added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (614 mg, 2.19 mmol) and 1-methylimidazole (524 mg, 6.38 mmol). The mixture was allowed to react at room temperature for 0.5 hour, followed by the addition of ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (577 mg, 2.01 mmol). After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 70-100%) to afford intermediate 9c (897 mg, 90.52%) as a white solid.

[0638] 1 H NMR(400MHz, DMSO-d6)δ9.41(s,1H),8.81(d,J=7.9Hz,1H),8.39(s,1H),8.28(s,1H),7.11(t,J= 53.6Hz,1H),6.82(d,J=8.0Hz,1H),4.45(s,2H),4.24(td,J=9.6,8.1,5.6Hz,1H),4.10–4.05(m,2 H),3.34(s,3H),2.68(s,2H),2.39(tt,J=12.0,3.4Hz,1H),2.09–1.99(m,4H),1.86(td,J=6.8,6. 1,3.2Hz,2H),1.82–1.78(m,1H),1.73(t,J=7.5Hz,2H),1.59–1.46(m,2H),1.19(t,J=7.1Hz,3H).

[0639] LC-MS(ESI):[M+H] + =544.38.

[0640] Step 4: (1R,4R)-4-(4-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 9)

[0641] To a solution of intermediate 9c (897 mg, 1.65 mmol) in methanol and water (5:1) was added sodium hydroxide (396 mg, 9.90 mmol) and allowed to react at 60°C for 1 hour. After the reaction, the solvent was evaporated and the pH was adjusted to 2-3 with 1N HCl. A pale yellow solid precipitated and was filtered to yield intermediate 9 (871 mg, 100%).

[0642] 1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.80(d,J=7.9Hz,1H),8.38(s,1H),8.28(s,1 H),7.10(t,J=53.6Hz,1H),6.81(d,J=7.9Hz,1H),4.44(d,J=4.9Hz,2H),4.23(ddt ,J=11.8,8.0,3.9Hz,2H),3.29–3.09(m,4H),2.30(ddt,J=12.2,8.7,3.6Hz,1H),2 .03(td,J=13.3,3.9Hz,4H),1.91–1.67(m,6H),1.50(qd,J=13.5,12.9,3.9Hz,2H).

[0643] LC-MS(ESI):[M+H] + =516.39.

[0644] 10) Synthesis of Intermediate 10

[0645] To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL) was added DIEA (5.73 g, 44.32 mmol) and (S)-piperine-3-ol (1.34 g, 13.30 mmol) under air. The mixture was allowed to react at room temperature for 2 h. The reaction solution was purified by preparative chromatography (DCM:MeOH = 0-20%) to afford Compound 10a (2.40 g, 93.26%) as a white solid.

[0646] 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=7.9Hz,1H),8.18(s,1H),6.82(d,J=8.0Hz,1H),4.95(d,J=4.5Hz,1H),4.19(q,J=7.1Hz ,2H),4.01(s,1H),3.56(dd,J=8.3,4.2Hz,2H),3.13(s,2H),2.00–1.69(m,2H),1.56–1.38(m,2H),1.28(t,J=7.1Hz,3H).

[0647] LCMS (ESI): [M+H]+=291.38.

[0648] To a solution of intermediate 10a (2.4 g, 8.27 mmol) in methanol (25 mL) was added NaOH (3.31 g, 82.67 mmol) under air, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was mostly removed by distillation under reduced pressure. 10 mL of water was added, and the mixture was acidified with 1 M hydrochloric acid until neutral. A white solid precipitated, which was filtered to afford intermediate 10b (2 g, 92.25%) as a white solid.

[0649] 1 H NMR (400MHz, DMSO-d6) δ11.69(s,1H),8.65(d,J=7.9Hz,1H),8.15(s,1H),6.81(d,J=7.9Hz,1H),5.00(s,1 H),3.98(d,J=13.3Hz,1H),3.56(td,J=8.0,4.0Hz,2H),3.12(s,2H),1.97–1.74(m,2H),1.56–1.40(m,2H).

[0650] LCMS (ESI): [M+H]+=263.27.

[0651] To a solution of Intermediate 10b (200 mg, 762.58 μmol) in acetonitrile (5 mL) was added TCFH (320.94 mg, 1.14 mmol), 1-methylimidazole (219.14 mg, 2.67 mmol), and Intermediate 2h (262.92 mg, 915.09 μmol) under air. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by preparative chromatography (EA:PE = 0-70%) to afford Intermediate 10c (325 mg, 80.18%) as a white solid.

[0652] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.72(d,J=8.0Hz,1H),8.38(s,1H),7.57(s,1H),7.10(t,J=1.4Hz,1H),6.88(s,1H),4.91(s,1H),4.25(tt, J=12.0,3.7Hz,1H),4.07(q,J=7.1Hz,2H),3.44(dd,J=13.2,7.2Hz,2H),2.39(tt,J=12.0,3.4Hz,1H),2.05–1.52(m,10H),1.19(t,J=7.1Hz,3H).

[0653] LCMS (ESI): [M+H]+=532.49.

[0654] To a solution of intermediate 10c (100 mg, 188.12 μmol) in methanol (25 mL) was added NaOH (75.24 mg, 1.88 mmol) under air, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was mostly removed by distillation under reduced pressure. 3 mL of water was added, and the acid was adjusted to neutral with 1 M hydrochloric acid to precipitate a white solid, which was filtered to afford Compound 10 (82 mg, 86.57%) as a white solid.

[0655] 1 H NMR(400MHz, DMSO-d6)δ9.37(s,1H),8.71(d,J=7.9Hz,1H),8.31(d,J=50.6Hz,2H),7.31–6.81(m,2H),4.23– 4.17(m,1H),3.89(s,1H),3.70–3.63(m,2H),3.43(dd,J=13.3,7.2Hz,2H),2.11(s,1H),2.03–1.47(m,10H).

[0656] LCMS (ESI): [M+H]+=504.39.

[0657] 11) Synthesis of Intermediate 11

[0658] Step 1: tert-Butyl 3-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (Intermediate 11a)

[0659] Under a nitrogen atmosphere, 1-Boc-3-iodoazetidine (1.56 g, 5.52 mmol) and potassium carbonate (2.54 g, 18.40 mmol) were added to a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (600 mg, 3.68 mmol) in N,N-dimethylformamide (10 mL). The mixture was allowed to react overnight at 100°C. After completion of the reaction, the solution was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography afforded Intermediate 11a (459 mg, 39.20%) as a yellow oil.

[0660] LC-MS(ESI):[M+H-Boc] + =219.26.

[0661] Step 2: tert-Butyl 3-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Intermediate 11b)

[0662] Under a hydrogen atmosphere, palladium on carbon (92 mg, 20 wt%) was slowly added portionwise to a solution of intermediate 4f (459 mg, 1.44 mmol) in tetrahydrofuran (5 mL). The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the palladium on carbon was filtered through celite, and the solvent was evaporated to afford intermediate 11b (327 mg, 78.65%) as a yellow oily liquid.

[0663] LC-MS(ESI):[M+H- t Bu] + =233.36.

[0664] Step 3: tert-Butyl 3-(4-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Intermediate 11c)

[0665] Under a nitrogen atmosphere, to a solution of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (218 mg, 0.84 mmol) in acetonitrile (5 mL) were added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (257 mg, 0.92 mmol) and 1-methylimidazole (220 mg, 2.67 mmol). The mixture was allowed to react at room temperature for 0.5 hours, followed by the addition of Intermediate 11b (220 mg, 0.76 mmol). After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 70-100%) to afford Intermediate 9c (317 mg, 78.30%) as a white solid.

[0666] 1 H NMR(400MHz,DMSO-d6)δ9.53(d,J=5.2Hz,1H),8.79(dd,J=7.8,1.9Hz,1H),8.51(d ,J=4.3Hz,1H),8.27(d,J=5.6Hz,1H),7.38–7.05(m,1H),6.90–6.42(m,1H),5.29– 5.05(m,1H),4.80–4.74(m,1H),4.30(t,J=8.7Hz,2H),4.11(s,2H),3.82(d,J=8.5 Hz,2H),3.65–3.56(m,2H),3.45(d,J=10.1Hz,1H),2.06–1.94(m,2H),1.41(s,9H).

[0667] LC-MS(ESI):[M+H] + =531.39.

[0668] Step 4: N-(1-(Aza-3-yl)-3-(difluoromethyl)-1H-pyrazol-4-yl)-5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 11)

[0669] To a solution of intermediate 11c (310 mg, 0.58 mmol) in dichloromethane (3 mL) was added hydrochloric acid-dioxane (4 mL) and allowed to react at room temperature for 1 hour. After the reaction, the solvent was evaporated to afford intermediate 11 (200 mg, 79.52%) as a pale yellow solid.

[0670] LC-MS(ESI):[M+H] + =431.39.

[0671] 12) Synthesis of Intermediate 12

[0672] Step 1: 5-Bromo-4-methoxy-2-nitrobenzaldehyde (Intermediate 12a)

[0673] To a solution of 5-bromo-4-fluoro-2-nitrobenzaldehyde (20 g, 80.64 mmol) in methanol (200 mL) was added sodium methoxide (8.71 g, 161.29 mmol) at 0°C. The reaction was allowed to proceed overnight at 60°C under nitrogen. After completion of the reaction, water (200 mL) was added to the reaction mixture, which was then filtered to yield intermediate 12a (16.39 g, 78.16%) as a yellow solid.

[0674] Step 2: (1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexane-1-carboxylic acid methyl ester (Intermediate 12b)

[0675] To a solution of intermediate 12a (2 g, 7.69 mmol) in isopropanol (20 mL) were added methyl (1r, 4r)-4-aminocyclohexane-1-carboxylate (1.33 g, 8.46 mmol) and N,N-diisopropylethylamine (1.09 g, 8.46 mmol) at room temperature. The reaction mixture was incubated at 80°C under nitrogen for 4 hours. Tributylphosphine (4.67 g, 23.07 mmol) was then added to the reaction mixture, and the reaction was continued at 80°C overnight. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-20%) to afford intermediate 12b (1.72 g, 60.90%) as a yellow solid.

[0676] LC-MS(ESI):[M+H] + =367.39.

[0677] Step 3: Methyl (1r,4r)-4-(5-(benzylamino)-6-methoxy-2H-indazol-2-yl)cyclohexane-1-carboxylate (Intermediate 12c)

[0678] To a solution of intermediate 12b (500 mg, 1.36 mmol) in 1,4-dioxane (5 mL) were added benzylamine (291.79 mg, 2.72 mmol), [dicyclohexyl[3-(1-methylethoxy)-2′,4′,6′-tri(1-methylethyl)[1,1′-diphenyl]-2-yl]phosphine-κP](methanesulfonic acid-κO)[2′-(methylamino-κN)[1,1′-diphenyl]-2-yl-κC]palladium (125.06 mg, 136.15 umol), and cesium carbonate (1.33 g, 4.08 mmol) at room temperature. The reaction was incubated at 60°C under nitrogen overnight. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-80%) to give intermediate 12c (429 mg, 80.08%) as a yellow oil.

[0679] LC-MS(ESI):[M+H] + =394.29.

[0680] Step 4: (1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexane-1-carboxylic acid methyl ester (Intermediate 12d)

[0681] At room temperature, palladium on carbon (111.36 mg, 940.31 μmol) was added to a solution of intermediate 12c (370 mg, 940.31 μmol) in hexafluoroisopropanol (50 mL). The reaction was allowed to proceed overnight under a hydrogen atmosphere. After completion of the reaction, the brown oily intermediate 12d (424 mg, 148.64%) was obtained by filtration.

[0682] LC-MS(ESI):[M+H] + =304.38.

[0683] Step 5: (1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexane-1-carboxylic acid methyl ester (Intermediate 12e)

[0684] To a solution of 6-(trifluoromethyl)picolinic acid (100 mg, 523.26 μmol) in acetonitrile (5 mL) at room temperature were added N-(chloro(dimethylamino)methylene)-N-methylmethanamine hexafluorophosphate (V) (176.18 mg, 627.91 μmol) and 1-methyl-1H-imidazole (150.37 mg, 1.83 mmol). The mixture was reacted at room temperature for 0.5 h. Intermediate 12d (174.61 mg, 575.59 μmol) was then added to the reaction mixture, and the reaction was continued at room temperature for 2 h. After the reaction, the solvent was evaporated and the product was purified by column chromatography (DCM:MeOH = 0-20%) to afford intermediate 12e (160 mg, 60.18%) as a white solid.

[0685] LC-MS(ESI):[M+H] + =477.39.

[0686] Step 6: (1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexane-1-carboxylic acid (Intermediate 12)

[0687] To a solution of intermediate 12e (160 mg, 335.81 μmol) in methanol and water (10 V / 1 V) (6 mL) was added sodium hydroxide (80.59 mg, 2.01 mmol) at room temperature and allowed to react at 60°C for 2 hours. After the reaction, the solvent was evaporated, and the reaction mixture was adjusted to pH 2 with hydrochloric acid. Filtering afforded intermediate 12 (42 mg, 27.05%) as a white solid.

[0688] LC-MS(ESI):[M+H] + =463.39.

[0689] 13) Synthesis of Intermediate 13

[0690] Step 1: Methyl 6-chloro-4-(methylamino)nicotinate (Intermediate 13a)

[0691] To a solution of methyl 4,6-dichloronicotinate (10 g, 48.54 mmol) in acetonitrile (120 mL) was added methylamine hydrochloride (16.39 g, 242.69 mmol) and DBU (36.95 g, 242.69 mmol) under air. The mixture was allowed to react at room temperature for 3 h. The reaction solution was purified by silica gel column chromatography (EA:PE = 0-60%) to afford Intermediate 13a (8.3 g, 85.23%) as a white solid.

[0692] 1H NMR (400MHz, DMSO-d6) δ8.50 (s, 1H), 8.04 (d, J = 5.4Hz, 1H), 6.74 (s, 1H), 3.82 (s, 3H), 2.88 (d, J = 5.0Hz, 3H).

[0693] LCMS (ESI): [M+H]+=201.45.

[0694] Step 2: 6-chloro-4-(methylamino)nicotinic acid hydrazide (Intermediate 13b)

[0695] To a solution of intermediate 13a (8.3 g, 41.37 mmol) in ethanol (100 mL) was added hydrazine hydrate (16.57 g, 330.97 mmol) under air, and the mixture was stirred at 80°C for 16 h. After the reaction, the solvent was mostly removed by distillation under reduced pressure to obtain a crude product, which was then purified on a silica gel column (MeOH:DCM = 0-25%) to obtain intermediate 13b (7.1 g, 85.54%) as a white solid.

[0696] 1 H NMR (600MHz, DMSO-d6) δ9.82 (s, 1H), 8.21 (s, 1H), 6.62 (s, 1H), 4.47 (s, 2H), 2.81 (d, J = 5.0Hz, 3H).

[0697] LCMS (ESI): [M+H]+=201.25.

[0698] Step 3: tert-Butyl ((1r,4r)-4-(2-(6-chloro-4-(methylamino)nicotinoyl)hydrazine-1-carbonyl)cyclohexyl)carbamate (Intermediate 13c)

[0699] To a solution of Intermediate 13b (1 g, 4.98 mmol) in DMF (15 mL) was added N-BOC-aminocyclohexylaminecarboxylic acid (1.58 g, 6.48 mmol), EDCI (1.14 g, 9.97 mmol), HOBT (1.35 g, 9.97 mmol), and DIEA (3.22 g, 24.92 mmol) under air, and stirred at room temperature for 6 h. After completion of the reaction, the reaction mixture was purified by column chromatography (EA:PE = 0-70%) to afford Intermediate 13c (1.20 g, 56.63%) as a white solid.

[0700] 1H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.79(s,1H),8.34(s,1H),8.11(q,J=5.0Hz,1H),6.76(d,J=8.1Hz,1H),6.66(s,1H),3.17 (t,J=5.6Hz,2H),2.82(d,J=5.0Hz,3H),2.14(tt,J=11.9,3.4Hz,1H),1.79(t,J=11.7Hz,4H),1.38(s,11H),1.23–1.10(m,2H).

[0701] LCMS(ESI):[M+H] + =532.49.

[0702] Step 4: tert-Butyl ((1r,4r)-4-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate (Intermediate 13d)

[0703] To a solution of 17c (200 mg, 469.58 μmol) in toluene (10 mL) under air atmosphere was added Lawesson's reagent (208.91 mg, 516.54 μmol), and the mixture was stirred at 120°C for 4 h. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove most of the solvent to obtain a crude product, which was then purified on a silica gel column (MeOH:DCM = 0-25%) to obtain intermediate 13d (100 mg, 50.23%) as a white solid.

[0704] 1 H NMR (600MHz, DMSO-d6) δ8.66(q,J=5.0Hz,1H),8.39(s,1H),6.85(d,J=8.0Hz,1H),6.82(s,1H),3.33–3.29(m,1H),3.13(tt, J=11.9,3.7Hz,1H),2.98(d,J=4.9Hz,3H),2.20–2.10(m,2H),1.95–1.85(m,2H),1.61(qd,J=13.1,3.3Hz,2H),1.39(s,11H).

[0705] LCMS(ESI):[M+H] + =504.39.

[0706] Step 5: tert-Butyl ((1r,4r)-4-(5-(6-(5-cyano-1h-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate (Intermediate 13e)

[0707] To a solution of 17d (84 mg, 198.13 μmol) in 1,4-dioxane (3 mL) was added 5-cyano-7-azaindole (34.03 mg, 237.76 μmol), Pd(dba) (58.06 mg, 63.40 μmol), Xantphos (36.69 mg, 63.40 μmol), and CsCO (200.12 mg, 614.21 μmol) under air, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by preparative chromatography (H2O:MeCN = 0-54%) to afford intermediate 13e (95 mg, 90.36%) as a white solid.

[0708] 1H NMR (600MHz, DMSO-d6) δ8.79 (dd, J=7.8, 2.0Hz, 1H), 8.69 (q, J=5.0Hz, 1H), 8.65–8.59(m,1H),8.57–8.51(m,1H),8.46(s,1H),8.18(d,J=14.1Hz,1H), 6.86(dd,J=8.9,5.8Hz,2H),4.12(d,J=5.3Hz,1H),3.17(d,J=5.2Hz,4H),2 .21–2.11(m,2H),1.92(d,J=11.9Hz,2H),1.64–1.55(m,2H),1.40(s,12H).

[0709] LCMS(ESI):[M+H] + =531.39.

[0710] Step 6: 1-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)-1h-pyrrolo[2,3-b]pyridine-5-carbonitrile (Intermediate 13f)

[0711] Under air, intermediate 13e (65 mg, 122.49 μmol) was added to a solution of DCM (3 mL) and TFA (1 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (H2O:MeCN = 0-54%) to afford intermediate 13 (50 mg, 94.81%) as a white solid.

[0712] 1H NMR(400MHz,DMSO-d6)δ8.85-8.82(m,1H),8.69-8.64(m,1H),8.55-8.54(m,1H),8.24–8.20(m,1H),7.88–7.69(m,1H),6.93-6.89(m,1H) ,3.27-3.20(m,1H),3.20–3.11(m,1H),3.09(d,J=4.9Hz,3H),2.29–2.17(m,2H),2.21-2.10(m,2H),1.76-1.62(m,2H),1.60-1.45(m,2H).

[0713] LCMS(ESI):[M+H] + =431.39.

[0714] 14) Synthesis of Intermediate 14

[0715] Step 1: Methyl (1R, 4R)-4-(hydroxymethyl)cyclohexane-1-carboxylate (Intermediate 14a)

[0716] Under a nitrogen atmosphere, BH3·THF (6.98 mL, 6.98 mmol) was added to a solution of (1R,4R)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.0 g, 5.37 mmol) in THF (5 mL) at -78°C. The mixture was then slowly allowed to react at room temperature for 34 h. After completion of the reaction, methanol was added to quench the reaction, and the product was dried to give intermediate 14a (1.03 g, 100%) as a colorless oil.

[0717] 1 H NMR (600MHz, CDCl3) δ3.69 (s, 3H), 3.49 (d, J = 6.3Hz, 2H), 2.31–2.25 (m, 1H), 2.08–2.00 (m, 2H),1.93–1.87(m,2H),1.54–1.49(m,1H),1.49–1.43(m,2H),1.02(qd,J=13.1,3.4Hz,2H).

[0718] Step 2: Methyl (1R,4R)-4-((tolyloxy)methyl)cyclohexane-1-carboxylate (Intermediate 14b)

[0719] To a solution of Intermediate 14a (1.03 mg, 5.98 mmol) in dichloromethane (15 mL) was added triethylamine (666.7 mg, 6.58 mmol), DMAP (73.1 mg, 0.60 mmol), and TsCl (1.25 g, 6.58 mmol) under air, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was mostly removed by distillation under reduced pressure to obtain the crude product, which was then purified on a silica gel column (EA:PE = 0-30%) to afford Intermediate 14b (589.7 mg, 30%) as a white solid.

[0720] 1 H NMR (600MHz, CDCl3) δ7.80(d,J=8.3Hz,2H),7.37(d,J=8.0Hz,2H),3.85(d,J=6.3Hz,2H),3.68(s,3H),2.48(s,3H),2.23(tt,J=12. 3,3.6Hz,1H),2.01(dd,J=13.9,3.1Hz,2H),1.85–1.79(m,2H),1.71–1.63(m,1H),1.46–1.37(m,2H),0.99(qd,J=13.2,3.5Hz,2H).

[0721] Step 3: Methyl (1R,4R)-4-((tolyloxy)methyl)cyclohexane-1-carboxylate (Intermediate 14c)

[0722] Under nitrogen atmosphere, K2CO3 (1.07 g, 7.73 mmol) was added to a DMF solution (15 mL) of Intermediate 14b (672.5 mg, 2.06 mmol) and Intermediate 4e (280 mg, 1.72 mmol) and allowed to react at 85°C overnight. After the reaction was complete, the mixture was extracted with EA, concentrated, and the crude product was purified on a silica gel column to obtain Intermediate 14c (329.7 mg, 60.5%) as a white solid.

[0723] 1 H NMR (600MHz, CDCl3) δ8.17(s,1H),7.13(t,J=53.3Hz,1H),4.05(d,J=7.2Hz,2H),3.70(s,3H),2.30(tt,J=12.3,3.4Hz,1H),2 .06(d,J=11.4Hz,2H),2.03–1.92(m,1H),1.76(d,J=11.4Hz,2H),1.47(qd,J=13.2,3.1Hz,2H),1.09(qd,J=13.0,3.2Hz,2H).

[0724] Step 4: ((1r,4r)-4-((3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol (Intermediate 14d)

[0725] Under a nitrogen atmosphere, lithium borohydride (45.3 mg, 2.08 mmol) was added to a solution of Intermediate 14c (329.7 mg, 1.04 mmol) in THF / MeOH (10:1) and stirred at 60°C for 5 h. After completion of the reaction, the mixture was quenched with water, extracted three times with EA, and concentrated. The crude product was purified on a silica gel column to afford Intermediate 14d (136.8 mg, 45.5%) as a white solid.

[0726] 1 H NMR (600MHz, DMSO-d6) δ9.03(s,1H),7.31(t,J=53.0Hz,1H),4.38(t,J=5.3Hz,1H),4.08(d,J=7.2Hz,2H),3.19(t,J=5.7Hz,2H),1.80(dt d,J=15.3,7.6,3.7Hz,1H),1.74(dd,J=18.5,8.0Hz,2H),1.55(d,J=10.8Hz,2H),0.97(ddd,J=24.7,12.7,3.0Hz,2H),0.90–0.80(m,10H).

[0727] Step 5: (1r,4r)-4-((4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol (Intermediate 14e)

[0728] To a solution of Intermediate 14d (136.8 mg, 0.473 mmol) in MeOH (10 mL) was added Pd / C (28 mg, 0.236 mmol) under a hydrogen atmosphere. The mixture was stirred at room temperature overnight. After the reaction, the crude product was filtered through Celite to afford Intermediate 14e (111.0 mg, 91%) as a colorless oil.

[0729] LCMS(ESI):[M+H] + =260.37.

[0730] Step 6: (1r,4r)-4-((4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)methyl)cyclohexyl)methanol (Intermediate 14f)

[0731] At room temperature, to a solution of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (158.9 mg, 0.61 mmol) in acetonitrile (5 mL) were added N-(chloro(dimethylamino)methylene)-N-methylmethanamine hexafluorophosphate (V) (205.52 mg, 1.20 mmol) and 1-methyl-1H-imidazole (175.4 mg, 2.14 mmol). The mixture was reacted at room temperature for 0.5 hours. Intermediate 14e (158.3 mg, 0.61 mmol) was then added to the reaction mixture, and the reaction was continued at room temperature for 2 hours. After the reaction, the solvent was dried and the product was purified by column chromatography (MeOH:DCM = 0-20%) to give intermediate 14f (301.8 mg, 98.6%) as a white solid.

[0732] 1 H NMR (400MHz, DMSO) δ9.51(d,J=6.9Hz,1H),8.74(dd,J=14.1,7.9Hz,1H),8.34(d,J=5.8Hz,1H),8.2 5(d,J=5.4Hz,1H),7.09(dd,J=53.7,3.6Hz,1H),6.88–6.40(m,1H),5.30–5.05(m,1H),4.76(d,J=1 6.0Hz,1H),4.40(s,1H),4.15(s,2H),4.04–3.90(m,3H),3.86–3.54(m,4H),2.07–1.91(m,3H),1.8 2–1.66(m,4H),1.56(d,J=10.6Hz,3H),1.17(t,J=7.1Hz,1H),1.05–0.91(m,3H),0.91–0.73(m,3H).

[0733] LCMS(ESI):[M+H] + =502.39.

[0734] Step 6: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-(((1R,4R)-4-formylcyclohexyl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 14)

[0735] Under nitrogen, IBX (337.0 mg, 1.20 mmol) was added to a solution of intermediate 14f (301.8 mg, 0.602 mmol) in ACN (10 mL). The mixture was stirred at 80°C for two hours. After the reaction, the crude product was filtered through celite to yield intermediate 14 (135.3 mg, 45%) as a colorless oil.

[0736] LCMS(ESI):[M+H] + =500.39.

[0737] 15) Synthesis of Intermediate 15

[0738] Step 1: tert-Butyl 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 15a)

[0739] Under nitrogen, to a DMF solution (5 mL) of intermediate tert-butyl 4-(tolyloxy)piperidine-1-carboxylate (271.4 mg, 0.76 mmol) and intermediate 4e (83 mg, 0.51 mmol) was added KCO (361.5 g, 2.29 mmol) and allowed to react overnight at 90°C. After completion of the reaction, the mixture was extracted with EA and concentrated. The crude product was purified on a silica gel column to obtain intermediate 15a (78.7 mg, 44%) as a white solid.

[0740] 1 H NMR (600MHz, CDCl3) δ8.31(s,1H),7.03(td,J=53.3,3.5Hz,1H),4.32(ddd,J=11.6,9.7,3.8Hz,1H),4.22(s,2H),3.74(ddd ,J=12.4,8.4,3.8Hz,1H),2.94(dd,J=22.1,7.7Hz,1H),2.12(d,J=12.3Hz,2H),1.88(qd,J=12.4,4.4Hz,2H),1.41(s,9H).

[0741] LCMS(ESI):[M+H-Boc] + =247.27.

[0742] Step 2: tert-Butyl 4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 15b)

[0743] Under a hydrogen atmosphere, to a solution of Intermediate 15a (700.0 mg, 2.02 mmol) in THF (10 mL) was added Pd / C (100 mg, 0.844 mmol) and stirred at room temperature overnight. After the reaction, the crude product was filtered through Celite to afford Intermediate 15b (178.5 mg, 28%) as a colorless oil.

[0744] LCMS(ESI):[M+H] + =317.28.

[0745] Step 3: tert-Butyl 4-(4-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate 15c)

[0746] To a solution of the intermediate tert-butyl 4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (106.95 mg, 0.41 mmol) in acetonitrile (5 mL) were added 1-methylimidazole (118.09 mg, 1.44 mmol) and tetramethyluronium chloride hexafluorophosphate (138.36 mg, 0.49 mmol) at room temperature. After half an hour at room temperature, the intermediate 12 g (130.00 mg, 0.41 mmol) was added and the reaction continued for three hours. After completion of the reaction, the product was purified by column chromatography (PE:EA = 0-100%) to afford Intermediate 15c (288.00 mg, 125%) as a white solid.

[0747] 1 H NMR (400MHz, DMSO-d6) δ9.51(d,J=5.6Hz,1H),8.78(d,J=7.7Hz,1H),8.42(d,J=3 .8Hz,1H),8.26(d,J=5.6Hz,1H),7.28–6.98(m,1H),6.89–6.42(m,1H),5.29–5.05 (m,1H),4.77(d,J=16.6Hz,1H),4.49–4.40(m,1H),4.05(d,J=11.1Hz,1H),3.86–3 .78(m,2H),3.67–3.52(m,2H),2.09–1.89(m,5H),1.85–1.67(m,2H),1.42(s,9H).

[0748] LC-MS(ESI):[M+H] + =559.38.

[0749] Step 4: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 15)

[0750] To a solution of intermediate 15c (36.10 mg, 0.64 mmol) in dichloromethane (1 mL) was added a solution of hydrogen chloride in dioxane (4.0 mol / L, 2 mL). After the reaction was complete, the solution was concentrated to afford intermediate 15 (36 mg, 121%) as a white solid.

[0751] 1 H NMR (400MHz, DMSO-d6) δ9.53(d,J=6.2Hz,1H),8.80(dd,J=7.8,1.2Hz,1H),8.43(d,J =3.0Hz,1H),8.27(d,J=5.7Hz,1H),7.31–7.01(m,1H),6.92–6.45(m,1H),5.31–5.08( m,1H),4.77(d,J=18.8Hz,1H),3.85–3.71(m,2H),3.68–3.55(m,2H),3.48–3.34(m,3 H),3.04(dd,J=21.9,10.6Hz,2H),2.25–2.11(m,4H),2.08–1.92(m,2H),1.91(s,1H).

[0752] LC-MS(ESI):[M+H] + =459.39.

[0753] 16) Synthesis of Intermediate 16

[0754] Step 1: tert-Butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16a)

[0755] To a solution of (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid methyl ester (5 g, 20.89 mmol) in methanol (40 mL) was slowly added sodium borohydride (1.19 g, 31.34 mmol) on ice. The mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, Intermediate 16a (3.89 g, 77.15%) was obtained as a white solid.

[0756] 1 H NMR(400MHz,DMSO-d6)δ4.93(d,J=6.1Hz,1H),4.06(dp,J=20.7,7.1Hz,1H),3.20(dt,J=20.4,5.6Hz,4 H),2.50(s,2H),2.11(ddd,J=9.9,7.4,2.8Hz,2H),1.59–1.49(m,2H),1.41–1.39(m,2H),1.37(s,9H).

[0757] Step 2: tert-Butyl 2-iodo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16b)

[0758] To a toluene solution of Intermediate 16a (2.0 g, 8.29 mmol) was slowly added imidazole (1.13 g, 16.57 mmol), triphenylphosphine (3.26 g, 12.43 mmol), and iodine (3.16 g, 12.43 mmol) on an ice bath. The mixture was allowed to react at room temperature for 1 hour, then heated to 60°C for 1 hour. After completion of the reaction, the solution was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography afforded Intermediate 16b (2.31 g, 79.36%) as a yellow solid.

[0759] 1 H NMR (600MHz, CDCl3) δ4.52(p,J=8.2Hz,1H),3.32(dt,J=31.5,5.6Hz,4H),2.68(ddd,J=11.1,8.1,3.1Hz,2 H), 2.44 (ddd, J = 11.1, 8.3, 3.1Hz, 2H), 1.69 (t, J = 5.5Hz, 2H), 1.58 (t, J = 5.6Hz, 2H), 1.46 (d, J = 1.1Hz, 9H).

[0760] LC-MS(ESI):[M+H-tBu] + =296.15.

[0761] Step 3: tert-Butyl 2-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16c)

[0762] To a 40 mL DMF solution of intermediate 16b (3.0 g, 8.54 mmol) were added potassium carbonate (5.90 g, 42.71 mmol) and intermediate 3-(difluoromethyl)-4-nitro-1H-pyrazole (1.39 g, 8.54 mmol). The reaction was allowed to proceed overnight in an oil bath at 120°C. After completion of the reaction, the reaction mixture was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 0-40%) to afford intermediate 16c (492 mg, 14.91%) as a yellow solid.

[0763] 1H NMR (400MHz, DMSO-d6) δ9.14(d,J=1.1Hz,1H),7.25(d,J=52.9Hz,1H),5.03(p,J=8.4Hz,1H),3.31(d,J=1 1.1Hz,2H),3.23(t,J=5.6Hz,2H),2.45–2.37(m,2H),2.31–2.22(m,2H),1.61–1.51(m,4H),1.39(s,9H).

[0764] LC-MS(ESI):[M+H] + =331.29.

[0765] Step 4: tert-Butyl 2-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16d)

[0766] To a methanol solution of intermediate 16c (500 mg, 1.29 mmol) was added Pd / C (200 mg), and the mixture was allowed to react overnight under a hydrogen atmosphere. After the reaction was complete, the palladium-carbon residue was filtered through celite, and the solvent was dried to afford intermediate 16d as a yellow oily solid, which was not further processed.

[0767] 1 H NMR(400MHz, DMSO-d6)δ7.19(s,1H),6.83(d,J=54.1Hz,1H),4.73(p,J=8.3Hz,1H),4.19–4.00(m,2H),3.30(s,2H), 3.21(t,J=5.5Hz,2H),2.33–2.26(m,2H),2.17–2.07(m,2H),1.56(t,J=5.6Hz,2H),1.51–1.47(m,2H),1.39(s,9H).

[0768] LC-MS(ESI):[M+H-tBu] + =301.58.

[0769] Step 5: (2-(4-(5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (Intermediate 16e)

[0770] To a 20 mL solution of intermediate 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (300 mg, 1.15 mmol) in acetonitrile were added 1-methylimidazole (331.26 mg, 4.03 mmol) and tetramethylchlorouronium hexafluorophosphate (388.12 mg, 1.38 mmol) at room temperature. After half an hour at room temperature, intermediate 16d (410.85 mg, 1.15 mmol) was added and the reaction continued for three hours. After completion of the reaction, the product was purified by column chromatography (PE:EA = 0-100%) to afford intermediate 16e (595 mg, 84.77%) as a white solid.

[0771] LC-MS(ESI):[M+H] + =599.48.

[0772] Step 6: (5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-(7-azaspiro[3.5]nonan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate 16)

[0773] To a solution of intermediate 16e (550 mg, mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in dioxane and allowed to react at room temperature for 2 hours. The solution was then concentrated to afford intermediate 16 (348 mg, 75.98%) as a white solid.

[0774] 1 H NMR (400MHz, DMSO-d6) δ9.51(d,J=5.4Hz,1H),8.80(dd,J=7.8,1.7Hz,1H),8.43(d,J=4.3Hz,1H),8. 26(d,J=5.6Hz,1H),7.15(td,J=53.6,2.9Hz,1H),6.67(m,1H),5.18(d,J=74.9Hz,2H),4.98(qt,J=9 .3,4.5Hz,1H),4.84–4.71(m,2H),3.81(d,J=3.2Hz,1H),3.66–3.51(m,2H),3.03(d,J=34.5Hz,4H), 2.48–2.38(m,2H),2.27(td,J=9.8,9.3,4.4Hz,2H),2.07–1.91(m,2H),1.80(dt,J=21.7,5.8Hz,4H).

[0775] LC-MS(ESI):[M+H] +=499.39.

[0776] 17) Synthesis of Intermediate 17

[0777] Step 1: 5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 17a)

[0778] To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 4.43 mmol) and (2R,6R)-2,6-dimethylmorpholine (765.69 mg, 6.65 mmol) in acetonitrile (20 mL) was added DIEA (2.86 g, 22.16 mmol). The mixture was heated to 60°C for 2 hours. After completion of the reaction, the mixture was concentrated and column chromatography was performed to yield intermediate 17a (1.27 g, 94.15%) as a white solid.

[0779] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.9Hz,1H),8.20(s,1H),6.86(d,J=7.9Hz,1H),4.18(qd,J=7.1,1.1Hz,2H),4.03( pd,J=6.3,3.3Hz,2H),3.99–3.74(m,2H),3.47(dd,J=13.2,6.4Hz,2H),1.28(t,J=7.1Hz,3H),1.14(d,J=6.4Hz,6H).

[0780] LC-MS(ESI):[M+H] + =305.30.

[0781] Step 2: 5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 17b)

[0782] To a solution of intermediate 17a (1.27 g, 4.17 mmol) in methanol / water (15 / 1, 20 mL) was slowly added sodium hydroxide (1.00 g, 25.04 mmol). The mixture was heated to 60°C and allowed to react for 12 hours. After the reaction, the solution was concentrated and the pH was adjusted to 2 with 1M hydrochloric acid. Filtering afforded intermediate 17b (960 mg, 83.27%) as a yellow solid.

[0783] 1H NMR (400MHz, DMSO-d6) δ9.70(s,1H),8.71(d,J=7.9Hz,1H),8.18(s,1H),6.83(d,J=7.9Hz,1H),4.02(tt,J=6.6,3.3Hz,2 H), 3.75 (dd, J=13.1, 3.4Hz, 1H), 3.44 (dd, J=13.1, 6.5Hz, 2H), 3.34 (dd, J=13.1, 6.5Hz, 1H), 1.13 (dd, J=6.4, 1.4Hz, 6H).

[0784] LC-MS(ESI):[M+H] + =277.25.

[0785] Step 3: Ethyl (1S,4r)-4-(3-(difluoromethyl)-4-(5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 17c)

[0786] To a 5 mL solution of intermediate 17b (50 mg, 180.97 μmol) in acetonitrile, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (60.93 mg, 217.16 μmol) and 1-methylimidazole (52.00 mg, 633.38 μmol) were added, respectively. The mixture was stirred at room temperature for half an hour, followed by the addition of ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (57.19 mg, 199.06 μmol). After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography to afford intermediate 17c (53 mg, 53.68%) as a yellow solid.

[0787] 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.41(s,1H),8.28(s,1H),7.14(s,1H),6.93(s,2H),4.29–4.18(m,2H),4.07(dd,J=7.1 ,3.2Hz,4H),2.89(s,2H),2.69(s,2H),2.05(s,4H),1.77(d,J=11.0Hz,2H),1.52(d,J=3.3Hz,2H),1.23(s,3H),1.18(s,6H).

[0788] LC-MS(ESI):[M+H] + =546.48.

[0789] Step 4: (1S,4r)-4-(3-(difluoromethyl)-4-(5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 17)

[0790] To a solution of intermediate 17c (50 mg, 91.54 μmol) in methanol / water (15 v / 1 v, 5 mL) was slowly added sodium hydroxide (21.99 mg, 549.86 mmol). The mixture was heated to 60°C and allowed to react for 4 hours. After the reaction, the solution was concentrated and the pH was adjusted to 2 with 1M hydrochloric acid. Filtering afforded intermediate 17 (41 mg, 86.44%) as a yellow solid.

[0791] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,2H),8.81(d,J=7.9Hz,1H),8.40(s,1H),8.28(s,1H),7.70(t,J=1.7Hz,2H),3.86(s,5 H),2.89(s,1H),2.69(s,1H),2.30(s,1H),2.04(s,4H),1.80–1.75(m,2H),1.50(d,J=13.5Hz,2H),1.25–1.21(m,6H).

[0792] LC-MS(ESI):[M+H] + =518.49.

[0793] 18) Synthesis of Intermediate 18

[0794] Step 1: 5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 18a)

[0795] Under nitrogen atmosphere, (2S,6S)-2,6-dimethylmorpholine (1.53 g, 13.30 mmol) and N,N-diisopropylethylamine (5.16 g, 39.89 mmol) were added to a solution of ethyl 5-chloropyrazolo[1,5-A]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL). The mixture was reacted at 60°C for two hours. After the reaction, the solvent was dried and the product was purified by column chromatography (PE:EA = 0-80%) to give intermediate 18a (2.75 g, 101%) as a white solid.

[0796] 1H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.9Hz,1H),8.20(s,1H),6.86(d,J=7.9Hz,1H),4.18(qd,J=7.0,1.0Hz,2H),4 .07–3.98(m,2H),3.93–3.79(m,2H),3.47(dd,J=13.2,6.4Hz,2H),1.28(t,J=7.1Hz,3H),1.14(d,J=6.4Hz,6H).

[0797] LC-MS(ESI):[M+H] + =305.38.

[0798] Step 2: 5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 18b)

[0799] Under a nitrogen atmosphere, sodium hydroxide (657.09 mg, 16.43 mmol) was added to a solution of intermediate 18a (1.0 g, 3.29 mmol) in water / tetrahydrofuran (20 mL, 5 / 1) and the mixture was allowed to react in an oil bath at 60°C for two hours. After the reaction, a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added to adjust the pH to a slightly acidic state. The solution was then concentrated to yield intermediate 18b (311 mg, 34%) as a white solid.

[0800] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.9Hz,1H),8.18(s,1H),6.86(d,J=7.9Hz,1H),4.0 9–3.99(m,2H),3.93–3.77(m,2H),3.46(dd,J=13.2,6.5Hz,2H),1.14(d,J=6.4Hz,6H).

[0801] LC-MS(ESI):[M+H] + =277.37.

[0802] Step 3: Ethyl (1S,4r)-4-(3-(difluoromethyl)-4-(5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 18c)

[0803] To a 5 mL solution of Intermediate 18b (57.70 mg, 0.20 mmol) in acetonitrile was added 1-methylimidazole (60.01 mg, 0.73 mmol) and tetramethyluronium chloride hexafluorophosphate (70.31 mg, 0.25 mmol) at room temperature. After half an hour at room temperature, ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (60 mg, 0.20 mmol) was added and the reaction continued for three hours. After completion of the reaction, the product was purified by column chromatography (PE:EA = 0-100%) to afford Intermediate 18c (178 mg, 156%) as a yellow solid.

[0804] 1 H NMR(400MHz, DMSO-d6)δ9.31(s,1H),8.81(d,J=8.0Hz,1H),8.41(s,1H),8.28(s,1H),7.30–7.02(m,1H),6.92(d,J=8.0Hz,1H),4.30–4.20(m,1H), 4.12–4.02(m,4H),3.97–3.86(m,1H),3.51(dd,J=13.3,6.8Hz,2H),2.45 –2.34(m,1H),2.10–1.97(m,4H),1.81(m,2H),1.52(m,2H),1.19(m,10H).

[0805] LC-MS(ESI):[M+H] + =546.38.

[0806] Step 4: (1S,4r)-4-(3-(difluoromethyl)-4-(5-((2S,6S)-2,6-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 18)

[0807] Under nitrogen, sodium hydroxide (54.25 mg, 1.36 mmol) was added to a solution of intermediate 18c (148.0 mg, 0.27 mmol) in water / tetrahydrofuran (20 mL, 5 / 1) and the mixture was allowed to react in an oil bath at 60°C for two hours. After the reaction, a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added to adjust the pH to a slightly acidic state. The solution was then concentrated to yield intermediate 18 (202 mg, 120%) as a white solid.

[0808] 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.81 (d, J = 7.9Hz, 1H), 8.39 (s, 1H), 8.28 (s,1H),7.28–7.01(m,1H),6.92(d,J=8.0Hz,1H),4.24–4.13(m,1H),4.12–4.0 1(m,2H),3.97–3.83(m,2H),3.51(dd,J=13.2,6.8Hz,2H),2.05–1.89(m,4H),1 .77–1.65(m,3H),1.49–1.36(m,2H),1.27–1.22(m,1H),1.17(d,J=6.4Hz,6H).

[0809] LC-MS(ESI):[M+H] + =518.39.

[0810] 19) Synthesis of Intermediate 19

[0811] Step 1: 5-(1,4-oxazopyrim-4-yl)pyrazolo[1,5-A]pyrimidine-3-carboxylate (Intermediate 19a)

[0812] To a solution of ethyl 5-chloropyrazolo[1,5-A]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL) were added 1,4-oxazepane (1.08 g, 10.64 mmol) and N,N-diisopropylethylamine (3.44 g, 26.59 mmol) and allowed to react overnight at 60°C. After completion of the reaction, the solvent was dried and the product was purified by column chromatography (PE:EA = 0-30%) to afford intermediate 19a (2 g, 77.72%) as a yellow oil.

[0813] 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=7.9Hz,1H),8.20(s,1H),6.78(d,J=8.0Hz,1H),4.19(t,J=7.1H z,2H),4.05–3.90(m,2H),3.76(s,4H),3.63(t,J=5.5Hz,2H),1.90(s,2H),1.27(t,J=7.1Hz,3H).

[0814] LC-MS(ESI):[M+H] + =291.32.

[0815] Step 2: 5-(1,4-oxazopyrim-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 19b)

[0816] To a solution of intermediate 19a (2.0 g, 6.89 mmol) in methanol / water (18 mL, v / v = 1:1) was added sodium hydroxide (1.38 g, 34.44 mmol) and allowed to react at 60°C for 2 hours. After completion of the reaction, the pH was adjusted to 4-5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield intermediate 19b (1.7 g, 94.1%) as a white solid.

[0817] LC-MS(ESI):[M+H] + =263.27.

[0818] Step 3: Ethyl (1R, 4R)-4-(4-(5-(1,4-oxazol-4-yl)pyrazolo[1,5-A]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 19c)

[0819] To a solution of Intermediate 19b (700 mg, 2.67 mmol) in acetonitrile (10 mL) were added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (898.6 mg, 3.20 mmol) and N-methylimidazole (767.0 mg, 9.34 mmol). The mixture was allowed to react at room temperature for half an hour. Ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (843.5 mg, 2.94 mmol) was then added and allowed to react at room temperature for 2 hours. After the reaction, the mixture was concentrated and purified by column chromatography to afford Intermediate 19c (800 mg, 56.4%) as a colorless oil.

[0820] LC-MS(ESI):[M+H] + =532.57.

[0821] Step 4: (1R,4R)-4-(4-(5-(1,4-oxazepin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 19)

[0822] To a solution of intermediate 19c (800 mg, 1.50 mmol) in methanol / water (6 mL, 1:1) was added sodium hydroxide (300.9 mg, 7.52 mmol) and allowed to react at 60°C for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 4-5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, intermediate 19 (600 mg, 79.18%) was obtained as a white solid.

[0823] LC-MS(ESI):[M+H] + =504.57.

[0824] 20) Synthesis of Intermediate 20

[0825] Step 1: Ethyl (S)-5-(3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 20a)

[0826] To a solution of ethyl 5-chloropyrazolo[1,5-A]pyrimidine-3-carboxylate (2 g, 8.86 mmol) in acetonitrile (20 mL) were added (S)-3-methylmorpholine (1.79 g, 17.73 mmol) and N,N-diisopropylethylamine (3.44 g, 26.59 mmol) and the mixture was allowed to react overnight at 60°C. After completion of the reaction, the solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford intermediate 20a (800 mg, 31.09%) as a yellow oil.

[0827] 1 H NMR(600MHz,DMSO-d6)δ8.76(d,J=7.9Hz,1H),8.22(s,1H),6.83(d,J=7.9Hz,1H) ,4.54(s,1H),4.24(s,1H),4.19(qt,J=7.3,3.7Hz,2H),3.97(dd,J=11.5,3.8Hz, 1H),3.76(d,J=11.5Hz,1H),3.63(dd,J=11.5,3.2Hz,1H),3.48(td,J=11.9,3.0H z,1H),3.24(td,J=13.1,3.9Hz,1H),1.28(t,J=7.1Hz,3H),1.24(d,J=6.8Hz,3H).

[0828] LC-MS(ESI):[M+H] + =291.32.

[0829] Step 2: (S)-5-(3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 20b)

[0830] To a solution of intermediate 20a (800 mg, 2.76 mmol) in methanol / water (18 mL, v / v = 2:1) was added sodium hydroxide (330.6 mg, 8.27 mmol) and allowed to react at 60°C for 2 hours. After completion of the reaction, the pH was adjusted to 4-5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, intermediate 20b (500 mg, 69.2%) was obtained as a white solid.

[0831] 1 H NMR (600MHz, DMSO-d6) δ11.74(s,1H),8.75(d,J=7.9Hz,1H),8.20(s,1H),6.81(d,J=7.9Hz,1H),4.52(s,1H),4.25(d,J=13.2Hz,1H),3.98(dd,J=11. 5,3.8Hz,1H),3.76(d,J=11.5Hz,1H),3.63(dd,J=11.6,3.2Hz,1H),3.47(t d,J=11.9,3.0Hz,1H),3.22(td,J=13.0,3.9Hz,1H),1.24(d,J=6.7Hz,3H).

[0832] LC-MS(ESI):[M+H] + =263.27.

[0833] Step 3: Ethyl (1S,4r)-4-(3-(difluoromethyl)-4-(5-(S)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 20c)

[0834] To a solution of Intermediate 20b (500 mg, 1.91 mmol) in acetonitrile (10 mL) were added N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (641.9 mg, 2.29 mmol) and N-methylimidazole (547.8 mg, 6.67 mmol). The mixture was allowed to react at room temperature for 0.3 h. Ethyl (1R,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (602.5 mg, 2.10 mmol) was then added and allowed to react at room temperature for 2 h. After the reaction, the mixture was concentrated and purified by column chromatography to afford Intermediate 20c (1.0 g, 98.68%) as a colorless oil.

[0835] 1H NMR (600MHz, DMSO-d6) δ9.36(s,1H),8.83(d,J=7.8Hz,1H),8.40(s,1H),8.29(s,1H),7.10(t,J=53.7Hz,1H),6.86(d,J= 8.0Hz,1H),4.61(s,1H),4.24(tt,J=12.1,3.2Hz,2H),4.07(q,J=7.1Hz,2H),3.95(dd,J=11.5,3.8Hz,1H),3.74(d,J=11. 5Hz,1H),3.66(dd,J=11.9,3.0Hz,1H),3.52(td,J=11.9,3.1Hz,1H),3.33–3.26(m,1H),2.39(tt,J=12.2,3.6Hz,1H),2. 08–1.99(m,4H),1.80(qd,J=12.6,3.3Hz,2H),1.53(qd,J=13.1,3.2Hz,2H),1.26(d,J=6.8Hz,3H),1.19(t,J=7.1Hz,3H).

[0836] LC-MS(ESI):[M+H] + =532.57.

[0837] Step 4: (1S,4r)-4-(3-(difluoromethyl)-4-(5-((S)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 20)

[0838] To a solution of intermediate 20c (1 g, 1.88 mmol) in methanol / water (18 mL, v / v = 2:1) was added sodium hydroxide (225.7 mg, 5.64 mmol) and allowed to react at 60°C for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 4-5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, intermediate 20 (830 mg, 87.62%) was obtained as a white solid.

[0839] LC-MS(ESI):[M+H] + =504.57.

[0840] 21) Synthesis of Intermediate 21

[0841] Step 1: Ethyl (R)-5-(3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate 21a)

[0842] To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (5 g, 22.16 mmol) in acetonitrile (50 mL) was added DIEA (14.32 g, 110.80 mmol) and (R)-3-methylmorpholine (3.36 g, 33.24 mmol) under air. The mixture was allowed to react at room temperature for 2 h. The reaction solution was purified by preparative chromatography (DCM:MeOH = 0-20%) to afford Intermediate 21a (3.1 g, 48.18%) as a white solid.

[0843] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=7.9Hz,1H),8.22(s,1H),6.82(d,J=7.9Hz,1H),4.19(qd,J=7.1,1.8Hz,4H),4.04 –3.71(m,2H),3.69–3.42(m,2H),3.22(ddd,J=26.3,13.4,4.5Hz,1H),1.28(t,J=7.1Hz,3H),1.24(d,J=6.8Hz,3H).

[0844] LCMS(ESI):[M+H] + =291.38.

[0845] Step 2: (R)-5-(3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate 21b)

[0846] To a solution of intermediate 21a (3.1 g, 10.68 mmol) in methanol (30 mL) was added NaOH (2.14 g, 53.39 mmol) under air, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was mostly removed by distillation under reduced pressure. 10 mL of water was added, and the mixture was acidified to neutrality with 1 M hydrochloric acid to precipitate a white solid, which was filtered to afford intermediate 21b (2.8 g, 99.98%) as a white solid.

[0847] 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=7.9Hz,1H),8.13(s,1H),6.75(d,J=7.9Hz,1H),4.56–4.17(m,2H),3.96(dd,J=11.5,3.6Hz,1H),3. 75(d,J=11.4Hz,1H), 3.62(dd,J=11.5,3.1Hz,1H), 3.46(td,J=11.9,3.0Hz,1H), 3.21(dd,J=13.2,3.9Hz,1H), 1.22(d,J=6.7Hz,3H).

[0848] LCMS(ESI):[M+H] + =263.27.

[0849] Step 3: Ethyl (1R,4R)-4-(3-(difluoromethyl)-4-(5-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylate (Intermediate 21c)

[0850] To a solution of Intermediate 21b (200 mg, 762.58 μmol) in acetonitrile (5 mL) was added TCFH (320.94 mg, 1.14 mmol), 1-methylimidazole (219.14 mg, 2.67 mmol), and 01a (262.92 mg, 915.09 μmol) under air and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by preparative chromatography (EA:PE = 0-70%) to afford Intermediate 21c (243 mg, 59.95%) as a white solid.

[0851] 1 H NMR(400MHz, DMSO-d6)δ9.36(s,1H),8.83(d,J=8.0Hz,1H),8.39(s,1H),8.29(s,1H),7.10(t,J=53.7Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 4.24 (ddt, J = 11.9, 7.3, 3.9Hz, 2H), 4.07 (q, J = 7.1Hz, 2H), 3.95 (dd, J = 11.6, 3. 7Hz,1H),3.81–3.62(m,2H),3.52(td,J=11.9,2.9Hz,1H),3.37–3.23(m,2H),2.39(tt,J=12.0,3.5Hz,1H ),2.08–1.99(m,4H),1.80(qd,J=12.9,3.7Hz,2H),1.53(qd,J=13.9,13.1,3.9Hz,2H),1.29–1.17(m,7H).

[0852] LCMS(ESI):[M+H] + =532.49.

[0853] Step 4: (1R,4r)-4-(3-(difluoromethyl)-4-(5-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (Intermediate 21)

[0854] To a solution of Intermediate 21c (240 mg, 451.50 μmol) in methanol (10 mL) was added NaOH (54.18 mg, 1.35 mmol) under air, and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was mostly removed by distillation under reduced pressure. 3 mL of water was added, and the mixture was acidified to neutrality with 1 M hydrochloric acid to precipitate a white solid, which was filtered to afford Intermediate 21 (210 mg, 92.38%) as a white solid.

[0855] 1 H NMR (400MHz, DMSO-d6) δ9.35(s,1H),8.82(d,J=7.9Hz,1H),8.34(d,J=37.4Hz,2H),7.10(t,J=53.7Hz,1H),6.86(d ,J=8.0Hz,1H),4.61(s,1H),4.22(tt,J=11.9,3.7Hz,2H),3.94(dd,J=11.5,3.7Hz,1H),3.74(d,J=11.5Hz,1H),3. 66(dd,J=11.6,3.1Hz,1H),3.51(td,J=11.9,2.9Hz,1H),3.29(td,J=13.0,3.9Hz,2H),2.23(tt,J=11.9,3.4Hz,1H ), 2.04 (d, J = 14.1Hz, 4H), 1.76 (qd, J = 13.4, 12.9, 3.9Hz, 2H), 1.50 (dd, J = 13.4, 10.4Hz, 2H), 1.25 (d, J = 6.7Hz, 3H).

[0856] LCMS(ESI):[M+H] + =504.39.

[0857] 2. Synthesis of CLM

[0858] 1) Synthesis of CLM2

[0859] 7-(2,6-dioxapiperidin-3-yl)-3,4-dihydro-6H-spiro[pyrano[2,3-f]isoindole-2,3'-pyrrolidine]-6,8(7H)-dione

[0860] Synthesis scheme:

[0861] Step 1: 1'-(tert-butyl) 6,7-dimethyl 4-oxaspiro[chroman-2,3'-pyrrolidine]-1',6,7-tricarboxylate (Compound 2a)

[0862] Compound 1d was prepared by following steps 1 to 3 of Example 1. Compound 1d (5.0 g, 19.8 mmol), 1-tert-butoxycarbonyl-3-pyrrolidone (1.4 g, 19.8 mmol), and tetrahydropyrrole (4.0 g, 19.8 mmol) were dissolved in methanol (50 mL). The mixture was stirred at 70°C overnight. The mixture was dried and purified by column chromatography (PE:EA = 0-35%) to afford compound 2a (5.0 g, 60%) as a yellow oil.

[0863] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.18(s,1H),3.95(s,3H),3.91(s,3H),3.89–3.83(m,1H),3.76–3.64(m,1H),3.62–3.50(m,1H),3. 40(dd,J=17.4,12.4Hz,1H),3.06–2.86(m,2H),2.36–2.25(m,1H),1.97(ddd,J=13.5,10.4,9.0Hz,1H),1.47(d,9H).LC-MS(ESI):[MH] + =418.40

[0864] Step 2: 1'-(tert-butyl) 6,7-dimethyl 4-hydroxyspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2b)

[0865] Under ice bath conditions, sodium borohydride (0.7 g, 17.9 mmol) was added to a solution of compound 2a (5.0 g, 11.5 mmol) in methanol (50 mL). The reaction was stirred at 70°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to give compound 2b (5.0 g, 99%) as a white solid. The resulting mixture was used directly in the next reaction. LC-MS (ESI): [M+Na] + =444.33

[0866] Step 3: Methyl spiro[chromene-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2c)

[0867] Compound 2b (3.0 g, 7.1 mmol) and triethylsilane (3.3 g, 28.5 mmol) were dissolved in trifluoroacetic acid (30 mL), and the mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give compound 2c (1.1 g, 51%) as a colorless oil.

[0868] 1H NMR (600MHz, CDCl3) δ7.53(s,1H),7.09(s,1H),6.61(d,J=9.8Hz,1H),5.79(d,J=9.9Hz,1H),4.53(br s,2H),3.91(s,3H),3.89(s,3H),3.70–3.55(m,3H),3.27(d,J=12.5Hz,1H),2.54 (dd,J=14.2,6.4Hz,1H),2.14(ddd,J=13.8,11.0,6.5Hz,1H).LC-MS(ESI):[M+H] + =304.27

[0869] Step 4: Dimethylspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Compound 2d)

[0870] Compound 2c (1.0 g, 3.3 mmol) was dissolved in methanol (20 mL) and palladium on carbon (0.1 g) was added. The reaction was stirred under hydrogen at room temperature overnight. The mixture was filtered and dried to give compound 2d (1.0 g, 99%) as a yellow oil.

[0871] 1 H NMR (600MHz, CDCl3) δ7.61(s,1H),7.09(s,1H),3.90(s,3H),3.88(s,3H),3.52(dtd,J=17.8,11.4,7.8Hz,2H),3.44(dd,J=12.7,1.6Hz,1H ),3.25(d,J=12.6Hz,1H),2.90(dtd,J=17.3,10.7,6.9Hz,2H),2.28–2.23(m,1H),2.14–2.10(m,2H),2.08–2.02(m,1H).LC-MS(ESI):[M+H] + =306.22

[0872] Step 5: Spiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylic acid (Compound 2e)

[0873] Compound 2d (1.0 g, 3.3 mmol) was dissolved in methanol and water, and lithium hydroxide (1.2 g, 49.1 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. LC-MS (ESI): [M+H] + =278.22

[0874] Step 6: 7-(2,6-dioxapiperidin-3-yl)-3,4-dihydro-6H-spiro[pyrano[2,3-f]isoindole-2,3'-pyrrolidine]-6,8(7H)-dione (CLM2)

[0875] Compound 2e (801 mg, 4.9 mmol) was dissolved in acetic acid (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.97 g, 6.0 mmol) and sodium acetate (1.3 g, 9.7 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse-phase column chromatography to obtain CLM2 (312 mg, 26%) as a white solid.

[0876] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.78(s,1H),7.18(s,1H),5.10(dd,J=12.9,5.4Hz,1H), 3.50–3.21(m,4H),3.03–2.84(m,4H),2.66–2.53(m,2H),2.24–2.00(m,4H).LC-MS(ESI):[M+H] + =370.34

[0877] 2) Synthesis of CLM5

[0878] 7'-(2,6-dioxapiperidin-3-yl)-7'-hydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-6',8'-dione

[0879] Synthesis scheme

[0880] Step 1: Dimethyl 4-fluorophthalate (Compound 5b)

[0881] To a solution of compound 5a (5.5 g, 30.0 mmol) in methanol (100 mL) was slowly added concentrated sulfuric acid (15 mL). The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentration under reduced pressure afforded compound 5b (5.7 g, 90%) as a colorless oil. The crude product was used in the next reaction without purification.

[0882] 1H NMR (400MHz, CDCl3) δ7.82(dd,J=8.6,5.3Hz,1H),7.38(dd,J=8.6,2.6Hz,1H),7.82(ddd,J=8.6,5.3,2.6Hz,1H),3.96(s,3H),3.92(s,3H)

[0883] Step 2: Methyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalate (Compound 5c)

[0884] Diboronic acid pinacol ester (4.5 g, 17.5 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.13 g, 0.47 mmol), and methoxy(cyclooctadiene)iridium dimer (0.16 g, 0.23 mmol) were added to a 10 mL solution of methyl tert-butyl ether. A solution of compound 5b (2.5 g, 11.8 mmol) in methyl tert-butyl ether (10 mL) was then added. The atmosphere was purged with nitrogen and the reaction was stirred at 100°C for 4 h. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain a crude product (3.2 g) which was used in the next step without purification.

[0885] Step 3: Dimethyl 4-fluoro-5-hydroxyphthalate (Compound 5d)

[0886] Potassium peroxymonosulfate (6.15 g) was added to a solution of compound 5c (3.38 g, 10 mmol) in acetonitrile (50 mL), and the reaction was stirred at room temperature overnight. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain compound 5d (1.6 g, 70%) as a white solid.

[0887] 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.50 (d, J = 10.8Hz, 1H), 7.19 (d, J = 8.1Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H). LC-MS (ESI): [M+H] + =229.18

[0888] Step 4: 1'-((Benzyloxy)carbonyl)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 5e)

[0889] Compound 5d (23 mg, 0.1 mmol) was dissolved in 1 ml of ultra-dry N,N-dimethylformamide, followed by the addition of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (25 mg, 0.1 mmol) and sodium hydride (6 mg, 0.25 mmol). The reaction was heated to 110°C and stirred for 2 days. The reaction mixture was then reversed to afford compound 5e (13 mg, 31%) as a white solid.

[0890] 1 H NMR(600MHz,CD3OD)δ7.41–7.35(m,4H),7.33(dd,J=5.9,2.9Hz,1H),7.29(s,1H),7.27(s,1H),5.15(s,2H),4.07(s ,2H),4.01(dt,J=13.6,4.0Hz,2H),3.42–3.32(m,2H),1.82(d,J=13.9Hz,2H),1.76–1.67(m,2H).LC-MS(ESI):[M+H] + =428.36

[0891] Step 5: Benzyl 7'-(2,6-dioxapiperidin-3-yl)-6',8'-dioxa-7',8'-dihydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-1-carboxylate (Compound 5f)

[0892] To a solution of compound 5e (13 mg, 0.03 mmol) in acetic acid (1 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (6 mg, 0.036 mmol) and sodium acetate (7 mg, 0.09 mmol). The reaction was heated to 110°C and stirred for 4 hours. After completion of the reaction, the reaction solution was purified by reverse transpiration to afford compound 5f (12 mg, 77%) as a white solid.

[0893] 1 H NMR(600MHz,CD3OD)δ7.42(s,1H),7.40–7.31(m,6H),5.15(s,2H),5.08(dd,J=12.9,5.5Hz,1H),4.14(s,2H),4.01(dt,J=13.8,4.0Hz,2H),3.43–3 .32(m,2H),2.91–2.83(m,1H),2.79–2.69(m,2H),2.14–2.09(m,1H),1.83 (d,J=13.9Hz,2H),1.74(td,J=14.4,12.9,4.8Hz,2H).LC-MS(ESI):[M+H] + =520.29.

[0894] Step 6: 7'-(2,6-dioxapiperidin-3-yl)-7'-hydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-6',8'-dione (CLM5)

[0895] Palladium carbon (5 mg) was added to a methanol solution of compound 5f (11 mg, 0.02 mmol), the atmosphere was replaced with hydrogen, and the reaction mixture was stirred under hydrogen for 6 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give CLM5 (7 mg, 90%) as a white solid.

[0896] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.50(s,1H),7.48(s,1H),5.09(dd,J=12.8,5.3Hz,1H),4.27(s,2H),3.25(d,J=12.7Hz,2H),3.18–3. 11(m,2H),2.89(ddd,J=16.7,13.7,5.3Hz,1H),2.64–2.53(m,2H),2.03(ddd,J=13.3,5.7,3.4Hz,1H),1.92–1.86(m,4H).LC-MS(ESI):[M+H] + =386.32

[0897] 3) Synthesis of CLM7

[0898] 2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione

[0899] Synthesis scheme

[0900] Step 1: 2-Benzyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (Compound 7b)

[0901] Compound 7a (5 g, 33 mmol) was dissolved in anhydrous acetonitrile (50 ml). Tetrabutylammonium bromide (1.23 g, 3.3 mmol) and anhydrous potassium carbonate (14 g, 99 mmol) were added to the solution. Benzyl chloride (5.5 g, 43 mmol) was slowly added to the system and allowed to react overnight at 30°C. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7b (7.5 g, 94%) as a white solid.

[0902] 1 H NMR (400MHz, CDCl3) δ7.37–7.20(m,5H),5.95–5.83(m,2H),4.63(s,2H),3.20–3.01(m,2H),2.61(m,2H),2.31–2.10(m,2H).LC-MS(ESI):[M+H] + =242.22

[0903] Step 2: 2-Benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (Compound 7c)

[0904] At 0°C, lithium aluminum tetrahydride (3.2 g, 82 mmol) was added to 40 mL of anhydrous tetrahydrofuran, followed by compound 7b (5 g, 20.7 mmol). After an ice bath for 5 minutes, the reaction system was moved to a 70°C oil bath and allowed to react for 3 hours. After the reaction, water was slowly added dropwise to the reaction solution in an ice bath until bubbles ceased. The filtrate was collected by filtration and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded compound 7c (3.2 g, 73%) as a yellow oil.

[0905] 1 H NMR (400MHz, CDCl3) δ7.43–7.24(m,5H),5.87(t,J=2.7Hz,2H),3.67(s,2H),3.05–2.90(m,2H),2.44(m,2H),2.29–2.16(m,4H),1.92(m,2H)

[0906] Step 3: 2-Benzyloctahydro-1H-isoindol-5-ol (Compound 7d)

[0907] Compound 7c (5 g, 23.44 mmol) was dissolved in 20 mL of tetrahydrofuran at 0°C. 25 mL of 2M borane-tetrahydrofuran complex was added under ice-cooling. After 12 h of reaction, 13 mL of anhydrous methanol, 10.5 mL of 3M NaOH solution, and 10.5 mL of hydrogen peroxide were added to the reaction solution. The reaction was then allowed to react at 60°C for 6 h. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate. The organic phase was saturated with brine and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography to afford compound 7d (1.2 g, 22.2%).

[0908] 1H NMR (400MHz, CDCl3) δ7.43–7.18(m,5H),3.84(m,1H),3.78(s,2H),2.94(dd,J=9.8,6.7Hz,1H),2.82(dd,J=9.5,7.7Hz,1H),2.64(dd,J=9 .5,8.4Hz,1H),2.60–2.44(m,2H),2.12(m,1H),1.89–1.72(m,3H),1.54(m,1H),1.47–1.35(m,1H),1.35–1.22(m,2H).LC-MS(ESI):[M+H] + =232.31

[0909] Step 4: 2-Benzyloctahydro-5H-isoindol-5-one (Compound 7e)

[0910] Compound 7d (1.2 g, 12.97 mmol) was dissolved in anhydrous dichloromethane. Dess-Martin periodinane (11 g, 25.95 mmol) was added in an ice bath and allowed to react for 12 h. The reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and saturated sodium thiosulfate. The filtrate was filtered and extracted with dichloromethane. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Concentration afforded a crude product (1 g), which was used directly in the next reaction.

[0911] Step 5: 2-Benzyl-6-bromo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carbaldehyde (Compound 7f)

[0912] Dissolve N,N-dimethylformamide (1.01 mL, 13.08 mmol) in 2 mL of dichloromethane at 0°C. Slowly add phosphorus tribromide (1.13 mL, 11.77 mmol) dropwise and stir at 0°C for 1 hour. Add a dichloro solution of compound 7e (1 g, 2.62 mmol) dropwise to the above system, warm to room temperature and react for 10 hours. After the reaction is completed, place the reaction solution at 0°C and add saturated sodium bicarbonate until no bubbles are generated. Extract with dichloromethane. Wash the organic phase with saturated brine and dry it over anhydrous sodium sulfate. Concentrate to obtain a crude product, which is purified by column chromatography to obtain the target compound 7f (270 mg, 20%).

[0913] 1H NMR (400MHz, CDCl3) δ10.04(s,1H),7.32(d,J=5.8Hz,5H),3.60(s,2H),3.21–3.10(m,2H),2.85–2.72(m,3H ),2.50–2.43(m,1H),2.33(dd,J=9.2,5.0Hz,1H),2.24–2.18(m,1H),1.83–1.74(m,2H).LC-MS(ESI):[M+H] + =320.16

[0914] Step 6: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid methyl ester (Compound 7g)

[0915] Compound 7f (270 mg, 0.84 mmol), dimethyl itaconate (133.4 mg, 0.84 mmol), palladium acetate (9.5 mg, 0.042 mmol), triphenylphosphine (22.11 mg, 0.084 mmol), and sodium acetate (207.5 mg, 2.53 mmol) were added sequentially to a pressure vessel, dissolved in tetrahydrofuran, replaced with nitrogen, and heated to 120°C for overnight reaction. After cooling the reaction system to room temperature, the tetrahydrofuran was dried, and then separated and purified by preparative liquid chromatography to obtain compound 7g (71 mg, 22%).

[0916] 1 H NMR (400MHz, CDCl3) δ7.52–7.39(m,7H),4.38–4.14(m,3H),3.91(d,J=2.8Hz,7H),3.27(s ,3H),2.94(d,J=12.0Hz,1H),2.85–2.72(m,3H),1.55(d,J=6.6Hz,1H).LC-MS(ESI):[M+H] + =380.36

[0917] Step 7: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid (Compound 7h)

[0918] Compound 7g (71 mg, 0.19 mmol) was dissolved in methanol and water, and lithium hydroxide (90 mg, 3.74 mmol) was added. The reaction was allowed to react at room temperature for 20 h. After the reaction, the water and methanol were dried to give a crude product (62 mg, 95%). The crude product was used directly in the next step. LC-MS (ESI): [M+H] + =352.34

[0919] Step 8: 7-Benzyl-2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (Compound 7i)

[0920] Compound 7h (62 mg, 0.18 mmol) was dissolved in glacial acetic acid, and sodium acetate (43.2 mg, 0.53 mmol) and 3-amino-2,6-piperidinedione hydrochloride (44 mg, 0.26 mmol) were added. The mixture was reacted in an oil bath at 110°C overnight. Methanol and water were then evaporated, and the product was purified by preparative liquid chromatography to obtain compound 7i (39 mg, 49%).

[0921] 1 H NMR(400MHz,DMSO-d6)δ11.14(s,1H),7.98–7.72(m,2H),7.64–7.41(m,5H),5. 14(dd,J=12.9,5.4Hz,1H),4.53–4.24(m,2H),4.01(dd,J=13.9,7.6Hz,1H),3. 76(s,3H),3.12(d,J=9.7Hz,1H),3.06–2.91(m,2H),2.92–2.76(m,3H),2.67–2 .54(m,2H),2.04(dd,J=12.5,6.2Hz,1H),1.90–1.59(m,2H).LC-MS(ESI):[M+H] + =444.41

[0922] Step 9: 2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (CLM7)

[0923] Compound 7i (39 mg, 0.088 mmol) was dissolved in 2 mL of methanol, 4 mg of palladium carbon was added, the atmosphere was replaced with hydrogen, and the mixture was reacted at room temperature overnight. The palladium carbon was removed by filtration, the methanol was dried, and CLM7 (12 mg, 38%) was purified by preparative liquid chromatography.

[0924] 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.07–8.95(m,1H),7.95–7.68(m,2H),5.14(dd,J=13.0,5.3Hz,1H),3.96–3.87(m,2H),3 .51(m,2H),3.12(m,1H),3.04–2.82(m,4H),2.72–2.55(m,2H),2.06(m,1H),1.86(m,1H),1.65–1.46(m,1H).LC-MS(ESI):[M+H] + =354.41

[0925] 4) Synthesis of CLM8

[0926] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione

[0927] Synthesis scheme

[0928] Step 1: 1,4-dioxa-9,13-dithiadispiro[4.2.5 8 .2 5 ]pentadecane (Compound 8b)

[0929] Compound 8a (10.0 g, 64.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 1,3-propanedithiol (7.0 g, 64.0 mmol). 32 mmol of boron trifluoride etherate was added dropwise at -18°C. After the addition was complete, the mixture was stirred at -18°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, 500 mL of water was added, and the solid was filtered and purified by C18 column chromatography to yield compound 8b (2 g, 12.7%).

[0930] 1 H NMR(400MHz,DMSO-d6)δ3.85(s,4H),2.84–2.78(m,4H),2.06-1.98(m,4H),1.93–1.80(m,2H),1.70–1.59(m,4H).LC-MS(ESI):[M+H] + =247.07

[0931] Step 2: 1,5-dithiaspiro[5.5]undecan-9-one (Compound 8c)

[0932] Compound 8b (2.0 g, 8.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 100 mL of trifluoroacetic acid at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. After completion of the reaction, sodium bicarbonate (aq) solution was added to the system to adjust the pH to 7. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford compound 8c (1.5 g, 91.0%).

[0933] 1 H NMR(400MHz,DMSO-d6)δ2.93–2.84(m,4H),2.41–2.33(m,4H),2.31-2.25(m,4H),1.94–1.88(m,2H).LC-MS(ESI):[M+H] + =203.05

[0934] Step 3: Dimethyl 4-oxadispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8d)

[0935] Compound 8c (2.0 g, 9.9 mmol) was dissolved in 200 mL of tetrahydrofuran, followed by the addition of compound 4 (2.0 g, 9.8 mmol) and tetrahydropyrrole (2.0 g, 28.0 mmol) at room temperature. After addition, the mixture was stirred at 70°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8d (2.0 g, 46.0%).

[0936] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.35(s,1H),3.83(s,3H),3.81(s,3H),2.92(s,2H),2. 90–2.85(m,2H),2.81–2.74(m,2H),2.14–2.10(m,2H),2.02–1.77(m,8H).LC-MS(ESI):[M+H] + =437.10

[0937] Step 4: Dimethyl 4-hydroxydispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8e)

[0938] Compound 8d (2.0 g, 4.5 mmol) was dissolved in 50 mL of methanol and 50 mL of tetrahydrofuran, followed by the addition of sodium borohydride (350.0 mg, 9.0 mmol) at room temperature. After the addition, the mixture was stirred at 70°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8e (1.5 g, 75.0%).

[0939] 1 H NMR (600MHz, DMSO-d6) δ7.90 (s, 1H), 7.00 (s, 1H), 5.68 (d, J = 6.2Hz, 1H), 4.77-4.71 (m, 1H), 3.79 (s, 6H),2.96–2.72(m,4H),2.16–2.01(m,4H),1.93–1.79(m,5H),1.77–1.70(m,3H).LC-MS(ESI):[M+H] + =439.12

[0940] Step 5: Dimethyldispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Compound 8f)

[0941] Compound 8e (700 mg, 1.5 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of triethylamine (480.0 mg, 4.5 mmol) and 4-dimethylaminopyridine (100.0 mg, 0.8 mmol) at room temperature. Sulfuryl chloride (720.0 mg, 6.0 mmol) was added dropwise at 0°C. After the addition, the mixture was stirred at 0°C for 4 h, and the reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed under reduced pressure. After the addition, the residue was dissolved in 100 mL of toluene, followed by the addition of 1,8-diazabicycloundec-7-ene (1.6 g, 10.0 mmol) at room temperature. The mixture was stirred at 110°C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8f (400 mg, 59.0%).

[0942] 1 H NMR (400MHz, DMSO-d6) δ7.58(s,1H),7.05(s,1H),6.59(d,J=9.9Hz,1H),5.95(d,J=11.4Hz,1H),3.78(s,3H),3.77(s, 3H),2.93–2.85(m,2H),2.82–2.73(m,2H),2.18-2.11(m,2H),2.09–1.96(m,2H),1.92–1.77(m,6H).LC-MS(ESI):[M+H] +=421.11

[0943] Step 6: Dispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylic acid (Compound 8g)

[0944] Compound 8f (400.0 mg, 0.9 mmol) was dissolved in 50 mL of methanol, 50 mL of tetrahydrofuran, and 50 mL of water, followed by the addition of lithium hydroxide (120.0 mg, 4.5 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 16 h. After completion of the reaction, 1.0 M dilute hydrochloric acid was added to the system, and the pH was adjusted to 6. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford compound 8g (350 mg, 94.0%).

[0945] 1 H NMR (600MHz, DMSO-d6) δ12.90(s,2H),7.52(s,1H),6.99(s,1H),6.57(d,J=9.9Hz,1H),5.90(d,J=9.9Hz,1H) ,2.92–2.86(m,2H),2.83–2.73(m,2H),2.11(m,2H),2.09–1.97(m,2H),1.94–1.76(m,6H).LC-MS(ESI):[M+H] + =393.08

[0946] Step 7: 7-(2,6-dioxapiperidin-3-yl)-6H-dispiro[pyrano[2,3-f]isoindole-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,8(7H)-dione (Compound 8h)

[0947] Compound 8g (300.0 mg, 0.7 mmol) was dissolved in 100 mL of acetic acid, followed by the addition of 3-aminopiperidine-2,6-dione hydrochloride (170.0 mg, 1.3 mmol) and sodium acetate (360.0 mg, 2.1 mmol) at room temperature. After the addition, the mixture was stirred at 110°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield compound 8h (280 mg, 75.0%).

[0948] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.72(s,1H),7.30(s,1H),6.70(d,J=8.0Hz,1H),6.03(d,J=8.8Hz,1H),5.13-5.07( m,1H),2.94–2.84(m,3H),2.84–2.76(m,2H),2.64-2.55(m,1H),2.18–1.98(m,6H),1.95–1.78(m,6H).LC-MS(ESI):[M+H] + =485.11

[0949] Step 8: 7'-(2,6-oxapiperidin-3-yl)-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (Compound 8i)

[0950] Compound 8h (280.0 mg, 0.5 mmol) was dissolved in 50 mL of acetonitrile, followed by the addition of 50 mL of sodium bicarbonate solution and iodine (1.5 g, 5.0 mmol) at room temperature. After addition, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the solvent was removed under reduced pressure. The organic phase was then extracted, dried, concentrated, and purified by column chromatography to afford compound 8i (100 mg, 44.0%).

[0951] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),7.77(s,1H),7.45(s,1H),6.76(d,J=10.0Hz,1H),6.09(d,J=9.9Hz,1H),5.13-5.09 (m,1H),2.92-2.84(m,1H),2.78-2.70(m,2H),2.63-2.57(m,1H),2.26-2.15(m,4H),2.12–2.00(m,4H).LC-MS(ESI):[M+H] + =395.12

[0952] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (CLM8)

[0953] Compound 8i (280.0 mg, 0.7 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by the addition of Pd / C (150.0 mg) at room temperature. After the addition, the mixture was stirred at 50°C under hydrogen for 4 h. Upon completion of the reaction, the reaction mixture was filtered through celite, the solvent was removed under reduced pressure, and CLM8 (195 mg, 70.0%) was purified by preparative liquid chromatography.

[0954] 1 H NMR(600MHz,DMSO-d6)δ11.11(s,1H),7.68(s,1H),7.35(s,1H),5.12-5.06(m,1H),2.99-2.93(m,2H),2.92- 2.84(m,1H),2.68–2.55(m,3H),2.23-2.15(m,2H),2.13–2.00(m,4H),1.99-1.91(m,4H).LC-MS(ESI):[M+H] + =397.13

[0955] 5) Synthesis of CLM9

[0956] 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0957] Synthesis scheme:

[0958] Step 1: 1'-(tert-Butyl)6,7-dimethyl-4,4-difluorospiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Compound 9a)

[0959] Diethylaminosulfur trifluoride (4 mL) was added to compound 1e (2 g, 4.6 mmol), and the reaction solution was stirred at 85°C for 2 hours. The resulting mixture was poured into ice water and extracted three times with ethyl acetate. The organic phase was concentrated in vacuo and the mixture was purified by reverse-phase column chromatography to obtain compound 9a (0.5 g, 24%) as a yellow oily liquid.

[0960] 1H NMR(600MHz,DMSO-d6)δ8.02(s,1H),7.29(s,1H),3.82(s,3H),3.81(s,3H),3.77–3.68(m,2H),3.22–3.02(m,2H),2. 72(t,J=14.7Hz,2H),1.85(d,J=13.9Hz,2H),1.70(td,J=14.0,11.6,4.7Hz,2H),1.40(s,9H).LC-MS(ESI):[M-tBu+H] + =400.31.

[0961] Step 2: 1'-(tert-Butyl)-4,4-difluorospiro[chroman-2,4'-piperidine]-6,7-dicarboxylic acid (Compound 9b)

[0962] To a solution of compound 9a (160 mg, 0.4 mmol) in methanol / tetrahydrofuran (2 ml) was slowly added lithium hydroxide (42 mg, 1.8 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted three times with dichloromethane / methanol (10:1) and the organic phase was concentrated in vacuo to afford compound 9b (0.1 g, 67%) as a white solid.

[0963] 1 H NMR(600MHz,DMSO-d6)δ13.27(br s,2H),8.12(s,1H),7.36(s,1H),3.21–3.06(m,2H),2.68(t,J=14.7Hz,2H),2.05–1.93(m,2H), 1.84(d,J=13.8Hz,2H),1.68(td,J=14.0,12.9,4.7Hz,2H),1.40(s,9H).LC-MS(ESI):[M-tBu+H] + =372.27.

[0964] Step 3: 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (CLM9)

[0965] To a solution of compound 9b (100 mg, 0.23 mmol) in acetic acid (1 ml) were slowly added 3-aminopiperidine-2,6-dione hydrochloride (77 mg, 0.5 mmol) and sodium acetate (96 mg, 1.2 mmol). The reaction was stirred at 110°C for 2 hours. After completion of the reaction, the mixture was purified by reverse-phase column chromatography to yield CLM9 (50 mg, 51%) as a brown solid.

[0966] 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.10(s,1H),7.68(s,1H),5.16(dd,J=13.0,5.4Hz,1H),3.27–3.15(m,4H),2.92–2.82(m,3H),2.61(d t,J=17.2,3.4Hz,1H),2.56–2.51(m,1H),2.11(d,J=14.4Hz,2H),2.05(ddt,J=12.9,5.6,2.5Hz,1H),1.97–1.90(m,2H).LC-MS(ESI):[M+H] + =420.36.

[0967] 6) Synthesis of CLM10

[0968] 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0969] Synthesis scheme:

[0970] Step 1: 1-(tert-Butyl)6',7'-dimethyl-4',4'-difluorospiro[azetidine-3,2'-chromane]-1,6',7'-tricarboxylate (Compound 10b)

[0971] Diethylaminosulfur trifluoride (5 mL) was slowly added to compound 10a (1 g, 2.5 mmol). The reaction mixture was stirred at 50°C overnight. The resulting mixture was poured into ice water to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 0-40%) to afford compound 10b (500 mg, 47%) as a light yellow solid.

[0972] 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.34(s,1H),4.13(d,J=9.7Hz,2H),3.91(d,J=9.7Hz, 2H),3.83(s,3H),3.82(s,3H),3.04(t,J=13.4Hz,2H),1.39(s,9H).LC-MS(ESI):[M-Boc+H] + =328.30.

[0973] Step 2: 1-(tert-Butyloxycarbonyl)-4',4'-difluorospi...

Claims

1. A compound, which is a compound represented by formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Formula (I): PTM-L-CLM; Wherein L is a bond or linker moiety connecting CLM and PTM, having the structure -(A L ) q -, A L Each occurrence is the same or different and each occurrence is independently selected from: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、S(O)、S(O)2、NR L3 、C(O)、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 The arylene group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 spirocyclylene, and optionally 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene; preferably, A L Each occurrence is the same or different and each occurrence is independently selected from: a covalent bond, a CR L1 R L2 , O, NR L3 , C(O), optionally substituted with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with a group, and optionally substituted with 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene; R L1 , R L2 and R L3 Each occurrence is independently selected from H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, -SR L4 、-NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、S(O)2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、C(O)R L6 、CN、NO2、SF5、S(O)2NR L4 R L5 、C(O)NR L4 R L5 、N(R L4 )C(O)NR L5 R L4 and N(R L4 )S(O)2NR L4 R L5 ; preferably R L1 , R L2 and R L3 Each occurrence is independently selected from H, halogen, alkyl, alkoxy, and CN; R L4 , R L5 and R L6 Each occurrence is independently selected from H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl and haloheteroaryl; preferably R L4 , R L5 and R L6 each occurrence is independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl; q is an integer greater than or equal to 1; preferably q is an integer greater than or equal to 1 and less than or equal to 20; preferably q is an integer greater than or equal to 1 and less than or equal to 15; The CLM is selected from the following structures: Among them, W n is O, C(R N )2, NR N , C(O) or C(O)NR N ; preferably W n is O, NR N or C(O); more preferably W n is O or NR N ; n1 and n2 are each independently 0, 1, 2 or 3 each time they appear; preferably n1 and n2 are each independently 1 or 2 each time they appear; n3 and n4 are each independently 1, 2 or 3 each time they appear; preferably n3 and n4 are each independently 1 or 2 each time they appear; R nn Each occurrence is independently selected from H, deuterium, cyano, F, Cl, Br, I, OH, NH2, NO2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C2-C6 unsaturated hydrocarbon group; preferably R nn Each occurrence is independently selected from H, deuterium, cyano, F, Cl, Br, I, OH, NH2, NO2, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; preferably R nn Each occurrence is independently selected from H, F, Cl, Br, I, OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; Cy1 is each independently selected from 6- to 10-membered arylene and 5- to 10-membered heteroarylene containing 1 to 3 heteroatoms each independently selected from N, O and S, wherein the 6- to 10-membered arylene and 5- to 10-membered heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro and cycloalkyl; Cy2 is each independently selected from 5- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms each independently selected from N, O and S and 5- to 10-membered heteroarylene containing 1 to 3 heteroatoms each independently selected from N, O and S; R n0 selected from CR a R b 、NR a 、O and S; R n1 is CR a or N; R n2 is CR a R b or C(=O); R n3 selected from CR a R b , NR a , O and S; preferably R n3 is CR a R b or O; Each occurrence of W1 and W2 is independently CR a R b , C(=O), NR a or SO2, and at least one of W1 and W2 is C(=O); preferably, each occurrence of W1 and W2 is independently CR a R b or C(=O)2, and at least one of W1 and W2 is C(=O); G and Z are each independently selected from O, S and Se each time they appear; preferably G and Z are each independently selected from O each time they appear; R 3a 、R 3b 、R 3c and R 3d each, when it appears, is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxy group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an aryl group, and a heteroaryl group; R 3a0 、R 3b0 、R 3c0 、 and R 3d0 each independently selected, each time it appears, from a single bond, O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, imino, cycloalkylene, heterocycloalkylene, alkylamino, arylene, and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkylamino, aryl, and heteroaryl; R 3a0 、R 3b0 、R 3c0 、 and R 3d0 each independently a single bond or O each time it appears; W 5 , and W 6 Each occurrence is independently C(R m )2, NR m , O or S; preferably W 5 , and W 6 Each occurrence is independently C(R m )2; W 11 is CR a R b , C(=O), NR a or S(O)2; preferably W 11 is C(=O); R 1 、R 2 、R a 、R N and R b each, when it appears, is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxy group, a haloalkyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an aryl group, and a heteroaryl group; R 22 selected from one or more combinations of a single bond, C(O), O, S, S(O)2, NR m , NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene and heteroalkylene; preferably R 22 selected from a single bond, NR m and NR m C(O); n is each independently 0, 1, 2 or 3 each time it appears; preferably n is each independently 1 each time it appears; R 32 and R 42 form with the carbon atom to which it is attached and R 52 、R 62 and R 72 each time it appears is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; or, R 42 and R 52 forms with the carbon atom to which it is attached and R 32 、R 62 and R 72 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; or, R 52 and R 62 together with the carbon atom to which it is attached form and R 32 、R 42 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; or, R 62 and R 72 together with the carbon atom to which they are attached form and R 32 、R 42 and R 52 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; or R 32 and R 82 together with the atoms to which they are attached form a heterocyclic group, and R 42 、R 52 、R 62 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; R d , R e , R f , R g , R D , R E , R F , R G , R f1 , R g1 , R F1 and R G1 Each occurrence is independently C(R m )2. NR m , O, C(O) or S, and R d , R e , R D and R E Where Each independently represents, each time it appears, a connection site to a carbon atom on the benzene ring, and the carbon atom on the benzene ring is a carbon atom connected to R 32 , R 42 , R 52 or R 62 ; Each occurrence of W3 and W4 is independently CR m or N; R t , R T , R t1 , and R T1 Each time it appears, it is independently CR m or N, R t , R T , R t1 , and R T1 Where represents the connection site to CLM or L; R m Each independently selected from H, deuterium atom, F, Cl, Br, I, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl each time it appears, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C5-C 15 heteroaryl and substituted by one or more substituents; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5 or 6 each time they appear, and m1 + m2 ≤ 6; m3 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time it appears, m4 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8 each time it appears, and m3 + m4 ≤ 8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time they appear, and m5 + m6 ≤ 7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time they appear, and m7 + m8 ≤ 7; m31 and m41 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time they appear, m31 and m41 are not both 0 at the same time, and m31 + m41 ≤ 7; m51 and m61 are each independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time they appear, m51 and m61 are not both 0 at the same time, and m51 + m61 ≤ 7; The PTM is selected from the following structures: Wherein, L P is a single bond, a C1-C6 alkylene group, NR m , O, C(O) or -NR m C(O)-; preferably L P is a single bond or -NR m C(O)-; Ring A is a 6- to 10-membered arylene, a 5- to 10-membered cycloalkylene containing 0 to 3 heteroatoms each independently selected from N, O, and S, a 7- to 12-membered bicycloalkylene, a 5- to 10-membered heteroalkylene or a 7- to 12-membered bisheteroalkylene, or a 5- to 10-membered heteroarylene or a 7- to 12-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably Ring A is a 5- to 6-membered heteroarylene or a 9- to 10-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; Ring B is a 6- to 10-membered arylene, a 5- to 10-membered cycloalkylene containing 0 to 3 heteroatoms each independently selected from N, O, and S, a 7- to 12-membered bicycloalkylene, a 5- to 10-membered heteroalkylene or a 7- to 12-membered bisheteroalkylene, or a 5- to 10-membered heteroarylene or a 7- to 12-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably Ring B is a 5- to 6-membered heteroarylene or a 9- to 10-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; Ring C is absent or is a 6- to 10-membered arylene, a 3- to 10-membered cycloalkylene, a 7- to 12-membered bicycloalkylene, a 3- to 10-membered heteroalkylene or a 7- to 12-membered bisheteroalkylene containing 1 to 3 heteroatoms each independently selected from N, O, and S, or a 5- to 10-membered heteroarylene or a 7- to 12-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably Ring C is absent or is a 6- to 10-membered arylene, a 4- to 6-membered cycloalkylene, a 7- to 12-membered bicycloalkylene, a 4- to 6-membered heteroalkylene or a 7- to 12-membered bisheteroalkylene containing 1 to 3 heteroatoms each independently selected from N, O, and S, or a 5- to 6-membered heteroarylene or a 9- to 10-membered bisheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; R P Each occurrence is independently selected from halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic group, -O-cycloalkyl, -O-heterocyclic group, aryl and heteroaryl, and the alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic group, hetero-bridged cyclic group, aryl and heteroaryl are optionally substituted by one or more substituents selected from R S3 ; R Q each independently selected from halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic group, heterobicyclic group, aryl and heteroaryl each time it appears, and the heterocyclic group and the heterobicyclic group are optionally substituted with one or more substituents selected from hydroxy, halogen and alkyl; R S1 selected from one or more combinations of a single bond, C(O), O, S, S(O)2, -NR m -, -NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; R S2 selected from one or more combinations of a single bond, C(O), O, S, S(O)2, -NR m -, -NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; R S3 each independently selected from hydroxy, halogen, alkyl, deuterated alkyl, heteroalkyl, cyano, amino, cycloalkyl and heterocycloalkyl each time it appears; m' is 0, 1, 2 or 3; and n' is 1, 2 or 3; preferably n' is 1.

2. The compound according to claim 1, wherein R 32 and R 42 forms with the carbon atom to which it is attached and R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, aryl group, and heteroaryl group; preferably, R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group; preferably, R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 42 and R 52 form with the carbon atom to which they are attached and R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group; preferably, R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group; preferably, R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 52 and R 62 together with the carbon atom to which they are attached form and R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, aryl group, and heteroaryl group; preferably, R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group; preferably, R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 62 and R 72 together with the carbon atom to which they are attached form and R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, F, Cl, Br, I,, a C1-C3 alkyl group, and a C1-C3 alkoxy group; or, R 32 and R 82 together with the atoms to which they are attached form a C4-C 10 heterocyclic group, and R 42 , R 52 , and R 62 each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy or C1-C6 haloalkyl; and / or R L1 , R L2 and R L3 each occurrence is independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 NR L4 R L5 , C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH、S(O)2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 、C(O)R L6 、CN、NO2、SF5、S(O)2NR L4 R L5 、C(O)NR L4 R L5 、N(R L4 )C(O)NR L5 R L4 or N(R L4 )S(O)2NR L4 R L5 , preferably R L1 , R L2 and R L3 Each occurrence is independently F, Cl, Br, , CN, OH, C1-C6 alkyl or C1-C6 alkoxy, more preferably R L1 , R L2 and R L3 is independently at each occurrence F, CN, OH, methyl or methoxy; and / or R L4 and R L5 each independently, when it appears, is H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C5-C 15 heteroaryl or C5-C 15 haloheteroaryl; and / or R L6 Each occurrence is independently H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic heterocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C5-C 15 heteroaryl or C5-C 15 haloheteroaryl; and / or Each occurrence of W1 and W2 is independently CH2, N(C1-C6 alkyl) or C(=O), preferably CH2 or C(=O), and at least one of W1 and W2 is C(=O); and / or G is O; and / or Z is O; and / or R d , R e , R D and R E Each occurrence is independently NR m , C(R m )2 or O, and R d , R e , R D and R E Where Each occurrence independently represents a bonding site to a carbon atom on the benzene ring, and the carbon atom on the benzene ring is a carbon atom bonded to R 32 , R 42 , R 52 or R 62 . Preferably, R d , R e , R D and R E are each C(R m )2 or O each time they occur; and / or R f , R g , R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or Each occurrence of m1 and m2 is independently an integer of 0, 1, 2, or 3, and m1 + m2 ≤ 3; preferably, m1 + m2 = 1 or m1 + m2 = 3; and / or Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, or 5, each occurrence of m4 is an integer of 1, 2, 3, 4, or 5, and m3 + m4 ≤ 5; preferably m3 + m4 = 2, m3 + m4 = 3 or m3 + m4 = 4; and / or Each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3 or 4, and m5 + m6 ≤ 4, preferably m5 + m6 = 2 or m5 + m6 = 3; and / or Each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3 or 4, and m7 + m8 ≤ 4, preferably m7 + m8 = 2 or m7 + m8 = 3; and / or Each occurrence of m31 and m41 is independently an integer of 0, 1, 2, 3, or 4, m31 and m41 are not both 0 at the same time, and m31 + m41 ≤ 4; preferably m31 + m41 = 2 or m31 + m41 = 3; and / or Each occurrence of m51 and m61 is independently an integer of 0, 1, 2, 3, or 4, m51 and m61 are not both 0 at the same time, and m51 + m61 ≤ 4; preferably m51 + m61 = 2 or m51 + m61 = 3; and / or W 3 and W 4 is CH or N; and / or W5 and W6 are C(R m )2 or N(R m ), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or R 3a 、R 3b 、R 3c and R 3d Each occurrence is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C6-C 15 aryl and C5-C 15 heteroaryl are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl; preferably, R 3a 、R 3b 、R 3c 、and R 3d are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or R 3a0 , R 3b0 , R 3c0 , and R 3d0 Each occurrence is independently selected from a single bond, O, C(O), NH, N(C1-C6 alkyl) and C1-C6 alkylene; preferably, R 3a0 , R 3b0 , R 3c0 , and R 3d0 Each occurrence is independently selected from a single bond, O, C(O) and C1-C3 alkylene; and / or R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 heterocyclic group, C6-C 15 aryl group and a C5-C 15 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group; preferably, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group and a C1-C3 alkoxy group; and / or R 1 、R 2 、R a 、and R b each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl and C1-C6 hydroxyalkyl each time it appears; and / or R N selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl; and / or R 22 selected from a single bond, -NR 2A -, -NR 2A C(O)-, C1-C6 alkylene, C1-C6 haloalkylene, R 2A selected from H and C1-C6 alkyl; and / or R P Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, -O-C3-C8 heterocyclic group, -O-C3-C6 cycloalkyl group, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)-CN, -NH-C3-C8 heterocyclic group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group, preferably, R P Each occurrence is independently selected from hydrogen, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C3 deuterated alkyl group, a C1-C3 heteroalkyl group, a C2-C3 alkenyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, -O-C3-C6 heterocyclic group, -O-C3-C6 cycloalkyl group, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)-CN, -NH-C3-C6 heterocyclic group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group, the heterocyclic group and the heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S; and / or R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C3-C 10 heterocyclic group, a C5-C 10 heterobicyclic group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group, and the heterocyclic group and the heterobicyclic group are optionally substituted by one or more substituents selected from a hydroxyl group, a halogen, and a C1-C6 alkyl group; preferably, R Q Each occurrence is independently selected from hydrogen, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 deuterated alkyl group, a C1-C3 heteroalkyl group, a C2-C6 alkenyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a hydroxyl group, a C1-C3 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C7 heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C5-C 10 heterobicyclic group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group, and the C3-C7 heterocyclic group and the C5-C 10 heterobicyclic group are optionally substituted by one or more substituents selected from a hydroxyl group, a halogen, and a C1-C3 alkyl group; and / or R S1 selected from one or more combinations of a single bond, C(O), O, S, C 1-3 alkylene, C 2-4 alkenylene, and C 2-4 alkynylene; preferably, R S1 selected from a single bond, C1-C3 alkylene, C2-C4 alkenylene and C2-C4 alkynylene; and / or R S2 Selected from single bond, C(O), O, -NR m -, -NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene, or a combination of one or more thereof, wherein said R m is selected from H or C 1-3 alkylene; preferably, R S2 is selected from single bond, C 1-3 alkylene, C(O), NH, a combination of C(O) and C 1-3 alkylene, a combination of C(O) and NH; preferably, R S2 is selected from single bond, C=O, CH2C=O, CH2, CH2CH2, NH, and NHC=O; preferably, R S2 is selected from covalent bond, C1-C3 alkyl, amino, and carbonyl; and / or L P is a covalent bond or -NHC(O)-; and / or Cy1 is selected from indazolyl, thienyl, furyl, phenyl and pyridyl, and indazolyl, thienyl, furyl, phenyl and pyridyl are optionally substituted by one or more substituents selected from C1-C6 alkyl groups; preferably from wherein the Optionally substituted by one or more substituents selected from C1-C6 alkyl; and / or Cy2 is selected from azaperidinyl, azaperidinyl, pyrazolyl, pyridinyl and pyrimidinyl, preferably 3. The compound according to any one of claims 1-2, wherein, CLM is selected from: R 3a0 、R 3b0 、R 3a 、R 3b 、R 3c 、R 3d 、W1, W2, R 32 、R 42 、R 52 、R 62 、R F 、R G 、R T 、R f 、R g 、R f 、R g 、R t 、m1, m3, m4, m5, m6, W3, W4, R F1 、R G1 、R T1 、m31, m41, m8, W7, R 72 、W n 、n1, R nn 、R n1 、R n2 、R n3 、R n0 、Z, G, W 5 、and W 6 as defined in claim 1 or 2; Each occurrence of m9 and m10 is independently an integer of 0, 1, 2, 3, 4, or 5, and m1 + m9 + m10 ≤ 5; preferably each occurrence of m1, m9, and m10 is independently an integer of 0, 1, or 2, and m1 + m9 + m10 ≤ 2, preferably m1 + m9 + m10 = 1 or m1 + m9 + m10 = 0; Each occurrence of m7, m11, and m12 is independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably each occurrence of m7, m11, and m12 is independently an integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; R 1 、R 2 、R a 、R N and R b each occurrence is independently selected from H, deuterium atom, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, hydroxy, haloalkyl and hydroxyalkyl; preferably, R 1 、R 2 、R a 、R N and R b are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 1d , R 1e , R 1D and R 1E Each occurrence is independently O, or C(R m )2; W 11 is C(=O); R 22 selected from a single bond, -NR 2A -, -NR 2A C(O)-, alkylene, and haloalkylene, R 2A each independently selected from H and C1-C6 alkyl each time it appears; preferably, R 22 selected from a single bond, -NR 2A -, -NR 2A C(O)-, C1-C6 alkylene, C1-C6 haloalkylene, R 2A selected from H and C1-C6 alkyl; preferably, R 22 is a single bond, NH, NHC(O), or N(CH3)C(O); W 7 each independently is CH or N; Each occurrence of B1 and B3 is independently selected from C(R m )2 and C(O); preferably, each occurrence of B1 and B3 is independently C(R m )2 or O; B2 is selected from C(R m )2, NR m , O and S; preferably, B2 is C(R m )2 or O; B4 and B5 are each independently selected from C, R m and N; preferably, B4 and B5 are each independently selected from C, H and N; Each occurrence of B6 is selected from C(R m )2, NR m , O, and S; n2, n3, n4, n5, and n6 are each independently 0, 1, 2, or 3; Each occurrence of C1 and C2 is independently C(R m )2; C3 is selected from C and N; the side where C3 is connected m ​ Represents a connection site between CLM or L; R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro, cyano and amino; preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy.

4. The compound according to any one of claims 1 - 3, wherein, The CLM is selected from the following structures: Wherein, W 1 、W 2 、R T 、R 1d 、R 1e 、R f 、Rg、R 1D 、R 1E 、R F 、R G 、R T 、R 1d 、R 1e 、R f 、R g 、R D 、R E 、R d 、R e 、R t 、m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, m11, m12, R N 、W 11 、W 3 、W 4 、R T1 、n2, n3, n4, n5, n6, R 22 、W n 、n1, R n1 、R n2 、R n3 、R n0 、W 5 、W 6 、as defined in any one of claims 1 - 4; R 3a 、R 3b 、R 3c 、R 3d 、R 3a1 、R 3b1 、R 3c1 、 and R 3d1 each independently selected from H, deuterium atom, halogen, C1-C3 alkyl, and C1-C3 alkoxy each time it appears; R F0 、R G0 、R d1 、R e1 、R f1 、R g1 、R D1 、R E1 、R F1 、 and R G1 each independently represents C(R m )2 or O each time it appears; R H1 、 and R h1 Each occurrence is independently selected from N and CR m ; Cyn is selected from 6- to 10-membered arylenes and 5- to 10-membered heteroarylenes containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably, Cyn is selected from R N is selected from H, a deuterium atom, a halogen, an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, and a hydroxyalkyl group; preferably, R N is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group; R nn Each occurrence is independently selected from H, F, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

5. The compound according to any one of claims 1-4, wherein, The CLM is selected from the following structures: Among them, W 1 、W 2 、W 11 、R 3a 、R 3b 、R 3c 、R 3d 、R T 、R T1 、R t 、R d 、R f1 、R g1 、R D 、R E 、R F 、R G 、m1, m2, m3, m4, m31, m41, m5, m6, m7, m8, R 1D 、R 1E 、R F0 、R G0 、R 1d 、R 1e 、R f 、R g 、R F1 、R G1 、R m 、R 52 and R 62 are defined as defined in any one of claims 1 - 4; R N is selected from H, a deuterium atom, a halogen, an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, and a hydroxyalkyl group; preferably, R N is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group; R 3a1 、R 3b1 、R 3c1 、 and R 3d1 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; R 1d1 、R 1e1 、R 1D1 and R 1E1 each independently represents O or C(R m )2; W 31 and W 41 each independently represents N, or CR each time it appears m ; R h1 and R H1 is N, or CR m .

6. The compound according to any one of claims 1-5, wherein, The CLM is selected from the following structures: wherein, R f1 , R g1 , R F1 , R G1 , m3, m4, m5, m6, and W 11 are as defined in any one of claims 1-4; R N is selected from H, a deuterium atom, a halogen, an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, a haloalkyl group, and a hydroxyalkyl group; preferably, R N is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, and a C1-C6 hydroxyalkyl group; R 1d1 , R 1e1 , R 1D1 , and R 1E1 Each occurrence is independently O or C(R m )2; R h1 and R H1 each independently selected from N or CR m ; and / or R 3a1 、R 3b1 、R 3c1 、and R 3d1 are each independently H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group.

7. The compound according to any one of claims 1-6, wherein, The CLM is selected from the following structures: Preferably, the CLM is selected from 8. The compound according to any one of claims 1-7, wherein, A L Each same or different when appearing each time, and each independently selected from: a covalent bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , C(O), a cycloalkylidene, a heterocycloalkylidene, a spirocycloalkylidene, a heterospirocycloalkylidene, an arylidene, and a heteroarylidene, wherein the cycloalkylidene, heterocycloalkylidene, spirocycloalkylidene, heterospirocycloalkylidene, arylidene, and heteroarylidene are optionally substituted with 0-6 R L1 and / or R L2 groups; and / or R L1 , R L2 and R L3 Each occurrence is independently selected from H, F, Cl, Br, I, C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl, C 5-10 Heteroaryl, C 1-8 Alkoxy, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, C(O)-C 1-8 Alkyl, C(O)OH, CN, CF3, CHF2, CH2F, NO2, C(O)NH-C 1-8 Alkyl, C(O)N(C 1-8 Alkyl)2, N(C 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 alkyl), NHC(O)N(C 1-8 alkyl)2, and NHC(O)NH2, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, aryl and heteroaryl; and / or q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

9. The compound according to any one of claims 1-8, wherein, A L One or more selected from the following structures, and the two linking sites of the following structures are interchangeable: covalent bond, -O-, -(CH2) k -, -C(O)-, -NH-, -N(CH3)-, and / or k is an integer selected from 1-13, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

11. The compound according to any one of claims 1-10, wherein L is selected from the following structures: Covalent bond, -(CH2) j -, -NH-(CH2) j -, -(CH2) j -NH-, -NH-(CH2) j -NH-, j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11; p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is an integer selected from 1-13, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, more preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; Preferably, L is selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 10 -, -(CH2) 11 -, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-, -C(O)-CH2-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -C(O)-NH-CH2-NH-, -C(O)-NH-(CH2)2-NH-, -C(O)-NH-(CH2)3-NH-, -C(O)-NH-(CH2)4-NH-, -C(O)-NH-(CH2)5-NH-, -C(O)-NH-(CH2)6-NH-, -C(O)-NH-(CH2)7-NH-, -C(O)-NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH--NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, -CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O-CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3-NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)3-NH-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2)10-O- 10 -O-, -(CH2)11 11 -O- 10. The compound according to any one of claims 1-9, wherein L-CLM is selected from the following structures:

11. The compound according to any one of claims 1-10, wherein, The PTM is as follows: Wherein, Ring A is a 6- to 10-membered arylene, a 5- to 10-membered cycloalkylene, a 7- to 12-membered bicycloalkylene, a 5- to 10-membered heteroalkylene or a 7- to 12-membered bicycloheteroalkylene each containing 0 to 3 heteroatoms independently selected from N, O, and S, or a 5- to 10-membered heteroarylene or a 7- to 12-membered bicycloheteroarylene containing 1 to 3 heteroatoms independently selected from N, O, and S; preferably, Ring A is a 6-membered arylene, a 5- to 6-membered heteroarylene containing 1 to 3 heteroatoms selected from N, O, and S, or a 9- to 10-membered bicycloheteroarylene containing 1 to 3 heteroatoms independently selected from N, O, and S; more preferably, Ring A is a 6-membered heteroarylene containing 1 N atom, or a 9-membered bicycloheteroarylene containing 2 or 3 N atoms; preferably, For Among them, Indicates the connection site with L P ; R Q is defined as in any one of claims 1-3, and each occurrence of n' is independently 1, 2 or 3; preferably, R Q each occurrence is independently selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C7 heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C 10 heterobridged ring group, and the C3-C7 heterocyclic group and C5-C 10 heterobridged ring group are optionally substituted by one or more substituents selected from hydroxy, halogen and C1-C3 alkyl; and / or Ring B is a 6- to 10-membered arylene, a 5- to 10-membered cycloalkylene containing 0 to 3 heteroatoms each independently selected from N, O, and S, a 7- to 12-membered bicycloalkylene, a 5- to 10-membered heteroalkylene, or a 7- to 12-membered bicycloheteroalkylene, or a 5- to 10-membered heteroarylene or a 7- to 12-membered bicycloheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably, Ring B is a 6-membered arylene, a 5- to 6-membered heteroarylene containing 1 to 3 heteroatoms selected from N, O, and S, or a 9- to 10-membered bicycloheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; more preferably, Ring B is a 5-membered heteroarylene containing 1 to 3 N atoms or a 9-membered bicycloheteroarylene containing 2 to 3 N atoms; preferably, For Preferably, For Preferably, For Among them, at Indicates the connection site to Lp, *R S1 at the represents the linking site with R S1 ; R P and Lp are as defined in any one of claims 1-3, and each m' is independently 0, 1, 2 or 3 each time it appears; preferably L P is a single bond or -NHC(O)-; and / or Ring C is absent or is a 6- to 10-membered arylene, 3- to 10-membered cycloalkylene, 7- to 12-membered bicycloalkylene, 3- to 10-membered heteroalkylene containing 1 to 3 heteroatoms each independently selected from N, O, and S, or 7- to 12-membered bicycloheteroalkylene, or 5- to 10-membered heteroarylene or 7- to 12-membered bicycloheteroarylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; preferably, Ring C is 5- to 6-membered cycloalkylene or 4- to 6-membered heteroalkylene containing 1 to 3 heteroatoms each independently selected from N, O, and S; more preferably, Ring C is cyclohexylene, azetidinylene, piperidinylene, or thiazolylene; more preferably, Ring C is More preferably Among them, *R S1 at the Indicates the connection site with R S1 , *R S2 at Indicates the connection site with R S2 ; and / or R P Each occurrence is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxy, C 1-6 hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8 membered heterocyclic group, -NHC 1-6 alkyl, -NHC 1-6 alkyl, -CN or -NH-3-8 membered heterocyclic group; preferably, R P is selected from C 1- 3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, hydroxy, C 1-3 hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8 membered oxygen-containing heterocyclic alkyl, -NHC 1- 3 alkyl, NHC 1-3 alkyl -CN or -NH-3-8 membered heterocyclic group; preferably, R P is independently C(CH3)2OH, OCH3, CH3, OCH(CH3)2, NHCH3, NHCH(CH3)2, NHCH2CN, CF3, or CHF2; and / or R Q each occurrence is independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, 4- to 8-membered cycloalkyl, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O, and S, 5- to 10-membered bridged heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered aryl, and the heterocyclic group and the bridged heterocyclic group are optionally substituted by 1, 2, or 3 substituents independently selected from hydroxy and C 1-6 alkyl; preferably, R Q is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, 5- to 8-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N and O, and 7-membered bridged heterocyclic group containing 1 to 3 heteroatoms independently selected from N and O, and the 5- to 8-membered monocyclic heterocycloalkyl group and the bridged heterocyclic group are optionally substituted by 1, 2, or 3 substituents selected from hydroxy and C 1-3 alkyl; preferably, R Q is independently CF3, F, CH3, CN, CHF2, OCH3, and / or R S1 selected from one or more combinations of a single bond, C(O), O, S, C 1-3 alkylene, C 2-3 alkenylene, and C 2-3 alkynylene; preferably, R S1 is a single bond; and / or R S2 selected from a single bond, C(O), O, -NR m -, -NR m C(O)-, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 haloalkylene, and C 1-6 a combination of one or more of heteroalkylene, wherein said R m is independently H or C 1-3 alkylene each time it appears; preferably, R S2 is selected from a single bond, C 1-3 alkylene, C(O), NH, a combination of C(O) and C 1-3 alkylene, a combination of C(O) and NH; preferably, R S2 is selected from a single bond, C=O, CH2C=O, CH2, CH2CH2, NH, and NHC=O.

12. The compound according to any one of claims 1-11, wherein, The PTM is selected from the following structures: wherein, each occurrence of Q1, Q2, Q3, Q4, Q5, Q6, Q7, and Q8 is independently selected from CH and N; Q9 is O, NR P1 or S; X is selected from the following structures, and the two linking sites of the following structures are interchangeable: wherein, R P1 each occurrence is independently selected from halogen, alkyl, deuterated alkyl, heteroalkyl, C 2-6 alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic group, -O-C3-C6 cycloalkyl, -O-3-8-membered heterocyclic group, -NH-heterocyclic group, -NHC 1-6 alkyl, -NHC 1-6 alkyl, aryl and heteroaryl; preferably F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclic group, NH-C3-C6 heterocyclic group, C6-C 15 aryl and C6-C 15 heteroaryl; preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C 1-4 aminoalkyl, or C1-C4 haloalkyl; preferably, R P each occurrence is independently selected from C 1- 3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, hydroxy, C 1-3 hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8-membered oxygen-containing heterocycloalkyl, -NHC 1- 3 alkyl, NHC 1-3 alkyl-CN or -NH-3-8-membered heterocyclic group; preferably, R P each occurrence is independently C(CH3)2OH, OCH3, CH3, OCH(CH3)2, NHCH3, NHCH(CH3)2, NHCH2CN, CF3, or CHF2 R P2 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C5-C 15 heteroaryl group; preferably a hydrogen atom, a cyano group, a C1-C4 alkyl group or a C1-C4 haloalkyl group; preferably R P2 Each occurrence is independently selected from a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a 4-8 membered cycloalkyl group, a 5-10 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, a 5-10 membered heterobicyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, and a 5-10 membered aryl group, wherein the heterocyclic group and the heterobicyclic group are optionally substituted with 1, 2, or 3 substituents each independently selected from a hydroxyl group and a C 1-6 alkyl group; preferably, R P2 is selected from a halogen, a cyano group, a C 1-3 alkyl group, a C 1-3 alkoxy group, a C 1-3 haloalkyl group, a 5-8 membered monocyclic heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N and O, and a 7 membered heterobicyclic group containing 1-3 heteroatoms each independently selected from N and O, wherein the 5-8 membered monocyclic heterocycloalkyl group and the heterobicyclic group are optionally substituted with 1, 2, or 3 substituents selected from a hydroxyl group and a C 1-3 alkyl group; preferably, R P2 Each occurrence is independently CF3, F, CH3, CN, CHF2, OCH3, and R P3 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group, and a C5-C 15 heteroaryl group; preferably a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; preferably, R P3 Each occurrence is independently selected from a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a hydroxyl group, a C 1-6 hydroxyalkyl group, -O-C3-C6 cycloalkyl group, -O-3-8-membered heterocyclic group, -NHC 1- 6 alkyl group, -NHC 1-6 alkyl group, -CN, or -NH-3-8-membered heterocyclic group; preferably, R P3 is selected from a C 1-3 alkyl group, a C 1-3 alkoxy group, a C 1-3 haloalkyl group, a hydroxyl group, a C 1-3 hydroxyalkyl group, -O-C3-C6 cycloalkyl group, -O-3-8-membered oxygen-containing heterocyclic alkyl group, -NHC 1-3 alkyl group, NHC 1-3 alkyl group -CN, or -NH-3-8-membered heterocyclic group; preferably, R P3 Each occurrence is independently C(CH3)2OH, OCH3, CH3, OCH(CH3)2, NHCH3, NHCH(CH3)2, NHCH2CN, CF3 or CHF 2； and R P4 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, a hetero-bridged cyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a 4-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from O, N, and S, a 4-8 membered hetero-bridged cyclic group containing 1-3 heteroatoms independently selected from O, N, and S, a C6-C 15 aryl group and a C5-C 15 heteroaryl group; preferably, R P4 Each occurrence is independently a 4-8 membered hetero-bridged cyclic group containing 1-3 heteroatoms independently selected from O, N, and S; preferably, R P4 Each occurrence is independently a 7 membered hetero-bridged cyclic group containing N or O; preferably R P4 Each occurrence is independently selected from a halogen, a cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, a 4-8 membered cycloalkyl group, a 5-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S, a 5-10 membered hetero-bridged cyclic group containing 1-3 heteroatoms independently selected from N, O, and S, and a 5-10 membered aryl group, wherein the heterocyclic group and the hetero-bridged cyclic group are optionally substituted with 1, 2, or 3 substituents independently selected from a hydroxyl group and C 1-6 alkyl group; preferably, R P4 is selected from a halogen, a cyano group, C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 haloalkyl group, a 5-8 membered monocyclic heterocyclic alkyl group containing 1-3 heteroatoms independently selected from N and O, and a 7 membered hetero-bridged cyclic group containing 1-3 heteroatoms independently selected from N and O, wherein the 5-8 membered monocyclic heterocyclic alkyl group and the hetero-bridged cyclic group are optionally substituted with 1, 2, or 3 substituents selected from a hydroxyl group and C 1-3 alkyl group; preferably, R P4 Each occurrence is independently CF3, F, CH3, CN, CHF2, OCH3, Preferably, the PTM is selected from More preferably, selected from More preferably, selected from Preferably R P2 and R P4 each occurrence is independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, 4- to 8-membered cycloalkyl, 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms each independently selected from N, O, and S, 5- to 10-membered heterobicyclic group containing 1 to 3 heteroatoms each independently selected from N, O, and S, and 5- to 10-membered aryl, and the heterocyclic group and heterobicyclic group are optionally substituted by 1, 2, or 3 substituents each independently selected from hydroxy and C 1-6 alkyl; preferably, R P2 is selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, 5- to 8-membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms each independently selected from N and O, and 7-membered heterobicyclic group containing 1 to 3 heteroatoms each independently selected from N and O, and the 5- to 8-membered monocyclic heterocycloalkyl and heterobicyclic group are optionally substituted by 1, 2, or 3 substituents selected from hydroxy and C 1-3 alkyl; preferably, R P2 R P2 and R P4 each occurrence is independently CF3, F, CH3, CN, CHF2, OCH3, Preferably, R P2 and R P4 each independently selected from a hydrogen atom, a cyano group, C 1-6 alkyl, C 1-6 haloalkyl, 4- to 8-membered cycloalkyl, a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S, a 5- to 10-membered heterobicyclic group containing 1 to 3 heteroatoms selected from N, O, S, and a 5- to 10-membered aryl group, wherein the 5- to 10-membered heterocyclic group and the 5- to 10-membered heterobicyclic group are optionally substituted with one or more substituents selected from a hydroxyl group and an alkyl group; preferably, R P2 and R P4 each independently selected from a hydrogen atom, a cyano group, C 1-3 alkyl, C 1-3 haloalkyl, a 5- to 8-membered heterocyclic group containing N, O heteroatoms, and a 7- to 8-membered heterobicyclic group containing N, O heteroatoms, the heterocyclic group and the heterobicyclic group being optionally substituted with 1 or 2 substituents selected from a hydroxyl group and C 1-3 alkyl; more preferably, R P2 and R P4 each independently selected from -CN, -CF3, Preferably, R P1 and R P3 each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxy, C 1- 6-hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8-membered heterocyclic group, -NHC 1-6 alkyl, -NHC 1-6 alkyl, -CN or -NH-3-8-membered heterocyclic group; preferably, R P1 and R P3 each independently selected from C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, hydroxy, C 1-3 hydroxyalkyl, -O-C3-C6 cycloalkyl, -O-3-8-membered oxygen-containing heterocyclic alkyl, -NHC 1-3 alkyl, NHC 1-3 alkyl-CN or -NH-3-8-membered heterocyclic group; preferably, R P1 and R P3 each independently C(CH3)2OH, OCH3, CH3, OCH(CH3)2, NHCH3, NHCH(CH3)2, NHCH2CN, CF3 or CHF 2； Preferably, R P1 and R P3 each independently selected from a hydrogen atom, a halogen, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, a hydroxyl group, and C 1-6 hydroxyalkyl; preferably, R P1 and R P3 each independently selected from a hydrogen atom, a cyano group, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, a hydroxyl group, and C 1-3 hydroxyalkyl; preferably, R P1 and R P3 each independently selected from H, -CN, -OCH3, -C(CH3)2OH and -CHF2; Preferably, X is selected from the following structures:

13. The compound according to any one of claims 1-12, wherein, The PTM is selected from the following structures: Preferably, the PTM is selected from the following structures:

14. The compound according to any one of claims 1-3, wherein Comprising a compound represented by the following formula (IA), formula (IB), formula (IC) or formula (ID): L and CLM are each defined as defined in any one of claims 1-11; X1 is CH or N; X2 is a single bond or C(O); n7 is 0 or 1; n8 is 0 or 1; R P1 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; preferably a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 hydroxyalkyl group, or a C1-C4 haloalkyl group; R P2 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; preferably a hydrogen atom, a cyano group, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; R P3 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; R P4 Each occurrence is independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, a heterobridged cyclic group, an aryl group, and a heteroaryl group; preferably a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a 4-8 membered heterocyclic group containing 1-3 independently selected from O, N, and S, a 4-8 membered heterobridged cyclic group containing 1-3 independently selected from O, N, and S, a C6-C 15 aryl group and a C5-C 15 heteroaryl group; preferably a hydrogen atom and a 4-8 membered heterobridged cyclic group containing 1-3 selected from O, N, and S; preferably a 7 membered heterobridged cyclic group containing N or O; Preferably, R P1 is hydrogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 hydroxyalkyl group or a C1-C4 haloalkyl group; R P2 is hydrogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; R P3 is hydrogen, a C1-C4 alkyl group or a C1-C4 haloalkyl group; R P4 is a 5- to 8-membered heterocyclic group containing H, N, or O heteroatoms or a 7- to 8-membered heterobridged cyclic group containing N or O heteroatoms, preferably -CN, -CF3, R P5 is hydrogen, NHC 1-6 alkyl, NHC 1-6 alkyl-CN or -NH-3- to 8-membered heterocyclic group, preferably H, NHCH3, NHCH(CH3)2, NHCH2CN or R P6 is hydrogen or cyano; and / or L is selected from the following structures: Preferably, L is p is 0, 1, or 2, and y is 0, 1, or 2; and / or The CLM is selected from wherein, W 7 is CH or N, preferably N; R 22 is a single bond, NH, NHC(O) or N(CH3)C(O); preferably a single bond or NH; R 32 、R 62 and R 72 are each independently selected from H, halogen, C1-C3 alkyl, C1-C3 alkoxy and cyano; preferably H, F, Cl, methyl, methoxy or cyano; and / or B1 is O, NH, or N(C1-C6 alkyl), preferably O or N(CH3); B2 is a single bond or a C1-C3 alkylene group, preferably a single bond or a methylene group; B6 is a single bond or a methylene group, preferably a single bond; Preferably, R 32 and R 62 are H, R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, a C1-C3 alkoxy group, and a cyano group, and R 72 is preferably H, F, Cl, a methyl group, a methoxy group, or a cyano group; Preferably, the CLM is 15. The compound according to claim 14, wherein, The compound is a compound represented by the following formula (IA1), formula (IB1), formula (IC1) or formula (ID1): Among them, R P1 、R P2 、R P3 、R P4 、R P5 、R P6 、L, X2, and CLM are each defined as in claim 15.

16. A compound, which is a compound represented by formula (II), formula (III) or formula (IV), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Formula (II): PTM-L-CLM; Wherein L is a bond or linker moiety connecting the CLM and PTM, having the structure -(A L ) q -, A L Each occurrence is the same or different and each occurrence is independently selected from: a covalent bond, an alkenylene group, an alkynylene group, a CR L1 R L2 、O、S、SO、SO2、NR L3 、CO、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 , C(=NCN), C(=CNO2), optionally with 0-6 R L1 and / or R L2 C3-C 11 Cycloalkylene, optionally substituted by 0-6 R L1 and / or R L2 C3-C 11 Heterocyclylene, optionally substituted by 0-6 R L1 and / or R L2 The arylene group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroarylene group substituted with 0-6 R L1 and / or R L2 C6-C 16 Spirocyclyl, optionally substituted by 0-6 R L1 and / or R L2 C6-C 16 Heterospirocyclylene; R L1 , R L2 and R L3 are each independently H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, -SR L4 、-NR L4 R L5 , cycloalkyl, aryl, heteroaryl, heterocyclic, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 , COR L6 、CN、NO2、SF5、SO2NR L4 R L5 ,CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ; R L4 each independently is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R L5 each independently is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R L6 each independently is H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; q is an integer greater than or equal to 1; The CLM is selected from the following structures: Among them, W n is O, NR N or C(O)NR N , n1, n2, n3, n4 are each independently 0, 1, 2 or 3; R nn is each independently selected from H, a deuterium atom, cyano, F, Cl, Br, I, -OH, -NH2, -NO2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 2-6 unsaturated hydrocarbyl each time it appears; Cyn is selected from a 6-10 membered aryl group and a 5-10 membered heteroaryl group containing 1-3 heteroatoms each independently selected from N, O and S; R n0 selected from CR a R b , NR a , O and S; R n1 is CR a or N, R n2 is CR a R b or C=O; R n3 selected from CR a R b , O and S; W 1 and W 2 each independently is CR a R b , C(=O), NR a or SO2, and W 1 and W 2 at least one of them is C(=O); G and Z are each independently selected from O, S and Se; R 3a 、R 3b 、R 3c and R 3d each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl; R 3a0 、R 3b0 、R 3c0 、R 3d0 each independently selected from a single bond, O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, imino, cycloalkylene, heterocyclo, alkylamino, arylene and heteroarylene, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, cycloalkylene, heterocyclo, arylene and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclo, alkylamino, aryl and heteroaryl; W 5 、W 6 Each time it appears, it is independently C(R m )2, NR m , O or S; W 11 is CR a R b , C(=O), NR a or SO2, R 1 、R 2 、R a 、R m 、R N and R b each time it appears is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, alkyl acyl, alkoxy acyl, alkylamino acyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl; R 22 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2 or 3; R 32 and R 42 The carbon atom connected thereto is capable of forming and R 52 、R 62 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; R 42 and R 52 The carbon atom connected thereto is capable of forming and R 32 、R 62 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group; R 52 and R 62 The carbon atom connected thereto is capable of forming and R 32 、R 42 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; R 62 and R 72 The carbon atom connected thereto can form and R 32 , R 42 and R 52 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; or R 32 and R N the atom connected thereto optionally forms a heterocyclic group, and R 42 、R 52 、R 62 、R 72 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkyl acyl, alkoxy acyl, alkylamino acyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkyl acyl, alkoxy acyl, alkylamino acyl, aryl and heteroaryl; R d 、R e 、R f 、R g 、R D 、R E 、R F 、R G 、R f1 、R g1 、R F1 and R G1 Each occurrence is independently C(R m )2, NR m , O, CO or S; W 3 and W 4 each independently is CR m or N; R t 、R T 、R t1 、R T1 Each independently is CR m or N, R t 、R T 、R t1 、R T1 connected to the side represents the connection site between CLM and L; R m Each, when it appears, is independently selected from H, a deuterium atom, F, Cl, Br, I, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl, and heteroaryl, where the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C6 alkylamino, C6-C 15 aryl, and C3-C 15 heteroaryl; m1 and m2 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 each occurrence is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m4 each occurrence is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m3 + m4 ≤ 8; m5 and m6 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; m7 and m8 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; m31 and m41 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m31 + m41 ≤ 7; m51 and m61 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m51 + m61 ≤ 7; The PTM is selected from the following structures: wherein ring A is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group or a 7-12 membered bicycloheteroalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered bicycloheteroaryl group containing 1-3 heteroatoms selected from N, O, S; ring B is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group or a 7-12 membered bicycloheteroalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered bicycloheteroaryl group containing 1-3 heteroatoms selected from N, O, S; ring C is a 6-10 membered aryl group, a 5-10 membered cycloalkyl group containing 0-3 heteroatoms selected from N, O, S, a 7-12 membered bicycloalkyl group, a 5-10 membered heterocycloalkyl group or a 7-12 membered bicycloheteroalkyl group, or a 5-10 membered heteroaryl group or a 7-12 membered bicycloheteroaryl group containing 1-3 heteroatoms selected from N, O, S; R P each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group each time it appears; R Q each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, a heterobridged cyclic group, an aryl group, and a heteroaryl group each time it appears; R S1 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; R S2 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; m' is 1, 2 or 3; n' is 1, 2 or 3; Alternatively, the compound is a compound represented by formula (III), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Formula (III): PTM-L-CLM; wherein L is a bond or linker portion connecting the CLM and PTM and has the structure -(A L ) q -, A L which is the same or different each time it appears and is independently selected each time it appears from: a covalent bond, an alkenylene, an alkynylene, CR L1 R L2 , O, S, SO, SO2, NR L3 , CO, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , C(=NCN), C(=CNO2), a C3-C L1 and / or R L2 substituted cycloalkyl, a C3-C 11 substituted heterocycloalkyl optionally substituted with 0-6 R L1 and / or R L2 groups, an arylene optionally substituted with 0-6 R 11 and / or R L1 groups, a heteroarylene optionally substituted with 0-6 R L2 and / or R L1 groups, a C6-C L2 substituted spirocycloalkyl, a C6-C L1 and / or R L2 substituted heterospirocycloalkyl optionally substituted with 0-6 R 16 and / or R L1 groups; L2 a C6-C 16 substituted heterospirocycloalkyl; R L1 、R L2 、and R L3 each independently is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SR L4 、NR L4 R L5 、cycloalkyl, aryl, heteroaryl, heterocyclic group, OR L4 、OH, SO2-R L4 、P(O)R L4 R L5 、Si(OH)3, Si R L4 R L5 R L6 、COR L6 、CN, NO2, SF5, SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ; R L4 、 and R L5 each independently is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R L6 each independently is H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; q is an integer greater than or equal to 1; The CLM is a cerebellin E3 ubiquitin ligase binding moiety and is selected from the following structures: Wherein, W 1 and W 2 are each independently CR a R b , C(=O), NR a or SO2, and at least one of W 1 and W 2 is C(=O); G and Z are each independently selected from O, S and Se; R 3a 、R 3b 、R 3c 、 and R 3d each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a hydroxy, a nitro, a cyano, an amino, a cycloalkyl, a heterocyclic group, an alkylamino, an aryl, and a heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a hydroxy, a haloalkyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclic group, an alkylamino, an aryl, and a heteroaryl; R 3a0 、R 3b0 、R 3c0 、R 3d0 are each independently selected from O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, imino, cycloalkylene, heterocyclo, alkyleneamino, arylene, and heteroarylene, wherein the alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, cycloalkylene, heterocyclo, arylene, and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclo, alkylamino, aryl, and heteroaryl; W 5 、W 6 Each time it appears independently is C(R m )2, NR m , O or S; W 11 is CR a R b , C(=O), NR a or SO2, R 1 、R 2 、R a 、R m 、R N 、 and R b each independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl each time it appears, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl; R 22 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2 or 3; R 32 and R 42 The carbon atom connected thereto can form and R 52 , R 62 and R 72 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; R 42 and R 52 The carbon atom connected thereto can form and R 32 、R 62 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted by one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group; R 52 and R 62 The carbon atom(s) connected thereto can form and R 32 、R 42 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group; R 62 and R 72 The carbon atom connected thereto can form and R 32 、R 42 and R 52 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; R d 、R e 、R f 、R g 、R D 、R E 、R F 、R G 、R f1 、R g1 、R F1 and R G1 Each occurrence is independently C(R m )2, NR m , O, CO or S; W 3 and W 4 each independently is CR m or N; R t 、R T 、R t1 、R T1 Each independently is CR m or N, R t 、R T R t1 、R T1 connected to the toilet represents the connection site between CLM and L; R m Each occurrence is independently selected from H, deuterium atom, F, Cl, Br, I, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl; m1 and m2 each occurrence is independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; Each occurrence of m3 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, each occurrence of m4 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m3 + m4 ≤ 8; Each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; Each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; Each occurrence of m31 and m41 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m31 + m41 ≤ 7; Each occurrence of m51 and m61 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m51 + m61 ≤ 7; The PTM is a protein targeting moiety of IRAK4 protein, and is selected from the following structures: Wherein ring A is a 5- to 10-membered aromatic ring, a 5- to 10-membered cycloalkyl group containing 0 to 3 heteroatoms selected from N, O, S, a 7- to 12-membered bicycloalkyl group, a 5- to 10-membered heterocycloalkyl group or a 7- to 12-membered bicyclic heterocycloalkyl group, or a 5- to 10-membered heteroaromatic ring or a 7- to 12-membered bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S; Ring B is a 5- to 10-membered aromatic ring, a 5- to 10-membered cycloalkyl group containing 0 to 3 heteroatoms selected from N, O, S, a 7- to 12-membered bicycloalkyl group, a 5- to 10-membered heterocycloalkyl group or a 7- to 12-membered bicyclic heterocycloalkyl group, or a 5- to 10-membered heteroaromatic ring or a 7- to 12-membered bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S; Ring C is a 5- to 10-membered aromatic ring, a 5- to 10-membered cycloalkyl group containing 0 to 3 heteroatoms selected from N, O, S, a 7- to 12-membered bicycloalkyl group, a 5- to 10-membered heterocycloalkyl group or a 7- to 12-membered bicyclic heterocycloalkyl group, or a 5- to 10-membered heteroaromatic ring or a 7- to 12-membered bicyclic heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S; R P each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group each time it appears; R Q each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, a heterobridged cyclic group, an aryl group, and a heteroaryl group each time it appears; R S1 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; R S2 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; m' is 1, 2 or 3; n' is 1, 2 or 3; Alternatively, the compound is a compound represented by formula (II), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: Formula (IV): PTM-L-CLM; where L is a bond or linker portion connecting the CLM and the PTM, having the structure -(A L ) q -, A L which are the same or different each time they occur and each independently selected from: covalent bond, alkenylene, alkynylene, CR L1 R L2 , O, S, SO, SO2, NR L3 , CO, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , C(=NCN), C(=CNO2), C3-C L1 and / or R L2 substituted cycloalkylidene, C3-C 11 optionally substituted with 0-6 R L1 and / or R L2 groups, C3-C 11 substituted heterocycloalkylidene, optionally substituted with 0-6 R L1 and / or R L2 groups, arylidene optionally substituted with 0-6 R L1 and / or R L2 groups, heteroarylidene optionally substituted with 0-6 R L1 and / or R L2 groups, C6-C 16 substituted spirocycloalkylidene, optionally substituted with 0-6 R L1 and / or R L2 groups, C6-C 16 substituted heterospirocycloalkylidene; R L1 、R L2 、and R L3 each independently is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, SR L4 、NR L4 R L5 、cycloalkyl, aryl, heteroaryl, heterocyclic group, OR L4 、OH, SO2-R L4 、P(O)R L4 R L5 、Si(OH)3, Si R L4 R L5 R L6 、COR L6 、CN, NO2, SF5, SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ; R L4 、 and R L5 each independently is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R L6 each independently is H, OH, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; q is an integer greater than or equal to 1; The CLM is a cerebellin E3 ubiquitin ligase-binding moiety and is selected from the following structures: Wherein, W 1 and W 2 are each independently CR a R b , C(=O), NR a or SO2, and at least one of W 1 and W 2 is C(=O); G and Z are each independently selected from O, S and Se; R 3a 、R 3b 、R 3c 、 and R 3d Each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl; R 3a0 、 R 3b0 、 R 3c0 、 R 3d0 each independently selected from O, S, C(=O), NR m , alkylene, deuterated alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, imino, cycloalkylene, heterocycloalkylene, alkylamino, arylene, and heteroarylene, wherein said alkylene, heteroalkylene, alkenylene, alkynylene, alkoxy, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkylamino, aryl, and heteroaryl; W 5 and W 6 each independently represents C(R m )2, NR m , O or S each time it appears; W 11 is CR a R b , C(=O), NR a or SO2, R 1 、R 2 、R a 、R m 、R N 、 and R b each independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic group, alkylamino, alkyl acyl, alkoxy acyl, alkylamino acyl, aryl and heteroaryl each time it appears, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkylamino, aryl and heteroaryl; R 22 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2 or 3; R 32 and R 42 The carbon atom connected thereto can form and R 52 、R 62 and R 72 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; R 42 and R 52 The carbon atom connected thereto can form and R 32 、R 62 and R 72 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aryl and heteroaryl; R 52 and R 62 The carbon atom connected thereto can form and R 32 、R 42 and R 72 each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylaminocarbonyl group, an aryl group, and a heteroaryl group; R 62 and R 72 the carbon atom connected thereto is capable of forming and R 32 、R 42 and R 52 each occurrence is independently selected from H, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkoxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkylacyl, alkoxyacyl, alkylaminoacyl, aryl and heteroaryl; R d 、R e 、R f 、R g 、R D 、R E 、R F and R G each independently represents C(R m )2, NR m , O, CO or S; W 3 and W 4 each independently is CR m or N; R t and R T each independently is CR m or N, R t and R T is connected to the toilet Represents the connection site between CLM and L; Each occurrence of m1 and m2 is independently an integer of 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; Each occurrence of m3 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, each occurrence of m4 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m3 + m4 ≤ 8; Each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; Each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; The PTM is a protein targeting moiety of IRAK4 protein and is selected from the following structures; Wherein ring A is a 5- to 10-membered aromatic ring or a 5- to 10-membered monocyclic or bicyclic ring containing 0 to 3 heteroatoms selected from N, O, S; Ring B is a 5- to 10-membered aromatic ring or a 5- to 10-membered monocyclic or bicyclic ring containing 0 to 3 heteroatoms selected from N, O, S; Ring C is a 5- to 10-membered aromatic ring or a 5- to 10-membered monocyclic or bicyclic ring containing 0 to 3 heteroatoms selected from N, O, S R P each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group each time it appears; R Q each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclic group, a heterobridged cyclic group, an aryl group, and a heteroaryl group each time it appears; R S1 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; R S2 selected from one or more combinations of a single bond, CO, O, S, SO2, -NR m -, -NR m CO-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; m' is 1, 2 or 3; n' is 1, 2 or 3.

17. The compound according to claim 16, wherein, R 32 and R 42 forms with the carbon atom to which it is attached and R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 42 and R 52 forms with the carbon atom to which it is attached and R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 52 and R 62 forms with the carbon atom to which it is attached and R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 62 and R 72 forms with the carbon atom to which it is attached and R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R L1 、R L2 、 and R L3 each independently is H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 、NR L4 R L5 、C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH, SO2-R L4 、P(O)R L4 R L5 、Si(OH)3, Si R L4 R L5 R L6 、COR L6 、CN, NO2, SF5, SO2NR L4 R L5 、CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ; and / or R L4 and R L5 each independently is H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic heterocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C6-C 15 heteroaryl or C6-C 15 haloheteroaryl; and / or R L6 each independently is H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic heterocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C6-C 15 heteroaryl or C6-C 15 haloheteroaryl; and / or W 1 and W 2 are the same or different and each independently is CH2 or C(=O), and W 1 and W 2 at least one of them is C(=O); and / or G is O; and / or Z is O; and / or R d , R e , R D and R E Each occurrence is independently C(R m )2 or 0; and / or R f , R g , R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or each occurrence of m1 and m2 is independently an integer of 0, 1, 2, 3, and m1 + m2 ≤ 3; preferably, m1 + m2 = 1 or m1 + m2 = 3; and / or each occurrence of m3 and m4 is independently an integer of 0, 1, 2, 3, 4, 5, and m3 + m4 ≤ 5, m3 and m4 are not both 0 at the same time; preferably m3 + m4 = 2, m3 + m4 = 3 or m3 + m4 = 4; and / or each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3 or 4, and m5 + m6 ≤ 4, preferably m5 + m6 = 2 or m5 + m6 = 3; and / or each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3 or 4, and m7 + m8 ≤ 4, preferably m7 + m8 = 2 or m7 + m8 = 3; and / or each occurrence of m31 and m41 is independently an integer of 0, 1, 2, 3 or 4, and m31 + m41 ≤ 4; preferably m31 + m41 = 2 or m31 + m41 = 3; and / or each occurrence of m51 and m61 is independently an integer of 0, 1, 2, 3 or 4, and m51 + m61 ≤ 4; preferably m51 + m61 = 2 or m51 + m61 = 3; and / or W 3 and W 4 is CH or N; and / or W 5 and W 6 is C(R m )2 or N(R m ), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or R 3a 、 R 3b 、 R 3c 、 and R 3d are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C6-C 15 aryl and C6-C 15 heteroaryl are each independently optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl; preferably, R 3a 、 R 3b 、 R 3c 、 and R 3d are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylaminocarbonyl group, a C6-C 15 aryl group, and a C6-C 15 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C6 cycloalkyl group, the C3-C6 heterocyclic group, the C6-C 15 aryl group, and the C6-C 15 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C6-C 15 aryl group, and a C6-C 15 heteroaryl group; preferably, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 1 、R 2 、R a 、 and R b are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, and C1-C6 hydroxyalkyl; and / or R N independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group; and / or R 22 selected from a single bond, -NR 2A -, -NR 2A CO-, C1-C6 alkyl, C1-C6 haloalkyl; and / or R P Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; and / or R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C3-C6 heterobicyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; and / or R S1 selected from a covalent bond, a C1-C3 alkyl group, a C2-C4 alkenyl group, and a C2-C4 alkynyl group; and / or R S2 selected from a covalent bond, a C1-C3 alkyl group, an amino group, and a carbonyl group.

18. The compound according to claim 16, wherein, R 32 and R 42 forms with the carbon atom to which it is attached and R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 52 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 42 and R 52 forms with the carbon atom to which it is attached and R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R3, R6, and R7 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 32 、R 62 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 52 and R 62 forms with the carbon atom to which it is attached and R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, preferably R 32 、R 42 and R 72 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 62 and R 72 forms with the carbon atom to which it is attached and R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more substituents selected from a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, an aryl group, and a heteroaryl group, and preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, wherein the C1-C6 alkyl group, the C1-C6 heteroalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C1-C6 alkoxy group, the C3-C8 cycloalkyl group, the C4-C 10 heterocyclic group, the C6-C 10 aryl group, and the C5-C 10 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I,, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C8 cycloalkyl group, a C4-C 10 heterocyclic group, a C6-C 10 aryl group, and a C5-C 10 heteroaryl group, and preferably R 32 、R 42 and R 52 are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R L1 , R L2 , and R L3 are independently H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, SR L4 NR L4 R L5 , C3-C6 cycloalkyl, aryl, heteroaryl, C3-C6 heterocyclic group, OR L4 、OH、SO2-R L4 、P(O)R L4 R L5 、Si(OH)3、Si R L4 R L5 R L6 , COR L6 、CN、NO2、SF5、SO2NR L4 R L5 ,CONR L4 R L5 、N(R L4 )CONR L5 R L4 or N(R L4 )SO2NR L4 R L5 ; and / or R L4 and R L5 each independently is H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic heterocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C6-C 15 heteroaryl or C6-C 15 haloheteroaryl; and / or R L6 each independently is H, OH, F, Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6 heterocyclic group, C3-C6 halocyclic heterocyclic group, C6-C 15 aryl, C6-C 15 haloaryl, C6-C 15 heteroaryl or C6-C 15 haloheteroaryl; and / or W 1 and W 2 are the same or different, each independently being CH2 or C(=O), and W 1 and W 2 at least one of them is C(=O); and / or G is O; and / or Z is O; and / or R d , R e , R D and R E Each occurrence is independently C(R m )2 or 0; and / or R f , R g , R F and R G Each occurrence is independently C(R m )2 or O, preferably C(R m )2; and / or each occurrence of m1 and m2 is independently an integer of 0, 1, 2, 3, and m1 + m2 ≤ 3; preferably, m1 + m2 = 1 or m1 + m2 = 3; and / or each occurrence of m3 and m4 is independently an integer of 0, 1, 2, 3, 4, 5, and m3 + m4 ≤ 5, m3 and m4 are not both 0 at the same time; preferably m3 + m4 = 2, m3 + m4 = 3 or m3 + m4 = 4; and / or each occurrence of m5 and m6 is independently an integer of 0, 1, 2, 3 or 4, and m5 + m6 ≤ 4, preferably m5 + m6 = 2 or m5 + m6 = 3; and / or each occurrence of m7 and m8 is independently an integer of 0, 1, 2, 3 or 4, and m7 + m8 ≤ 4, preferably m7 + m8 = 2 or m7 + m8 = 3; and / or W 3 and W 4 is CH or N; and / or W 5 and W 6 is C(R m )2 or N(R m ), preferably CH2, CH(C1-C6 alkyl), CH(C1-C6 haloalkyl), CH(OH) or NH; and / or R 3a 、R 3b 、R 3c 、 and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group, wherein the C1-C6 alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 heterocyclic group, C6-C 15 aryl group and a C6-C 15 heteroaryl group are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a nitro group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C1-C6 alkylamino group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; preferably, R 3a 、R 3b 、R 3c 、 and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group and a C1-C3 alkoxy group; and / or R m Each occurrence is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminocarbonyl, C6-C 15 aryl and C6-C 15 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C6-C 15 aryl and C6-C 15 heteroaryl are each independently optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclic group, C1-C6 alkylamino, C6-C 15 aryl and C6-C 15 heteroaryl; preferably, R m Each occurrence is independently selected from H, deuterium atom, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy; and / or R 1 、R 2 、R a 、and R b are each independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, C1-C6 haloalkyl and C1-C6 hydroxyalkyl; and / or R N independently selected from H, deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl are each independently optionally substituted with one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 heterocyclic group, C6-C 10 aryl and C5-C 10 heteroaryl; and / or R 22 selected from a single bond, -NR 2A -, -NR 2A CO-, C1-C6 alkyl, C1-C6 haloalkyl; and / or R P Each independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; and / or R Q Each occurrence is independently selected from a hydrogen atom, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxy group, a C1-C6 hydroxyalkyl group, a cyano group, an amino group, a C3-C6 cycloalkyl group, a C3-C6 heterocyclic group, a C3-C6 heterobicyclic group, a C6-C 15 aryl group and a C6-C 15 heteroaryl group; and / or R S1 selected from a covalent bond, a C1-C3 alkyl group, a C2-C4 alkenyl group, and a C2-C4 alkynyl group; and / or R S2 selected from a covalent bond, a C1-C3 alkyl group, an amino group, and a carbonyl group.

19. The compound according to any one of claims 1-18, which is selected from the following compounds: the compound of Table A; Preferably, the compound is selected from the compounds in Table A. A compound represented by formula (V) or formula (VI), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate thereof: L z1 Each occurrence is independently selected from a single bond, C(O), O, -NR m -, -NR m C(O)-, alkylene, alkenylene, alkynylene, haloalkylene, and heteroalkylene; preferably, L z1 Each occurrence is independently selected from a single bond, C(O), O, -NH-, -NHC(O)-, C 1-6 alkylene, C 1-6 haloalkylene; preferably, L z1 Each occurrence is independently selected from a single bond, C(O), O, -NH-, -NHC(O)-, C 1-3 alkylene, C 1-3 haloalkylene; Among them, R 1 、R 2 、W 5 、W 6 、W7、R 32 、R 52 、R 62 、R 72 、R 1D 、R 1E 、R F 、R G 、R T 、B1, B2, B3, B4, B5, B6, C1, C2, m3, m4, m7, m8, W 1 、W 2 、n2, n3, n4, n5, n6, R m as defined in claim 1 or 2; Each occurrence of Cys is independently selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocyclic group, heterospirocyclic group, fused ring group, hetero fused ring group, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocyclic group, heterospirocyclic group, fused ring group, hetero fused ring group are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, carboxyl, amino, nitro, cycloalkyl, heterocyclic group, alkenyl, alkynyl, alkylamino, alkyl acyl, alkoxy acyl, alkylamino acyl, aryl and heteroaryl; Preferably, each occurrence of Cys is independently selected from C3-C6 cycloalkyl, C5-C 13 spirocyclic group, C3-C7 heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C 13 heterospirocyclic group, and the C3-C6 cycloalkyl, C5-C 13 spirocyclic group, C3-C7 heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O or S, C5-C 13 heterospirocyclic group is each independently optionally substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, cyano, carboxyl, amino; preferably substituted by one or more substituents selected from F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, carboxyl, amino; Preferably, the compound is selected from the following compounds:

21. The following compounds, or their isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, said compounds being selected from the following structures: wherein E is hydrogen or a leaving group; preferably, the leaving group is selected from halogen, hydroxy, carbonyl, -Ots and -ONO2; Preferably, the compound is an inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) protein; Preferably, the compound is selected from:

22. A pharmaceutical composition, which contains the compound, its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates according to any one of claims 1-21, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

23. Use of the compound, its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates according to any one of claims 1-21 or the pharmaceutical composition according to claim 22 in the preparation of a drug for preventing or treating a disease or disorder mediated by IRAK4, wherein the disease or disorder mediated by IRAK4 includes immune diseases, inflammatory diseases and cancers.

24. A method for treating a disease or disorder mediated by IRAK4, which includes administering to a subject in need a therapeutically effective amount of the compound, its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates according to any one of claims 1-21 or the pharmaceutical composition according to claim 22; preferably, the subject expresses IRAK4; preferably, the disease mediated by IRAK4 is leukemia, preferably acute monocytic leukemia.

25. The compound, its isomers, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates according to any one of claims 1-21 or the pharmaceutical composition according to claim 22, for treating a disease or disorder mediated by IRAK4; preferably, the disease mediated by IRAK4 is leukemia, preferably acute monocytic leukemia.

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