WO2022161414A1

WO2022161414A1 - Aromatic compound, pharmaceutical composition containing same, and application thereof

Info

Publication number: WO2022161414A1
Application number: PCT/CN2022/074129
Authority: WO
Inventors: 张登友; 王波; 陈勇; 李亮; 吴天强; 宴斌
Original assignee: 成都茵创园医药科技有限公司
Priority date: 2021-01-26
Filing date: 2022-01-26
Publication date: 2022-08-04
Also published as: CN116648248A

Abstract

An aromatic compound containing an E3 ligand fragment, a pharmaceutical composition containing same, and an application thereof. An aromatic compound as represented by general formula E, an enantiomer, a diastereomer, a racemate and a mixture, or a pharmaceutically acceptable salt thereof. Such compound containing the E3 ligand fragment can be used for preparing a PROTAC compound, which can recruit target proteins to a CRBN E3 ubiquitin ligase for degradation, or inhibit the activity of the target proteins in other ways. A degrading agent of an enzyme IRAK4 containing same can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways. The compound has good application prospect in IRAK4-mediated diseases such as immune diseases, tumors, Alzheimer's disease, and fibrotic diseases, and provides a new choice in clinic for screening and/or preparing drugs for the diseases related to the activity of IRAK4.

Description

Aromatic compounds, pharmaceutical compositions containing the same and uses thereof

This application claims the priority of the Chinese patent application 202110100562.3 with the filing date of 2021/1/26; claims the priority of the Chinese patent application 202110427240.X with the filing date of 2021/04/21; claims the priority of the Chinese patent application with the filing date of 2021/12/15 The priority of Chinese patent application 2021115401175; the priority of Chinese patent application 2021115401160 with the filing date of 2021/12/15 is claimed. This application cites the full text of the above Chinese patent application.

technical field

The present invention relates to an aromatic compound, a pharmaceutical composition containing the same and its application.

Background technique

Protein degradation is a highly regulated process essential for maintaining cellular homeostasis. The role of the ubiquitin-proteasome pathway (UPP) in vivo is to selectively identify and remove excess proteins, and to degrade misfolded or abnormal proteins. The ubiquitin molecule is covalently linked to the terminal lysine residue by E3 ubiquitin ligase, thereby labeling the protein and then degrading it into a small peptide by the proteasome, and finally digesting it into its constituent amino acids. Used as building blocks for new proteins. UPP is central to multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of various diseases. UPP is central to the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscle degeneration, neural network Morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular modulators, ribosome biogenesis and viral infection. Defective proteasomal degradation is associated with a variety of clinical conditions including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease and cancer, among others.

Protein degradation targeting chimera (PROTAC) is an effective means of degrading pathogenic proteins, combining small molecules that can bind to target proteins with E3 ligases including CRBN, VHL, MDM2, DRAF, etc. The molecule forms a heterobifunctional molecule that ubiquitinates the target protein by mimicking the ubiquitin-proteasome pathway (UPP), thereby achieving the degradation of the target protein by the proteasome. A potential advantage of protein degradation-targeted chimeras over small-molecule inhibitors is that they can remove all functions of disease-causing proteins.

More than 600 E3 ubiquitin ligases have been found to promote in vivo ubiquitination of different proteins, which can be divided into four families: HECT domain E3 family, U-box E3 family, monomeric RINGE3 family and multi-subunit E3 family. Cereblon (CRBN) ligase is the most widely used E3 ligase in PROTAC technology. Cereblon belongs to the Cullin RING E3 ubiquitin ligase, a 442 amino acid protein that forms the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and interacts with the adaptor protein damaged DNA binding protein 1 (DDB1) . In the CRL4 complex, CRBN acts as a substrate-specific receptor. Known CRBN ligands include thalidomide and other derived immunomodulatory imide drugs. Upon ligand binding of CRBN, the E3 ubiquitin ligase activity of CRBN is reregulated, leading to increased recruitment of the transcription factors Ikaros and Aiolos, which trigger subsequent ubiquitination and proteasomal degradation. Currently, CRBN, as an E3 ligase in PROTAC, has been successfully used to target more than 30 different proteins, including proteins associated with various cancers (Sun X. et al., 2019), immune dysfunction-related proteins ( Bassi et al., 2018), neurodegenerative disease-related proteins (Silva et al., 2019), and hepatitis C virus proteins (de Wispelaere et al., 2019). Most CRBN-targeted PROTACs employ pomalidomide, 4-hydroxythalidomide, alkyl-linked thalidomide derivatives, or derivatives of lenalidomide. However, it is possible to develop better CRBN ligands. These new CRBN ligands will provide more options for the development of PROTAC technology.

IRAK4 belongs to the class of serine/threonine kinases that mediate the interleukin-1 (IL-1) receptor family (IL-1, IL-18 and IL-33 receptors) and pathogen recognition Toll-like receptors (TLRs) key protein in signaling. Studies have shown that when recognizing foreign pathogens and inflammatory stress, under the action of extracellular ligands, interleukin-1 receptors or TLR receptors recruit the adaptor protein myeloid differentiation primary response protein (Myd88), which in turn forms a complex with IRAK4, Activation of NF-κB light chain enhancer and activator protein 1 (AP-1) leads to the production of various inflammatory factors in cells, such as tumor necrosis factor alpha (TNFα), IL-6, etc., thereby inducing various immune diseases, such as The occurrence of psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, etc. In addition, IRAK4 has been implicated in lymphocytic leukemia and lymphoma, Alzheimer's disease, and fibrotic diseases. Therefore, IRAK4 is an attractive target for drug development.

At this stage, major pharmaceutical companies, including Pfizer, Gilead, Bayer, Curis, etc., have successively advanced IRAK4 small molecule inhibitors into the clinic for hematological tumors, psoriasis, Rheumatoid arthritis, enteritis, systemic lupus erythematosus, etc. Among them, the IRAK4 inhibitor PF-06650833 researched by Pfizer has entered the phase II clinical research stage. Early clinical results show that PF-06650833 has a good safety profile, and its efficacy shows that PF-06650833 can inhibit the inflammatory pathway mediated by IRAK4. These clinical data fully demonstrate that IRAK4 is a clinically validated drug target that is expected to treat various diseases.

Recent studies have shown that in addition to the inflammatory signaling pathways mediated by the kinase activity of IRAK4, the IRAK4 protein scaffold can also activate certain inflammatory signaling pathways. In human skin fibroblasts, inhibition of IRAK4 by ATP-competitive small molecules was not able to effectively inhibit IL-1β-stimulated IL-6 and TNF-α release. In addition, knockdown of IRAK4 effectively abolished the inflammatory response mediated by IL-1, IL-8 and TLR ligands. Therefore, the inflammatory signaling pathway mediated by IRAK4 protein cannot be completely abolished by ATP-competitive small-molecule inhibitors. Thus, targeting IRAK4 with small-molecule inhibitors has its therapeutic limitations.

Protein degradation targeting chimera (PROTAC) is an effective means of degrading pathogenic proteins, combining small molecules that can bind to the target protein with E3 ligases including CRBN, VHL, MDM2, DRAF, etc. The molecule forms a heterobifunctional molecule that ubiquitinates the target protein by mimicking the ubiquitin-proteasome pathway (UPP), thereby achieving the degradation of the target protein by the proteasome. A potential advantage of protein degradation-targeted chimeras over small-molecule inhibitors is that they can remove all functions of disease-causing proteins. In addition, scientists from GSK demonstrated that the degradation of IRAK4 protein can be achieved by combining a small molecule inhibitor of IRAK4 with ligands of E3 ligase CRBN and VHL to form a protein degradation targeting chimera (PROTAC). At the same time, Kymera and Avinas designed the corresponding PROTAC for IRAK4. These emerging technologies provide a novel therapeutic approach for targeting IRAK4.

SUMMARY OF THE INVENTION

Provided herein are a class of compounds containing E3 ligand fragments, pharmaceutical compositions containing the same, and uses. The degrader consists of CRBN ligands, linking groups and target protein ligands. Such compounds containing E3 ligand fragments can be used to prepare PROTAC compounds capable of recruiting target proteins to CRBN E3 ubiquitin ligase for degradation or otherwise inhibiting the activity of target proteins. Also provided herein are compounds that are degraders of the enzyme IRAK4, pharmaceutical compositions containing such compounds, and uses. The degrader can recruit IRAK4 to E3 ubiquitin ligase and degrade it or otherwise inhibit the activity of IRAK4. The compound has the structure shown in formula I, I', Ia-e, II, III, IV or V, or a pharmaceutically acceptable salt, metabolite, prodrug or derivative thereof.

The present invention solves the above technical problems through the following technical solutions.

first

The present invention provides compounds of formula I and pharmaceutically acceptable compositions thereof that are effective as degraders of IRAK4. The present invention solves the above technical problems through the following technical solutions.

The present invention provides a compound represented by formula (I), its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,

in,

Q is selected from CR ^2a , N;

V is selected from C, N;

U is selected from CR ² , NR ² (eg N);

W is selected from CR ³ , N;

X is selected from C (when attached to L), ^CR4 , N;

Y is selected from C (when attached to L), ^CR5 , N;

Z is selected from C (when attached to L), CR6, N ^;

R ¹ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted Saturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from 5-10 membered aromatic heterocycles substituted with 0-4 R ⁷ ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

^Re , R ^2a , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered Heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 Ring-membered hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered Cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched chain alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3 -10-membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3- C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring, 3-10-membered cycloalkyl, C1-C6 straight or branched chain alkyl-C(=O) -, 3-10 membered cycloalkyl-C(=O)-; Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 selected from oxygen, sulfur and nitrogen of heteroatoms;

L is selected from linking groups that are non-hydrogen.

in,

Indicates a single or double bond.

In some preferred embodiments of the present invention, the compound shown in formula I, its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof Some of the groups are as defined below (unmentioned groups are described in any scheme of this application, hereinafter referred to as "in a certain scheme"), and the compound shown in formula I is such as formula Ia or formula Ib shown,

Another example is shown in formula Ic or formula Id,

Also as shown in (Ie), (If) and (Ig):

^In one aspect, U is selected from CR2, N.

^In a certain aspect, U is selected from NR2.

In a certain scheme, R ¹ is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, 3-10 membered cycloalkyl, wherein said substituted The group is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy; the number of substitutions is 1, 2 or 3;

For example R ¹ is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, Monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl; another example _-CF2 .

In a certain scheme,

for

In a certain scheme,

wherein, V is selected from N, U is selected from CR ² , W is selected from CR ³ and N.

In a certain scheme, R ^e , R ^2a , R ² , R ³ are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted Substituted C1-C6 straight-chain or branched alkoxy; for example, H-substituted or unsubstituted C1-C6 straight-chain or branched alkyl, another example is H or methyl.

^In one aspect, X is selected from CR4, N; Y is selected from ^CR5 , N; Z is selected from C, CR6, N ^; and at most one of X, Y, and Z is N.

In a certain scheme, R ⁴ , R ⁵ , R ⁶ are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1 -C6 straight or branched alkoxy; for example H, halogen or substituted or unsubstituted C1-C6 straight or branched alkyl, also for example H, F or methyl.

In a certain scheme, R ⁴ , R ⁵ , R ⁶ are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1 -C6 linear or branched alkoxy; for example H or substituted or unsubstituted C1-C6 linear or branched alkyl, also for example H or methyl.

In a certain scheme, A ring is independently selected from 0-4 R ⁷ substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;

For example, ring A is independently selected from the following rings substituted with 0, 1, 2, 3 or 4 R ⁷ :

Wherein the number of R ⁷ substitutions is 0-4; another example

In one aspect, ring A is independently selected from:

In a certain scheme, R ⁷ is selected from substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocycle base, substituted or unsubstituted C1-C6 linear or branched alkylamino;

The substituents can be independently selected from deuterium, halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 4-10-membered heterocyclyl, 3-10-membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

The substituents can be independently selected from deuterium, halogen, C1-C6 straight or branched chain alkyl, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, C1-C6 straight or branched chain Alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

In a certain scheme, R ⁷ is selected from:

In one scheme, L is

in,

L1 is selected from none,

a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, -N(R ⁸ )-, -C, respectively (=O)-R ⁹ -, -SO2R ¹⁰ -; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring, substituted or unsubstituted Unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain or Branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group , substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ can be respectively combined with R ^L111 , R ^L112 , ^{RL113 , RL114 , RL123} ^, ^RL124 ^{, RL125} ^, ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 form substituted or unsubstituted 3-10-membered through C, N, O, S Ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight Chain or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, - R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amino group, substituted or unsubstituted C1-C6 linear or branched alkanoyl group, substituted or unsubstituted 3-10 membered cycloalkanoyl group; the substituent group is independently selected from deuterium, halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered Heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group , heterospirocyclyl, aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^a' , L ^i' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , RL118, ^RL119 , ^RL120 , ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 ^{, RL132} ^are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkane group, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted Substituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or Unsubstituted 3- to 10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1- C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ - , -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ²³ R ³⁴ -,

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L21, L2m, L2n, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' are independently selected from In none, O, S, NR ³⁹ , COR ⁴⁰ , -SO2R ⁴¹ ;

L ^2b' , L ^2c' , L ^2d' , L ^21' are selected from N, CR ⁴⁴ ;

R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴⁴ , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L241 , R ^L242 , R ^L243 , R ^L244 , R ^L245 , R ^L246 are independently selected from hydrogen, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted heterocyclyl C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, - R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁹ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1 -C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ⁴⁴ and R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 can pass C, N, O, S form a substituted or unsubstituted 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched chain alkyl, C2-C6 Linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered Cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²³ -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

In one scheme, L is

Wherein, L1 is selected from none,

f, g, h, i, j, k, l, m, n, o, p are independently selected from 0, 1 or 2;

Ld and Le are independently selected from none (connection bond), -C(=O)-R ⁹ - or -N(R ⁸ )-; R ⁸ is selected from hydrogen, substituted or unsubstituted C1-C6 straight chain or Branched alkyl; R ⁹ is selected from unsubstituted, substituted or unsubstituted C1-C6 straight or branched alkyl;

L ^a' , ^Le' , L ^f' , L ^g' , L ^h' are independently selected from none (connection bond);

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

^R38 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L25 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

Ring B is selected from the group consisting of no (representing a connecting bond), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged cyclyl, Substituted or unsubstituted C3-C12 heterospirocyclyl;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0, 1, 2 or 3;

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L21, L2m, L2n are independently selected from none (linker), -C(=O) ^-R40- , O, S or -N(R ³⁹ )-; R ³⁹ is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; R ⁴⁰ is selected from unsubstituted, substituted or unsubstituted C1-C6 linear or branched alkyl;

L ^2a' , L ^2e' , L ^2f' , L ^2g' , L ^2h' are independently selected from None; L ^2b' , L ^2c' , L ^2d' , L ^2i' are selected from N, CR ⁴⁴ ;

^R44 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L241 , R ^L242 , R ^L243 , R ^L244 , R ^L245 , R ^L246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; or R ⁴⁴ and R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 can form substituted or unsubstituted through C, N, O, S 3-10 ring;

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10-membered aromatic heterocycle;

The substituents are independently selected from deuterium, halogen, C1-C6 linear or branched alkyl;

And at least one of L1, B ring, L2 and C ring is not null.

In one scheme, L is

in,

L1 is selected from none,

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, NR ⁸ (-N(R ⁸ )- ), COR ⁹ (-C(=O)-R ⁹ -), -SO2R ¹⁰ -; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 Heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted Substituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2-C6 straight Chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 Linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ^34- ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ can be respectively combined with R ^L111 , R ^L112 , ^{RL113 , RL114 , RL123} ^, ^RL124 ^{, RL125} ^, ^RL126 , ^RL127 , ^RL128 , ^RL139 , ^RL130 through C, N, O, S form substituted or unsubstituted 3-10-membered Ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight Chain or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, - R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2 ^R31 -, -R ³² SO2 NR ³³ R ³⁴ -,

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , RL118, ^RL119 , ^RL120 , ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 ^{, RL132} ^are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkane group, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted Substituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or Unsubstituted 3- to 10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1- C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ - , -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ³⁹ NR ³⁰ SO2R ³¹ - , -R ³² SO2NR ³³ R ³⁴ -,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, deuterium, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

L2 is selected from none,

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L21, L2m, L2n, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' independently selected from In none, O, S, NR ³⁹ (-N(R ³⁹ )-), COR ⁴⁰ (-C(=O)-R ⁴⁰ -), -SO2R ⁴¹ ; R ³⁹ , R ⁴⁰ , R ⁴¹ , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L241 , R ^L242 , R ^L243 , R ^L244 , R ^L244 and R ^L245 are independently selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkane group, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted Substituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or Unsubstituted 3- to 10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁷ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1 -C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2 ^R31 -, -R ³² SO2 NR ³³ R ³⁴ - ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

In a certain aspect, at least one of L1, B-ring, L2 and C-rings is not null; eg, two, three or four of L1, B-ring, L2 and C-rings are not null.

In a certain scheme, in L, L ^2b' , L ^2c' , L ^2d' , L ^2i' are selected from N, CR ⁴⁴ ; R ⁴⁴ is independently selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic Cyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5 -10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkane Oxy group, substituted or unsubstituted C1-C6 linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, - R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

Or R ⁴⁴ and R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 can pass C, N , O, S form a substituted or unsubstituted 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2- C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 Membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2 NR ³³ R ³⁴ -,

In a certain scheme, in L, R ³⁹ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, and S; The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, -R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, -R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

In one scheme, L is

Wherein, L1 is selected from none,

f, g, h, i, j, k, l, m, n, o, p are independently selected from 0, 1 or 2;

L ^a' , L ^e' , L ^f' , L ^g' , L ^h' are independently selected from none (connection bond);

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

L2 is selected from none,

L ^2a' , L ^2e' , L ^2f' , L ^2g' , L ^2h' are independently selected from none;

R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L241 , R ^L242 , ^RL243 , ^RL244 , ^RL245 , and ^RL246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

And at least one of L1, B ring, L2 and C ring is not null.

In a certain scheme,

for

In a certain scheme,

E.g

Another example

In a certain scheme,

In a certain scheme,

Selected from:

In one aspect, ring A is selected from:

In one scheme, L is selected from: (connected to V on the left)

Its single cis, trans isomer or mixtures thereof; for example

In a certain scheme, the compound represented by formula I,

in,

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ¹ is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3 -10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 linear or branched alkane Oxy group, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkanoyl, 3- 10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted Substituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched Saturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamine, C1 -C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10 A membered aromatic ring, a 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

For example, the compound represented by formula I is the compound of formula (Ia) shown below,

In a certain scheme, in the compound,

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ¹ is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R ⁷ substituted:

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted Substituted 3-10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched Saturated hydrocarbon group, C1-C6 straight or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10 membered cycloalkylamine, C1 -C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10 A membered aromatic ring, a 5-10 membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group that is non-hydrogen; for example, the compound represented by formula I is the compound of formula (Ia) shown below,

In a certain scheme, in the compound,

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

Ring ^A is independently selected from 0-4 R substituted:

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10-membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10-membered cycloalkylamino, substituted or unsubstituted C1 -C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched chain Alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkoxy Amine group, 3-10-membered cycloalkylamino group, C1-C6 straight or branched chain alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring base, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1 - 4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

L1 is selected from none,

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, NR ⁸ , COR ⁹ , -SO2R ¹⁰ ; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , - R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridge ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ can be respectively combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , ^R36 , R ³⁷ are independently selected from none, hydrogen, halogen, cyano, hydroxyl, Amine group, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkane base, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy group, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, Substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1- C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear Chain or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched chain alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic, C5 -C12 heterobridged cyclyl, C3-C10 heterospirocyclyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; the heterocyclyl, heterobridged, heterospirocyclyl , the aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , RL118, ^RL119 , ^RL120 , ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 ^{, RL132} ^are independent Selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, Substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted The 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight Chain or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or Branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' independently selected from None, O, S, ^NR39 , ^COR40 , ^-SO2R41 ; R ³⁹ , R ⁴⁰ , R ⁴¹ are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1 -C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁷ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 Linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear Or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Wherein, L ^2b' , L ^2c' , L ^2d' , L ^2i' are selected from N, CR ⁴⁴ ; R ⁴⁴ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or R ⁴⁴ and R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 can form substituted or unsubstituted through C, N, O, S 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² -, -R ¹³ OCOR ¹⁴ -, -R ¹⁵ COOR ¹⁶ -, - R ¹⁷ NR ¹⁸ COR ¹⁹ -, -R ²⁰ CONR ²¹ R ²² -, -R ²³ SO2R ²⁴ -, -R ²⁵ OSO2R ²⁶ -, - R ²⁷ SO2OR ²⁸ -, -R ²⁹ NR ³⁰ SO2R ³¹ -, -R ³² SO2NR ³³ R ³⁴ -,

R ³⁹ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, Cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

In a certain scheme,

The structures of the compounds are shown in (II) and (III):

V is selected from C, N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

Ring A is independently selected from 0-4 R ⁷ substituted:

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 Heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain Or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear Chain or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered The cycloalkanoyl group; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 Linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched Chain alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5 -10-membered aromatic heterocycle; said heterocyclyl, heterobridged ring, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R ⁴² and R ⁴³ are selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted Substituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1 -C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3 -10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear Chain or branched alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aryl group ring, 5-10-membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Its fragments are selected from:

Or, also:

In a certain scheme,

The structures of the compounds are shown in (IV), (V) or (VI):

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ⁴ , R ⁵ and R ⁶ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, and substituted or unsubstituted C5-C12 heterobridged ring base, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1- C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched Chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched chain alkanoyl, substituted or unsubstituted 3-10 membered cycloalkane Acyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon groups , C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 Linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10-membered Aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from 0-4 R ⁷ substituted:

R ⁷ is selected from:

Alternatively, it can also be

Its fragments are selected from:

Alternatively, it can also be:

Another aspect of the present invention also provides a compound represented by formula I', its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,

in,

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ¹ is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl Substituted C2-C6 straight-chain or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkane Oxy group, C1-C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, C1-C6 linear or branched chain alkanoyl group, C1-C6 cycloalkanoyl group, C3-C10 heterocyclic group cyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from a 5-10 membered aromatic heterocycle substituted with 0-4 R ⁷ ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine base, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents Independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy , C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkane Acyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from linking groups that are non-hydrogen.

In a certain scheme,

Wherein, V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

Ring A is independently selected from 0-4 R ⁷ substituted:

L is selected from linking groups that are non-hydrogen.

In a certain scheme,

in,

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

Ring A is independently selected from 0-4 R ⁷ substituted:

L1 is selected from none,

a, b, d are independently selected from 1-6;

c, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, NR ⁸ ; R ⁸ is selected from hydrogen, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aryl ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, Substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, Substituted or unsubstituted C1-C6 linear or branched alkylamino groups, substituted or unsubstituted C1-C6 cycloalkylamino groups, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , _- R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; ^Heterocyclic group, ^hetero - ^bridged ring group, ^{heterospirocyclic} group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, ^sulfur and nitrogen; R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched cycloalkyl, substituted or unsubstituted Substituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 cycloalkoxy Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted The C1-C6 cycloalkanoyl group; the substituents are independently selected from halogen, cyano, hydroxyl, amine group, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group , C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear Or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5- The aromatic heterocycle of 10; the heterocyclyl, heterobridged ring, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^d' , L ^i' are independently selected from N, CR ³⁶ , respectively;

^R36 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , RL118, ^RL119 , ^RL120 , ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 ^{, RL132} ^are independent Selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterocyclic group Heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted Substituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy , substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , - R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; Heterocyclyl, heterobridged, heterospiro, and aromatic heterocycles contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁶ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 forms a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkane base, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamine, Cycloalkylamino of C1-C6, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , - R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2NR ³¹ R ³² ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, heterobridge Ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

L2a, L2b, L2c, L2d, L2e, L2f, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' are independently selected from none, O, S, ^{NR37; R37} ^is selected from hydrogen, Substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 Aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl , substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy , substituted or unsubstituted C1-C6 linear or branched alkylamino groups, substituted or unsubstituted C1-C6 cycloalkylamino groups, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; Heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁷ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 forms a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituent is independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain Alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino group , C1-C6 cycloalkylamino group, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 Wherein any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R ⁹ COR ¹⁰ , -R ¹¹ OCOR ¹² , -R ¹³ COOR ¹⁴ , -R ¹⁵ NR ¹⁶ COR ¹⁷ , -R ¹⁸ CONR ¹⁹ R ²⁰ , -R ²¹ SO2R ²² , -R ²³ OSO2R ²⁴ , -R ²⁵ SO2OR ²⁶ , -R ²⁷ NR ²⁸ SO2R ²⁹ , -R ³⁰ SO2 NR ³¹ R ³² ,

C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, heterobridge Cyclic, heterospiro, and aromatic heterocycles contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

In a certain aspect, the compound of general formula (I'), its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,

in,

The structures of the compounds are as (II') and (III'):

V is selected from C, N;

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

Ring A is independently selected from 0-4 R ⁷ substituted:

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterocyclic group Bridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1- C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano group, hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 ring Alkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 Heterocyclyl, C3-C10 heterobridged ring, C3-C10 heterospirocyclyl, C5-10 aromatic ring, C5-10 aromatic heterocycle; Spirocyclyl, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Its preferred fragment is:

Wherein, the definitions of R ³⁸ and R ³⁹ are as described for R ² .

In a certain scheme,

Wherein, the structures of the compounds are as (IV') and (V'):

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ⁴ , R ⁵ , R ⁶ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged cyclic group , substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain Or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1- C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1- C6 cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl , amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy , C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic , C3-C10 heterobridged cyclyl, C3-C10 heterospirocyclyl, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclyl, heterobridged, heterospirocyclyl , the aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from 0-4 R ⁷ substituted:

R ⁷ is selected from:

Its preferred fragment is:

Wherein, the definitions of R ³⁸ and R ³⁹ are as described for R ² .

In the present invention, each of said halogens may independently be fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.

In the present invention, the C1-C6 alkyl group in each of the substituted or unsubstituted C1-C6 straight or branched chain alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including the various isomers of hexyl); such as methyl, ethyl or propyl.

In the present invention, the 3-10-membered cycloalkyl group in each of the substituted or unsubstituted 3-10-membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl ,

In the present invention, C1-C6 cycloalkyl in each of the substituted or unsubstituted C1-C6 linear or branched cycloalkyl, C1-C6 in C1-C6 cycloalkylamino Cycloalkyl, C1-C6 cycloalkyl in substituted or unsubstituted C1-C6 cycloalkoxy, C1-C6 cycloalkyl in C1-C6 cycloalkanoyl may independently be cyclopropyl , cyclobutyl, cyclopentyl, cyclobutyl.

In the present invention, the 4-10-membered heterocyclic group in each of the substituted or unsubstituted 4-10-membered heterocyclic groups can be independently

E.g

In the present invention, the C3-C10 heterocyclic group in each of the substituted or unsubstituted C3-C10 heterocyclic groups may be independently

E.g

In the present invention, the C3-C10 heterospirocyclyl group in each of the substituted or unsubstituted C3-C10 heterospirocyclyl groups may independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 6-azaspiro[3.4] Octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro Cyclo[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example

In the present invention, the C5-C12 heterobridged ring group in each of the substituted or unsubstituted C5-C12 heterobridged ring groups is independently octahydrocyclopenta[C]pyrrolyl, octahydro Pyrro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3 - azabicyclo[3.2.1]octyl; for example

In the present invention, C5 in each of said substituted or unsubstituted substituted 6-10-membered aromatic rings, 6-10-membered aromatic rings, substituted or unsubstituted substituted C5-10 aromatic rings The aromatic ring of -10 is independently a benzene ring or a naphthalene ring.

In the present invention, the 5-10-membered aromatic heterocycle in each of the substituted or unsubstituted substituted 5-10-membered aromatic heterocycles can be independently

In the present invention, the C5-10 aromatic heterocycle in each of the substituted or unsubstituted substituted C5-10 aromatic heterocycles may be independently

In a certain scheme, the compound represented by the formula I or formula I' is selected from:

In a certain embodiment, the pharmaceutically acceptable salt of the present invention is a salt formed by the direct reaction of the compound of general formula (I) or (I') with inorganic acid, organic acid and inorganic base.

the second aspect

The present invention provides an aromatic compound represented by formula E, its enantiomer, diastereomer, racemate and mixture or a pharmaceutically acceptable salt thereof,

in,

Indicates a single bond or a double bond;

R ^a is halogen, H, OH, O= or C1-C6 linear or branched alkyl-O-;

L is selected from a linking bond or a non-hydrogen linking group;

The definitions of V, U, W, X, Y, Z, Q, ^Re are as described above. V, U, W, X, Y, Z, Q, as defined in any scheme of ^Re .

In some preferred embodiments of the present invention, some groups in the compound represented by the formula E are defined as follows (the unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain scheme”), where,

Indicates a single bond or a double bond;

R ^a is halogen, H, OH, O=(when it is substituted for geminal hydrogen) or C1-C6 straight or branched alkyl-O-;

L is selected from a linking bond or a non-hydrogen linking group;

Q is selected from CR ^2a , N;

V is selected from C, N;

U is selected from CR ² , NR ² (eg N);

W is selected from CR ³ , N;

X is selected from C (when attached to L), ^CR4 , N;

Y is selected from C (when attached to L), ^CR5 , N;

Z is selected from C (when attached to L), CR6, N ^;

R ² is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted Saturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, hydroxyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10-membered cycloalkoxy, substituted or unsubstituted amino group; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, amino, C1-C6 linear or branched alkoxy , 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 3-10-membered cycloalkyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

^Re , R ^2a , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5- 10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group , substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy base, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkane Acyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2-C6 Linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino group, C1-C6 straight or branched chain alkanoyl group, 3-10 membered cycloalkanoyl group, 4-10 membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterocyclic group Spirocyclic group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1- 4 heteroatoms selected from oxygen, sulfur and nitrogen. In some preferred embodiments of the present invention, some groups in the compound represented by the formula E are defined as follows (unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain "In the scheme"), the compound shown in the formula I is shown in the formula Ea or the formula Eb,

Another example is shown in formula Ec, formula Ed or Ee,

In one embodiment, when R ^a is halo, it can be bromo or chloro.

In a certain scheme, when R ^a is C1-C6 linear or branched alkyl-O-, the C1-C6 linear or branched alkyl can be methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In a certain scheme, R ² is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, wherein the substituents are independently selected from deuterium, halogen, hydroxyl, amino, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, 3- 10-membered cycloalkyl, 4-10-membered heterocyclyl; the number of the substitution is 1, 2 or 3;

For example R ² is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl base, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetane base, 2-azetidinyl, 3-azetidinyl.

In a certain scheme,

wherein U is selected from CR ^2a , N; X is selected from C, CR ⁴ , N; Y is selected from C, CR ⁵ , N; Z is selected from C, CR ⁶ , N; is N; one or both of U, V, and W are N.

In a certain scheme, R ^e , R ^2a , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain Alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy; for example H or methyl.

In a certain scheme,

for

E.g

Another example

In a certain scheme,

for

E.g

In a certain scheme,

Selected from:

In the present invention, when the L is a non-hydrogen linking group, it can be a conventional linking group in PROTAC in the field.

In a certain scheme, when L is a non-hydrogen linking group, L is as defined in any one of the schemes for L in compounds of Formula I or Formula I' as previously described.

In one embodiment, L is selected from a non-hydrogen linking group; the general formula for the linking group is expressed as:

in,

L1 is selected from none,

La, Lb, Lc, Ld, Le, Lf, Lg, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from None, O, S, NR ⁸ (-N( R ⁸ )-), COR ⁹ (-C(=O)-R ⁹ -), -SO2R ¹⁰ ; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle ( base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted Substituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Unsubstituted C1-C6 linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , - R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5 -10-membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ can form with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 through C, N, O, S, respectively. Substituted or unsubstituted 3-10 membered rings; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino , -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or Unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1- C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3 -10-membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10-membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Member cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl , 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocycle (base) ; Said heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^d' , L ^i' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L25 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 , R ^L133 , R ^L134 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, Substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted Substituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2-C6 straight Chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 Linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5 -10-membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano , hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered ring Alkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ .

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from oxo ( O=), deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched Alkoxy, 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , - R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocyclic ring (base); Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' independently selected from in none, O, S, NR ³⁹ (-N(R ³⁹ )-), COR ⁴⁰ (-C(=O)-R ⁴⁰ -), -SO2R ⁴¹ (-SO2-R ⁴¹ -); L ^2b' , L ^2c' , L ^2d' , L ^2i' are selected from N, CR ⁴⁴ ; R ³⁹ , R ⁴⁰ , R ⁴¹ , R ⁴⁴ , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , ^RL214 , ^RL223 , ^{RL224, RL225, RL226} ^, ^RL227 , ^RL228 , ^RL229 , ^RL230 , ^RL241 , ^RL242 , ^RL243 , ^RL244 , ^RL245 , ^RL246 ^are independently selected from hydrogen, Deuterium, halogen, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear Chain or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 Membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5 -10-membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁹ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, Halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3- 10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , - R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from deuterium , halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocyclic ring (base); Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; and in L1, B ring, L2 and C ring , at least one is not none.

In a certain aspect, two, three or four of the L1, B ring, L2 and C rings are not none.

In one scheme, L is

Wherein, L1 is selected from none,

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, NR ⁸ , COR ⁹ , -SO2R ¹⁰ ; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , - R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ can be respectively combined with R ^L111 , R ^L112 , ^{RL113 , RL114 , RL123} ^, ^RL124 ^{, RL125} ^, ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 form substituted or unsubstituted 3-10-membered through C, N, O, S ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight Chain or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered Heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group , heterospirocyclyl, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , RL118, ^RL119 , ^RL120 , ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 ^{, RL132} ^are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkane group, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted Substituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or Unsubstituted 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1- C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

L2 is selected from none,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁷ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1 -C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2 NR ³³ R ³⁴ ,

Its fragment is: (connected to T on the left)

or its single cis-trans isomer or a mixture thereof (when cis-trans isomer exists);

E.g

In a certain scheme, the compound of formula E or a pharmaceutically acceptable salt thereof is selected from the following structures:

the third aspect

The present invention provides a ligand of a ubiquitin ligase connected to a ligand-linker targeting a degraded protein as shown in formula E3,

Wherein, the definitions of Q, U, V, W, X, Y, Z and ^Re are as described above. The aromatic compounds represented by formula E, their enantiomers, diastereomers and racemates and Q, U, V, W, X, Y, Z and ^Re in a mixture or a pharmaceutically acceptable salt thereof are as defined.

The present invention provides a ligand of ubiquitin ligase, which contains the structure shown in formula E3,

The ligand of the ubiquitin ligase is connected with the linker, and further connected with the target degradation protein ligand.

In one scheme, its 1-position is linked to a linker,

Fourth aspect

The present invention provides a linker-ubiquitin ligase ligand that is linked to a ligand targeting degraded proteins as shown in formula E2,

Wherein, the definitions of L, Q, U, V, W, X, Y, Z and ^Re are as described above. The aromatic compounds represented by formula E, their enantiomers, diastereomers, L, Q, U, V, W, X, Y, Z and R ^e are as defined in the convolved forms and mixtures or pharmaceutically acceptable salts thereof.

The present invention provides a linker-ubiquitin ligase ligand, which contains the structure shown in formula E2,

The linker-ubiquitin ligase ligand is connected with the target degradation protein ligand through the linker.

In a certain scheme, its 1-position is linked to a ligand targeting degradation proteins,

Fifth aspect

The present invention provides an aromatic compound represented by formula E as described above, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, as described above The ligand of the ubiquitin ligase (as shown in formula E3 linked to a ligand-targeted degradation protein)-linker, or as described above (as shown in formula E2 linked to a ligand targeted to degraded protein) ) use of a ligand of a linker-ubiquitin ligase for the preparation of ligand-drug conjugates; wherein, the E3 fragment shown below can be used as a (recruitment) ligand for E3 ubiquitin ligase,

Said (recruiting) ligand for E3 ubiquitin ligase can bind to Cereblon (CRBN) ligase.

Wherein, the ligand-drug conjugate may be a protein-targeted degradation chimera (PROTAC) or an antibody-drug conjugate (ADC).

Sixth aspect

The present invention provides an aromatic compound (PROTAC compound) represented by formula X, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,

Wherein, T is the ligand group targeting degradation protein;

The definitions of L, Q, U, V, W, X, Y, Z and ^Re are as defined by L, Q, U, V, W, X, Y, Z and ^Re in the aromatic compound represented by formula Y above described.

In some preferred embodiments of the present invention, some groups in the compound represented by the formula X are defined as follows (unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain "In the scheme"), the compound shown in the formula X is shown in the formula Xa or the formula Xb,

Another example is shown in formula Xc, formula Xd or formula Xe,

In one aspect, the T is selected from the group consisting of:

The MAT2A targeting ligand group can be:

The SOS1 targeting ligand group can be:

The DGKα targeting ligand group can be:

SIK2 and SIK3 targeting ligand groups can be:

The KRAS G12D targeting ligand group can be:

The POLθ targeting ligand group can be:

The Cbl-b targeting ligand group can be:

PARG targeting ligand groups can be:

The DNA-PK targeting ligand group can be:

The ATR targeting ligand group can be:

The NMT targeting ligand group can be:

The STAT3 targeting ligand group can be:

In a certain scheme, the ligand group T targeting the degraded protein is

Its definition is as described in any one of the preceding formula I or formula I',

For example, V is selected from C, N;

Ring A is independently selected from: 5-10-membered aromatic heterocycle, or 5-6-membered aromatic heterocycle-5-6-membered aromatic heterocycle substituted by 0-4 R ⁷ ; the aromatic heterocycle (base) contains 1- 4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁷ are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon groups , C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 Linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10-membered Aromatic ring, 5-10-membered aromatic heterocycle, 3-10-membered cycloalkyl, C1-C6 straight or branched chain alkyl-C(=O)-, 3-10-membered cycloalkyl-C (=O)-; Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.

In a certain scheme, the ligand group T targeting the degraded protein is

Wherein, R ¹ is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, 3-10 membered cycloalkyl, wherein said substituent is independently selected from halogen, Hydroxyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy; the number of substitutions is 1, 2 or 3;

For example ^R1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoro Methyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl; eg _-CF2 .

In a certain scheme, the ligand group T targeting the degraded protein is

in,

for

In a certain scheme, the ligand group T targeting the degraded protein is

Wherein, the A ring is independently selected from 0-4 R ⁷ substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;

For example, ring A is independently selected from 0-4 R ⁷ substituted:

E.g

In one aspect, ring A is independently selected from:

In a certain scheme, R ⁷ is selected from: substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospiro Cyclic, substituted or unsubstituted C1-C6 straight or branched chain alkylamino;

The substituents can be independently selected from halogen, C1-C6 straight or branched chain alkyl, 4-10 membered heterocyclic group, substituted or unsubstituted 3-10 membered cycloalkyl, C1-C6 straight chain Or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-.

In a certain scheme, R ⁷ is selected from:

E.g,

In a certain scheme,

for

In one aspect, ring A is selected from:

In a certain scheme, the ligand group T targeting the degraded protein is

, it is the IRAK4 targeting ligand group.

In a certain scheme, the targeted degradation protein is selected from the group consisting of SOS1, SIK2, SIK3, IRAK4, MAT2A, HPK1, menin, MLL, Cb1-b, POLθ, DNA-PK, STAT3, PARG, KIT, EPHA2, PDE4D, SRC, BRAF, KYN, ITK, PARP1, EPHB2, BLK, IGF1R, TGFBR1, AKT2, AKT1, PTK2, MAPK1, MAPK14, MCL1, BRD3, BRD4, AKT3, PAK4, MAPKAPK2, TNK2, SIRT2, DAPK1, ABL2, PRKAA2, KAT2A, PBRM1, EIF2AK2, MAP3K7, MAPT, RIPK1, IRAK1, MAP4K1, MARK4, BRD9, RIPK2, LIMK1, STK38, TRIM24, SMARCA4, PRKAA1, TBK1, KRAS, SMARCA2, PCNA, BRD7, SUZ12, IKZF1, HTT, SNCA, SLC9A1, FER, MAP4K2, DLG4, IKZF3, SMAD3, PDE4A, HMGCR, ABL1, RARA, FLT3, RARGFLT1, EZH2, EPHA1, AURKB, PLK4, PLK1, WEE1, CHEK1, CDC7, MDM2, MAPK6, BUB1, ESRRA, BCL6, MAPK12, CRABP2, HIPK1, ADRM1, CDC20, BUB1B, CD274, PDCD1, ERBB2, EPHA3, PIK3CG, MAP2K1, LCK, MAP2K2, PDE6D, GSK3B, PRKCI, FKBP1A, DHODH, PIK3CA, PDE4B, FYN, TYK2, PDK1, PDK2, PDK3, YES1, GSK3A, CSNK2A1, PTK2B, MAPK10, MAPK9, MAPK8, METAP2, BRD, 2, MAPK3, MAPK3K11, RPS6KB1, CSK, MERTK, STK17B, CSNK2A2, RPS6KA1, MAPK13, GAK, CLK1, STK4, EIF4E, STK10, LRRK2, TAOK3, MARK2, CSNK1D, AAK1, IRAK3, CAMKK1, EED, CSNK1A1, NEK1, BMP2K, MAPK7, ULK1, RPS6KA3, PTPN11, LIMK2, CSNK1E, EIF2AK4, MAP2K5, MAP4K5, SNRK, EEF2K, SGK3, AHR, NEK4, NEK9, CIT, LATS1 , MINK1, RPS6KA4, NEK3, MAST3, STK32C, EPHB4, PARP2, PTK6, PARP3, BRDT, MAPKAPK5, MAPKAPK5, MAP3K1, TTK, PIM2, PKMYT1, MKNK2, KAT2B, NEK2, HASPIN, PIR, CYP1B1, ERN1, MELK, COQ8A , RIOK2, RPS6KA6, MAP3K20, MAPKAPK3, ULK3, MAP3K21, COQ8B, TNK1, BMPR1A, STK17A, TESK2, NLK, STK35, PKN3, STK33, SBK1, SLC9A2, CSNK2A3, TACC3, GSPT1, SLC9A7, RPS6KC1, TBCK, CRABP1, BCKDK , TRPM7, TRIB3, UHMK1, PDIK1L, STK40, SLC9A4, EPHB3, MAP3K12, DDR2, RARB, PDE4C, IDO1, SLC9B1, PEAG1, TOP1, TOP2A, CXCR4, ERBB4, HCK, SYK, ACLY, IMPDH2, TOP2B, KEAP1, NR3C1 , DNMT1, TXNRD1, PDGFRA, TUBB, TUBB2B, GABRA5, EPHB1, KCNQ2, GRIK2, CALM1, DNMT3A, KIF5B, POLD1, CUL4A, TUBB2A, PDGFRB, FGR, PRKCG, SCN3A, BACE1, HSP90AA1, HSP90AB1, PDPK1, BIRC2, CHEK2 , MAP3K5, CASP1, NAE1, PIK3R1, IKBKB, PSMA1, ITGB1, PRKDC, PIK3R2, FGF2, ZAP70, PIP4K2B, GAPDH, FASN, PKM, VCP, KDM1A, TAB1, EP300, VRK1, RPS6KA5, UBA2, LDHA, TKT, HPRT1 , KDM2A, EHMT1, CAMK1D, WDR5, EHMT2, RAC1, OGT, NCOA1, PHGDH, ARHGDIA, RBBP4, BPTF, KAT5, NOTCH1, PPIA, FKBP4, CREBBP, POLB, APEX1, CCNT1, EIF4A1, USP7, CTNNB1, TXN, DDX3X , NLRP3TNKS, PAK3, PKN1, CISD1, WNK1, BRD1, XIAP, PRDX1, KMT2A, KDM5C, RPA1, CAMK1, EIF4A3, TAF1, ALKBH3 , MAP3K2, RELA, NCOR2, PRPF4B, RPS3, RPSA, RPS27A, RPS20, RPL18, RPS5, RPL6, RPLP0, RPL3, RPL18A, RPL28, RPL19, RPL34, RPS13, RPL14, RPS15, RPL5, BPS10, RPL35, RPS6, RPS24 , RPS2, RPL11, RPS8, RPL32, RPS3A, RPL10, RPL7A, RPL30, RPL8, RPL26, RPS14, RPL13, RPS9, RPS21, RPS7, RPL38, RPL4, RPL15, RPS17, RPS23, RPL14, RPL12, RPS4X, RPL23A, RPL10A , RPS18, SLC7A5, ORAI1PI4K2A, SUMO1, HSPA8, HSPD1, CSNK2B, PPP2CA, FSCN1, BID, DCUN1D1, USP28, TP53BP1, KDM5B, KDM5A, BAZ2A, UBE2I, SPIN1, TDP2, RBBP5, PRMT1, MLLT1, SETDB1, ARNT, SNRNP200 , WRN, ATAD2, SQSTM1, DPY30, JMJD1C, MDM4, L3MBTL3, LDLR, GLUL, HRAS, APOBEC3G, TSG101, LRP6, ENO1, ANXA2, SOD1, KAT6A, CBS, RUVBL1, UHRF1, HSPA5, SQLE, NEDD4, RBBP7, UBE2N , NRAS, PTEN, RHOA, RNF31, PIN4, TPI1, PPIG, NCOA2, FOXO1, PSIP1, MACROD2, SETD2, NFKBIA, PLA2G4A, ICAM1, ACVR1B, CYBB, STAMBP, NFKB1, PAK2, ITPR1, ELAVL1, NFKB2, STAT1, RIPK3 , STAT5A, BRSK2, ERCC4, NPM1, IKBKG, PBK, CD22, APC, PLCG1, ING2, ERCC1, KDM2B, ETV6, CBX4, USP25, HSF1, TRIM33, HNRNPA1, TERF2, PTBP1, NR2C2, NOTCH2, USP8, RGS12, ATF1 , PPM1B, PDCD4, LMNA, MITF, ADCY3, EEF1A1, MYH9, BCL3, XRCC6, USP10, MAGI3, DVL1, VDAC2, MDH1, CBX5, CBX1, BRD8, TSNAX, CREB 1. RBCK1, UBA1, MACROD1, PELP1, BAP1, TERF2IP, LARP7, UBA7, SUMO2, SUMO3, GICYF2, S100A10, GRIK3, TLR8, DYRK2, NOS1, WNK3, TLR2, BCL2L11, SLC11A2, ABCB11, ITGAL, CA12, PDE2A, EPHA1, PRKCA, CA2, EPHA4, ACE, RAF1, GLA, MAOB, AKR1B1, GSR, UMPS, THRA, GART, FDPS, ADH5, RXRB, DHFR, PDE10A, IDH1, ITGB2, COMT, PRKCQ, IMPDH1, TUBB3, TUBA1A, ADA, GABRG2, GABBR2, GABRB2, GABRB3, GABBR1, PRKCE, SIGMAR1, MTOR, SLC29A1KCNJ11, GAA, PRKCH, PIK3CD, MAOA, SOAT1, BCR, PSMB5, XPO1, MALT1, IDH2, RRM1, NDUFA10, EPHA5, TUBB4A, TUBB1, TUBB6, TUBA4A, TUBA1C, CACNB1, ATP1A2, ATP1A3, GRIA1, GABRB1, ATP1A1, KCNQ5, PRKCD, CACNA1H, GRIA4, KCNA3, S1PR3, NISCH, PRKCB, TLR7, CACNA18, CACNA2D2, CPT2, FAAH, UGCG, PDE1A, HPD, CA5B, CA5A, ANO1, DHCR24, CCDC6, EML4, KCNA2, KCNB2, PLA2G2A, MIF, GBA, ONSR, GSTP1, PNP, FDFT1, CASP8, CASP9, CASP6, CASP7, CASP3, ERAP1, UBA3, PSEN1, FNTA, METAP1, CASP2, ITGA4, ABCB1, NTSR1, GRM3, LNPEP, APH1A, NCSTN, PSMB1, PSMA2, PSMA7, PSMB7, PSMA5, PSMA4, PSMA3, PSMA6, PSMB2, EGLN1, PSMB6, PSMB4, PSMB8, PSMB9, PSMB10, FNTB, PSMB3, ERAP2, DNPEP, STS, SELL, CCR1, PIK3CB, PORCN, P4HTM, ATR, CASP10, NPEPPS, RNPEP, LAP3, DPYD, XPNPEP1, NAMPT, PRKACA, PSMD14, AR AF, PRKACB, ITGAV, TGM2, ACE2, PAK1, CAPN1, CDC42, NMT1, CAMK2D, AKR1B10, P4HB, CDC42BPB, CAMK2G, PTP4A1, G6PD, LSS, ALB, ECE1, CTSD, CTSB, ILK, MGLL, CASK, ADAM17, PYGL, ATIC, HSD17B10, SRPK1, LTA4H, STK16, ADK, GRK6, ACVR1, CES1, CSNK1G3, CAMK2A, BCAT1, MAP2K4, ACACB, MTAP, AHCY, STK24, GALK1, MAP2K6, DCPS, SAE1, CARM1, CAMK4, TNIK, DCK, PHKG2, DYRK1A, CBR1, DAPK3, FEN1, OXSR1, CLK3, UPP1, AKR1C1, AKR1C3, CD38, SORT1, GALNT2, LGALS1, HK2, HK1, HMOX1, PARP14, GRB2, HMOX2, DDAH1, PARP12, OAT, SIRT6, PGK1, KAT8, SPR, CTH, SIRT5, GSTO1, PFKFB3, CTBP2, PARP10, SMYD3, SULT1A1, AKR1C4, GSTM2, STRADA, BMPR2, PIK3C2A, PTPN1, IDE, CAPNS1, GLO1, UCHL1, NPC1, FES, CSNK1G1, SLK, MAP2K7, PIK3C3, HAO1, PASK, STK25, KYNU, DUT, PTPN22, NEK7, NNMT, NRP1, RPS27, DDR1, LPL, ABCC1, ASIC1, SLC2A1, PTPRS, ABCG2, SLC1A3, ALC1A1, TRPM2, GRM1, MLKL, RAB7A, AHCYL1, NAAA, CAMK2B, NT5E, CTSL, HSPA1A, FABP5, CTSC, ACVR2A, MMP14, HSP90B1, GLB1, PTPRF, ST14, PKN2, AGR1, PGAM1, PPP1CA, PTP4A2, MAST1, PI4KB, VRK2, SCD, MUDT1, CSNK1G2, EBP, EIF2AK3, ATP2A2, MAN1B1, CDKL5, MAP4K4, DPP8, MKNK1, PREP, FKBP5, SIRT1, STK3, LIG1, DUSP3, CAMKK2, PRKAB1, MTR, UCHL3, ESRRB, RIOK, TRAP1, PIN1, A LDH1A2, PAK6, AOX1, DPP9, ACP1, PTPN7, TLK2, SMG1, YWHAZ, ALDH1A1, PHF8, PRKAG1, PEMT3, SF3B3, AKT1S1, CHUK, RPL36A, RPL31, RPL19, RPL16, RPL22, RPL12, RPL25, RPL21, RPL23, RPL36, RPS4Y1, RPL27, RPS15A, RPS11, RPL13A, RPL37, RPL7, RPL29, RPL27A, RPL35A, RPS26, RPL37A, RPS29, RPS28, RPL17, FAU, SLC2A3, ASAH1, BTN3A1, NMT2, PI4KA, GNG2, GNA11, PRMT8, LYPLA1, LGALS3, UBE2D3, S100A4, LGALS9, PIP4K2A, LGMN, GNB1, HINT1, FTO, BRPF1, ST6GAL1, INPPL1, PI4K2B, PARP16, HEXA, SGPL1, MGAT2, LGALS8, ASH2L, SARM1, LYPLA2, ASNS, PABPC1, PRMT5, DNPH1, WDR48, WDR77, ATAD2B, COPS5, PFKFB2, KDM4B, PRKAB2, MEN1, PMM2, RPTOR, MLST8, DTYMK, PTPN9, SHMT2, PARG, GLS, APAF1, KSR2, SORD, SMS, GALE, PGD, HNMT, QDPR, GSTK1, SRM, FARS2, GNAI3, CLTC, RHOC, DNM1, GALNT10, MTHFD1, RAB2A, USP5, GDA, UCK2, HIF1AN, MDH2, YWHAG, CFPT1, FN1, PLAUR, NCS1, GNAI1, HCN2, QSOX1, TLR1, USP14, KSR1, RAB9A, CCR7, PLCG2, GFER, PTPRG, FUT8, POR, RECQL, UNG, CAD, NCOA3, CTSDP1, KDM1B, TEAD1, DDO, SLC1A5, CD81, GGT1, ADIPOR1, RAP1A, RAB29, GOPC, UTRN, GNAO1, DDOST, PYGB, RABGGTB, VAV1, SDHA, QTRT1, CISD2, DHPS, PPP2R5A, PANK2, NEDD8, DOHH, UBE2M, RNASEL, SYNJ1, DUS2, CYCS, PPP1CC, HMBS, PNPO, PPIF, DP P7, MARK1, PRCP, PIP4K2C, AKR1A1, ME1, ACACA, CD74, NFATC1, RUNX1, PTPRC, CAPN2, RB1, ITGA5, ITGA2, ADAM10, DAGLB, SLC16A1, ABCC2, SCARB1, DAGLA, SLC47A1, PIK3C2B, GBA2, NCEH1, WNK2, LIPE, SLC27A1, PTPRA, PTPN2, ITGB5, CTSH, MAN2B1, ITPR2, ITPR3, ABHD12, CTSZ, SL6A12, SL6A11, KCNN3, SLC27A4, PTPN6, AMPD3, PLEC, PLD1, PAM, PRKD2, TYRO3, RYR2, PIP5K1C, LIPA, PPIB, ATP2A3, CPT1A, ICMT, HSD17B7, ELOVL6, DHCR7, ATP2A1, RIOK3, HSPB1, PTPN12, PLAA, MPI, MATK, UBA6, MAP2K3, RPS6KA2, MAP3K4, PARP4, EIF4H, TESK1, MLX, NEK6, ADH1B1, ATM, CDYL, TAOK1, STAT6, MGMT, PPID, STAT5B, TXNRD2, TXNRD3, STK39, STK38L, CDC42BPA, ATG4B, DCLK2, TUBAL3, MAP3K3, PPME1, RPLP1, GSDMD, C9, HMGB1, DAB2IP, PHLPP1, PHKA2, PHKA1, PHKB, EWSR1, SLC16A3, PTPRE, NEU1, PCSK6, ANTXR2, STIM1, DNM2, SDHB, MAPKAP1, PTGES2, TMEM97, SPPL2A, SLC7A11, ABHD6, DGKA, NAPRT, BAX, SPTLC1, SPTLC2, MGAT1, EPHX1, FADS1, ABHD5, CBFB, POLR1A, MPG, GYS1, PRKAG2, ASF1A, MED23, PFKFB4, KDM3A, USP9X, MAX, MBD2, CBX8, FLI1, ATRIP, RICTOR, UBLCP1, DCTPP1, TCF4, CNOT7, OGFRL1, MVD, IL6ST, DOCK2, C3, PPM1A, SHC1DVL2, NPR3, GSTM1, PPP3CA, SLC12A2, ABCC3, ABCC4, GGH, HCN3, ADCY1, ADCY5, HKDC1, PPT1, PRNP, CXCR5 , SMPD2, SLC6A15, MANBA, AGPAT2, ABHD16A, GCLC, HAGH, SENP1, DNAJA1, SCP2, AMPD2, ERCC5, SENP7, NADK, RBBP9, CD2, CD44, CD47, CD63, SLC27A2, PLEKHA1, ITGA3, SPPL2B, PLTP, SLC20A2 , ADCY6, IGF2R, EZR, GNAQ, INPP5A, CRACR2A, LANCL2, SMPD3, EHD1, PDIA6, CHN2, CDH2, TFPI, CD58, SLC2A8, PTPRM, STIM2, ADCY7, SLC20A1, ITGA1, RABGGTA, MAP1B, PAFAH1B2, RIN1, PLCD1 , RGS19, PNPLA2, ST3GAL3, GALNT1, ATP6V1B2, ATP6AP1, PHLPP2, GNPAT, PPP3CB, SLC25A20, ELOVL1, MAN2A1, SLC33A1, GAB1, ARHGEF12, MAP2, MBTD1, PNKP, NLRP1, TXN2, EEF1A2, GOT1, PRMT7, MYH10, TPP2 , EYA3, SSU72, AMDHD2, CLPX, MECP2, KPNA2, PSMG1, CBX6, PPP2R2A, UBE2V1, PPIC, PGK2.

E.g

In the present invention, the C3-C10 heterospirocyclyl group in each of the substituted or unsubstituted C3-C10 heterospirocyclyl groups may independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 6-azaspiro[3.4] Octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro Cyclo[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example

In certain preferred embodiments of the present invention, the aromatic compound represented by formula X, its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof Some of the groups are defined as follows (the unmentioned groups are described in any scheme of this application, hereinafter referred to as "in a certain scheme"), and the compound represented by the formula X is as described in any of the previous schemes. Said compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof or as described in any of the preceding schemes, such as formula I' The represented compounds, their enantiomers, diastereomers, racemates and mixtures or their pharmaceutically acceptable salts are shown.

In a certain scheme, in the compound represented by the formula X,

Q is selected from CR ^2a , N;

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

R ² is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, mono Fluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetanyl, 2 - azetidine, 3-azetidine;

^Re , R ^2a , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5-10 membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkane Oxy group, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched Alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched chain alkyl, C2-C6 straight Chain or branched unsaturated hydrocarbon group, C1-C6 straight or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched alkylamino, 3-10 membered Cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospiro Ring group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocycle (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

T is a ligand targeting degraded proteins.

In a certain scheme, in the compound represented by the formula X,

Q is selected from CR ^2a , N;

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N

X is selected from CR ⁴ , N;

Y is selected from CR ⁵ , N;

Z is selected from CR ⁶ , N;

^Re , R ^2a , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5-10 membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkane Oxy group, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched Alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2-C6 straight Chain or branched unsaturated hydrocarbon group, C1-C6 straight-chain or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 straight-chain or branched alkylamino, 3-10-membered Cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospiro Ring group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocycle (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L1 is selected from none,

La, Lb, Lc, Ld, Le, L ^a' , Le ^' , L ^f' , L ^g' , L ^h' are independently selected from none, O, S, NR ⁸ , COR ⁹ , -SO2R ¹⁰ ; R ⁸ is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or Unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1- C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3 -10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , - R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10 A membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ⁸ ^It ^can ^form ^substituted ^or ^_ ^_ ^_ ^_ ^_ ^_ ^_ Unsubstituted 3-10-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group , C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , - R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ are independently selected from none, hydrogen, halogen, cyano, hydroxyl , amine group, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear Chain or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 A membered heterocyclic group, a C5-C12 heterobridged ring group, a C3-C10 heterospirocyclic group, a 6-10-membered aromatic ring (base), a 5-10-membered aromatic heterocyclic ring (base); the described Heterocyclic group, heterobridged ring group, heterospirocyclic group, aromatic heterocyclic group (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L ^b' , L ^c' , L ^d' , ^Li' are independently selected from N, CR ³⁸ ;

^R38 , R ^L11 , R ^L12 , R ^L13 , R ^L14 , R ^L15 , R ^L16 , R ^L17 , R ^L18 , R ^L19 , R ^L110 , R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , ^RL117 , ^RL118 , ^RL119 , RL120, ^RL121 , ^RL122 , ^RL123 , ^RL124 , ^RL25 , ^RL126 , ^RL127 , ^RL128 , ^RL129 , ^RL130 , ^RL131 , ^RL132 From hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight chain or branched Chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, Substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino , substituted or unsubstituted 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10 A membered aromatic heterocyclic ring (base); the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁸ can be combined with R ^L111 , R ^L112 , R ^L113 , R ^L114 , R ^L115 , R ^L116 , R ^L117 , R ^L118 , R ^L119 , R ^L120 , R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 , R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amine base, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , - R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L111 , R ^L112 , R ^L113 , R ^L114 , RL115, RL116, RL117, RL118, RL119, RL120 any two groups can form a substituted or unsubstituted 3-12-membered ring through C, N, O, S; The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L121 , R ^L122 , R ^L123 , R ^L124 , R ^L125 , R ^L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L127 , R ^L128 , R ^L129 , R ^L130 , R ^L131 , R ^L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

L2 is selected from none,

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2i, L2a', ^L2e ^' , ^L2f ^' , L2g', L2h ^' are independently selected from None, O, S, NR ³⁹ , COR ⁴⁰ , -SO2R ⁴¹ ; R ³⁹ , R ⁴⁰ , R ⁴¹ are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted Or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain Or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear Chain or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (group), 5-10 A membered aromatic heterocyclic ring (base); the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R ³⁷ can be respectively combined with R ^L21 , R ^L22 , R ^L23 , R ^L24 , R ^L25 , R ^L26 , R ^L27 , R ^L28 , R ^L29 , R ^L210 , R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L223 , R ^L224 , R ^L225 , R ^L226 , R ^L227 , R ^L228 , R ^L229 , R ^L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L211 , R ^L212 , R ^L213 , R ^L214 , R ^L215 , R ^L216 , R ^L217 , R ^L218 , R ^L219 , R ^L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L221 , R ^L222 , R ^L223 , R ^L224 , R ^L225 , R ^L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

R ^L227 , R ^L228 , R ^L229 , R ^L230 , R ^L231 , R ^L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R ¹¹ COR ¹² , -R ¹³ OCOR ¹⁴ , -R ¹⁵ COOR ¹⁶ , -R ¹⁷ NR ¹⁸ COR ¹⁹ , -R ²⁰ CONR ²¹ R ²² , -R ²³ SO2R ²⁴ , -R ²⁵ OSO2R ²⁶ , -R ²⁷ SO2OR ²⁸ , -R ²⁹ NR ³⁰ SO2R ³¹ , -R ³² SO2NR ³³ R ³⁴ ,

4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring (base), 5-10-membered aromatic heterocyclic ring (base); Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring (base) contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

T is a ligand targeting degraded proteins.

In a certain scheme,

Q is selected from CR ^2a , N;

V is selected from C, N;

U is selected from CR ² , N;

W is selected from CR ³ , N;

X is selected from C, CR ⁴ , N;

Y is selected from C, CR ⁵ , N;

Z is selected from C, CR ⁶ , N;

Its snippet is:

its single cis-trans isomer or a mixture thereof;

T is a ligand targeting degraded proteins.

Seventh aspect

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of Substance B and one or more pharmaceutically acceptable carriers; the Substance B is according to any one of claims 1-5 or 8 Described compound shown in formula I, its enantiomer, diastereomer, racemate and its mixture or its pharmaceutically acceptable salt, as described in any one of claim 6-8 The compound represented by the formula I', its enantiomer, diastereomer, racemate and mixture or pharmaceutically acceptable salt thereof, as described in any one of claims 9-12 Aromatic compounds, enantiomers, diastereomers, racemates and mixtures as represented by formula E or pharmaceutically acceptable salts thereof, or as claimed in any one of claims 16-18 Aromatic compounds, enantiomers, diastereomers, racemates and mixtures as represented by formula X or pharmaceutically acceptable salts thereof. The pharmaceutical composition can be used to treat and prevent diseases related to or mediated by kinase 4 (IRAK4); the kinase 4 (IRAK4) can be related to tumor necrosis factor alpha (TNFα) and/or interleukin-1 receptor Kinase 4 (IRAK4); The tumor necrosis factor alpha (TNFα) and/or interleukin-1 receptor-associated kinase 4 (IRAK4)-related or mediated disease may be an autoimmune disease or cancer.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above general formula (I) or (I'), its enantiomers, diastereomers, external Racemates and mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutically acceptable excipients such as diluents or excipients). The pharmaceutical composition can be used for the treatment and prevention of autoimmune diseases or cancers related to or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4).

The present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), which comprises the general formula (I) or (I) ') The compounds, their enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts, pharmaceutically acceptable carriers, diluents or excipients.

Further, the pharmaceutically acceptable salt thereof accounts for 1-99 wt% of the total weight of the composition.

The present invention provides the use of a substance B in the preparation of a medicine; the substance B is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and mixtures thereof or their pharmaceutically acceptable salts, the compounds represented by the general formula E as described above, their enantiomers, diastereomers, racemates and their mixtures or Its pharmaceutically acceptable salts, or the compounds represented by the general formula X as described above, its enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts. The medicament can be used for the treatment and/or prevention of interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and tumor necrosis factor alpha (TNFα). of one or more related or mediated diseases.

The present invention provides the use of a substance C in the preparation of a medicine; the substance C is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and their mixtures or their pharmaceutically acceptable salts, or the compounds represented by the general formula X as described above, their enantiomers, diastereomers, racemates and their mixtures or a pharmaceutically acceptable salt thereof; the medicament can be used for the treatment and/or prevention of interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and Drugs for one or more related or mediated diseases in tumor necrosis factor alpha (TNFα); the drugs can be used for the treatment and/or prevention of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, Inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, T Pathological changes caused by cell activation, drugs for cardiovascular diseases, such as drugs for the treatment and/or prevention of autoimmune diseases and/or cancer or proliferative diseases.

The present invention provides the use of a substance X in the preparation of a medicine; the substance X is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and mixtures thereof or their pharmaceutically acceptable salts. The medicament can be a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

The present invention provides compounds of general formula (I) or (I'), their enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts in the preparation for treatment Use in medicaments for preventing diseases related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

The present invention provides a pharmaceutical composition containing a therapeutically effective amount of the aromatic compound, enantiomer, diastereomer, racemate and The mixture, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutically acceptable excipients such as diluents or excipients). The pharmaceutical composition can be used for the treatment and prevention of interleukin-6 (IL-6) receptor-related or mediated diseases, such as autoimmune diseases or cancer.

The present invention provides the application of a substance A in the preparation of medicine, wherein the substance A is the aromatic compound, enantiomer, diastereomer, Racemates and mixtures or pharmaceutically acceptable salts thereof. The medicament may be a medicament for treating and preventing diseases related to or mediated by interleukin-6 (IL-6) receptors.

The present invention provides a pharmaceutical composition for the treatment and prevention of interleukin-6 (IL-6) receptor-related or mediated diseases (such as autoimmune diseases or cancer), comprising the general formula E Or the compound of formula X, its enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts, pharmaceutically acceptable carriers, diluents or excipients.

The present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), comprising the compound of general formula X, its Enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carriers, diluents or excipients.

The present invention provides the use of a substance X in the preparation of a medicine; the substance X is the compound represented by the general formula X, its enantiomer, diastereomer and racemate as described above. and mixtures or pharmaceutically acceptable salts thereof. The medicament can be a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.

The present invention provides compounds of general formula X, their enantiomers, diastereomers, racemates and their mixtures or their pharmaceutically acceptable salts in preparation for the treatment and prevention of interleukin-1 receptors Use in the medicament of a disease associated or mediated by the body-associated kinase 4 (IRAK4) signaling pathway.

Further, the diseases described in any of the above schemes include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation. Diseases, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, cardiovascular diseases.

Further, the cancer or proliferative disease is selected from brain cancer, kidney cancer, liver cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, esophageal cancer, lung cancer, prostate cancer, pancreatic cancer, vaginal cancer, cervical cancer Cancer, testicular cancer, genitourinary tract cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, head and neck cancer, epidermoid cancer, large cell cancer , non-small cell lung cancer, lymphoma, Hodgkin or non-Hodgkin lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma (DLBCL), ABCDLBCL, chronic lymphocytic leukemia (CLL) , chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia WM, splenic marginal zone lymphoma, plasmacytoma or intravascular large B-cell lymphoma; epidermal hyperproliferative disease, psoriasis, benign prostatic hyperplasia, IL-1 driven disease, MyD88 driven disease.

Further, the MyD88-driven disease is selected from the group consisting of ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia.

Further, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, traumatic neurodegenerative disease, and graft-versus-host disease.

Further, the inflammatory disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, phlebitis conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic Thrombocytopenia, cutaneous acne; or another inflammatory disease resulting from an autoimmune response, selected from systemic lupus erythema, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatophytosis Myositis, chronic active hepatitis, myasthenia gravis, Stephen Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac Disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary bile cirrhosis, uveitis, Sjögren's syndrome, uveitis, keratoconjunctivitis, interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, Glomerulonephritis, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, chronic obstructive pulmonary disease, Lung disease, cystic fibrosis, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, conjunctivitis, Cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, fasciitis, fibritis, gastritis, gastroenteritis, allergic purpura, hepatitis, suppurative Hidradenitis, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps , pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, enteritis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vagina inflammation, vasculitis, vulvitis, alopecia areata, dermatitis herpetiformis, subcutaneous dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, pemphigus bullosa, pemphigus vulgaris, pemphigus phyllox, epidermone bullosa Treatment of symptoms, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis.

The compounds and derivatives described in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be based on the disclosure and context. , give their meanings that those skilled in the art can give them.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography. Stereoisomers of the compounds of the present invention may be (R)- or (S)-isomers.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives using, for example, chiral high performance liquid chromatography) ), see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3 : 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem .Res.1990, 23, 128.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

As used herein, the term "pharmaceutically acceptable" refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable adjuvant (or carrier)" includes, but is not limited to, any adjuvant, carrier, excipient, glidant approved by the relevant governmental administration as acceptable for human or livestock use , sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

As used herein, the terms "prophylactic", "preventing" and "preventing" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder;

(ii) inhibiting the disease or disorder, i.e. arresting its development;

(iii) alleviating the disease or disorder, i.e. causing the state of the disease or disorder to resolve; or

(iv) alleviating symptoms caused by the disease or disorder.

As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to at least one agent or compound sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated upon administration. amount. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.

The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

"Substitution" refers to the replacement of a hydrogen atom in a molecule by a different atom or chemical group. When the number of substituents is not specified, the substituents can be one or more; when the substitution position is not specified, the substitution can be in any position, but only if a stable or chemically feasible chemical is formed Allowed.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

When a listed substituent does not indicate through which atom it is attached to a general chemical structure (including but not specifically mentioned compounds), such substituent may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and "alkyl" is listed for the definition of a Markush group for that variable, it should be understood that the "alkyl" represents the attached alkylene group.

In some specific structures, when an alkyl group is clearly represented as a linking group, then the alkyl group represents the alkylene group to which it is attached, eg, the group "halo- _C1 _- C6alkane" C ₁ -C ₆ alkyl in "radical" is to be understood as C ₁ -C ₆ alkylene.

In addition, it should be noted that, unless clearly stated otherwise, the description method "...independently" used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other, Can be independently the same or different specific groups. In more detail, the description mode "...independently" can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same The specific options expressed by the symbols do not affect each other.

It should be understood that singular forms such as "a" used in the present invention include plural referents unless stated otherwise.

The term "one(s) or more(s)" or "one(s) or two(s) or more" means i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or More.

It can be understood by those skilled in the art that, according to the conventions used in the art, the formula used in the structural formula of the group described in this application

and

It means that the corresponding group R is connected with other fragments and groups in the compound through this site.

"Hydroxy" refers to the -OH group.

"Carbonyl" refers to a -C(=O)- group. when

When R in is carbonyl,

for

"Cyano" refers to -CN.

"Amino" refers to _-NH2 .

"Carboxyl" refers to -COOH.

"Halogen" refers to a halogen group: fluorine, chlorine, bromine or iodine.

Minimum and maximum carbon content in a hydrocarbon group are indicated by prefixes, eg, the prefix (Ca-Cb)alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C1-C6 alkyl refers to an alkyl group containing 1-6 carbon atoms.

In the present invention "alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including various identities of hexyl). isomer). Alkyl groups can also be part of other groups such as C1-C6 alkylamino groups. In this application, "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not.

In the present invention, the Ca-Cb unsaturated hydrocarbon group refers to an aliphatic hydrocarbon group containing "a" to "b" carbon atoms and containing one or ethylenic bond and one or more alkyne bonds. Unsaturated hydrocarbon groups include branched and straight chain groups. Olefinic bonds include cis double bonds and trans double bonds.

In the present invention, Ca-Cb alkoxy refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding oxygen atom.

In the present invention, the Ca-Cb alkylamino group refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding nitrogen atom.

In the present invention, Ca-Cb alkanoyl refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding acyl group.

The ab-membered cycloalkyl in the present invention refers to a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms. For example, 3-10 membered cycloalkyl, another example is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

The cycloalkyl group of Ca-Cb in the present invention refers to a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms. For example, C1-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl.

In the present invention, the a-b membered unsaturated cyclic hydrocarbon group refers to an unsaturated cyclic hydrocarbon containing "a" to "b" carbon atoms and containing one or more olefinic bonds or one or more alkyne bonds.

In the present invention, a-b membered cycloalkoxy refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms with a corresponding oxygen atom. The cycloalkoxy group of Ca-Cb refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms with a corresponding oxygen atom.

In the present invention, the a-b membered cycloalkylamino group refers to a group obtained by connecting a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms with a corresponding nitrogen atom. The cycloalkylamino group of Ca-Cb refers to a group obtained by connecting a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms to a corresponding nitrogen atom.

In the present invention, the a-b membered cycloalkanoyl group refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms with a corresponding acyl group. The cycloalkanoyl group of Ca-Cb refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms with the corresponding acyl group.

The ab-membered heterocyclic group in the present invention refers to a group composed of "a" to "b" carbons and heteroatoms in total, and the heterocyclic group contains 1-4 selected from oxygen, sulfur and nitrogen The heteroatom of Ca-Cb; the heterocyclic group of Ca-Cb refers to a group composed of a total of "a" to "b" carbons and a ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated; such as 4-10 membered heterocycloalkyl, which can be

(E.g

),

(E.g

),

(E.g

)

(E.g

),

(E.g

),

(E.g

),

(E.g

).

The ab-membered aromatic heterocycle in the present invention refers to an aromatic ring composed of "a" to "b" carbons and heteroatoms in total. The heterocyclyl group of Ca-Cb refers to an aromatic ring composed of "a" to "b" carbons in total and containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. E.g

The a-b-membered aromatic ring in the present invention refers to an aromatic ring composed of "a" to "b" carbon atoms in total, such as a benzene ring and a naphthalene ring.

In the present invention, the heterospirocyclic group of Ca-Cb refers to a group containing "a" to "b" carbon atoms, and one carbon atom is shared by two rings, and the heterospirocyclic group contains 1 -4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated non-aromatic heterospirocyclic groups; such as 4-10 membered heterospirocycloalkyl, which can be 2-azaspiro[ 3.3] Heptyl (e.g.

), 7-azaspiro[3.5]nonanyl (e.g.

), 2-azaspiro[3.5]nonanyl (e.g.

), 2,7-diazaspiro[3.5]nonanyl (e.g.

), 6-azaspiro[3.4]octyl (e.g.

), 4-oxa-7-azaspiro[2.5]octyl (e.g.

), 5-oxa-8-azaspiro[3.5]nonanyl (e.g.

), 2-oxa-6-azaspiro[3.3]heptyl (e.g.

), 2-oxa-6-azaspiro[3.4]octyl (e.g.

), 4,7-diazaspiro[2.5]octyl (e.g.

).

The heterobridged cyclic group of Ca-Cb in the present invention refers to a group containing "a" to "b" carbon atoms, and two rings share two carbon atoms or heteroatoms, and the heterobridged cyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen. Including saturated or partially unsaturated non-aromatic heterobridged ring groups; such as 4-10 membered heterobridged cycloalkyl; may be octahydrocyclopenta[C]pyrrolyl (eg

), octahydropyrro[3,4-c]pyrrolyl (e.g.

), 3-azabicyclo[3.1.0]hexyl (e.g.

), 2-oxa-5-azabicyclo[2.2.1]heptyl (e.g.

), 8-oxa-3-azabicyclo[3.2.1]octyl (e.g.

).

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive improvement effect of the present invention is that the aromatic compounds provided by the present invention can be used as E3 ligands to prepare PROTAC compounds that can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways, as well as interleukin-6 (IL-6) receptors Intermediates for inhibitors (CRBN ligand-linker compounds). The interleukin-6 (IL-6) receptor inhibitor and PROTAC compound have better activities, and provide a new choice for clinical screening and/or preparation of drugs for related diseases.

Description of drawings

Figure 1 is a comparison of the middle ear thickness effect of Test Example 11.

Figure 2 is a comparison of the effects of silver flakes in Test Example 11.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

Without special instructions in the examples, the reaction temperature is room temperature, and room temperature refers to 20-25°C. All temperatures are expressed in °C (degrees Celsius).

14±1h overnight.

High performance liquid chromatography (HPLC) measurement conditions: Shimadzu high pressure liquid chromatography (Shimadzu LC-20A). Analytical high performance liquid chromatography conditions: C18 column (5μm, 4.6x 150mm), UV detection bands are 214 and 254nm, elution conditions 0-90% acetonitrile (containing 0.03% V/VTFA) gradient washing for 30 minutes.

Reversed-phase purification was performed using a Gilson GX-281 Preparative Reversed-Phase Chromatograph or the Biotage Isolera One Rapid Purification System.

NMR measurements were carried out on a Bruker Avance III 400 nuclear magnetometer, and NMR shifts (δ) are given in units of 10-6 (ppm). The solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc., and the internal standard is tetramethylsilane (TMS).

The hydrogenation reaction needs to be evacuated to discharge the air, filled with hydrogen, then evacuated to discharge the gas, filled with hydrogen, and the operation is repeated 3 times.

The known starting materials, reagents and solvents of the present invention can be synthesized using or according to methods known in the art, or can be purchased from Shaoyuan Chemical Technology, Bailingwei Technology, Shanghai Bide Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd. etc.

In the above discussion and the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has the generally accepted meaning. MPLC is medium pressure preparative chromatography; TLC is thin layer chromatography; MeOH is methanol; EtOH is ethanol; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; Methylacetamide; EA is ethyl acetate; THF is tetrahydrofuran; DMSO is dimethyl sulfoxide; DCM is dichloromethane; DCE is dichloroethane; MTBE is methyl tert-butyl ether; tert-butyl ester; Boc is tert-butyloxycarbonyl; SEMCl is 2-(trisilyl)ethoxymethyl chloride; SEM is 2-(trisilyl)ethoxymethyl; CbzCl is benzyloxycarbonyl chloride; Cbz is Benzyloxyformyl; FmocCl is 9-fluorenyl methyl chloroformate; Fmoc is 9-fluorenylmethoxyformyl; MsCl is methanesulfonyl chloride; Ms is methanesulfonyl; TBSCl is tert-butyldimethyl chloride Silane; TBS is tert-butyldimethylsilyl chloride; TBDPSCl is tert-butyldiphenylsilyl chloride; TBDPS is tert-butyldiphenylsilyl; TBAF is tetrabutylammonium fluoride; NBS is N-bromine Succinimide; TFA is trifluoroacetic acid; DBU is 1,8-diazabicycloundec-7-ene; DIPEA is N,N-diisopropylethylamine; TEA is triethylamine ; HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; HBTU is 2-(benzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate.

Example

Synthesis of Intermediate One: ((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol

Step 1. Synthesis of cis-4-methanesulfonyloxycyclohexyl-1-carboxylic acid methyl ester

Methyl cis-4-hydroxycyclohexyl-1-carboxylate (10 g, 63.2 mmol) was dissolved in 100 mL of dichloromethane, then triethylamine (12.5 g, 123 mmol) and methanesulfonyl chloride (10.9 g) were added under ice bath , 94.8 mmol), gradually warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. cis-4-methanesulfonyloxycyclohexyl-1-carboxylic acid methyl ester (12.45 g, 83% yield) was obtained.

Step 2. Synthesis of (trans)-4-(3-formyl-1H-pyrazol-1-yl-cyclohexylcarboxylate methyl ester

Methyl cis-4-methanesulfonyloxycyclohexyl-1-carboxylate (6.22 g, 26.3 mmol) and 3-aldehyde-1H-pyrazole (1.68 g, 17.5 mmol) were dissolved in 50 mL of DMF, then Cesium carbonate (10.26 g, 31.6 mmol) was added, followed by stirring at 80°C overnight. After the reaction was completed, the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to obtain (trans)-4-(3-aldehyde-1H-pyrazol-1-yl-cyclohexylcarboxylate methyl ester 2.1 g (8.9 mmol, 51% yield). LCMS (ESI) m/z: [M+1]=237.

Step 3. Synthesis of (trans)-4-(3-difluoromethyl-1H-pyrazol-1-yl-cyclohexylcarboxylate methyl ester

Methyl (trans)-4-(3-aldehyde-1H-pyrazol-1-yl-cyclohexylcarboxylate (2.1 g, 8.9 mmol) was dissolved in 20 mL of dichloromethane and DAST ( 2.87 g, 17.8 mmol), then stirred at room temperature to room temperature overnight. After the reaction was completed, methanol was added at 0 °C to quench, then the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate, and the organic The phases were washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was purified by column chromatography to obtain (trans)-4-(3-difluoromethyl-1H-pyridine) Methyl azol-1-yl-cyclohexylcarboxylate 1.8 g (7.0 mmol, 78% yield). LCMS (ESI) m/z: [M+1]=259.

Step 4. Synthesis of (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid

(trans)-4-(3-difluoromethyl-1H-pyrazol-1-yl-cyclohexylcarboxylate methyl ester (1.8 g, 7.0 mmol) was dissolved in 10 mL of concentrated sulfuric acid, and then 65 % concentrated nitric acid (1.55g, 16mmol), heated to 100°C and stirred for 4 hours, after the reaction was complete, the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate, and the organic phase was collected and evaporated by rotary evaporation. The solvent was removed by using MgO. The residue was purified by reverse-phase MPLC to give (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid 1.3 g ( 4.5 mmol, 64% yield). LCMS (ESI) m/z: [M+1]=290.

Step 5. Synthesis of (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylmethanol

Dissolve (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid (1.3 g, 4.5 mmol) in 10 mL of tetrahydrofuran, and cool to - At 10°C, isobutyloxyacyl chloride (0.59 mL, 5.34 mmol) was added, followed by N-methylmorpholine (0.56 mg, 5.5 mmol). After stirring at this temperature for 10 minutes, sodium borohydride (570 mg, 15 mmol) was added ), then the temperature was raised to 0 ° C, and 2 ml of methanol was added dropwise, and the reaction was continued for 30 minutes. After the reaction was completed, the solvent was removed with a rotary evaporator, the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed with ethyl acetate. In two passes, the organic phase was collected and the solvent was removed on a rotary evaporator. The residue was then purified by reverse-phase MPLC to give (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazole-1 -yl-cyclohexylmethanol 1.1 g (3.9 mmol, 87% yield) LCMS (ESI) m/z: [M+1]=276.

Step 6. Synthesis of (trans)-4-(3-difluoromethyl-4-amino-1H-pyrazol-1-yl-cyclohexylmethanol

Dissolve (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylmethanol (1.1 g, 3.9 mmol) in 10 mL of tetrahydrofuran and add 100 mg 20% palladium-carbon catalyst, stirred overnight in hydrogen at room temperature, then filtered to remove the palladium-carbon catalyst, the filtrate was collected and the solvent was removed to obtain (trans)-4-(3-difluoromethyl-4-amino-1H- Pyrazol-1-yl-cyclohexylmethanol 864 mg (3.44 mmol, 88% yield). LCMS (ESI) m/z: [M+1]=246.

Synthesis of Intermediate II: tert-butyl(3-(difluoromethyl)-1-((trans)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamate

Step 1. Preparation of tert-butyl (3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)-cyclohexyl)-1H-pyrazol-4-yl)carbamate synthesis

(trans)-4-(3-Difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylmethanol (1 g, 3.6 mmol) was dissolved in 20 mL of ethanol, Pd/C (0.5 g) and Boc O (1.6g, 7.2mmol). Vacuum, change hydrogen, the reaction is stirred at room temperature for 16h, suction filtration, the filtrate is concentrated, and the target product is obtained through column chromatography (PE/EA=10/1to 5/1), White solid, 88% yield. LCMS (ESI) m/z: (M+H)+=346.1.

Step 2. Synthesis of tert-butyl (3-(difluoromethyl)-1-((trans)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamate

tert-Butyl (3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)-cyclohexyl)-1H-pyrazol-4-yl)carbamate (1.1 g, 3.2 mmol) was dissolved in 30 mL of dichloromethane and Dess-Martin oxidant (1.8 g, 4.1 mmol) was added at 0°C. The reaction was stirred at room temperature for 4 h, and the reaction solution was subjected to column chromatography (PE/EA=100/1 to 5/1) to obtain 0.8 g of the target product with a yield of 73%. LCMS (ESI) m/z: (M+H)+=344.1; 1H NMR (400MHz, CDCl3) δ 9.68 (s, 1H), 7.93 (s, 1H), 6.86-6.54 (m, 2H), 4.01 (ddd, J=11.9, 8.1, 3.8Hz, 1H), 2.41-2.08 (m, 5H), 1.92-1.68 (m, 3H), 1.43 (td, J=13.0, 3.1Hz, 11H).

Synthesis of Intermediate Three: Synthesis of N-Boc-4-propargyloxypiperidine

N-Boc-4-hydroxypiperidine (4.02 g, 20 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, then sodium hydride (1.20 g, 30 mmol) was added at 0 °C, and after stirring for 30 minutes, propargyl bromide (3.56 g) was added. g, 30 mmol) and stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to obtain N-Boc-4-propargyloxypiperidine 3.91 g (1.63 mmol, 82% yield). LCMS (ESI) m/z: [M+1]=240.

Synthesis of Intermediate Four: N-(3-(difluoromethyl)-1-((trans)-4-(aldehyde)cyclohexyl)-1H-pyrazol-4-yl)-5-- Linopyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate

Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (2.25 g, 10 mmol) was dissolved in 10 mL of acetonitrile, followed by the addition of morpholine (1.31 g, 15 mmol) and DIPEA (2.58 g, 20 mmol), then heated to reflux for 2 hours. After the reaction was completed, 10 ml of water was added to precipitate a solid, cooled and filtered, and the filter cake was washed with water, the solid was collected, and dried to obtain ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate Ester 2.55 g (9.2 mmol, 92% yield). LCMS (ESI) m/z: [M+1]=277.

Step 2. Synthesis of 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (2.55 g, 9.2 mmol) was dissolved in 20 mL methanol, then sodium hydroxide (800 mg) in water (10 mL) was added. mL) solution and stirred at room temperature for 16 hours. After the reaction was completed, 1M dilute hydrochloric acid was added to adjust the pH value to about 5-6 and a solid was precipitated. The organic solvent was removed under reduced pressure, then filtered, and the solids were rinsed with water. The solid was collected and dried to give 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2.01 g (8.1 mmol, 88% yield). LCMS (ESI) m/z: [M+1]=249. Step 3, N-(3-(difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinyl Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxamide

Combine 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.01 g, 8.1 mmol) and (trans)-4-(3-difluoromethyl-4-amino- 1H-pyrazol-1-yl-cyclohexylmethanol 2.03 g (8.1 mmol) was dissolved in 30 mL of DMF, HATU (3.42 g, 9 mmol) and DIPEA (2.04 g, 16 mmol) were added afterward. Then water and ethyl acetate were added for extraction , the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and the solvent was removed with a rotary evaporator. The residue was purified by reverse-phase MPLC to give N-(3-(difluoromethyl)-1-(( trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide 1.91 g ( 4.0 mmol, 49% yield). LCMS (ESI) m/z: [M+1]=476.

Step 4, N-(3-(difluoromethyl)-1-((trans)-4-(aldehyde group)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyridine Synthesis of azolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(Difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazole And [1,5-a]pyrimidine-3-carboxamide (1.91 g, 4.0 mmol) was dissolved in 20 mL of dichloromethane, then Dess-Martin oxidant (2.54 g, 6.0 mmol) was added and reacted at room temperature overnight. After the reaction was completed, an aqueous sodium bicarbonate solution was added for extraction, the aqueous phase was washed twice with dichloromethane, the organic phase was collected and the solvent was removed by a rotary evaporator. The residue was further purified by column chromatography to give N-(3-(difluoromethyl)-1-((trans)-4-(aldehyde)cyclohexyl)-1H-pyrazol-4-yl) -5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide 1.43 g (3.0 mmol, 75% yield). LCMS (ESI) m/z: [M+1]=474.

Synthesis of Intermediate Five: 4-(3-(Difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazole-1 -yl)piperidine

Step 1 to Step 3, Synthesis of 4-(3-(difluoromethyl)-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester

The cis-4-hydroxycyclohexyl-1-carboxylate methyl ester was replaced with N-Boc-4-hydroxyoxypiperidine, and the rest of the required raw materials, reagents and preparation methods were the same as those of the intermediate four synthetic steps 1 to 3, the product After separation and purification by rapid separation column chromatography, the total yield of the three steps is 21%. LCMS (ESI) m/z: [M+1]=302.

Step 4. Synthesis of 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester

4-(3-(Difluoromethyl)-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester (903 mg, 3 mmol) was dissolved in 5 mL of concentrated sulfuric acid, and then 65% of Concentrated nitric acid (0.77g, 8mmol) was heated to 100°C and stirred for 4 hours. After the reaction was complete, the reaction solution was slowly poured into 50 ml of ice water, and sodium hydroxide was slowly added to pH=10, and then Boc2O (1.09g, 5 mmol) and sodium carbonate (0.53 g, 5 mmol). The reaction was then extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and the solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography to give 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester 466 mg (1.35 mg) mmol, 45% yield). LCMS (ESI) m/z: [M+1]=347.

Step 5. Synthesis of 4-(3-(difluoromethyl)-4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

4-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester (466 mg, 1.35 mmol) was dissolved in 10 mL of tetrahydrofuran, and 40 mg of 20% palladium-carbon catalyst, stirred at room temperature in hydrogen overnight, then filtered to remove the palladium-carbon catalyst, the filtrate was collected and the solvent was removed to give 4-(3-(difluoromethyl)-4-amino-1H-pyrazole -1 yl)piperidine-1-carboxylic acid tert-butyl ester 402 mg (1.27 mmol, 94% yield). LCMS (ESI) m/z: [M+1]=317.

Step six, 4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl) Synthesis of tert-butyl piperidine-1-carboxylate

5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (315 mg, 1.27 mmol) and (4-(3-(difluoromethyl)-4-amino-1H-pyridine) Azol-1yl)piperidine-1-carboxylate tert-butyl ester (402 mg, 1.27 mmol) was dissolved in 5 mL of DMF, then HATU (569 mg, 1.5 mmol) and DIPEA (581 mg, 4.5 mmol) were added, and the reaction was carried out at 80 °C for 16 hours Then add water and ethyl acetate for extraction, then wash the aqueous phase twice with ethyl acetate, collect the organic phase and remove the solvent with a rotary evaporator. Then the residue is purified by silica gel column chromatography to obtain 4-(3-( Difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester 610 mg (1.12 mmol, 88% yield). LCMS (ESI) m/z: [M+1]=547.

Step seven, 4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl) Synthesis of Piperidine

4-(3-(Difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H-pyrazol-1-yl)piperidine tert-Butyl-1-carboxylate (610 mg, 1.12 mmol) was dissolved in 5 mL of 2M HCl in ethyl acetate, 2 mL of methanol was added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the solvent was removed with a rotary evaporator to obtain 4-(3-(difluoromethyl)-4-(5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide)-1H -Pyrazol-1-yl)piperidine hydrochloride 580 mg (1.12 mmol, 100% yield). LCMS (ESI) m/z: [M+1]=447.

Synthesis of Intermediate Six: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-Aldolcyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 4, 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) - Synthesis of 1-((1R,4R)-4-aldocyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace morpholine with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, and the rest of the required raw materials, reagents and preparation methods are the same as those of intermediate two synthesis steps one to four, three The overall yield of the step was 36%. LCMS (ESI) m/z: [M+1]=486.

Synthesis of Intermediate Seven: 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl -1-yl)oxy)piperidine

Step 1. Synthesis of 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

3-Methyl-4-bromoindazole (210 mg, 1 mmol) was dissolved in 5 mL of anhydrous THF/DMSO (1/1) mixed solvent, then sodium hydride (120 mg, 3 mmol, 60% purity) was added at 0°C, After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (288 mg, 1.5 mmol) and potassium iodide (133 mg, 0.8 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 10 mL of saturated aqueous ammonium chloride solution was added to quench, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was then purified by column chromatography to give (3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione 151 mg (0.47 mmol, yield) 48%). LCMS (ESI) m/z: [M+1]=322/324.

Step 2, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1- Synthesis of tert-butyl)oxy)piperidine-1-carboxylate.

(3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (151 mg, 0.47 mmol) was dissolved in 5 mL of DMF and N-Boc- 4-Propargyloxypiperidine (124 mg, 0.52 mmol), bistriphenylphosphonium palladium dichloride (33 mg, 47 umol) and cesium carbonate (306 mg, 0.94 mmol). The reaction was then blanketed with nitrogen and heated at 100 ℃ stirred overnight. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator The residue was then purified by column chromatography to give 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl) Prop-2-ynyl-1-yl)oxy)piperidine-1-carboxylate tert-butyl ester 144 mg (0.30 mmol, 64% yield). LCMS (ESI) m/z: [M+1]=481.

Step three, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1- Synthesis of base)oxy)piperidine

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxygen) piperidine-1-carboxylate tert-butyl ester is dissolved in dioxane, then 4M HCl dioxane solution is added, and the raw material disappears, and then the solvent is removed with a rotary evaporator to obtain 4-((3-(1- (2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl)oxy)piperidine hydrochloride. LCMS (ESI) m/z: [M+1]=381.

Synthesis of Intermediate Eight: 3-(4-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole-1- yl)cyclohexyl)methyl)-piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidin-2,6- diketone

Step 1, (3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-1-1H-indazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of tert-butyl carbamate

Intermediate seven (700 mg, 2.0 mmol) was dissolved in DMF/THF (1.0 mL/15.0 mL), the reaction solution was cooled to -10°C, intermediate two (776 mg, 2.0 mmol), TEA (412 mg, 4 mmol) were added, Under the protection of argon, stir for 0.5h. Then HOAc (367 mg, 6 mmol) and NaBH(OAc) 3 (1.3 g, 6 mmol) were added to the reaction solution and stirred for 3 h. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column ((MeOH/DCM=100/1 to 20/1) to give a white solid in 77% yield. LCMS (ESI) m/z: [M+1]=708.0.

Step 2, 3-(4-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) ring Hexyl)methyl)-piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione synthesis

The product of step 1 (1 g, 1.4 mmol) was dissolved in 5 mL of dioxane, a dioxane hydrochloric acid solution (4 M) was added, and the reaction solution was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was concentrated to obtain the target product, which was directly used in the next reaction without purification. LCMS (ESI) m/z: [M+1]==608.0.

Synthesis of Intermediate Nine: 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl -1-yl)oxy)piperidine

Step 1. 3-(4-Bromo-3-methyl-1H-indol-1-yl)piperidine-2,6-dione

The 3-methyl-4-bromoindazole was replaced with 3-methyl-4-bromoindole, and the rest of the required raw materials, reagents and preparation methods were the same as the synthesis step 1 of the intermediate five, and the product was separated and purified by rapid separation column chromatography , the yield is 23%. LCMS (ESI) m/z: [M+1]=321/323.

Step 2, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl-1- base)oxy)piperidine

(3-(4-Bromo-3-methyl-1H-indol-1-yl)piperidine-2,6-dione (161 mg, 0.5 mmol) was dissolved in 3 mL of DMF, followed by the addition of 4-propargyl Oxypiperidine (208 mg, 0.75 mmol), ditriphenylphosphonium palladium dichloride (35 mg, 50 umol) and cesium carbonate (325 mg, 1.0 mmol). The reaction was then blanketed with nitrogen and stirred at 100°C overnight. After completion of the reaction, it was purified by reverse MPLC to give 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)propane- 2-Alkynyl-1-yl)oxy)piperidine 96 mg (0.25 mmol, 51% yield). LCMS (ESI) m/z: [M+1]=380.

Synthesis of Intermediate Ten: 3-(3-Methyl-4-(3-(piperidin-1-yloxy)prop-1-yn-1-yl)-1H-pyrrole[2,3-b] Pyridin-1-yl)piperidine-2,6-dione trifluoroacetate

Step 1 to Step 3, 3-(3-methyl-4-(3-(piperidin-1-yloxy)prop-1-yn-1-yl)-1H-pyrrole[2,3-b] Synthesis of Pyridin-1-yl)piperidine-2,6-dione trifluoroacetate

The 4-bromo-3-methyl-indazole is replaced with 4-bromo-3-methyl-7-azaindazole, and the rest of the required raw materials, reagents and preparation methods are the same as those of the intermediate five synthesis steps 1 to 3, The three-step overall yield was 25%. LCMS (ESI) m/z: [M+1]=381.

Synthesis of Intermediate Eleven: (1r,4r)-4-((3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl )prop-2-yn-1-yl)oxy)cyclohexane-1-carbaldehyde

Step 1. Synthesis of trans-4-(tert-butyldimethylsiloxymethyl)cyclohexanol

Trans-4-(hydroxymethyl)cyclohexanol (1.3 g, 10 mmol) was dissolved in 15 mL of DMF, then TBSCl (1.51 g, 10 mmol), imidazole (1.36 g, 20 mmol) and DMAP ( 122 mg, 1 mmol). Stir at room temperature for 4 hours. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to obtain 1.41 g (5.80 mmol, 58% yield) of trans-4-(tert-butyldimethylsiloxymethyl)cyclohexanol.

Step 2. Synthesis of trans-4-(tert-butyldimethylsiloxymethyl)cyclohexyl propargyl ether

Trans-4-(tert-butyldimethylsiloxymethyl)cyclohexanol (1.41 g, 5.80 mmol) was dissolved in ultra-dry DMF, then sodium hydride (580 mg, 14.5 mmol) was added at 0°C and stirred for 0.5 Hour. Finally, propyne bromide (1.38 g, 11.6 mmol) was added and the mixture was returned to room temperature and stirred overnight. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to obtain 716 mg (2.53 mmol, 44% yield) of trans-4-(tert-butyldimethylsiloxymethyl)cyclohexyl propargyl ether.

Step 3. Synthesis of trans-(4-hydroxymethyl) cyclohexyl propargyl ether

Trans-4-(tert-butyldimethylsiloxymethyl)cyclohexyl propargyl ether (716 mg, 2.53 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of a 2M solution of TBAF in tetrahydrofuran (5 mL, 10 mmol). It was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain 317 mg (1.89 mmol) of trans-trans-(4-hydroxymethyl)cyclohexyl propargyl ether. , the yield is 75%).

Step 4. 3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indium Synthesis of oxazol-1-yl)piperidine-2,6-dione

(3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (322 mg, 1 mmol) was dissolved in 5 mL of DMF and trans-(4 -Hydroxymethyl)cyclohexyl propargyl ether (168 mg, 1 mmol), ditriphenylphosphonium palladium dichloride (70 mg, 0.1 mmol) and cesium carbonate (650 mg, 2.0 mmol). The reaction system was then protected with nitrogen, and stirred overnight at 100° C. After completion of the reaction it was purified by reverse MPLC to give 3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yne -1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione, 312 mg (0.76 mmol, 76% yield). LCMS (ESI) m/z: [M+1]=410.

Step 5. (1r,4r)-4-((3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)propane-2 Synthesis of -alkyn-1-yl)oxy)cyclohexane-1-carbaldehyde

3-(4-(3-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazole- 1-yl)piperidine-2,6-dione (312 mg, 0.76 mmol) was dissolved in 5 mL of dichloromethane, then Dess-Martin oxidant (356 mg, 0.84 mmol) was added and allowed to react overnight at room temperature. After the reaction was completed, an aqueous sodium bicarbonate solution was added for extraction, the aqueous phase was washed twice with dichloromethane, the organic phase was collected and the solvent was removed by a rotary evaporator. The residue was further purified by column chromatography to give (1r,4r)-4-((3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazole -4-yl)prop-2-yn-1-yl)oxy)cyclohexane-1-carbaldehyde (0.66 mmol, 87% yield). LCMS (ESI) m/z: [M+1]=408.

Synthesis of Intermediate Twelve: 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H -Pyrazol-1-yl)ethyl)piperidine hydrochloride

Step 1. Synthesis of tert-butyl 4-(2-(methanesulfonyloxyethyl)piperidine-1-carboxylate)

Dissolve tert-butyl 4-(2-(hydroxyethyl)piperidine-1-carboxylate (4.59 g, 20 mmol) in 50 mL of dichloromethane, then add triethylamine (4.04 g, 40 mmol) and methyl benzene under an ice bath Sulfonyl chloride (2.52 g, 22 mmol) was gradually raised to room temperature and stirred for 2 hours. After the reaction was completed, the reaction was extracted with dichloromethane and water, and the aqueous phase was washed twice with dichloromethane. The organic phase was collected and dried over anhydrous sodium sulfate. And the solvent was removed to give tert-butyl 4-(2-(methanesulfonyloxyethyl)piperidine-1-carboxylate (5.92 g, 19.3 mmol, 96% yield).

Step 2. Synthesis of tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate

Dissolve tert-butyl 4-(2-(methanesulfonyloxyethyl)piperidine-1-carboxylate (5.92 g, 19.3 mmol) and 3-bromo-1H-pyrazole (2.94 g, 20 mmol) in 50 mL DMF , then add cesium carbonate (13.0 g, 40 mmol), then stir at 80 ° C overnight. After the reaction is complete, extract the reaction with ethyl acetate and water, then wash the aqueous phase twice with ethyl acetate, collect the organic phase and wash with saturated brine once, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was purified by column chromatography to obtain 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine tert-Butyl pyridine-1-carboxylate (4.97 g, 13.9 mmol, 72% yield). LCMS (ESI) m/z: [M+1]=359.

Step three, 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole-1- Synthesis of tert-butyl)ethyl)piperidine-1-carboxylate

Combine tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (4.97 g, 13.9 mmol) and pinacol biboronate (7.06 g, 27.8 mmol) was dissolved in 80 mL of ethylene glycol dimethyl ether, then potassium acetate (2.95 g, 30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (509 mg, 30 mmol) were added. 0.7 mmol). 20 ml of water was added, the air in the reaction system was replaced by nitrogen, and then nitrogen was protected and the reaction was refluxed for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)) -1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (3.90 g, 9.6 mmol, 69% yield). LCMS (ESI) m/z: [M+1]=406.

Step 4. 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazole- Synthesis of 1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester

4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl) Ethyl)piperidine-1-carboxylate tert-butyl ester (3.90 g, 9.6 mmol) and 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (3.09 g, 9.6 mmol) was dissolved in 30 mL of N,N-dimethylformamide, then sodium carbonate (204 g, 19.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene were added ] Palladium dichloride (703 mg, 0.96 mmol), the air in the reaction system was replaced by nitrogen, then nitrogen protected and reacted at 90° C. for 4 hours. After the reaction was completed, the reaction was extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4- (876 mg, 1.68 mmol, 18% yield). LCMS (ESI) m/z: [M+1]=521.

Step five, 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazole- Synthesis of 1-yl)ethyl)piperidine hydrochloride

4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1- tert-butyl)ethyl)piperidine-1-carboxylate (876 mg, 1.68 mmol) was dissolved in 4 mL of tetrahydrofuran, 4 mL of 4M hydrochloric acid in ethyl acetate was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solvent was removed with a rotary evaporator to obtain 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole- 4-yl)-1H-pyrazol-1-yl)ethyl)piperidine hydrochloride 770 mg (1.68 mmol, 100% yield). LCMS (ESI) m/z: [M+1]=421.

Synthesis of Intermediate Thirteen: 3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine- 2,6-Dione

Step 1. Synthesis of 4-((p-tolyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

N-Boc-4-piperidinemethanol (5.0 g, 23.3 mmol) was dissolved in 30 mL of dichloromethane, Et ₃ N (7.1 g, 69.9 mmol) was added, and p-toluenesulfonyl chloride (6.7 g, 35.9 mmol) was added at 0° C. mmol), the reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane, washed twice with water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain the target product, which was directly used in the one-step reaction with a yield of 97%.

Step 2, 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-yl)methyl) Synthesis of Piperidine-1-Carboxylic Acid tert-Butyl Ester

4-Pyrazole boronic acid pinacol ester (2.0 g, 10.3 mmol) was dissolved in 10 mL of DMF, cooled to 0 °C, and sodium hydrogen (620 mg, 15.5 mmol) was slowly added under nitrogen protection, and the reaction solution was stirred for 30 minutes. , and tert-butyl 4-((p-tolyloxy)methyl)piperidine-1-carboxylate (4.6 g, 12.4 mmol) was added. After the addition was completed, the reaction solution was stirred overnight. After the reaction was completed, the reaction was quenched with water, extracted with ethyl ester, washed with water, combined with the organic layers, dried over sodium sulfate, filtered with suction, and the filtrate was concentrated, and subjected to column chromatography (PE/EA=10/ 1to2/1) to obtain 2.1 g of product with a yield of 52%. LCMS (ESI) m/z: (M+H) ⁺ = 392.2.

Step three, 4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl ) methyl) piperidine-1-carboxylate tert-butyl ester synthesis

3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (1.0 g, 3.1 mmol) was dissolved in a mixed solvent of dioxane and water ( V/V=10/1), add 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole -1-yl)methyl)piperidine-1-carboxylate tert-butyl ester (1.8 g, 4.7 mmol), K2CO3 (61.6 g, 9.3 mmol), Pd(dppf)2Cl2 (243 mg, 0.3 mmol), under nitrogen under, heated to 90 ℃, and reacted for 4 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (PE/EA=10/1 to 1/1) to obtain the target product in a yield of 31.9%. LCMS (ESI) m/z: (M+H-56) ⁺ = 451.2; 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H), 7.41 -7.37(m, 1H), 7.28(s, 1H), 7.02(d, J=7.0Hz, 1H), 5.28(dd, J=10.4, 5.1Hz, 1H), 4.20-4.10(m, 2H), 4.07(d, J=7.2Hz, 2H), 3.08(dt, J=17.4, 4.3Hz, 1H), 2.95-2.78(m, 2H), 2.71(t, J=13.6Hz, 2H), 2.45(dt , J=13.3, 5.0Hz, 1H), 2.33 (s, 3H), 2.21-2.12 (m, 1H), 1.45 (s, 9H), 1.22 (dd, J=24.1, 11.9Hz, 4H).

Step 4. 3-(3-methyl-4-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2 , the synthesis of 6-diketone

The product of step 3 (500 mg, 1.0 mmol) was dissolved in 4 mL of dioxane, 5 mL of 4M hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 5 h. After the completion of the reaction, the reaction solution was concentrated to obtain the target product, which was directly used in the next step without purification. LCMS (ESI) m/z: (M+H)+=407.2.

Synthesis of Intermediate Fourteen: 3-(4-((1-(((1r,4r)-4-(4)-amino-3-(difluoromethyl)-1H-pyrazol-1-yl )cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-di ketone

One-to-two, 3-(4-((1-(((1r,4r)-4-(4)-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione Synthesis.

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) oxy) piperidine was replaced with 3-(3-methyl-4-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine Pyridin-2,6-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of intermediate eight. LCMS (ESI) m/z: (M+H)+=634.3.

Synthesis of intermediate fifteen: 3-(3-methyl-4-(1-(2-(piperidin-4-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-indone oxazol-1-yl)piperidine-2,6-dione

Step 1. Synthesis of 4-(2-methoxy-2-oxoethoxy) piperidine-1-carboxylic acid tert-butyl ester

N-Boc-4-hydroxypiperidine (4.02 g, 20 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, then sodium hydride (880 mg, 22 mmol) was added at 0°C, and after stirring for 30 minutes, ethyl bromoacetate (5.01 g) was added. , 30 mmol), and stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give tert-butyl 4-(2-methoxy-2-oxoethoxy)piperidine-1-carboxylate (2.91 g, 10.1 mmol, 51% yield).

Step 2. Synthesis of 4-(2-hydroxyethoxy) piperidine-1-carboxylic acid tert-butyl ester

4-(2-Methoxy-2-oxoethoxy)piperidine-1-carboxylic acid tert-butyl ester (2.91 g, 10.1 mmol) was dissolved in 30 mL of dry tetrahydrofuran, and lithium tetrahydride was added at 0°C Aluminum (460 mmol, 12.1 mmol) and warmed to room temperature and stirred for 2 hours. After the reaction was completed, 20 ml of 2M sodium hydroxide aqueous solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (1.39 g, 5.67 mmol, 56% yield).

Step 3 to Step 7, 3-(3-methyl-4-(1-(2-(piperidin-4-yloxy)ethyl)-1H-pyrazol-4-yl)-1H-indazole Synthesis of -1-yl)piperidine-2,6-dione

Replace 4-(2-(hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester with 4-(2-hydroxyethoxy)piperidine-1-carboxylic acid tert-butyl ester, the remaining required raw materials, reagents and preparations The method is the same as the synthesis step 1 to step 5 of the intermediate 12, and the total yield of the three steps is 8.6%. LCMS (ESI) m/z: [M+1]=437.

Synthesis of intermediate sixteen: 4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy) ring butoxy)piperidine

Step 1. Synthesis of 4-(3-(benzyloxy)cyclobutoxy)piperidine

4-Hydroxypyridine (3.8 g, 40 mmol), 3-benzyloxycyclobutanol (7.12 g, 40 mmol) and triphenylphosphine (15.8 g, 60 mmol) were dissolved in 100 mL of dry tetrahydrofuran. Then under nitrogen protection, diisopropyl azodicarboxylate (12.1 g, 60 mmol) was added at 0°C, and the temperature was raised to 60°C for 16 hours. After the reaction was completed, the organic solvent was removed with a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 4-(3-(benzyloxy)cyclobutoxy)piperidine (7.60 g, 29.8 mmol, 75% yield). LCMS (ESI) m/z: [M+1]=256.

Step 2. Synthesis of 1-benzyl-4-(3-benzyloxycyclobutyl)pyridine-1-bromonium salt

4-(3-(Benzyloxy)cyclobutoxy)piperidine (7.60 g, 29.8 mmol) was dissolved in 100 mL of toluene, then benzyl bromide (5.13 g, 30 mmol) was added and stirred at 80°C for 16 hours . After the reaction was completed, the organic solvent was removed with a rotary evaporator, and 100 ml of petroleum ether was added, stirred for 1 hour, and then filtered to collect the solid to obtain 1-benzyl-4-(3-benzyloxycyclobutyl)pyridine-1- Bromonium salt (12.3 g, 28.6 mmol, 96%). LCMS (ESI) m/z: [M+1]=347.

Step 3. Synthesis of 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine

1-Benzyl-4-(3-benzyloxycyclobutyl)piperidine-1-bromonium salt (12.3 g, 28.6 mmol) was dissolved in 150 mL of ethanol, then sodium borohydride (8.69 g) was added slowly at 0°C , 229 mmol), warmed to room temperature and stirred for 5 hours. After the reaction was completed, the organic solvent was removed with a rotary evaporator, and then extracted with ethyl acetate and water. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was purified by column chromatography to give 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine (5.15 g, 14.7 mmol, 55% yield). ). LCMS (ESI) m/z: [M+1]=350.

Step 4. Synthesis of 4-(3-hydroxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester

Dissolve 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine (5.15 g, 14.7 mmol) in 50 mL of ethanol, then add di-tert-butyl dicarbonate ester (6.42 g, 29.4 mmol) and 20% palladium hydroxide on carbon (500 mg). It was stirred at 60°C for 48 hours under a hydrogen atmosphere. After the reaction was completed, the catalyst was removed by filtration, the organic solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain tert-butyl 4-(3-hydroxycyclobutyl)-piperidine-1-carboxylate (3.23 g). , 11.9 mmol, 81% yield). LCMS (ESI) m/z: [M+1]=272. Step 5. Synthesis of tert-butyl 4-(3-((3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy)piperidine-1-carboxylate

3-Methyl-4-hydroxyindazole (1.48 g, 10 mmol), 4-(3-benzyloxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester (2.71 g, 10 mmol) and triphenylphosphine (5.25 g, 20 mmol) dissolved in 50 mL of dry tetrahydrofuran. Then under nitrogen protection, diisoethyl azodicarboxylate (3.48 g, 20 mmol) was added at 0° C., and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the organic solvent was removed with a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was then purified by column chromatography to give tert-butyl 4-(3-((3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy)piperidine-1-carboxylate (1.49 g, 3.58 mmol, 36% yield). LCMS (ESI) m/z: [M+1]=402.

Step six, 4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy) Synthesis of tert-butyl piperidine-1-carboxylate

Dissolve tert-butyl 4-(3-((3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy)piperidine-1-carboxylate (1.49 g, 3.58 mmol) in 15 mL Anhydrous THF/DMSO (1/1) mixed solvent, then sodium hydride (430 mg, 10.74 mmol, 60% purity) was added at 0 °C, and after stirring for 30 minutes, 3-bromopiperidine-2,6-dione ( 288 mg, 1.5 mmol) and potassium iodide (475 mg, 2.86 mmol), stirred at room temperature overnight. After the reaction was completed, 10 mL of saturated aqueous ammonium chloride solution was added to quench, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl) oxy)cyclobutoxy)piperidine-1-carboxylate tert-butyl ester (620 mg, 1.21 mmol, 34% yield). LCMS (ESI) m/z: [M+1]=513.

Step seven, 4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy) Synthesis of Piperidine

4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy)piperidine tert-Butyl 1-carboxylate (620 mg, 1.21 mmol) was dissolved in 5 mL of dichloromethane, then 5 mL of trifluoroacetic acid was added, and stirred at room temperature overnight. After the reaction was completed, the solvent was removed by a rotary evaporator to obtain 4-(3- ((1-(2,6-Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutoxy)piperidine trifluoroacetate ( 635 mg, 1.21 mmol, 100% yield). LCMS (ESI) m/z: [M+1]=413.

Synthesis of intermediate seventeen: tert-butyl 7-methanesulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylate

Dissolve tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (2.41 g, 1.0 mmol) in 25 mL of dichloromethane, then add triethylamine (2.02 g, 2 mmol) under ice bath ) and methanesulfonyl chloride (1.72 g, 1.5 mmol), gradually warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. Obtained tert-butyl 7-methanesulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylate (2.62 g, 8.2 mmol, 82% yield. LCMS (ESI) m/z: [M+1 ]=320.

Synthesis of Intermediate Eighteen: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-(2-Azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of 3-difluoromethyl-4-nitropyrazole

Dissolve 1.18 g (10 mmol) of 3-difluoromethylpyrazole in 6 ml of concentrated sulfuric acid, then add 2 ml of 65% concentrated nitric acid at 0°C, then heat to 100°C and stir for 16 hours. Poured into 100 ml of ice water, followed by extraction with ethyl acetate. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 3-difluoromethyl-4-nitropyrazole (981 mg, 6.02 mmol, 60% yield).

Step 2. Synthesis of tert-butyl 7-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate

7-Methanesulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (2.62 g, 8.2 mmol) and 3-difluoromethyl-4-nitropyrazole (978 mg, 6.00 mmol) was dissolved in 20 mL of DMF, then cesium carbonate (4.85 g, 15 mmol) was added, followed by stirring at 80°C overnight. After the reaction was completed, the reaction was extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 7-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2 - tert-Butyl formate (1.18 g, 3.05 mmol, 51% yield). LCMS (ESI) m/z: [M+1]=387.

Step 3 to Step 5, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- Synthesis of 1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace 4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1 yl)piperidine-1-carboxylate tert-butyl ester with 7-(3-(difluoromethyl)-4 -Nitro-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester, the rest of the required raw materials, reagents and preparation methods are the same as those of the intermediate five synthesis steps five to steps Seven, the overall yield of three steps was 66%. LCMS (ESI) m/z: [M+1]=499.

Synthesis of Intermediate Nineteen: N-(3-(difluoromethyl)-1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)-5- Synthesis of Morpholinylpyrazole[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 2, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1 Synthesis of -(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was replaced by 5- Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, the other required raw materials, reagents and preparation methods are the same as those of intermediate eighteen synthesis steps 4 to 5, and the total yield of the two steps is 75%. LCMS (ESI) m/z: [M+1]=487.

Synthesis of Intermediate Twenty: 3-(3-methyl-4-(3-((4-oxocyclohexyl)oxy)prop-1-yn-1-yl)-1H-indazol-1- yl)piperidine-2,6-dione

step one,

4-Hydroxycyclohexanone ethylene glycol acetal (3.16 g, 20 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, then sodium hydride (880 mg, 22 mmol) was added at 0 °C, and after stirring for 30 minutes, ethyl bromoacetate ( 5.01 g, 30 mmol), stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 4-propargyloxycyclohexanone ethylene glycol acetal (2.43 g, 12.4 mmol, 62% yield).

Step 2, the synthesis of 4-propargyloxy cyclobutanone

4-Propargyloxycyclohexanone ethylene glycol acetal (2.43 g, 12.4 mmol) was dissolved in 25 ml of acetone, then 5 ml of concentrated hydrochloric acid was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the organic solvent was removed with a rotary evaporator, extracted with ethyl acetate and water, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator to obtain 4-propargyloxycyclobutanone (1.75g, 11.5 g) mmol, 93% yield).

Step 3, 3-(3-methyl-4-(3-((4-oxocyclohexyl)oxy)prop-1-yn-1-yl)-1H-indazol-1-yl)piperidine Synthesis of -2,6-dione

The N-Boc-4-propargyloxypiperidine was replaced with 4-propargyloxycyclohexanone, and the rest of the required raw materials, reagents and preparation methods were the same as those of the intermediate five in the synthesis step 2, and the yield was 41%. LCMS (ESI) m/z: [M+1]=394.

Synthesis of Intermediate Twenty-One: 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5- a]Pyrimidine-3-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2- Azaspiro[3.5]nonane-2-carbaldehyde

Step 1. Synthesis of methyl 6-hydroxy-spiro[3.3]heptane-2-carboxylate

Methyl 6-oxospiro[3.3]heptane-2-carboxylate (20 mmol, 3.36 g) was dissolved in 40 mL of methanol, then sodium borohydride (30 mmol, 1.14 g) was added at 0°C, stirred for 2 hours, and then Return to room temperature and stir for 16 hours. After the reaction was completed, the reaction was extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, the organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator to obtain 6 -Hydroxy-spiro[3.3]heptane-2-carboxylate methyl ester (2.99 g, 17.6 mmol, 88% yield).

Step 2. Synthesis of methyl 6-methanesulfonyloxy-spiro[3.3]heptane-2-carboxylate

Methyl 6-hydroxy-spiro[3.3]heptane-2-carboxylate (2.99 g, 17.6 mmol) was dissolved in 20 mL of dichloromethane, then triethylamine (3.03 g, 30 mmol) and methanesulfonyl chloride were added under ice bath (2.62 g, 22.9 mmol), gradually warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. 6-Methanesulfonyloxy-spiro[3.3]heptane-2-carboxylic acid methyl ester (4.20 g, 16.9 mmol, 96% yield) was obtained.

Step 3 to Step 5, 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazole[1,5-a] Pyrimidine-3-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methylsulfonyloxy-2-aza Synthesis of Methyl Spiro[3.5]nonane-2-carboxylate

7-Methanesulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was replaced by 6-(4-amino-3-(difluoromethyl)-1H-pyrazole-1 - base) spiro[3.3]heptane-2-methyl carboxylate, the other required raw materials, reagents and preparation methods are the same as those of intermediate thirteen synthesis steps two to four, and the yield is 19%. LCMS (ESI) m/z: [M+1]=528.

Step 6. 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5 Synthesis of ]nonane-2-carboxylic acid

-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide )-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5]nonane Methyl 2-formate (512mg, 0.97mmol) was dissolved in 5ml methanol and 5ml water, then LiOH.H2O (142mg, 3.39mmol) was added, stirred at room temperature for 6 hours, and the organic solvent was removed with a rotary evaporator after the reaction was completed, And the pH value was adjusted to 5-6 with dilute hydrochloric acid, then extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-methan was obtained amide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methylsulfonyloxy-2-azaspiro[3.5]nonane Alkane-2-carboxylic acid (452 mg, 0.88 mmol, 91% yield). LCMS (ESI) m/z: [M+1]=514. Step 7. 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5 Synthesis of ]nonane-2-methanol

6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide )-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5]nonane -2-carboxylic acid (452 mg, 0.88 mmol) was dissolved in tetrahydrofuran (5.0 mL), then nitrogen blanketed and N-methylmorpholine NMM (133 mg, 1.32 mmol) and isobutyl chloroformate (120 mg, 0.88 mmol) were added at -10°C mmol), after stirring at this temperature for 10 minutes sodium borohydride (100 mg, 2.64 mmol) was added and stirred at 0°C for 1 hour. After the reaction was completed, methanol was added to quench, and the organic solvent was removed by a rotary evaporator, then extracted with dichloromethane and water, and the aqueous phase was washed twice with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed. . 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-methan was obtained amide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methylsulfonyloxy-2-azaspiro[3.5]nonane Alkane-2-methanol (399 mg, 0.8 mmol, 91% yield). LCMS (ESI) m/z: [M+1]=500.

Step 8. 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5 Synthesis of ]nonane-2-carbaldehyde

6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3-methyl amide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methylsulfonyloxy-2-azaspiro[3.5]nonane Alkane-2-methanol (399 mg, 0.8 mmol) was dissolved in 5 mL of dichloromethane, then Dess-Martin oxidant (424 mg, 1 mmol) was added and allowed to react overnight at room temperature. After the reaction was completed, an aqueous sodium bicarbonate solution was added for extraction, the aqueous phase was washed twice with dichloromethane, the organic phase was collected and the solvent was removed by a rotary evaporator. The residue was further purified by column chromatography to give 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazo[1] , 5-a]pyrimidine-3-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy -2-Azaspiro[3.5]nonane-2-carbaldehyde (302 mg, 0.61 mmol, 76% yield). LCMS (ESI) m/z: [M+1]=498.

Synthesis of Intermediate Twenty-two: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)- 4-Formylcyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Step 1. Synthesis of (4-bromopyridin-2-yl) (cyclopropylmethyl) tert-butyl carbamate

Tert-butyl(4-bromopyrimidin-2-yl)carbamate (2.73 g, 10 mmol) was dissolved in 30 mL of dry DMF, then sodium hydride (800 mg, 20 mmol, 60% purity) was added at 0 °C. After stirring at 0°C for 20 minutes, bromomethylcyclopropane (1.62 g, 12 mmol) was added and the temperature was warmed to room temperature and stirred overnight. After the reaction was completed, it was quenched with 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give tert-butyl (4-bromopyridin-2-yl)(cyclopropylmethyl)carbamate (1.77 g, 5.4 mmol, 54% yield). LCMS (ESI) m/z: [M+1]=327,329.

Step 2. Synthesis of ethyl 2-(2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxylate

tert-butyl (4-bromopyridin-2-yl)(cyclopropylmethyl)carbamate (1.77 g, 5.4 mmol) and ethyl oxazole-4-carboxylate (761 mg, 5.4 mmol), tri-o-tolylphosphine ( 329 mg, 1.08 mmol), Pd(OAc) ₂ (121 mg, 0.54 mmol) and Cs ₂ CO ₃ (3.51 g, 108 mmol) were dissolved in DMF (20 mL) and stirred at 80° C. overnight under nitrogen protection. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was then purified by column chromatography to give ethyl 2-(2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxylate (1.28 g, 3.3 g mmol, 61% yield).

LCMS (ESI) m/z: [M+1]=388.

Step 3 to Step 5, (Cyclopropylmethyl)(4-(4-((3-(difluoromethyl)-1-((1R,4R)-4-formylcyclohexyl)-1H-pyrazole- Synthesis of tert-butyl 4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

Replacing ethyl 5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate with 2-(2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridine-4- base) oxazole-4-ethyl carboxylate, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps 2 to 4 of intermediate 4, and the yield is 36%.

LCMS (ESI) m/z: [M+1]=585.

Step 6. 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-formyl ring Synthesis of Hexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide trifluoroacetate

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine-1-carboxylate tert-butyl ester was replaced by (cyclopropylmethyl)(4-(4-((3-(difluoromethyl)-1-((1R,4R)-4-formylcyclohexyl) )-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamic acid tert-butyl ester, the rest of the required raw materials, reagents and preparation methods are the same as the intermediate seven synthesis step three , the yield is 100%.

Synthesis of intermediate twenty-three: N-(3-(difluoromethyl)-1-((trans)-4-(carboxy)cyclohexyl)-1H-pyrazol-4-yl)-5-- Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester

(trans)-4-(3-Difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid (870 mg, 3.0 mmol) was dissolved in DMF (10 mL), then potassium carbonate was added (828 mg, 6 mmol) and methyl iodide (639 mg, 4.5 mmol), stirred at room temperature for 4 hours, when the reaction was completed, extracted with ethyl acetate and water, the aqueous phase was washed twice with ethyl acetate, and the organic phases were combined with Washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporator to obtain (trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexyl Methyl formate (854 mg, 2.82 mmol, 94% yield).

Step 2. Synthesis of (trans)-4-(3-difluoromethyl-4-amino-1H-pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester

(trans)-4-(3-difluoromethyl-4-nitro-1H-pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester (854 mg, 2.82 mmol) was dissolved in 10 mL of tetrahydrofuran, and 100 mg of 20% palladium-carbon catalyst, stirred overnight in hydrogen at room temperature, then filtered to remove the palladium-carbon catalyst, the filtrate was collected and the solvent was removed to give ((trans)-4-(3-difluoromethyl-4-amino- 1H-Pyrazol-1-yl-cyclohexylcarboxylic acid methyl ester (676 mg, 2.47 mmol, 88% yield).

LCMS (ESI) m/z: [M+1]=274.

Step three, N-(3-(difluoromethyl)-1-((trans)-4-(methoxycarbonyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholine Synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4.96 mg, 2 mmol) and (trans)-4-(3-difluoromethyl-4-amino-1H -Pyrazol-1-yl-cyclohexylmethanol (546 mg, 2 mmol) was dissolved in 3 mL of DMF, HATU (836 mg, 2.2 mmol) and DIPEA (516 mg, 4 mmol) were added afterward. Then water and ethyl acetate were added for extraction, and then The aqueous phase was washed twice with ethyl acetate, the organic phase was collected and the solvent was removed with a rotary evaporator. The residue was purified by column chromatography to give N-(3-(difluoromethyl)-1-((trans )-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide (659 mg, 1.31 mmol , yield 66%). LCMS (ESI) m/z: [M+1]=504.

Step 4. N-(3-(difluoromethyl)-1-((trans)-4-(carboxy)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazole Synthesis of [1,5-a]pyrimidine-3-carboxamide

N-(3-(Difluoromethyl)-1-((trans)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazole He[1,5-a]pyrimidine-3-carboxamide (659 mg, 1.31 mmol) was dissolved in 5 mL of methanol, then a solution of sodium hydroxide (120 mg, 3 mmol) in water (4 mL) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction is complete, add 1M dilute hydrochloric acid to adjust the pH value to about 5-6. The organic solvent was removed under reduced pressure, then extracted with ethyl acetate, and the aqueous phase was washed twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the organic solvent was removed with a rotary evaporator to obtain N-(3-(difluoromethyl)-1-((trans)-4-(carboxy)cyclohexyl)- 1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.02 mmol, 78% yield). LCMS (ESI) m/z: [M+1]=490.

Synthesis of Intermediate Twenty-Four: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) yl)-1-((1r,4r)-4-carboxycyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Morpholinylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid was replaced by 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane Alkyl-5-ylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, other required raw materials, reagents and preparation methods are the same as intermediate twenty-two steps three and four, and the yield is 54%. LCMS ( ESI) m/z: [M+1]=502.

Synthesis of Intermediate Twenty-Five: 3-(3-Methyl-4-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1H-indazol-1-yl)piperidine Pyridin-2,6-dione

Step 1 to Step 2, 3-(3-methyl-4-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1H-indazol-1-yl)piperidine- Synthesis of 2,6-diketone trifluoroacetate

Replace N-Boc-4-propargyloxypiperidine with tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate, and the other required raw materials, reagents and preparation methods are the same as intermediates Seven synthesis steps two to three, the total yield of two steps is 51%. LCMS (ESI) m/z: [M+1]=366.

Synthesis of Intermediate Twenty-Six: 3-(3-Methyl-4-(4-(piperazin-1-yloxy)but-1-yn-1-yl)-1H-pyrro[2,3- b]pyridin-1-yl)piperidine-2,6-dione

Step 1 to Step 2, 3-(3-methyl-4-(4-(piperazin-1-yloxy)but-1-yn-1-yl)-1H-pyrrole[2,3-b] Synthesis of Pyridin-1-yl)piperidine-2,6-dione trifluoroacetate

Replace N-Boc-4-propargyloxypiperidine with tert-butyl 4-(but-3-yn-1-yl)piperazine-1-carboxylate, and the other required raw materials, reagents and preparation methods are the same as intermediates Seven synthesis steps two to three, the total yield of two steps is 59%. LCMS (ESI) m/z: [M+1]=380.

Synthesis of intermediate twenty-seven: 3-(4-(3-(hexahydropyrrolo[3,4-c]pyrrolidin-2(1H)-yl)prop-1-yn-1-yl)- 3-Methyl-1H-indazol-1-yl)piperidine-2,6-dione

Step 1 to Step 2, 3-(4-(3-(hexahydropyrrolo[3,4-c]pyrrolidinyl-2(1H)-yl)prop-1-yn-1-yl)-3- Methyl-1H-indazol-1-yl)piperidine-2,6-dione.

Replace N-Boc-4-propargyloxypiperidine with tert-5-(prop-2-yn-1-yl)hexahydropyrrolo[3,4-c]pyrrolidinyl-2(1H)-carboxylic acid Butyl ester, the other required raw materials, reagents and preparation methods are the same as the synthesis steps 2 to 3 of intermediate seven, and the total yield of the two steps is 71%. LCMS (ESI) m/z: [M+1]=392.

Synthesis of Intermediate Twenty-Eight: 3-(4-(3-(((S)-1-(((1r,4S)-4-(4-amino-3-(difluoromethyl)-1H) -Pyrazol-1-yl)cyclohexyl)methyl)pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine -2,6-Dione

Step poly-1, (3-(difluoromethyl)-1-((1S,4r)-4-(((3S)-3-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of tert-butyl 4-yl)carbamate

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced with 3-(3-methyl-4-(3-(((S)-pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-1H-indazole- 1-yl)piperidine-2,6-dione (replace N-Boc-4-propargyloxypiperidine with (S)-3-(prop-2-yn-1-yloxy)pyrrolidine- The raw materials, reagents and preparation methods required for 1-carboxylate tert-butyl ester are the same as the synthesis of intermediate seven), and the remaining required raw materials, reagents and preparation methods are the same as the synthesis step one of intermediate eight. LCMS (ESI) m/z: [M+1]=694.3.

Step polydi, 3-(4-(3-(((S)-1-(((1r,4S)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole- 1-yl)cyclohexyl)methyl)pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6 - Synthesis of diketones

(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1-1H-indazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) tert-Butyl carbamate was replaced with (3-(difluoromethyl)-1-((1S,4r)-4-(((3S)-3-((3-(1-(2,6-di Oxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H -Pyrazol-4-yl) tert-butyl carbamate, the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven), and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis step two of intermediate eight. LCMS (ESI) m/z: [M+1]=594.2.

Synthesis of Intermediate Twenty-Nine: 3-(4-(3-(((R)-1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)-1H -Pyrazol-1-yl)cyclohexyl)methyl)pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine -2,6-Dione

Step poly-one, (3-(difluoromethyl)-1-((1R,4r)-4-(((3R)-3-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of tert-butyl 4-yl)carbamate

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced with 3-(3-methyl-4-(3-(((R)-pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-1H-indazole- 1-yl)piperidine-2,6-dione (replace N-Boc-4-propargyloxypiperidine with (R)-3-(prop-2-yn-1-yloxy)pyrrolidine- The raw materials, reagents and preparation methods required for 1-carboxylate tert-butyl ester are the same as the synthesis of intermediate seven), and the remaining required raw materials, reagents and preparation methods are the same as the synthesis step one of intermediate eight. LCMS (ESI) m/z: [M+1]=694.3.

Step polydi, 3-(4-(3-(((R)-1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole- 1-yl)cyclohexyl)methyl)pyrrolidin-3-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6 - Synthesis of diketones

(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1-1H-indazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) tert-Butyl carbamate was replaced with (3-(difluoromethyl)-1-((1R,4r)-4-(((3R)-3-((3-(1-(2,6-di Oxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H -Pyrazol-4-yl) tert-butyl carbamate, the other required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven, and the remaining required raw materials, reagents and preparation methods are the same as the synthesis step two of intermediate eight. LCMS (ESI) m/z: [M+1]=594.2.

Synthesis of Intermediate Thirty: 3-(3-methyl-4-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-1H-indazole- 1-yl)piperidine-2,6-dione

N-Boc-4-piperidinemethanol was replaced with 5-hydroxyhexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester, and the remaining required raw materials, reagents and preparation methods were the same as those of intermediate thirteen Synthesis of steps one, two, three and four. LCMS (ESI) m/z: [M+1]=419.2.

Synthesis of Intermediate Thirty-One: 3-(3-Methyl-4-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2 , 6-dione

The N-Boc-4-piperidine methanol was replaced with N-Boc-4-hydroxypiperidine, and the rest of the required raw materials, reagents and preparation methods were the same as the synthesis of

steps

1, 2, 3 and 4 of intermediate 13. LCMS (ESI) m/z: [M+1]=393.1.

Synthesis of intermediate thirty-two: 3-(4-(1-((3-azacyclo[3.1.0]cyclohexane-6-yl)methyl)-1H-pyrazol-4-yl)- 3-Methyl-1H-indazol-1-yl)piperidine-2,6-dione

Replace N-Boc-4-piperidinemethanol with (1R,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester, the rest The required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1, 2, 3 and 4 of intermediate thirteen. LCMS (ESI) m/z: [M+1]=405.1.

Synthesis of Intermediate Thirty-Three: 3-(4-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-methyl-1H- Indazol-1-yl)piperidine-2,6-dione

Steps one to three, 6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1- Synthesis of tert-butyl)-2-azaspiro[3.3]hept-2-carboxylate

N-Boc-4-piperidinemethanol was replaced with 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, and the rest of the required raw materials, reagents and preparation methods were the same as the steps of intermediate thirteen Synthesis of one, two and three. LCMS (ESI) m/z: [M+1]=505.2.

Step 4. 3-(4-(1-(2-azaspiro[3.3]heptane-6-yl)-1H-pyrazol-4-yl)-3-methyl-1H-indazole-1- Synthesis of yl)piperidine-2,6-dione

The intermediate obtained in step 3 was dissolved in dichloromethane, cooled to 0° C., TFA was added, and the temperature was returned to room temperature. After the reaction was completed, the reaction solution was concentrated to dryness, and the obtained residue was directly used in the next reaction. LCMS (ESI) m/z: [M+1]=405.2.

Synthesis of intermediate thirty-four: 3-(3-methyl-4-(1-((octahydrocyclopenta[c]pyrrol-5-yl)methyl)-1H-pyrazol-4-yl)- 1H-Indazol-1-yl)piperidine-2,6-dione

Replace N-Boc-4-piperidinemethanol with 5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, and the rest of the required raw materials, reagents and preparation methods are the same as those in the middle Synthesis of

steps

1, 2, 3, and 4 of body thirteen. LCMS (ESI) m/z: [M+1]=433.2.

Synthesis of Intermediate Thirty-Five: 3-(4-(1-(2-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole-1) -yl)cyclohexyl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine- 2,6-Dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(3-methyl-4-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine The pyridine-2,6-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=646.3.

Synthesis of Intermediate Thirty-Six: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione replaced with 3-(3-methyl-4-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione, The other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=620.3.

Synthesis of Intermediate Thirty-Seven: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)-3-azabicyclo[3.1.0]cyclohex-6-yl)-methyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazole-1 -yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(4-(1-((3-azacyclo[3.1.0]cyclohexane-6-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-1H -Indazol-1-yl)piperidine-2,6-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=632.3.

Synthesis of Intermediate Thirty-Eight: 3-(4-(1-(2-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole-1) -yl)cyclohexyl)methyl)-2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine Pyridin-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(4-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl ) piperidine-2,6-dione, the other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=632.3.

Synthesis of Intermediate Thirty-Nine: 3-(4-(1-(2-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole-1) -yl)cyclohexyl)methyl)-octahydrocyclopenta[c]pyrrol-5-yl)methyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl ) piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(3-methyl-4-(1-((octahydrocyclopenta[c]pyrrol-5-yl)methyl)-1H-pyrazol-4-yl)-1H-indazol-1 - base) piperidine-2,6-dione, the other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=660.3.

Synthesis of Intermediate Forty: 1-(7-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

The synthesis of 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione refers to 1-(6-bromo-1 in patent WO2021127561 -Methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione prepared by the method of synthesis. LCMS (ESI) m/z: [M+1]=323.0. ¹ H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.66 (dd, J=7.7, 6.0 Hz, 2H), 7.03 (t, J=7.8 Hz, 1H), 4.29 (s, 3H) ), 3.90 (t, J=6.6 Hz, 2H), 2.77 (t, J=6.6 Hz, 2H).

Synthesis of intermediate forty-one: 1-(1-methyl-7-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-1H-indazol-3-yl) Dihydropyrimidine-2,4(1H,3H)-dione

3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione was replaced by 1-(7-bromo-1-methyl-1H-indazole- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of steps two and three of intermediate seven. LCMS (ESI) m/z: [M+1]=382.2.

Synthesis of intermediate forty-two: 1-(7-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole- 1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2, 4(1H,3H)-dione

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) oxy) piperidine was replaced by 1-(1-methyl-7-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-1H-indazol-3-yl)dihydro Pyrimidine-2,4(1H,3H)-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate eight. LCMS (ESI) m/z: [M+1]=609.3.

Synthesis of intermediate forty-three: 1-(1-methyl-7-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-1H-indazole -3-yl)dihydropyrimidine-2,4(1H,3H)-dione

4-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-yl)methyl)piperidine -1-Carboxylic acid tert-butyl ester was replaced with 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole-1 -yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester, 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6 -Diketone is replaced with 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, and the remaining required raw materials, reagents and preparations The method is the same as the synthesis of steps two and three of intermediate thirteen. LCMS (ESI) m/z: [M+1]=420.2.

Synthesis of Intermediate Forty-Four: 1-(7-(1-(2-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole-1) -yl)cyclohexyl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine -2,4(1H,3H)-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 1-(1-methyl-7-(1-(octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)di Hydropyrimidine-2,4(1H,3H)-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=647.3.

Synthesis of Intermediate Forty-Five: 1-(7-(1-((3-azabicyclo[3.1.0]cyclohex-6-yl)methyl)-1H-pyrazol-4-yl)-1 -Methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

4-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-yl)methyl)piperidine -1-Carboxylic acid tert-butyl ester was replaced with 6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole- 1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester, 3-(4-bromo-3-methyl-1H-indazol-1-yl) Piperidine-2,6-dione was replaced with 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, and the remaining The required raw materials, reagents and preparation methods are the same as the synthesis of steps two and three of intermediate thirteen. LCMS (ESI) m/z: [M+1]=390.2.

Synthesis of Intermediate Forty Six: 1-(7-(1-((3-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole- 1-yl)cyclohexyl)methyl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1H-indium oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 1-(7-(1-((3-azabicyclo[3.1.0]cyclohex-6-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1H- Indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate fourteen. LCMS (ESI) m/z: [M+1]=633.3.

Synthesis of intermediate forty-seven: 3-(4-(1-(2-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyridine) azol-1-yl)cyclohexyl)methyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazol-1-yl)piperidine- 2,6-Dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of intermediate fourteen. LCMS (ESI) m/z: [M+1]=648.3.

Synthesis of Intermediate Forty-Eight: 3-(3-Methyl-4-(3-(piperazin-1-yl)propoxy)-1H-indazol-1-yl)piperidine-2,6-dione

Step 1. Synthesis of 3-methyl-1H-indazol-4-ol

2,6-Dihydroxyacetophenone (2 g, 13.2 mmol) was dissolved in 20 mL of ethylene glycol, 10 mL of hydrazine hydrate was added, and the reaction solution was stirred at 160° C. for 3 hours. After the reaction was completed, ethyl acetate was added for extraction, the organic layer was washed with water, dried over sodium sulfate, filtered, concentrated, and the target product was obtained by column chromatography (PE/EA=10/1 to 5/1) with a yield of 77%. LCMS (ESI) m/z: [M+1]=149.2.

Step 2. Synthesis of tert-butyl 4-(3-((3-methyl-1H-indazol-4-yl)oxy)propyl)piperazine-1-carboxylate

3-Methyl-1H-indazol-4-ol (500 mg, 3.4 mmol) was dissolved in 10 mL of tetrahydrofuran, followed by the addition of 1-tert-butoxycarbonyl-4-(3-hydroxypropane)piperazine (907 mg, 3.7 mmol) , _PPh3 (1.2 g, 4.4 mmol) and DIAD (1.0 g, 5.1 mmol). After the addition was completed, the reaction solution was refluxed overnight, filtered with suction, the filtrate was concentrated, and subjected to column chromatography (PE/EA=10/1 to 1/1) to obtain 600 mg of product. Yield 48%. LCMS (ESI) m/z: [M+1]=375.1.

Step three, 4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)propyl)piperazine-1 -Synthesis of tert-butyl carboxylate

4-(3-((3-Methyl-1H-indazol-4-yl)oxy)propyl)piperazine-1-carboxylate tert-butyl ester was dissolved in (570 mg, 1.5 mmol) DMSO/THF (v /v=15mL/15mL), at 0 ℃, under nitrogen protection, add NaH (305mg, 7.6mmol), stir for 30min, then add KI (202mg, 1.2mmol) in 5mL DMSO solution and 3-bromopiperidine-2 , 6-dione (732 mg, 3.8 mmol) in tetrahydrofuran, gradually warmed to room temperature and stirred for 1 hour. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and the target product was obtained by column chromatography (PE/EA=3/1) in a yield of 30 %. LCMS (ESI) m/z: [M+1]=486.3.

Step 4. Synthesis of 3-(3-methyl-4-(3-(piperazin-1-yl)propoxy)-1H-indazol-1-yl)piperidine-2,6-dione

4-(3-((1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)propyl)piperazine-1-carboxylate Acid tert-butyl ester (220 mg, 0.45 mmol) was dissolved in 2 mL of dioxane, 3 mL of 4M HCl in dioxane solution was added, and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, it was concentrated and used directly for the next reaction. LCMS (ESI) m/z: [M+1]=386.2.

Synthesis of Intermediate Forty-Nine: 3-(4-(1-(6-azaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-3-methyl-1H- Indazol-1-yl)piperidine-2,6-dione

N-Boc-4-piperidinemethanol was replaced with 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester, and the remaining required raw materials, reagents and preparation methods were the same as those of intermediate thirteen Synthesis of steps one, two, three and four. LCMS (ESI) m/z: [M+1]=419.2.

Synthesis of intermediate fifty: 3-(3-methyl-4-(1-((R)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazol-1- yl)piperidine-2,6-dione

Replace N-Boc-4-piperidine methanol with (S)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine, and the rest of the required raw materials, reagents and preparation methods are the same as

steps

1 and 2 of intermediate thirteen , three, four synthesis. LCMS (ESI) m/z: [M+1]=379.1.

Synthesis of intermediate fifty-one: 3-(3-methyl-4-(1-((S)-pyrrolidin-3-yl)-1H-pyrazol-4-yl)-1H-indazole-1 -yl)piperidine-2,6-dione

Replace N-Boc-4-piperidinemethanol with (R)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine, and the rest of the required raw materials, reagents and preparation methods are the same as

steps

Synthesis of Intermediate fifty-two: (1r,4r)-4-(4-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-pyrazol-1-yl ) cyclohexane-1-carbaldehyde

Step 1. Synthesis of (1s, 4s)-4-(hydroxymethyl)cyclohexan-1-ol

Methyl cis-4-hydroxy-cyclohexylcarboxylate (90 g) was dissolved in THF, cooled to 0°C, and LiAlH4 (23 g) was added portionwise. After the addition was completed, react for half an hour, add aqueous sodium hydroxide solution, stir at 0 °C for 15 minutes, suction filtration, extract the filtrate with ethyl acetate, wash with water, dry over sodium sulfate, and concentrate to obtain a colorless oil, 60.88 g, which was produced rate 82%.

Step 2. Synthesis of (1s, 4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexan-1-ol

Dissolve (1s,4s)-4-(hydroxymethyl)cyclohexan-1-ol (60g) in dichloromethane, add triethylamine (49g), cool to 0°C, add DMAP (0.6g), TBSCl was added dropwise. After the dropping was completed, the reaction solution was stirred overnight, a saturated sodium bicarbonate solution was added to separate the layers, the organic layer was collected, dried over sodium sulfate, filtered with suction, and concentrated to obtain the product, 110 g, with a yield of 98%.

Step 3. Synthesis of (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexylmethanesulfonate

(1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexan-1-ol (10g) was dissolved in dichloromethane, triethylamine (12.5g) was added and DMAP (0.25 g), cooled to 0° C., methanesulfonic anhydride (10.7 g) was added, the reaction solution was gradually returned to room temperature, and stirred overnight. After the reaction was completed, water was added, extracted with dichloromethane, the organic layer was washed with dilute hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product, which was subjected to column chromatography to obtain compound 6.6 g with a yield of 50%.

Step 4. (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-4-(4,4,5,5-tetramethyl-1,3 , Synthesis of 2-dioxaboran-2-yl)-1H-pyrazole

4-Pyrazole boronic acid pinacol ester (2.0 g) was dissolved in 9 mL of DMF, Cs ₂ CO ₃ (3.4 g) was added, the temperature was raised to 90 ° C, and (1s, 4s)-4-(((tert-butyldi Methylsilyl)oxy)methyl)cyclohexylmethanesulfonate (2.2 g). Under nitrogen protection, it was stirred overnight. After the reaction, water was added, extracted with ethyl acetate, the organic layer was washed with water and saturated brine, concentrated and evaporated to dryness to obtain 2.5 g of crude product, which was obtained by column chromatography (5-10% EAinPE) to obtain 0.31 g of crude product.

Step 5. 3-(4-(1-((1r,4r)-4-(((tert-butyldimethylsilyl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-3 Synthesis of -methyl-1H-indazol-1-yl)piperidine-2,6-dione

4-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol-1-yl)methyl)piperidine -1-Carboxylic acid tert-butyl ester was replaced by (1s,4s)-4-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole, other required raw materials, reagents and preparation methods are the same as the synthesis of step 3 of intermediate thirteen. LCMS (ESI) m/z: [M+1]=536.3.

Step 6. 3-(4-(1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)-3-methyl-1H-indazole-1 -Synthesis of piperidine-2,6-dione.

3-(4-(1-((1r,4r)-4-(((tert-butyldimethylsilyl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-3-methyl yl-1H-indazol-1-yl)piperidine-2,6-dione (31mg) was dissolved in 2mL THF, 10uL pyridine hydrofluoric acid solution was added, stirred at room temperature overnight, added water, extracted with ethyl acetate, organic The layer was washed with water, NaHCO ₃ solution, saturated brine, dried over sodium sulfate, concentrated and evaporated to dryness to obtain a white solid, which was directly used in the next reaction. LCMS (ESI) m/z: [M+1]=422.2.

Step 7. (1r,4r)-4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyridine Synthesis of azol-1-yl)cyclohexane-1-carbaldehyde

The product of step 6 was dissolved in dichloromethane, cooled in an ice bath, added DMP (29.5 mg), reacted at room temperature overnight, quenched by adding NaHCO ₃ aqueous solution, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over sodium sulfate, Concentrated and evaporated to dryness to obtain the product. used directly in the next reaction.

Synthesis of intermediate fifty-three: 1-(1-methyl-7-(1-(piperidin-4-ylmethyl)-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H , 3H)-dione

3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione was replaced by 1-(7-bromo-1-methyl-1H-indazole- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of steps two and three of intermediate thirteen. LCMS (ESI) m/z: [M+1]=408.2.

Synthesis of Intermediate fifty-four: 1-(7-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H , 3H)-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 1-(1-methyl-7-(1-(piperidin-4-ylmethyl)-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione , and the other required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate 14. LCMS (ESI) m/z: [M+1]=635.3.

Synthesis of Intermediate Fifty-Five: Synthesis of (R)-2-methyl-1,4-homomorpholine

Step 1. Synthesis of 3-((4-methoxybenzyl)amino)propan-1-ol

3-Amino-1-propanol (2.0 g) was dissolved in 20 mL of THF, 0.16 mL of acetic acid and p-methoxybenzaldehyde (3.96 g) were added, the reaction was carried out at room temperature for 1 hour, NaBH(OAc) ₃ was added, and continued React overnight. After the completion of the reaction, the reaction solution was concentrated and used directly for the next reaction.

Step 2. Synthesis of (3-hydroxypropyl) (4-methoxybenzyl) tert-butyl carbamate.

3-((4-Methoxybenzyl)amino)propan-1-ol (2.0 g) was dissolved in 20 mL of methanol, and 1.7 mL of triethylamine and 2.68 g of (Boc) ₂ O were added at 0°C. , gradually warmed to room temperature, and stirred overnight. After completion of the reaction, it was concentrated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography (PE/EA=10/1 to 2/1) to obtain 1.37 g of pale yellow oil. LCMS (ESI) m/z (M+H-C4H8) ⁺ = 240.3.

Step 3. Synthesis of 3-((4-methoxybenzyl)amino)propan-1-ol hydrochloride

Dissolve 1.0 g of step 2 in dichloromethane, add 4M HCl, and stir at room temperature. When the reaction is completed, concentrate, and directly put into the next reaction. LCMS (ESI) m/z (M+H) ⁺ = 196.3.

Step 4. Synthesis of (S)-ethyl 2-(p-toluenesulfonyloxy) propionate

Dissolve 10 g of L(-)-ethyl lactate, 15.3 mL, and 1.03 g of DMAP in 100 mL of dichloromethane, add 17.75 g of p-toluoyl chloride, and stir at room temperature for 16 h. After the reaction was completed, water was added and extracted with ethyl ester. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography (PE/EA=100/1 to 10/1) to obtain 22.06 g of a yellow oil.

Step 5. Synthesis of (S)-2-(p-toluenesulfonyloxy) propionic acid

Dissolve NaOH (4.07g) in 25mL of water, add (S)-ethyl 2-(p-toluenesulfonyloxy)propionate (23.04g) in ethanol and aqueous solution (v/v=1.5:1), the addition is complete , the reaction solution was stirred at room temperature for 16 hours. The reaction solution was extracted with dichloromethane, the aqueous solution was collected, adjusted to pH 3-4, and extracted twice with ethyl acetate. The organic layer was collected, washed with saturated brine, dried over sodium sulfate, and concentrated to obtain 20.1 g of a pale yellow oil, which was directly used in the next reaction.

Step 6. Synthesis of 4-methyl-(S)-1-((3-hydroxypropyl)(4-methoxybenzyl)amino)-1-oxoprop-2-ylbenzenesulfonate

(S)-2-(p-toluenesulfonyloxy)propionic acid (627.3 mg) was dissolved in 6 mL of dichloromethane, 19.0 mg of DMF was added, cooled to 0°C, and oxalyl chloride (424.0 mg) was added dropwise. After dropping, the reaction solution was reacted at room temperature for 1 hour. The reaction solution was concentrated in vacuo at 25°C, the crude product was dissolved in THF, and at 0°C, 3-((4-methoxybenzyl)amino)propan-1-ol hydrochloride (675.4 mg) and trisodium chloride were added. In the THF and DMF solution (v/v=10/3) of ethylamine (3.56 mL), the reaction solution was reacted at room temperature for 3 hours, and after completion, concentrated to obtain the crude product, which was directly used in the next step. LCMS (ESI) m/z (M+H) ⁺ = 422.3.

Step 7. (R)-4-(4-methoxybenzyl)-2-methyl-1,4-oxazepan-3-one

4-Methyl-(S)-1-((3-hydroxypropyl)(4-methoxybenzyl)amino)-1-oxoprop-2-ylbenzenesulfonate (1.08 g) was dissolved in To 6 mL of THF, 4 mL of water was added, and at 0°C, NaOH (308.4 mg) was added, and the mixture was heated to 60°C and reacted for 16 hours. After the reaction was completed, water was added and extracted with ethyl ester. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography (PE/EA=10/1 to 2/1) to obtain 450 mg of yellow oil. LCMS (ESI) m/z (M+H) ⁺ = 250.2.

Step 8, (R)-4-(4-methoxybenzyl)-2-methyl-1,4-oxazepane

(R)-4-(4-methoxybenzyl)-2-methyl-1,4-oxazepin-3-one (300.0 mg) was dissolved in 10 mL of THF, at 0 °C, added 2M BH ₃ ·SMe ₂ (1.8 mL) was heated to 70°C and reacted for 3 hours. After the reaction was completed, 10 mL of methanol was added, the mixture was stirred at room temperature for 30 minutes, 6N NaOH was added, and the stirring was continued for 30 minutes. Water was added and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography (DCM/MeOH=100/1 to 20/1) to obtain the target product. LCMS (ESI) m/z (M+H) ⁺ = 236.4.

Step 9. Synthesis of (R)-2-methyl-1,4-homomorpholine

(R)-4-(4-Methoxybenzyl)-2-methyl-1,4-oxazepane (100 mg) was dissolved in 2 mL of DCE, and 1-chloroethane was added at 0°C Chloroformate (304.2 mg), the addition was completed, and the reaction was allowed to react at 80° C. for 4 hours. 2 mL of methanol was added, the reaction was carried out at 70° C. for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography (DCM/MeOH=100/1 to 20/1) to obtain the target product. LCMS (ESI) m/z (M+H) ⁺ = 116.4.

Synthesis of Intermediate fifty-six: (pyridin-4-yl)triphenylphosphorus triflate

Pyridine (20g, 0.25mol) was added to the dry reaction flask under nitrogen protection, cooled to -70°C, trifluoromethanesulfonic anhydride (71.33g, 0.25mol) was added dropwise, stirred for 30 minutes, triphenylphosphorus (72.95 mol) was added dropwise g, 0.28 mol), continue to stir for 30 minutes, add triethylamine (25.59 g, 0.25 mol) dropwise, warm to room temperature, add 200 ml of water, extract 3 times with dichloromethane, combine the dichloromethane layers, and dry over anhydrous magnesium sulfate , filtered, concentrated, added an appropriate amount of methyl tert-butyl ether, stirred for crystallization, filtered, and dried in vacuo at 50°C to give (pyridin-4-yl)triphenylphosphorus trifluoromethanesulfonate (110g), LCMS ( ESI) m/z: [M-TfO ⁻ ]=340.

Synthesis of Intermediate fifty-seven: N-Boc-4-((1r,3r)-3-hydroxy-1-methylcyclobutoxy)piperidine

Step 1. Synthesis of 3-benzyloxy-1-methylcyclobutanol

3-(benzyloxy)cyclobutanone (6.5g, 36.89mmol) was dissolved in 65ml of anhydrous tetrahydrofuran, the temperature was lowered to -10～0°C under nitrogen protection, and methylmagnesium chloride tetrahydrofuran solution (37ml, 3M, 110.66 mmol), then returned to room temperature and reacted for 3 hours, TLC showed that the reaction was complete, methanol (39 ml) was added dropwise to quench the reaction, concentrated to remove the solvent, and then the reaction was extracted with ethyl acetate and water, and then the water was mixed with ethyl acetate. The phases were extracted twice, and the organic phases were combined three times, washed with water and saturated aqueous sodium chloride solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain 3-benzyloxy -1-Methylcyclobutanol (5.56g) ¹ H NMR (600 MHz, Chloroform-d) δ 7.36-7.31 (m, 4H), 7.30-7.27 (m, 1H), 4.42 (s, 2H), 3.72 (p, J=6.8 Hz, 1H), 2.46-2.41 (m, 2H), 2.13-2.08 (m, 2H), 1.44 (s, 1H), 1.30 (s, 3H).

Step 2. Synthesis of 4-(3-benzyloxy-1-methylcyclobutoxy)pyridine

Sodium hydrogen (1.39 g, 34.7 mmol) was added to the reaction flask, anhydrous tetrahydrofuran (58 ml) was added, 3-benzyloxy-1-methylcyclobutanol (5.56 g, 28.92 mmol) was added, and the mixture was stirred at room temperature for 30 minutes , added (pyridin-4-yl) triphenylphosphorus trifluoromethanesulfonate (21.2g, 43.4mmol), stirred and heated to reflux and reacted overnight, added an appropriate amount of water to quench the reaction, concentrated to remove the solvent, and then used acetic acid Extracted with ethyl ester three times, combined the three extracted organic phases, washed sequentially with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified the residue by column chromatography to obtain 4-(3 -benzyloxy-1-methylcyclobutoxy)pyridine (2.9g). LCMS (ESI+) m/z: [M+1]=270.

Step 3. Synthesis of 1-benzyl-4-(3-benzyloxy-1-methylcyclobutoxy)pyridine-1-bromonium salt

Replace 4-(3-(benzyloxy)cyclobutoxy)pyridine with 4-(3-benzyloxy-1-methylcyclobutoxy)pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as those in the middle The second step of the synthesis of body sixteen, the yield is 80%. LCMS (ESI) m/z: [M-Br ⁻ ]=360.

Step 4. Synthesis of 1-benzyl-4-(3-benzyloxy-1-methylcyclobutoxy)-1,2,3,6-tetrahydropyridine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)piperidine-1-bromonium salt with 1-benzyl-4-(3-benzyloxy-1-methylcyclobutoxy) Pyridine-1-bromonium salt, other required raw materials, reagents and preparation methods are the same as the synthesis step 3 of intermediate sixteen, and the yield is 50%. LCMS (ESI) m/z: [M+1]=364.

Step 5. Synthesis of N-Boc-4-((1r,3r)-3-hydroxy-1-methylcyclobutoxy)piperidine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine with 1-benzyl-4-(3-benzyloxy-1-methyl) Cyclobutoxy)-1,2,3,6-tetrahydropyridine, the other required raw materials, reagents and preparation methods are the same as those of intermediate 16 synthesis step 4, and the yield is 80%. LCMS (ESI) m/z: [M+1]=286.

Synthesis of Intermediate fifty-eight: N-Boc-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)piperidine

Step 1. Synthesis of (1s,3s)-3-(hydroxymethyl)cyclobutanol

Under nitrogen protection, lithium tetrahydroaluminum (2.66 g, 0.07 mol) was dispersed in anhydrous tetrahydrofuran (90 mL), cooled to 0-5 °C in an ice-water bath, and methyl cis-3-hydroxycyclobutylcarboxylate (9.1 ℃) was added dropwise. g, 0.07mol) and 20ml of tetrahydrofuran, after adding, keep stirring and react at 0～5℃ for 3 hours, TLC shows that the reaction is complete, add water (2.66ml) dropwise under temperature control at 0～10℃, and then add 15% Aqueous sodium hydroxide solution (2.66ml), water (7.98ml) was added dropwise, stirred to warm to room temperature, then an appropriate amount of tetrahydrofuran and anhydrous sodium sulfate were added, stirred for 1 hour, filtered, and concentrated under reduced pressure to remove the solvent to obtain (1s, 3s )-3-(hydroxymethyl)cyclobutanol (5.7 g, 80.0% yield).

Step 2. Synthesis of (1s, 3s)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol

(1s, 3s)-3-(hydroxymethyl)cyclobutanol (5.7 g, 55.9 mmol) was dissolved in dichloromethane (50 mL), imidazole (5.7 g, 83.8 mmol) was added, cooled in an ice-water bath, and added dropwise tert-butyldimethylsilyl chloride (9.27g, 61.5mmol), continue to react for 3 hours, TLC shows that the reaction is complete, add water, extract with ethyl acetate, combine the organic phases, wash with water and saturated aqueous sodium chloride solution, anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain (1s, 3s)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol (9.0 g, yield: 75%) ). Step 3. Synthesis of ((1s,3s)-3-(pyridine-4-oxy)cyclobutyl)methanol

Sodium hydrogen (1.39g, 34.7mmol) was added to the reaction flask, anhydrous tetrahydrofuran (58ml) was added, and (1s, 3s)-3-(((tert-butyldimethylsilyl)oxy)methyl was added ) cyclobutanol (6.26g, 28.92mmol), stir at room temperature for 30 minutes, add (pyridin-4-yl) triphenylphosphorus trifluoromethanesulfonate (21.2g, 43.4mmol), stir and warm up to react under reflux Over night, add appropriate amount of water to quench the reaction, concentrate to remove the solvent, and then extract three times with ethyl acetate, combine the three times to extract the organic phase, add 1M hydrochloric acid to the organic phase to adjust the pH to 1-2, stir for 1 hour, separate the liquids, and extract the organic phase. The phases were washed once with 1M hydrochloric acid, and the two acid aqueous phases were combined, and the pH was adjusted to 8-9 by adding sodium carbonate, and then extracted three times with ethyl acetate. Washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain 4-(3-benzyloxy-1-methylcyclobutoxy)pyridine (2.0 g, 38.5%) ). LCMS (ESI+) m/z: [M+1]=180.

Step 4. Synthesis of 1-benzyl-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)pyridine-1-bromonium salt

Replace 4-(3-(benzyloxy)cyclobutoxy)pyridine with 4-(3-benzyloxy-1-methylcyclobutoxy)pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as those in the middle The second step of the synthesis of body sixteen, the yield is 80%. LCMS (ESI) m/z: [M-Br ⁻ ]=270.

Step 5. Synthesis of ((1s,3s)-3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)cyclobutyl)methanol

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)piperidine-1-bromonium salt with 1-benzyl-4-((1s,3s)-3-(hydroxymethyl)cyclobutane Oxy)pyridine-1-bromonium salt, other required raw materials, reagents and preparation methods are the same as the synthesis step 3 of intermediate sixteen, and the yield is 50%. LCMS (ESI) m/z: [M+1]=274.

Step 6. Synthesis of N-Boc-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)piperidine

Synthesis of Intermediate fifty-nine: N-Boc-4-(((1s,3s)-3-hydroxycyclobutyl)methoxy)piperidine

Step 1. Synthesis of (((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)(tert-butyl)dimethylsilane

(1s,3s)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol (2.16 g, 10 mmol) was dissolved in dry tetrahydrofuran (20 mL), followed by the addition of sodium hydrogen (0.48 g, 12 mmol), the reaction was stirred at room temperature for 10 minutes, and then benzyl bromide (2.05 g, 12 mmol) was added; after the reaction was completed, water was added, the solvent was removed by a rotary evaporator, and extracted twice with ethyl acetate, and the two extractions were combined. The obtained organic phase was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain (((1s, 3s)-3-(benzyloxy) yl)cyclobutyl)methoxy)(tert-butyl)dimethylsilane (1.84 g, yield: 60%).

Step 2. Synthesis of ((1s,3s)-3-(benzyloxy)cyclobutyl)methanol

(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)(tert-butyl)dimethylsilane (1.84 g, 6 mmol) was dissolved in tetrahydrofuran (18 mL), followed by the addition of hydrogen fluoride Pyridine (1.19 g, 12 mmol) was reacted at room temperature for 5 hours. After the completion of the reaction, add aqueous sodium carbonate solution, extract with ethyl acetate, combine the organic phases, wash with water and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain ((1s, 3s)- 3-(benzyloxy)cyclobutyl)methanol (1.11 g, yield: 96%).

Step 3. Synthesis of 4-(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)pyridine

Sodium hydrogen (0.20g, 5mmol) was added to the reaction flask, anhydrous tetrahydrofuran (10ml) was added, and ((1s,3s)-3-(benzyloxy)cyclobutyl)methanol (0.96g, 5mmol) was added, Stir at room temperature for 30 minutes, add (pyridin-4-yl) triphenylphosphonium triflate (3.67 g, 7.5 mmol), stir and warm up to reflux and react overnight, add an appropriate amount of water to quench the reaction, and concentrate to remove the solvent , extracted three times with ethyl acetate, combined the three extracted organic phases, washed sequentially with 0.5M hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and then used the residue with Purification by column chromatography gave 4-(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)pyridine (0.6 g, 44.5%). LCMS (ESI+) m/z: [M+1]=270.

Step 4. Synthesis of 1-benzyl-4-(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)pyridine-1-bromonium salt

Replace 4-(3-(benzyloxy)cyclobutoxy)pyridine with 4-(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)pyridine and the rest of the required starting materials , the reagents and the preparation method are the same as the second step of the synthesis of the intermediate sixteen, and the yield is 80%. LCMS (ESI) m/z: [M-Br ⁻ ]=360.

Step 5. Synthesis of 1-benzyl-4-(((1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)-1,2,3,6-tetrahydropyridine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)piperidine-1-bromonium salt with 1-benzyl-4-(((1s,3s)-3-(benzyloxy)ring Butyl)methoxy)pyridine-1-bromonium salt, the other required raw materials, reagents and preparation methods are the same as those of intermediate 16 synthesis step 3, and the yield is 50%. LCMS (ESI) m/z: [M+1]=364.

Step 6. Synthesis of N-Boc-4-(((1s,3s)-3-hydroxycyclobutyl)methoxy)piperidine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine with 1-benzyl-4-(((1s,3s)-3-( Benzyloxy)cyclobutyl)methoxy)-1,2,3,6-tetrahydropyridine, the rest of the required raw materials, reagents and preparation methods are the same as those of the intermediate 16 synthesis step 4, and the yield is 80%. LCMS (ESI) m/z: [M+1]=286.

Synthesis of Intermediate Sixty: 7-Hydroxy-4-methyl-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6-carbonitrile

Step 1. Synthesis of (1r,3r)-3-(hydroxymethyl)cyclobutanol

The cis-methyl 3-hydroxycyclobutylcarboxylate was replaced with methyl trans-3-hydroxycyclobutylcarboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as those of the intermediate fifty-eight synthesis step 1, and the yield was 80%. %.

Step 2. Synthesis of (1r,3r)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol

Replace (1s, 3s)-3-(hydroxymethyl) cyclobutanol with (1r, 3r)-3-(hydroxymethyl) cyclobutanol, and other required raw materials, reagents and preparation methods are the same as those of intermediate fifty Eight synthetic steps two, the yield is 78%.

Step 3. Synthesis of ((1r,3r)-3-(pyridine-4-oxy)cyclobutyl)methanol

Replace (1s,3s)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol with (1r,3r)-3-(((tert-butyldimethylsilyl) base) oxy) methyl) cyclobutanol, the rest of the required raw materials, reagents and preparation methods are the same as the synthesis step 3 of intermediate fifty-eight, and the yield is 40%. LCMS (ESI) m/z: [M+1]=180.

Step 4. Synthesis of 1-benzyl-4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)pyridine-1-bromonium salt

Replace (1s,3s)-3-(pyridin-4-oxy)cyclobutyl)methanol with ((1r,3r)-3-(pyridin-4-oxy)cyclobutyl)methanol, the rest required The raw materials, reagents and preparation method are the same as the synthesis step 4 of intermediate fifty-eight, and the yield is 80%. LCMS (ESI) m/z: [M-Br-]=270.

Step 5. Synthesis of ((1r,3r)-3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)cyclobutyl)methanol

Replace 1-benzyl-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)pyridine-1-bromonium salt with 1-benzyl-4-((1r,3r)- 3-(Hydroxymethyl)cyclobutoxy)pyridine-1-bromonium salt, other required raw materials, reagents and preparation method are the same as the synthesis step 5 of intermediate fifty-eight, and the yield is 50%. LCMS (ESI) m/z: [M+1]=274.

Step 6. Synthesis of N-Boc-4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)piperidine

Replace ((1s,3s)-3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)cyclobutyl)methanol with ((1r,3r)- 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)cyclobutyl)methanol, other required raw materials, reagents and preparation methods are synthesized with the intermediate fifty-eight In the sixth step, the yield is 50%. LCMS (ESI) m/z: [M+1]=286.

Synthesis of Intermediate Sixty-one: N-Boc-4-(((1r,3r)-3-hydroxycyclobutyl)methoxy)piperidine

Step 1. Synthesis of (((1r,3r)-3-(benzyloxy)cyclobutyl)methoxy)(tert-butyl)dimethylsilane

Replace (1s,3s)-3-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanol with (1r,3r)-3-(((tert-butyldimethylsilyl) base) oxy) methyl) cyclobutanol, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis step 1 of intermediate fifty-nine, and the yield is 60%.

Step 2. Synthesis of ((1r,3r)-3-(benzyloxy)cyclobutyl)methanol

Replace (1s,3s)-3-(benzyloxy)cyclobutyl)methoxy)(tert-butyl)dimethylsilane with (((1r,3r)-3-(benzyloxy)cyclobutane base) methoxy) (tert-butyl) dimethylsilane, the rest of the required raw materials, reagents and preparation methods are the same as the synthesis step 2 of intermediate fifty-nine, and the yield is 95%. Step 3. Synthesis of 4-(((1r,3r)-3-(benzyloxy)cyclobutyl)methoxy)pyridine

Replace (1s,3s)-3-(benzyloxy)cyclobutyl)methanol with ((1r,3r)-3-(benzyloxy)cyclobutyl)methanol, and other required raw materials, reagents and preparation methods Synthesis step 3 with intermediate fifty-nine, yield 40%. LCMS (ESI+) m/z: [M+1]=270.

Step 4. Synthesis of 1-benzyl-4-(((1r,3r)-3-(benzyloxy)cyclobutyl)methoxy)pyridine-1-bromonium salt

Replace 4-(3-(benzyloxy)cyclobutoxy)pyridine with 4-(((1r,3r)-3-(benzyloxy)cyclobutyl)methoxy)pyridine and the rest of the required starting materials , the reagents and the preparation method are the same as the second step of the synthesis of the intermediate sixteen, and the yield is 80%. LCMS (ESI) m/z: [M-Br-]=360.

Step 5. Synthesis of 1-benzyl-4-(((1r,3r)-3-(benzyloxy)cyclobutyl)methoxy)-1,2,3,6-tetrahydropyridine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)piperidine-1-bromonium salt with 1-benzyl-4-(((1r,3r)-3-(benzyloxy)ring Butyl)methoxy)pyridine-1-bromonium salt, the other required raw materials, reagents and preparation methods are the same as those of intermediate 16 synthesis step 3, and the yield is 50%. LCMS (ESI) m/z: [M+1]=364.

Step 6. Synthesis of N-Boc-4-(((1r,3r)-3-hydroxycyclobutyl)methoxy)piperidine

Replace 1-benzyl-4-(3-benzyloxycyclobutyl)-1,2,3,6-tetrahydropiperidine with 1-benzyl-4-((((1r,3r)-3-( Benzyloxy)cyclobutyl)methoxy)-1,2,3,6-tetrahydropyridine, the rest of the required raw materials, reagents and preparation methods are the same as those of the intermediate 16 synthesis step 4, and the yield is 80%. LCMS (ESI) m/z: [M+1]=286.

Synthesis of Intermediate Sixty-two: 3-(4-(((1S,3s)-3-((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)) -1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piper Pyridin-2,6-dione

Step 1 to Step 3: 3-(3-methyl-4-(((1s,3s)-3-(piperidin-4-oxy)cyclobutyl)methoxy)-1H-indazole-1- Synthesis of yl)piperidine-2,6-dione

4-(3-Benzyloxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester was replaced by N-Boc-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)piperidine pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps five, six and seven of the intermediate sixteen, and the yield of the three steps is 20%. LCMS (ESI) m/z: [M+1]=427.

Step 4 to Step 5: 3-(4-(((1S, 3s)-3-((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)-1H- Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piperidine-2 , the synthesis of 6-diketone

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced by 3-(4-(((1S,3s)-3-((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)-1H) -Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piperidine- 2,6-Diketone, other required raw materials, reagents and preparation methods are the same as the synthesis steps 1 and 2 of intermediate eight, and the yield of the second step is 50%. LCMS (ESI) m/z: [M+1]=654.

Synthesis of intermediate sixty-three: 3-(4-(((1R, 3r)-3-((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)) -1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piper Pyridin-2,6-dione

Step 1 to Step 3: 3-(3-methyl-4-(((1R,3r)-3-(piperidin-4-oxy)cyclobutyl)methoxy)-1H-indazole-1- Synthesis of yl)piperidine-2,6-dione

4-(3-Benzyloxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester was replaced by N-Boc-4-((1r,3r)-3-(hydroxymethyl)cyclobutoxy)piperidine pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps five, six and seven of the intermediate sixteen, and the yield of the three steps is 20%. LCMS (ESI) m/z: [M+1]=427.

Step 4 to Step 5: 3-(4-(((1R, 3r)-3-((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)-1H- Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piperidine-2 , the synthesis of 6-diketone

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced by 3-(4-(((1R,3r)-3-((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)-1H) -Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)cyclobutyl)methoxy)-3-methyl-1H-indazol-1-yl)piperidine- 2,6-Diketone, other required raw materials, reagents and preparation methods are the same as the synthesis steps 1 and 2 of intermediate eight, and the yield of the second step is 50%. LCMS (ESI) m/z: [M+1]=654.

Synthesis of intermediate sixty-four: 3-(4-((1S,3s)-3-(((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)- 1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)methyl)cyclobutoxy)-3-methyl-1H-indazol-1-yl)piperidine Synthesis of -2,6-dione

Step 1 to Step 3: 3-(3-methyl-4-((1s,3s)-3-((piperidin-4-oxy)methyl)cyclobutoxy)-1H-indazole-1- Synthesis of yl)piperidine-2,6-dione

4-(3-Benzyloxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester was replaced by N-Boc-4-(((1r,3r)-3-hydroxycyclobutyl)methoxy)piperidine pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps five, six and seven of the intermediate sixteen, and the yield of the three steps is 20%. LCMS (ESI) m/z: [M+1]=427.

Step 4 to Step 5: 3-(4-((1S, 3s)-3-(((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)-1H- Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)methyl)cyclobutoxy)-3-methyl-1H-indazol-1-yl)piperidine-2 , the synthesis of 6-diketone

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced by 3-(3-methyl-4-((1s,3s)-3-((piperidin-4-oxy)methyl)cyclobutoxy)-1H-indazole-1 - base) piperidine-2,6-dione, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps 1 and 2 of intermediate eight, and the yield of the second step is 50%. LCMS (ESI) m/z: [M+1]=654.

Synthesis of Intermediate Sixty-Five: 3-(4-((1R, 3r)-3-((((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)) -1H-Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)methyl)cyclobutoxy)-3-methyl-1H-indazol-1-yl)piperidine Pyridin-2,6-dione

Step 1 to Step 3: 3-(3-methyl-4-((1r,3r)-3-((piperidin-4-oxy)methyl)cyclobutoxy)-1H-indazole-1- Synthesis of yl)piperidine-2,6-dione

Replace 4-(3-benzyloxycyclobutyl)-piperidine-1-carboxylic acid tert-butyl ester with N-Boc-4-(((1s,3s)-3-hydroxycyclobutyl)methoxy)piperidine pyridine, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps five, six and seven of the intermediate sixteen, and the yield of the three steps is 20%. LCMS (ESI) m/z: [M+1]=427.

Step 4 to Step 5: 3-(4-((1R, 3r)-3-((((1-(((1r, 4R)-4-(4-amino-3-(difluoromethyl)-1H- Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)methyl)cyclobutoxy)-3-methyl-1H-indazol-1-yl)piperidine-2 , the synthesis of 6-diketone

4-((3-(1-(2,6-Dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1-yl) Oxy)piperidine was replaced by 3-(3-methyl-4-((1r,3r)-3-((piperidin-4-oxy)methyl)cyclobutoxy)-1H-indazole-1 - base) piperidine-2,6-dione, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis steps 1 and 2 of intermediate eight, and the yield of the second step is 50%. LCMS (ESI) m/z: [M+1]=654.

Synthesis of Intermediate Sixty-Six: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione replaced with 3-(4-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione ( The preparation method is similar to that of intermediate fourteen), and the other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=620.4.

Synthesis of Intermediate Sixty-Seven: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione (preparation method Similar to intermediate fourteen), other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=606.3.

Synthesis of intermediate sixty-eight: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione synthesis

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(6-fluoro-4-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidin-2,6 -diketone (the preparation method is similar to that of intermediate fourteen), and the other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=638.3.

Synthesis of intermediate sixty-nine: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(6-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-di Ketone (the preparation method is similar to that of intermediate fourteen), and other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=624.2.

Synthesis of Intermediate Seventy: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)ring Hexyl)methyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-5-fluoro-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(5-fluoro-4-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidin-2,6 -diketone (the preparation method is similar to that of intermediate fourteen), and the other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=638.3.

Synthesis of intermediate seventy-one: 3-(4-(1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) Cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-fluoro-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 3-(5-fluoro-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-di Ketone (the preparation method is similar to that of intermediate fourteen), and other required raw materials, reagents and preparation methods are the same as the synthesis steps one and two of intermediate fourteen. LCMS (ESI) m/z: [M+1]=624.2.

Synthesis of Intermediate Seventy-two: 1-(7-(1-(1-(((1r,4r)-4-(amino-3-(difluoromethyl)-1H-pyrazol-1-yl) )cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H )-dione

3-(3-Methyl-4-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with 1-(1-methyl-7-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, the rest The required raw materials, reagents and preparation methods are the same as the synthesis of

steps

1 and 2 of intermediate 14. LCMS (ESI) m/z: [M+1]=621.3.

Synthesis of intermediate seventy-three: 3-(4-((1S,3s)-3-((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl)) -1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-3-methylcyclobutoxy)-3-methyl-1H-indazol-1-yl ) piperidine-2,6-dione

Replace N-Boc-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)piperidine with N-Boc-4-((1r,3r)-3-hydroxy-1-methyl cyclobutoxy) piperidine, other required raw materials, reagents and preparation methods are the same as the synthesis of steps 1 to 5 of intermediate sixty-two. LCMS (ESI) m/z: [M+1]=654.4.

Synthesis of intermediate seventy-four: 3-(4-((1R,3r)-3-((1-(((1r,4R)-4-(4-amino-3-(difluoromethyl) -1H-Pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)oxy)-3-methylcyclobutoxy)-3-methyl-1H-indazol-1-yl ) piperidine-2,6-dione

Replace N-Boc-4-((1s,3s)-3-(hydroxymethyl)cyclobutoxy)piperidine with N-Boc-4-((1s,3s)-3-hydroxy-1-methyl cyclobutoxy) piperidine, other required raw materials, reagents and preparation methods are the same as the synthesis of steps 1 to 5 of intermediate sixty-two. LCMS (ESI) m/z: [M+1]=654.4.

The following is the synthesis of the compounds of the present invention.

Example 1: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of 4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Intermediate four (30.0 mg, 0.063 mmol) and intermediate nine (24.1 mg, 0.063 mmol) were dissolved in a mixed solution of DMF (0.2 mL) and THF (1 mL), and then acetic acid (11.4 mg, 0.19 mmol) and NaBH(OAc) ₃ (40.3 mg, 0.19 mmol), then under nitrogen protection, stirred at room temperature for 1 hour, when the reaction was completed, the organic solvent was removed by a rotary evaporator, and then purified by reverse MPLC to obtain N-( 3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl yl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Morpholinopyrazole[1,5-a]pyrimidine-3-carboxamide 25.6 mg (0.031 mmol, yield 48%). LCMS (ESI) m/z: [M+1]=837.

Embodiment 2: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinyl Synthesis of Pyrazole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazole[1,5-a]pyrimidine-3-carboxamide (15.6 mg, 0.019 mmol) was dissolved in a mixed solvent of 1 mL of tetrahydrofuran and 0.5 mL of methanol, and 10 mg of 20% hydrogen was added Palladium-carbon catalyst was oxidized, and then stirred at room temperature for 6 hours under a hydrogen atmosphere. When the reaction was completed, the catalyst was removed by filtration, the organic solvent was removed by a rotary evaporator, and purified by reverse-phase MPLC to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indol-4-yl)propoxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide (9.6 mg, 0.011 mmol, 60% yield) . LCMS (ESI) m/z: [M+1]=841.

Embodiment 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of 4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Intermediate four (50 mg) and intermediate seven (52.5 mg) were dissolved in a mixed solution of DMF (0.2 mL) and THF (1 mL), and then triethylamine (21.4 mg), acetic acid (19.0 mg) were added at -10°C and NaBH(OAc) ₃ (67.2 mg), then under nitrogen protection, stirred at room temperature for 1 hour, when the reaction was completed, the organic solvent was removed by a rotary evaporator, and then purified by reverse-phase MPLC to obtain N-(3-(difluoro) Methyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indole azol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazole [1,5-a]pyrimidine-3-carboxamide 31 mg, yield 35%. ¹ H NMR (400MHz, CDCl3) δ 9.45(s, 1H), 8.45(s, 1H), 8.35(d, J=8.0Hz, 1H), 8.45(br, 1H), 7.24-7.36(m, 3H) ), 6.74(t, J=54.4Hz, 1H), 6.41(d, J=8.0Hz, 1H), 5.24(dd, J=10.4, 5.2Hz, 1H), 4.49(s, 2H), 4.01-4.07 (m, 1H), 3.83-3.86 (m, 4H), 3.78-3.80 (m, 4H), 2.99-3.10 (m, 4H), 2.77-2.94 (m, 3H), 2.73 (s, 3H), 2.66 (m, 2H), 2.31-2.45 (m, 3H), 2.20-2.23 (m, 2H), 2.10-2.13 (m, 2H), 2.01-2.02 (m, 2H), 1.76-1.84 (m, 5H) , 1.19-1.25 (m, 2H). LCMS (ESI) m/z: [M+1]=838.

Embodiment 4: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinyl Synthesis of Pyrazole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazole[1,5-a]pyrimidine-3-carboxamide (20 mg, 0.024 mmol) was dissolved in a mixed solvent of 1 ml of tetrahydrofuran and 0.5 ml of methanol, and 10 mg of 20% hydroxide was added Palladium on carbon catalyst, then stirred at room temperature for 6 hours under a hydrogen atmosphere. When the reaction was completed, the catalyst was removed by filtration, the organic solvent was removed by a rotary evaporator, and purified by reverse-phase MPLC to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide (11 mg, 0.013 mmol, 54% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.45 (s, 1H), 8.40 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.26-7.32 (m, 2H), 7.15 (d, J=8.4Hz, 1H), 6.93 (d, J=7.2Hz, 1H), 6.78 (t, J=54Hz, 1H), 6.41 (d, J=7.6Hz, 1H), 5.24(dd, J=10.4, 5.6Hz, 1H), 4.02-4.09(m, 1H), 3.84-3.89(m, 4H), 3.78-3.81(m, 4H), 3.52(t, J=6.0Hz, 2H), 3.03-3.20(m, 3H), 2.76-2.90(m, 5H), 2.71(s, 3H), 2.61-2.66(m, 2H), 2.39-2.43(m, 1H), 2.20-2.23( m, 4H), 2.05-2.10 (m, 2H), 1.98-2.05 (m, 2H), 1.52-1.87 (m, 7H), 1.19-1.33 (m, 2H). LCMS (ESI) m/z: [ M+1]=842.

Embodiment 5: 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-( (1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indol-4-yl)propane -2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis

The intermediate 4 was replaced with the intermediate 6, and the other required raw materials, reagents and preparation methods were the same as those in Example 1, and the yield was 41%. LCMS (ESI) m/z: [M+1]=849.

Example 6: 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-( (1r,4R)-4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indol-4-yl)propoxy Synthesis of yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptane- 5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole -4-yl)pyrazo[1,5-a]pyrimidine-3-carboxamide, the other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 73%. LCMS (ESI) m/z: [M+1]=853.

Embodiment 7: 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptane-5-yl)-N-(3-(difluoromethyl)-1-( (1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propane -2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis

The intermediate 4 was replaced by the intermediate 6, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 3, and the yield was 23%. LCMS (ESI) m/z: [M+1]=850.

Example 8: 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-( (1r,4R)-4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy Synthesis of yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by 5-((4R)-2-oxa--5-azabicyclo[2.2.1]heptane- 5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole -4-yl)pyrazo[1,5-a]pyrimidine-3-carboxamide, the other required raw materials, reagents and preparation methods were the same as those in Example 2, and the yield was 79%. LCMS (ESI) m/z: [M+1]=854.

Example 9: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-pyrro[2,3-b]pyridin-4yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl) Synthesis of -1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced by the intermediate ten, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 50%. LCMS (ESI) m/z: [M+1]=838.3.

Example ten: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-pyrro[2,3-b]pyridin-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide synthesis

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-pyrro[2,3-b]pyridin-4yl)prop-2-yn- 1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine-3-methyl amide, the other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 81%. LCMS (ESI) m/z: [M+1]=842.

Example eleven: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1 -((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-pyrro[2,3- b] Pyridin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5 Synthesis of -a]pyrimidine-3-carboxamide

The intermediate four was replaced by the intermediate six, and the intermediate seven was replaced by the intermediate ten, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 23%. LCMS (ESI) m/z: [M+1]=850.

Example twelve: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-pyrrole[2,3- b]Pyridin-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide to 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane -5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-pyrro[2,3-b]pyridin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods were the same as those in Example 2, and the yield was 53%. LCMS (ESI) m/z: [M+1]=854.

Example thirteen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-7-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)- Synthesis of 1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 3, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-7-azaindazol-4-yl)propane- Synthesis of 2-alkynyl-1-yl)oxy)piperidine

3-methyl-4-bromo-1H-indazole is replaced with 3-methyl-4-bromo-1H-7-azaindazole, and the other required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven, to give 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-7-azaindazol-4-yl)prop-2-ynyl- 1-yl)oxy)piperidine in 16% overall yield over three steps. LCMS (ESI) m/z: [M+1]=382.

Step 4. N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-7-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-7-azaindazol-4-yl)propane- 2-Alkynyl-1-yl)oxy)piperidine, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 82%. LCMS (ESI) m/z: [M+1]=839.

Example fourteen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-1H-7-azaindazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-7-azaindazol-4-yl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, The other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 55%. LCMS (ESI) m/z: [M+1]=843.

Example fifteen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-6-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)- Synthesis of 1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 3, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-6-azaindazol-4-yl)propane- Synthesis of 2-alkynyl-1-yl)oxy)piperidine

3-methyl-4-bromo-1H-indazole is replaced with 3-methyl-4-bromo-1H-6-azaindazole, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven, to give 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-6-azaindazol-4-yl)prop-2-ynyl- 1-yl)oxy)piperidine in 11% overall yield over three steps. LCMS (ESI) m/z: [M+1]=382.

Step 4. N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-6-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-6-azaindazol-4-yl)propane- 2-Alkynyl-1-yl)oxy)piperidine, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 65%. LCMS (ESI) m/z: [M+1]=839.

Example sixteen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine)-3 -yl)-3-methyl-1H-6-azaindazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-6-azaindazol-4-yl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, The rest of the required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 44%. LCMS (ESI) m/z: [M+1]=843.

Example seventeen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-5-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)- Synthesis of 1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 3, 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-5-azaindazol-4-yl)propane- Synthesis of 2-alkynyl-1-yl)oxy)piperidine

3-methyl-4-bromo-1H-indazole is replaced with 3-methyl-4-chloro-1H-5-azaindazole, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven, to give 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-6-azaindazol-4-yl)prop-2-ynyl- 1-yl)oxy)piperidine in 17% overall yield over three steps. LCMS (ESI) m/z: [M+1]=382.

Step 4. N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-5-azaindazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-5-azaindazol-4-yl)propane- 2-Alkynyl-1-yl)oxy)piperidine, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 69%. LCMS (ESI) m/z: [M+1]=839.

Example 18: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-1H-5-azaindazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-5-azaindazol-4-yl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, The rest of the required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 76%. LCMS (ESI) m/z: [M+1]=843.

Example nineteen: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(2-(4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced with the intermediate twelve, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 63%. LCMS(ESI) m/z: [M+1]=878; (400MHz, DMSO-d6) δ 11.08(s, 1H), 9.40(s, 1H), 8.83(d, J=8.0Hz, 1H) , 8.44-8.36(m, 1H), 8.29(2s, 1H), 8.02(s, 1H), 7.63(s, 1H), 7.49(2s, 1H), 7.40-7.33(m, 1H), 7.23-6.95 (m, 2H), 6.91 (d, J=8.0Hz, 1H), 5.82-5.74 (m, 1H), 4.28-4.15 (m, 3H), 3.84-3.77 (m, 4H), 3.75-3.68 (m , 4H), 2.88-2.68(m, 5H), 2.31-2.20(m, 4H), 2.11-1.99(m, 4H), 1.90-1.82(m, 2H), 1.80-1.65(m, 8H), 1.40 -0.93(m, 6H).

Example 20: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(2-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethoxypiperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced with the intermediate fifteen, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 71%. LCMS (ESI) m/z: [M+1]=894.

Example 21: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-(2-(4-(1-(dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)propyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 5, 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H- Synthesis of Pyrazol-1-yl)propyl)piperidine Hydrochloride

Replace 4-(2-(hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester with 4-(2-(hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester), and the remaining required raw materials, reagents and preparations The method is the same as the synthesis of intermediate twelve to obtain 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl) )-1H-pyrazol-1-yl)propyl)piperidine hydrochloride, 9.2% overall yield over five steps. LCMS (ESI) m/z: [M+1]=435.

Step six, N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-(2-(4-(1-(dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)propyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl) Synthesis of -5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with 4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H- Pyrazol-1-yl)propyl)piperidine hydrochloride, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 63%. LCMS (ESI) m/z: [M+1]=892.

Example 22: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-morpholinimidazo[1,2-b]pyridazine-3-carboxamide

Step 1 to Step 4, N-(3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazol-4-yl)-6-morpholinyl Synthesis of Imidazo[1,2-b]pyridazine-3-carboxamide

Replacing ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate with ethyl 5-chloroimidazo[1,2-b]pyridazine-3-carboxylate, the rest of the required starting materials , reagents and preparation methods are the same as the synthesis of intermediate four to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazol-4-yl )-6-morpholinimidazo[1,2-b]pyridazine-3-carboxamide in 39% overall yield over four steps. LCMS (ESI) m/z: [M+1]=474.

Step five, N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-morpholinimidazo[1,2-b]pyridazine-3-carboxamide

Replace intermediate four with N-(3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazol-4-yl)-6-morpholinyl Imidazo[1,2-b]pyridazine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 84%. LCMS (ESI) m/z: [M+1]=838.

Example 23: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine) 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Synthesis of Linylimidazo[1,2-b]pyridazine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinimidazo[1,2-b]pyridazine-3-carboxamide, the rest required The raw materials, reagents and preparation method are the same as those in Example 2, and the yield is 75%. LCMS (ESI) m/z: [M+1]=842.

Example 24: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)hexahydrocyclopenta[C]pyrrol-2(1H)-yl)methan Synthesis of cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of 5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester

5-Hydroxyhexahydrocyclopenta[C]pyrrole-2(1H)-carboxylate tert-butyl ester (2.27 g, 10 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran, then sodium hydride (600 mg, 15 mmol) was added at 0°C, After stirring for 30 minutes, propargyl bromide (1.78 g, 15 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate. It was then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was then purified by column chromatography to obtain 5-(prop-2-yn-1-yloxy)hexahydrocyclopenta[C]pyrrole-2(1H)-carboxylate tert-butyl ester 1.81 g (6.82 mmol, yield 68%). LCMS (ESI) m/z: [M+1]=265.

Step 2 and Step 3, 3-(3-methyl-4-(3-((octahydrocyclopentane[c]pyrrol-5-yl)oxy)prop-1-yn-1-yl)-1H -Synthesis of indazol-1-yl)piperidine-2,6-dione

Replace N-Boc-4-propargyloxypiperidine with 3-(3-methyl-4-(3-((octahydrocyclopentane[c]pyrrol-5-yl)oxy)propan-1 -alkyn-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of intermediate seven steps two and three to obtain 3 -(3-Methyl-4-(3-((octahydrocyclopentane[c]pyrrol-5-yl)oxy)prop-1-yn-1-yl)-1H-indazol-1-yl ) piperidine-2,6-dione in 52% overall yield over two steps. LCMS (ESI) m/z: [M+1]=407.

Step 4. N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)hexahydrocyclopenta[C]pyrrol-2(1H)-yl)methyl)cycle Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate four with 3-(3-methyl-4-(3-((octahydrocyclopentane[c]pyrrol-5-yl)oxy)prop-1-yn-1-yl)-1H -Indazol-1-yl)piperidine-2,6-dione, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 67%. LCMS (ESI) m/z: [M+1]=864.

Example 25: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)hexahydrocyclopenta[C]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazole Synthesis of -4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((5 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy ) hexahydrocyclopenta[C]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine- 3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 48%. LCMS (ESI) m/z: [M+1]=868.

Example 26: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-((1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) Synthesis of -5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced by the intermediate sixteen, and the other required raw materials, reagents and preparation methods were the same as those in Example 3, and the yield was 43%.

LCMS (ESI) m/z: [M+1]=870; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz, 1H), 8.37(s, 1H), 8.29(s, 1H), 7.24-7.22(m, 1H), 7.20-7.10(m, 1H), 7.05(d, J=8.4Hz, 1H), 6.91 (d, J=8.0Hz, 1H), 6.36 (d, J=7.6Hz, 1H), 5.68-5.63 (m, 1H), 4.48 (t, J=7.2Hz, 1H), 4.17 (s, 1H) , 3.86(t, J=7.2Hz, 1H), 3.79(s, 4H), 3.72(s, 4H), 2.96-2.93(m, 2H), 2.86-2.80(m, 1H), 2.74-2.64(m , 4H), 2.55(s, 3H), 2.33-2.32(m, 1H), 2.24-2.17(m, 1H), 2.10-2.08(m, 2H), 2.03-1.97(m, 6H), 1.89-1.84 (m, 2H), 1.82-1.78 (m, 2H), 1.75-1.69 (m, 2H), 1.56-1.53 (m, 1H), 1.46-1.39 (m, 2H), 1.06-1.00 (m, 2H) .

Example 27: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-((1-(2,6-dioxopiperidine) Perid-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole Synthesis of -4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of (3-(benzyloxy)cyclobutyl)methanol

(3-(benzyloxy)cyclobutyl)carboxylic acid (2.06 g, 10 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, then lithium aluminum tetrahydride (760 mg, 20 mmol) was added at 0°C, followed by stirring at room temperature overnight. After the reaction was completed, 2M aqueous sodium hydroxide solution (10 mL) was added to quench. Then, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate, then dried over anhydrous sodium sulfate, and the solvent was removed by a rotary evaporator. The residue was further purified by column chromatography to obtain (3-(benzyloxy)cyclobutyl)methanol 1.54 g (8.0 mmol, 80% yield).

Step 2 to Step 8, 3-(3-methyl-4-(3-((piperidin-4-yloxy)methyl)cyclobutoxy)-1H-indazol-1-yl)piperidine Synthesis of -2,6-dione

The 3-benzyloxycyclobutanol was replaced with (3-(benzyloxy)cyclobutyl)methanol, and the rest of the required raw materials, reagents and preparation methods were the same as the synthesis of intermediate sixteen, and the total yield was 7%. LCMS (ESI) m/z: [M+1]=427.

Step 9, N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-((1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4- Synthesis of yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with 3-(3-methyl-4-(3-((piperidin-4-yloxy)methyl)cyclobutoxy)-1H-indazol-1-yl)piperidine -2,6-dione, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 66%. LCMS (ESI) m/z: [M+1]=884.

Example 28: N-(3-(difluoromethyl)-1-(2-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexyl)-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazole Synthesis of -4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced by the intermediate nineteen, and the intermediate four was replaced by the intermediate twenty, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 55%. LCMS (ESI) m/z: [M+1]=864.

Example 29: N-(3-(difluoromethyl)-1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1H-indazol-4-yl)propoxy)cyclohexyl)-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)-5-morpholine Synthesis of Pyrazole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-(2-(4-(((3-(1 -(2,6-Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexyl)-2- Azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, other required raw materials, The reagents and preparation method were the same as those in Example 2, and the yield was 83%. LCMS (ESI) m/z: [M+1]=868.

Example 30: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1 -(2-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn- 1-yl)oxy)cyclohexyl)-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-methan amide synthesis

The intermediate seven was replaced by the intermediate eighteen, and the intermediate four was replaced by the intermediate eighteen, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 61%. LCMS (ESI) m/z: [M+1]=876.

Example 31: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy)cyclohexyl )-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide to 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane -5-yl)-N-(3-(difluoromethyl)-1-(2-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexyl)-2-azaspiro[3.5]nonan-7-yl)-1H-pyrazole -4-yl)pyrazo[1,5-a]pyrimidine-3-carboxamide, the other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 72%. LCMS (ESI) m/z: [M+1]=880.

Example 32: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((R)-2-methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1 to Step 2, Synthesis of (R)-5-(2-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxylic acid

Replace morpholine with (R)-2-methylmorpholine, and the other required raw materials, reagents and preparation methods are the same as the synthesis of intermediate four steps one to two to obtain (R)-5-(2-methylmorpholine) ) Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxylic acid. LCMS (ESI) m/z: [M+1]=263.1.

Step three, N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-((R)-2-methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide synthesis of (R)-5-(2-methylmorpholine ) pyrazo[1,5-a]pyrimidine-3-carboxylic acid (80 mg) was dissolved in 3 mL of acetonitrile, TCFH (90 mg) and NMI (81 mg) were added successively. After 1 hour, 2 mL of intermediate eight (150 mg) was added DMF solution. The reaction was continued at room temperature for 16 hours. The acetonitrile was evaporated under reduced pressure, 50 mL of water was added, the solid was removed, and the filter cake was washed with 10 mL of water. The collected filter cake was dissolved in 2 mL of DMF, and purified by preparative HPLC to obtain 80 mg of white solid. LCMS (ESI) m/z: [M+1]=852; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.33 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.40(2s, 1H), 8.29(2s, 1H), 7.60(2s, 1H), 7.41-7.33(m, 1H), 7.28-6.99(m, 2H), 6.93(d, J=8.0 Hz, 1H), 5.82-5.73(m, 1H), 4.52(s, 2H), 4.22-4.11(m, 1H), 3.96-3.89(m, 1H), 3.66-3.51(m, 3H), 3.17- 3.05(m, 1H), 2.88-2.67(m, 6H), 2.65(s, 3H), 2.35-2.17(m, 2H), 2.13-1.98(m, 6H), 1.95-1.84(m, 4H), 1.81-1.43 (m, 6H), 1.19 (d, J=6.4Hz, 3H), 1.09-0.95 (m, 2H).

Example 33: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of (R)-2-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methylmorpholinyl)pyrazo[1,5-a]pyrimidine -3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 59%. LCMS (ESI) m/z: [M+1]=856; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.34 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.41(2s, 1H), 8.29(2s, 1H), 7.36(2s, 1H), 7.29-7.25(m, 1H), 7.25-6.97(m, 1H), 6.93(d, J=8.0 Hz, 1H), 6.88(d, J=6.8Hz, 1H), 5.76-5.67(m, 1H), 4.56-4.22(m, 2H), 4.21-4.11(m, 1H), 3.97-3.88(m, 1H), 3.65-3.53(m, 2H), 3.48(t, J=6.0Hz, 2H), 3.30-3.23(m, 1H), 3.18-2.97(m, 3H), 2.92-2.63(m, 6H) , 2.61(s, 3H), 2.24-2.18(m, 1H), 2.14-1.95(m, 6H), 1.90-1.74(m, 7H), 1.69-1.38(m, 4H), 1.19(d, J= 6.0 Hz, 3H), 1.12-0.91 (m, 2H).

Example 34: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((S)-2-methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with (S)-2-methylmorpholine, and the rest of the required raw materials, reagents and preparation method were the same as those of Example 32 to obtain N-(3-(two) Fluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H- Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((S) -2-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=852. ¹ H NMR (400MHz, DMSO-d6) δ 11.10 (s, 1H), 9.34 (s, 1H), 8.83 (d, J=8.0Hz, 1H), 8.41 (2s, 1H), 8.29 (2s, 1H) ), 7.60(2s, 1H), 7.40-7.34(m, 1H), 7.29-6.98(m, 2H), 6.93(d, J=8.0Hz, 1H), 5.86-5.72(m, 1H), 4.52( s, 2H), 4.45-4.31 (m, 1H), 4.29-4.13 (m, 1H), 3.96-3.89 (m, 1H), 3.67-3.51 (m, 3H), 3.16-3.03 (m, 1H), 2.92-2.66(m, 6H), 2.66(s, 3H), 2.28-2.20(m, 1H), 2.16-1.94(m, 6H), 1.95-1.70(m, 6H), 1.70-1.41(m, 4H) ), 1.19 (d, J=6.0 Hz, 3H), 1.12-0.90 (m, 2H).

Example thirty-five: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine) 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of (S)-2-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((S)-2-methylmorpholinyl)pyrazolo[1,5-a]pyrimidine -3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 54%. LCMS (ESI) m/z: [M+1]=856.

Example 36: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((R)-3-methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 3-(R)-3-methylmorpholine, and the rest of the required raw materials, reagents and preparation methods were the same as those in Example 32 to obtain N-(3- (Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(( R)-3-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=852.

Example thirty-seven: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of (R)-3-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-3-methylmorpholinyl)pyrazo[1,5-a]pyrimidine -3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 71%. LCMS (ESI) m/z: [M+1]=856.

Example thirty-eight: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((S)-3-methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 3-(S)-3-methylmorpholine, and the rest of the required raw materials, reagents and preparation method were the same as those in Example 32 to obtain N-(3- (Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(( S)-3-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=852.4.

Example 39: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of (S)-3-Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((S)-3-methylmorpholinyl)pyrazo[1,5-a]pyrimidine -3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 80%. LCMS (ESI) m/z: [M+1]=856.4.

Example 40: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole Synthesis of -4-yl)-5-(2,2-dimethylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 2,2-methylmorpholine, and the rest of the required raw materials, reagents and preparation methods were the same as those in Example 32 to obtain N-(3-(difluoromethyl) yl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole -4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2,2-di Methylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=866.4; ¹ H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.29 (s, 1H), 8.81 (d, J=7.9 Hz, 1H ), 8.38(s, 1H), 8.27(s, 1H), 7.60(d, J=8.5Hz, 1H), 7.39-7.35(m, 1H), 7.27-7.00(m, 2H), 6.93(d, J=7.9Hz, 1H), 5.80-5.76(m, 1H), 4.51(s, 2H), 4.20-4.14(m, 1H), 3.75-3.71(m, 4H), 3.67-3.62(m, 2H) , 3.60-3.58(m, 1H), 2.86-2.65(m, 8H), 2.27-2.23(m.1H), 2.10-2.01(m, 6H), 2.00-1.89(m, 4H), 1.75-1.72( m, 2H), 1.55-1.46 (m, 3H), 1.19, (s, 6H), 1.06-0.98 (m, 2H).

Example 41: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 2,2-Dimethylmorpholinyl)pyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2,2-dimethylmorpholinyl)pyrazolo[1,5-a]pyrimidine- 3-formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 69%. LCMS (ESI) m/z: [M+1]=870.4.

Example 42: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 4-oxa-7-azaspiro[2.5]octane, and the rest of the required raw materials, reagents and preparation methods were the same as those of Example 32 to obtain N- (3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5 -(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.0; ¹ H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.29 (s, 1H), 8.81 (d, J=7.9 Hz, 1H ), 8.41(m, 1H), 8.28(s, 1H), 7.60(d, J=8.5Hz, 1H), 7.39-7.35(m, 1H), 7.26-6.98(m, 2H), 6.92(d, J=7.9Hz, 1H), 5.80-5.75(m, 1H), 4.52(s, 2H), 4.20-4.14(m, 1H), 3.86-3.79(m, 2H), 3.79-3.77(m, 4H) , 3.63-3.57(m, 1H), 2.88-2.65(m, 8H), 2.44-2.32(m, 1H), 2.27-2.22(m, 6H), 1.91-1.89(m, 4H), 1.77-1.78( m, 2H), 1.57-1.48 (m, 3H), 1.06-0.97, (m, 2H), 0.77-0.71 (m, 2H), 0.67-0.64 (m, 2H).

Example forty-three: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazole [1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods were the same as those in Example 2, and the yield was 49%. LCMS (ESI) m/z: [M+1]=868.0.

Example forty-four: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of azol-4-yl)-5-(2-oxa-6-aza-spiro[3,4]octan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 2-oxa-6-aza-spiro[3,4]octane, and the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two, yields N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-(2-oxa-6-aza-spiro[3,4]octan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.5; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.62, 9.51 (2s, 1H), 8.77 (d, J= 7.2Hz, 1H), 8.39(s, 1H), 8.25(s, 1H), 7.60(d, J=8.4Hz, 1H), 7.39-7.35(m, 1H), 7.31-7.04(m, 2H), 6.56(d, J=7.7Hz, 1H), 5.80-5.76(m, 1H), 4.60-4.49(m, 6H), 4.20-4.15(m, 1H), 3.88-3.85(m, 2H), 3.65- 3.50(m, 3H), 2.86-2.65(m, 8H), 2.35-2.23(m, 3H), 2.11-2.02(m, 6H), 1.90-1.88(m, 4H), 1.78-1.69(m, 2H) ), 1.56-1.48 (m, 3H), 1.07-1.01 (m, 2H).

Example 45: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 2-oxa-6-aza-spiro[3,4]octan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2-oxa-6-aza-spiro[3,4]octan-6-yl ) Pyrazole[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 82%. LCMS (ESI) m/z: [M+1]=868.4.

Example 46: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of azol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 1,4-oxazepane, and all the other required raw materials, reagents and preparation method were the same as the synthesis of embodiment thirty-two to obtain N-(3-( Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H -Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(1, 4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=851.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.12-11.05 (m, 1H), 9.31 (s, 1H), 8.79 (d, J= 8.0Hz, 1H), 8.40(2s, 1H), 8.27(2s, 1H), 7.60(2s, 1H), 7.41-7.33(m, 1H), 7.27-6.94(m, 2H), 6.83(d, J =8.0Hz, 1H), 5.82-5.73(m, 1H), 4.52(s, 2H), 4.28-4.12(m, 1H), 4.09-3.81(m, 4H), 3.80-3.74(m, 2H), 3.70-3.63(m, 2H), 3.64-3.55(m, 1H), 2.91-2.67(m, 5H), 2.65(s, 3H), 2.28-2.20(m, 1H), 2.12-2.00(m, 5H) ), 1.96-1.84(m, 6H), 1.80-1.70(m, 2H), 1.70-1.41(m, 4H), 1.25-0.94(m, 2H).

Example forty-seven: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazol[1,5 -a] Pyrimidine-3-carboxamide, the other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 73%. LCMS (ESI) m/z: [M+1]=855.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.31 (s, 1H), 8.79 (d, J=8.0 Hz , 1H), 8.40(2s, 1H), 8.27(2s, 1H), 7.36(2s, 1H), 7.30-6.95(m, 2H), 6.90-6.86(m, 1H), 6.85-6.81(m, 1H) ), 5.76-5.68(m, 1H), 4.29-4.11(m, 1H), 4.11-3.80(m, 4H), 3.80-3.73(m, 2H), 3.70-3.63(m, 2H), 3.51-3.44 (m, 2H), 3.28-3.23 (m, 1H), 3.07-2.98 (m, 2H), 2.88-2.79 (m, 1H), 2.78-2.64 (m, 4H), 2.61 (s, 3H), 2.24 -2.18(m, 1H), 2.10-2.00(m, 5H), 1.91-1.69(m, 10H), 1.63-1.37(m, 4H), 1.12-0.94(m, 2H).

Example forty-eight: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of 4-yl)-5-(4-acetylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1-acetylpiperazine, and all the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl)- 1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-acetylpiperazine-1- yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=879.3.

Example 49: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 4-Acetylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-acetylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 60%. LCMS (ESI) m/z: [M+1]=883.

Example fifty: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole Synthesis of -4-yl)-5-(4-cyclopropanoylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1-cyclopropanecarbonylpiperazine, and the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl) yl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole -4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-cyclopropanemethyl) Acylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=905.4.

Embodiment fifty-one: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-( Synthesis of 4-Cyclopropanoylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-cyclopropanoylpiperazin-1-yl)pyrazol[1,5-a] Pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 75%. LCMS (ESI) m/z: [M+1]=909.

Embodiment fifty-two: N-(3-(difluoromethyl)-1-(1-(((1r, 4r)-4-(((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)cyclohexyl)methyl)piperidin-4-yl)-1H-pyridine Synthesis of oxazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced by the intermediate five, and the intermediate four was replaced by the intermediate eleven, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 78%. LCMS (ESI) m/z: [M+1]=838.1.

Embodiment fifty-three: N-(3-(difluoromethyl)-1-(1-(((1r,4r)-4-(3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)propoxy)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5- Synthesis of Linopyrazole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-(1-(((1r,4r)-4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, the rest of the required raw materials , reagents and preparation method are the same as those in Example 2, and the yield is 52%. LCMS (ESI) m/z: [M+1]=842.

Embodiment fifty-four: N-(3-(difluoromethyl)-1-(5-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)octahydropenten-2-yl)-1H-pyrazole-4 -yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of Bicyclo[3.3.0]octane-3,7-diol

Bicyclo[3.3.0]octane-3,7-dione (100 mmol, 13.8 g) was dissolved in 150 mL of methanol, then sodium borohydride (250 mmol, 9.5 g) was added at 0°C, stirred for 2 hours, and then recovered Stir to room temperature for 16 hours. After the reaction is completed, the reaction is extracted with ethyl acetate and water, and the aqueous phase is washed twice with ethyl acetate. The organic phase is collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent is removed with a rotary evaporator to obtain two. Cyclo[3.3.0]octane-3,7-diol (8.54 g, 61 mmol, 61% yield).

Step 2. Synthesis of 5-(tert-butyldimethylsiloxy) octahydropentalen-2-ol

Bicyclo[3.3.0]octane-3,7-diol (1.40 g, 10 mmol) was dissolved in 15 mL of DMF, and then TBSCl (1.51 g, 10 mmol) and imidazole (1.36 g, 20 mmol) were added at 0°C, respectively. and DMAP (122 mg, 1 mmol). Stir at room temperature for 4 hours. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and washed once with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was removed with a rotary evaporator. The residue was further purified by column chromatography to give 5-(tert-butyldimethylsiloxy)octahydropenten-2-ol (1.56 g, 6.10 mmol, 61% yield).

Step 3. Synthesis of 2-methanesulfonyloxy-5-(tert-butyldimethylsiloxy) octahydropentalyne

5-(tert-butyldimethylsiloxy)octahydropenta-2-ol (1.56 g, 6.10 mmol) was dissolved in 20 mL of dichloromethane, and then triethylamine (2.02 g, 20 mmol) and methanesulfonyl chloride (1.05 g, 9.15 mmol), gradually warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. 2-Methanesulfonyloxy-5-(tert-butyldimethylsilyloxy)octahydropentahydropentene (1.74 g, 5.2 mmol, 85% yield) was obtained.

Step 4 to Step 6, N-(3-(difluoromethyl)-1-(5-(tert-butyldimethylsiloxyoctahydropenta-2-yl)-1H-pyrazole-4 -yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

-Methanesulfonyloxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester was replaced by 2-methanesulfonyloxy-5-(tert-butyldimethylsiloxy)octahydro Pentyrene, the other required raw materials, reagents and preparation methods are the same as the synthesis steps 2 to 4 of the intermediate 18, and the yield is 21%. LCMS (ESI) m/z: [M+1]=602.

Step 7, N-(3-(difluoromethyl)-1-(5-hydroxyoctahydropentalyn-2-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazole[ Synthesis of 1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-(5-(tert-butyldimethylsiloxyoctahydropentalyn-2-yl)-1H-pyrazol-4-yl)-5 -Morpholinylpyrazole[1,5-a]pyrimidine-3-carboxamide (301 mg, 0.5 mmol) was dissolved in 3 mL of tetrahydrofuran, then 2M TBAF solution in tetrahydrofuran (3 mL, 10 mmol) was added. Stir at room temperature for 4 hours, wait for After the reaction was completed, the solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain N-(3-(difluoromethyl)-1-(5-hydroxyoctahydropentalyn-2-yl) -1H-Pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide (185 mg, 0.38 mmol, 76% yield). LCMS (ESI) m/z : [M+1]=488.

Step 8, N-(3-(difluoromethyl)-1-(5-oxooctahydropentalyn-2-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazole Synthesis of [1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-(5-hydroxyoctahydropentaven-2-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1, 5-a]Pyrimidine-3-carboxamide (185 mg, 0.38 mmol) was dissolved in 5 mL of dichloromethane, then Dess-Martin oxidant (191 mg, 0.45 mmol) was added and allowed to react overnight at room temperature. After the reaction was completed, an aqueous sodium bicarbonate solution was added for extraction, the aqueous phase was washed twice with dichloromethane, the organic phase was collected and the solvent was removed by a rotary evaporator. The residue was further purified by column chromatography to give N-(3-(difluoromethyl)-1-(5-oxooctahydropenten-2-yl)-1H-pyrazol-4-yl) -5-Morpholinylpyrazo[1,5-a]pyrimidine-3-carboxamide (123 mg, 0.25 mmol, 67% yield). LCMS (ESI) m/z: [M+1]=486.

Step 9, N-(3-(difluoromethyl)-1-(5-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)octahydropenten-2-yl)-1H-pyrazol-4-yl) Synthesis of -5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

Replaced intermediate four with N-(3-(difluoromethyl)-1-(5-oxooctahydropentalyn-2-yl)-1H-pyrazol-4-yl)-5-morpholine Pyrazole[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 3, and the yield is 62%. LCMS (ESI) m/z: [M+1]=850.3.

Embodiment fifty-five: N-(3-(difluoromethyl)-1-(5-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl)octahydropenten-2-yl)-1H-pyrazol-4-yl)-5-morpholinylpyridine Synthesis of Azole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-(5-(4-(((3-(1 -(2,6-Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl ) Octahydropentalyn-2-yl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and The preparation method is the same as that of Example 2, and the yield is 80%. LCMS (ESI) m/z: [M+1]=854.4.

Example fifty-six: 5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1- (6-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn- 1-yl)oxy)piperidin-1-yl)methyl)spiro[3.3]heptane-2-)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

The intermediate two was replaced with the intermediate twenty-one, and the remaining required raw materials, reagents and preparation methods were the same as those of the third embodiment, and the yield was 62%. LCMS (ESI) m/z: [M+1]=862.3.

Example fifty-seven: 5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1- (6-((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidine- Synthesis of 1-yl)methyl)spiro[3.3]heptane-2-)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by 5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5 -yl)-N-(3-(difluoromethyl)-1-(6-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)spiro[3.3]heptane-2-)-1H-pyrazole -4-yl)pyrazo[1,5-a]pyrimidine-3-carboxamide, the other required raw materials, reagents and preparation methods were the same as those in Example 2, and the yield was 47%. LCMS (ESI) m/z: [M+1]=866.

Example fifty-eight: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl )oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

The intermediate two was replaced by the intermediate twenty-two, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 42%. LCMS (ESI) m/z: [M+1]=849.3.

Example fifty-nine: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide synthesis

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide to 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3- (Difluoromethyl)-1-((1R,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazol-4- Formamide, other required raw materials, reagents and preparation methods are the same as in Example 2, and the yield is 47%. LCMS (ESI) m/z: [M+1]=853.3.

Example 60: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)-5 -Synthesis of morpholinopyrazole[1,5-a]pyrimidine-3-carboxamide

Intermediate twenty-three (49 mg, 0.1 mmol) and intermediate twenty-five (37 mg, 0.1 mmol) were dissolved in 1 mL of DMF, followed by the addition of HATU (42 mg, 1.1 mmol) and DIPEA (39 mg, 0.3 mmol). The reaction was carried out at room temperature for 16 hours, then water and ethyl acetate were added for extraction, and the aqueous phase was washed twice with ethyl acetate. The organic phase was collected and the solvent was removed by a rotary evaporator. The residue was then purified by reverse MPLC to give N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxo) piperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazole- 4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide (41 mg, 0.049 mmol, 49% yield). LCMS (ESI) m/z: [M+1]=837; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.38(s, 1H), 8.29(s, 1H), 7.58(2s, 1H), 7.39-7.32(m, 1H), 7.25-6.94(m, 2H), 6.91(d, J=8.0 Hz, 1H), 5.83-5.70(m, 1H), 4.32-4.19(m, 1H), 3.81-3.65(m, 10H), 3.62-3.48(m, 4H), 2.87-2.67(m, 4H), 2.65(s, 3H), 2.63-2.52(m, 4H), 2.29-2.20(m, 1H), 2.08-1.99(m, 2H), 1.92-1.75(m, 4H), 1.62-1.48(m, 2H) ).

Example 61: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidine)-3 -yl)-3-methyl-1H-indazol-4-yl)propyl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazole Synthesis of [1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-(4- (3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1 -Formyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as the implementation Example 2, the yield was 56%. LCMS (ESI) m/z: [M+1]=840.9; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.41 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(s, 1H), 8.29(s, 1H), 7.36(2s, 1H), 7.29-7.24(m, 1H), 7.10(t, J=53.6Hz, 1H), 6.93-6.87( m, 2H), 5.75-5.67 (m, 1H), 4.32-4.19 (m, 1H), 3.82-3.68 (m, 8H), 3.56-3.43 (m, 4H), 3.04-2.95 (m, 2H), 2.92-2.80(m, 1H), 2.74-2.66(m, 3H), 2.62(s, 3H), 2.42-2.30(m, 6H), 2.25-2.17(m, 1H), 2.08-1.98(m, 2H) ), 1.89-1.75 (m, 6H), 1.62-1.49 (m, 2H).

Example 62: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl )Prop-2-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

The intermediate twenty-three was replaced by the intermediate twenty-four, and the other required raw materials, reagents and preparation methods were the same as those in Example 60, and the yield was 56%. LCMS (ESI) m/z: [M+1]=849.

Example 63: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl ) Propyl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptyl Alk-5-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidine)- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl) Pyrazole[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 39%. LCMS (ESI) m/z: [M+1]=853.

Example 64: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl ) But-3-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

The intermediate twenty-five was replaced by the intermediate twenty-six, and the remaining required raw materials, reagents and preparation methods were the same as those in Example 60, and the yield was 50%. LCMS (ESI) m/z: [M+1]=851; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.41 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(s, 1H), 8.29(s, 1H), 7.53(2s, 1H), 7.36-7.30(m, 1H), 7.25-6.95(m, 2H), 6.91(d, J=8.0 Hz, 1H), 5.79-5.71(m, 1H), 4.31-4.18(m, 1H), 3.82-3.70(m, 8H), 3.58-3.53(m, 5H), 3.50-3.44(m, 2H), 2.76-2.70(m, 4H), 2.69-2.63(m, 6H), 2.44-2.39(m, 2H), 2.28-2.20(m, 1H), 2.06-1.99(m, 2H), 1.91-1.75(m , 4H), 1.62-1.48 (m, 2H).

Example 65: 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl )Butyl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptyl Alkyl-5-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(4-(1-(2,6-dioxopiperidine)- 3-yl)-3-methyl-1H-indazol-4-yl)but-3-yn-1-yl)piperazine-1-formyl)cyclohexyl)-1H-pyrazol-4-yl) Pyrazole[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 29%. LCMS (ESI) m/z: [M+1]=855; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.41 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(s, 1H), 8.29(s, 1H), 7.36(2s, 1H), 7.29-7.24(m, 1H), 7.10(t, J=54.0Hz, 1H), 6.94-6.86( m, 2H), 5.76-5.65 (m, 1H), 4.31-4.20 (m, 1H), 3.82-3.69 (m, 8H), 3.53-3.41 (m, 4H), 3.01-2.94 (m, 2H), 2.90-2.79(m, 1H), 2.75-2.65(m, 3H), 2.62(s, 3H), 2.39-2.31(m, 4H), 2.31-2.17(m, 3H), 2.08-1.99(m, 2H) ), 1.90-1.74 (m, 4H), 1.69-1.50 (m, 6H).

Example 66: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidine)-3 -yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1-methylene)cyclohexyl)-1H-pyrazol-4-yl) Synthesis of -5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced with the intermediate twenty-five, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 61%. LCMS (ESI) m/z: [M+1]=823.

Example 67: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-1H-indazol-4-yl)propyl)piperazine-1-methylene)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyridine Synthesis of Azole[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-(4- (3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)piperazine-1 -Methylene)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same Example 2, the yield was 66%. LCMS (ESI) m/z: [M+1]=827.

Example 68: N-(3-(difluoromethyl)-1-((1r,4r)-4-(5-(3-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)octahydropyrrole[3,4-C]opyrrole-2-formyl)cyclohexyl)- Synthesis of 1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate twenty-five was replaced by the intermediate twenty-seven, and the other required raw materials, reagents and preparation methods were the same as those in Example 60, and the yield was 36%. LCMS (ESI) m/z: [M+1]=862.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.37(2s, 1H), 8.30(s, 1H), 7.57(2s, 1H), 7.37-7.31(m, 1H), 7.25-6.95(m, 2H), 6.91(d, J=8.0 Hz, 1H), 5.82-5.72(m, 1H), 4.25-4.13(m, 1H), 3.83-3.70(m, 11H), 3.53-3.42(m, 2H), 2.93-2.76(m, 5H), 2.75-2.54 (m, 8H), 2.23-2.12 (m, 1H), 2.06-1.88 (m, 2H), 1.85-1.66 (m, 5H), 1.57-1.37 (m, 2H).

Example 69: N-(3-(difluoromethyl)-1-((1r,4r)-4-(5-(3-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-1H-indazol-4-yl)propyl)octahydropyrrole[3,4-C]opyrrole-2-formyl)cyclohexyl)-1H-pyrazole-4- yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide synthesis

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-(5- (3-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)octahydropyrrole[ 3,4-C]Pyrropyrrole-2-formyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide, the rest The required raw materials, reagents and preparation method are the same as those in Example 2, and the yield is 38%. LCMS (ESI) m/z: [M+1]=867; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.38(s, 1H), 8.29(s, 1H), 7.35(2s, 1H), 7.28-7.23(m, 1H), 7.10(t, J=54.0Hz, 1H), 6.93-6.86( m, 2H), 5.75-5.65 (m, 1H), 4.30-4.19 (m, 1H), 3.82-3.68 (m, 9H), 3.57-3.50 (m, 1H), 3.42-3.37 (m, 1H), 3.26-3.21(m, 1H), 3.03-2.93(m, 2H), 2.89-2.78(m, 2H), 2.75-2.66(m, 3H), 2.60(s, 3H), 2.48-2.30(m, 7H) ), 2.24-2.17 (m, 1H), 2.08-1.98 (m, 2H), 1.87-1.74 (m, 6H), 1.62-1.45 (m, 2H).

Example seventy: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-(2-(4-(1-(dioxopiperidine-3- (yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by morpholine, intermediate eight was replaced by intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods were the same as those in the synthesis of embodiment thirty-two to obtain N-(3- (Difluoromethyl)-1-((1r,4r)-4-((4-(2-(4-(1-(dioxopiperidin-3-yl)-3-methyl-1H- Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinylpyrazole [1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=863.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0Hz, 1H), 8.40 (2s, 1H), 8.29 (2s, 1H), 7.99-7.93 (m, 1H), 7.64 (2s, 1H), 7.49 ( 2s, 1H), 7.40-7.33(m, 1H), 7.29-7.08(m, 1H), 6.98-6.95(m, 1H), 6.93-6.89(m, 1H), 5.83-5.71(m, 1H), 4.25-4.13(m, 1H), 4.11-4.03(m, 2H), 3.83-3.76(m, 4H), 3.75-3.69(m, 4H), 2.90-2.69(m, 5H), 2.30-2.21(m , 4H), 2.10-2.00 (m, 3H), 1.89-1.70 (m, 7H), 1.60-1.44 (m, 4H), 1.30-1.20 (m, 2H), 1.16-0.94 (m, 2H).

Example 71: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-(2-oxa-6-aza-spiro[3,3]heptan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 2-oxa-6-aza-spiro[3,3]heptane, and the rest of the required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two, yields N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-(2-oxa-6-aza-spiro[3,3]heptan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=849.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.69 (s, 1H), 8.76 (d, J=8.0 Hz , 1H), 8.39(2s, 1H), 8.25(2s, 1H), 7.60(2s, 1H), 7.40-7.34(m, 1H), 7.31-7.00(m, 2H), 6.38(d, J=7.6 Hz, 1H), 5.81-5.75(m, 1H), 4.74(s, 4H), 4.52(s, 2H), 4.38(s, 4H), 4.28-4.11(m, 1H), 3.67-3.57(m, 1H), 2.87-2.68(m, 4H), 2.66(s, 3H), 2.34-2.17(m, 2H), 2.15-1.82(m, 10H), 1.76-1.44(m, 5H), 1.24-0.93( m, 2H).

Example seventy-two: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)propyl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-(2-oxa-6-aza-spiro[3,3]heptan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((4 -((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy )piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2-oxa-6-aza-spiro[3,3]heptan-6-yl ) Pyrazole[1,5-a]pyrimidine-3-carboxamide, other required raw materials, reagents and preparation methods are the same as those in Example 2, and the yield is 51%. LCMS (ESI) m/z: [M+1]=853.9; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.69 (s, 1H), 8.76 (d, J=7.6 Hz , 1H), 8.39(2s, 1H), 8.25(2s, 1H), 7.36(2s, 1H), 7.30-7.25(m, 1H), 7.25-7.01(m, 1H), 6.89(d, J=7.2 Hz, 1H), 6.38 (d, J=7.6Hz, 1H), 5.76-5.66 (m, 1H), δ4.74 (s, 4H), 4.39 (s, 4H), 4.24-4.12 (m, 1H) , 3.48(t, J=6.0Hz, 2H), 3.06-2.99(m, 2H), 2.89-2.81(m, 1H), 2.75-2.65(m, 4H), 2.62(s, 3H), 2.23-2.19 (m, 1H), 2.12-2.00 (m, 6H), 1.88-1.73 (m, 8H), 1.60-1.39 (m, 4H), 1.11-0.95 (m, 2H).

Example seventy-three: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-7-azaindol-4-yl)prop-2-yne Synthesis of -1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

The intermediate four was replaced by the intermediate twenty-two, and the intermediate seven was replaced by the intermediate ten, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 42%. LCMS (ESI) m/z: [M+1]=849.

Example seventy-four: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-7-azaindol-4-yl)propoxy)piperidine Synthesis of -1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide to 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3- (Difluoromethyl)-1-((1R,4R)-4-((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H Synthesis of -7-azaindol-4-yl)propoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide, the rest The required raw materials, reagents and preparation method are the same as those in Example 2, and the yield is 45%. LCMS (ESI) m/z: [M+1]=855.

Example 75: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)propoxy Synthesis of (methyl)propyl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Replace N-Boc-4-propargyloxypiperidine with tert-butylmethyl(3-(prop-2-yn-1-yloxy)propyl)carbamoyl tert-butyl ester in the synthesis of intermediate ten . The rest of the required raw materials, reagents and preparation methods are the same as the synthesis of the compound in Example 74. LCMS (ESI) m/z: [M+1]=841.

Example seventy-six: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4- ((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propoxy)propyl)(methyl ) Amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide synthesis

Replace N-Boc-4-propargyloxypiperidine with tert-butylmethyl(3-(prop-2-yn-1-yloxy)propyl)carbamoyl tert-butyl ester in the synthesis of intermediate ten . The rest of the required raw materials, reagents and preparation methods are the same as the synthesis of the compound in Example 59. LCMS (ESI) m/z: [M+1]=841.

Example 77: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl )-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

Replace (R)-2-methylmorpholine with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, and replace intermediate eight with intermediate fourteen, and the rest are required The raw materials, reagents and preparation methods are the same as those in the synthesis of Example 32, to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N- (3-(Difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl base-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazole 1,5-a]pyrimidine-3-carboxamide. LCMS(ESI) m/z: [M+1]=875.9;

¹ H NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 9.50 (d, J=6.4Hz, 1H), 8.79 (d, J=7.6Hz, 1H), 8.45-8.35 (m, 1H) ), 8.28-8.22(m, 1H), 8.01-7.90(m, 1H), 7.66-7.61(m, 1H), 7.52-7.46(m, 1H), 7.40-7.32(m, 1H), 7.30-7.07 (m, 1H), 7.01-6.93 (m, 1H), 6.91-6.42 (m, 1H), 5.81-5.74 (m, 1H), 5.18 (2s, 1H), 4.83-4.71 (m, 1H), 4.30 -4.12(m, 1H), 4.07(d, J=6.8Hz, 2H), 3.85-3.70(m, 2H), 3.68-3.41(m, 2H), 2.99-2.79(m, 3H), 2.80-2.59 (m, 2H), 2.31-2.21 (m, 4H), 2.13-1.92 (m, 6H), 1.90-1.73 (m, 6H), 1.63-1.42 (m, 4H), 1.33-0.92 (m, 4H) .

Example seventy-eight: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(difluoromethyl)-1-( (1r,4R)-4-((4-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)- Synthesis of 1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate forty-seven, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(Difluoromethyl)-1-((1r,4R)-4-((4-2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=889.8, ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.79 (d , J=7.6Hz, 1H), 8.45-8.34(m, 1H), 8.29-8.20(m, 1H), 8.02(s, 1H), 7.63(s, 1H), 7.49(2s, 1H), 7.41- 7.31(m, 1H), 7.28-6.92(m, 2H), 6.89-6.42(m, 1H), 5.83-5.71(m, 1H), 5.18(2s, 1H), 4.81-4.71(m, 1H), 4.26-4.13(m, 3H), 3.85-3.71(m, 2H), 3.68-3.41(m, 2H), 2.90-2.68(m, 5H), 2.30-2.21(m, 4H), 2.10-1.93(m , 6H), 1.92-1.84 (m, 2H), 1.80-1.73 (m, 5H), 1.69-1.51 (m, 4H), 1.21-1.11 (m, 3H), 1.09-0.92 (m, 2H).

Example 79: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-(2-(4-(1-(2,6-dioxopipine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide.

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate forty-seven, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-(((4-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl) yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)ethyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.44-8.36(m, 1H), 8.29(2s, 1H), 8.02(s, 1H), 7.63(s, 1H), 7.49(2s, 1H), 7.40-7.33(m, 1H), 7.23-6.95(m, 2H), 6.91(d, J=8.0Hz, 1H), 5.82-5.74(m, 1H), 4.28-4.15(m, 3H), 3.84-3.77(m, 4H), 3.75- 3.68(m, 4H), 2.88-2.68(m, 5H), 2.31-2.20(m, 4H), 2.11-1.99(m, 4H), 1.90-1.82(m, 2H), 1.80-1.65(m, 8H) ), 1.40-0.93 (m, 6H).

Example 80: N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl )-3-Methyl-1H-indazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4-carbaldehyde

3-(4-Bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (1.5 g, 4.7 mmol) was dissolved in 30 mL of DMF and TEA (1.4 g, 4.7 mmol) was added successively. 14 mmol), Pd(dppf)Cl2 (0.4 _g , 0.5 mmol) and _Et3SiH (1.6 g, 14 mmol). The reaction solution was stirred at 80°C for 16 hours under carbon monoxide gas. After the reaction was completed, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were combined, washed with saturated NaCl water, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and 1-(2,6-dioxopiperidine) was obtained by column chromatography (MeOH/DCM=100/1 to 30/1) Perid-3-yl)-3-methyl-1H-indazole-4-carbaldehyde, 31% yield, pale yellow solid.

Step 2, (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)methyl)piperidin-4-yl (methyl) Synthesis of tert-butyl carboxylate

The product of step one (400 mg, 1.4 mmol) was dissolved in DMF/THF (v/v, 1 mL/15 mL), cooled to -10°C, and tert-butyl methyl(piperidin-4-yl)carboxylate ( 380 mg, 1.7 mmol), TEA (450 mg, 4.2 mmol), and stirred at this temperature for half an hour under argon. After that, HOAc (270 mg, 4.2 mmol), NaBH(OAc) ₃ (940 mg, 4.2 mmol) were added, and the reaction was continued for 5 hours at 40°C. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate, the organic layer was washed with saturated NaCl water, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and subjected to column chromatography (MeOH/DCM=100/1 to 30 /1) to obtain (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)methyl)piperidin-4-yl ( tert-Butyl methyl)carboxylate (280 mg), 40% yield. LCMS (ESI) m/z: [M+1]=470.0. Step three, 3-(3-methyl-4-((4- Synthesis of (methylamino)piperidin-1-yl)methyl)-1H-indazol-1-yl)piperidine-2,6-dione

The product of step 2 (280 mg, 0.6 mmol) was dissolved in 5 mL of dioxane, and 3 mL of 4M HCl in dioxane was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain 3-(3-methyl-4-((4-(methylamino)piperidin-1-yl)methyl)-1H-indazol-1-yl)piperidine - The hydrochloride salt of 2,6-dione, without purification, was used in the next step by Czochralski. LCMS (ESI) m/z: [M+1]=370.2. Step four, (3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl)-3- Methyl-1H-indazol-4-yl)methyl)piperidin-4-yl)(methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)carbamate tert-butyl ester.

The product of step 3 (280 mg, 0.8 mmol) was dissolved in DMF/THF (v/v, 1 mL/15 mL), cooled to -10°C, and tert-butyl methyl(piperidin-4-yl)carboxylate ( 280 mg, 0.76 mmol), TEA (160 mg, 1.6 mmol), and stirred at this temperature for half an hour under argon. After that, HOAc (150 mg, 2.4 mmol), NaBH(OAc) ₃ (520 mg, 2.4 mmol) were added, and the reaction was continued for 4 hours at -10°C. After the reaction was completed, water was added to quench the reaction, extracted with ethyl acetate, the organic layer was washed with saturated NaCl water, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and subjected to column chromatography (MeOH/DCM=100/1 to 20). /1) to obtain (3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl)-3 -Methyl-1H-indazol-4-yl)methyl)piperidin-4-yl)(methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H- Pyrazol-4-yl)carbamate tert-butyl ester 300 mg, 53% yield, white solid. LCMS (ESI) m/z: [M+1]=697.3. Step five, 3-(4-((4-((((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl) Synthesis of methyl)(methyl)amino)piperidin-1-yl)methyl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

3-(3-Methyl-4-((4-(methylamino)piperidin-1-yl)methyl)-1H-indazol-1-yl)piperidine-2,6-dione Replaced with (3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl)-3-methyl yl-1H-indazol-4-yl)methyl)piperidin-4-yl)(methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole -4-yl) tert-butyl carbamate, the other required raw materials, reagents and preparation methods are the same as the synthesis in step 3 to obtain the target product. LCMS (ESI) m/z: [M+1]=597.2.

Step six, N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl)- 3-Methyl-1H-indazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Synthesis of Morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide

5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 0.33 mmol) was dissolved in 3 mL of acetonitrile, TCFH (92 mg, 0.33 mmol) and NMI (81 mg, 1 mmol) were added. After 1 hour of reaction, 2 mL of DMF solution of the product of step 5 (150 mg, 0.25 mmol) was added, and the reaction was continued at room temperature for 16 hours, concentrated and evaporated to remove acetonitrile, 50 mL of water was added, the white solid was removed, suction filtered, and 10 mL of water was used for the solid. After washing, the collected solid was dissolved in 2 mL of DMF and purified by preparative HPLC to give 43 mg of product in 21% yield as a white solid. LCMS (ESI) m/z: [M+1]=826.9; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.39 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(2s, 1H), 8.29(s, 1H), 7.47-7.41(m, 1H), 7.29-7.24(m, 1H), 7.09(t, J=54.0Hz, 1H), 6.94- 6.87(m, 2H), 5.76-5.68(m, 1H), 4.20-4.09(m, 1H), 3.83-3.76(m, 4H), 3.74-3.66(m, 6H), 2.95-2.80(m, 3H ), 2.78-2.68(m, 2H), 2.66(s, 3H), 2.34-2.28(m, 1H), 2.20-2.13(m, 5H), 2.05-1.95(m, 4H), 1.91-1.83(m , 2H), 1.74-1.56 (m, 4H), 1.53-1.20 (m, 4H), 1.07-0.91 (m, 2H).

Example 81: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(((1-((1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)methan Synthesis of (methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxylic acid was replaced by 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5 -yl)pyrazole[1,5-a]pyrimidine-3-carboxylic acid, the other required raw materials, reagents and preparation methods are the same as the synthesis in step 3 to obtain the target product. LCMS (ESI) m/z: [M+1]=838.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=8.0 Hz , 1H), 8.38(2s, 1H), 8.25(2s, 1H), 7.45(2s, 1H), 7.30-6.96(m, 2H), 6.93(2s, 1H), 6.89-6.43(m, 1H), 5.79-5.66(m, 1H), 5.17(2s, 1H), 4.82-4.71(m, 1H), 4.20-4.08(m, 1H), 3.85-3.72(m, 2H), 3.71-3.42(m, 4H) ), 2.96-2.78(m, 3H), 2.77-2.67(m, 2H), 2.66(s, 3H), 2.34-2.27(m, 1H), 2.21-2.12(m, 5H), 2.07-1.92(m , 6H), 1.90-1.82 (m, 2H), 1.81-1.52 (m, 5H), 1.48-1.29 (m, 3H), 1.08-0.89 (m, 2H).

Example 82: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(5-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propane -2-yn-1-yl)octahydropyrrole[3,4-c]pyrrole-2-carbonyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazo[1,5-a]pyrimidine-3 -Synthesis of formamide

The intermediate twenty-three is replaced by the intermediate twenty-four, the intermediate twenty-five is replaced by the intermediate twenty-seven, and the other required raw materials, reagents and preparation methods are the same as those in the embodiment sixty, and the yield is 56%. LCMS (ESI) m/z: [M+1]=874.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.51 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.40-8.33(m, 1H), 8.26(2s, 1H), 7.57(2s, 1H), 7.37-7.31(m, 1H), 7.26-6.96(m, 2H), 6.89-6.42(m , 1H), 5.81-5.70(m, 1H), 5.18(2s, 1H), 4.81-4.73(m, 1H), 4.26-4.14(m, 1H), 3.83-3.71(m, 5H), 3.67-3.57 (m, 2H), 3.51-3.42 (m, 3H), 2.92-2.77 (m, 5H), 2.76-2.57 (m, 8H), 2.29-2.15 (m, 1H), 2.05-1.94 (m, 3H) , 1.86-1.69 (m, 5H), 1.58-1.38 (m, 2H).

Example 83: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(5-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)propane yl)octahydropyrrole[3,4-c]pyrrole-2-carbonyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide to 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane -5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-(5-(3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)octahydropyrrole[3,4-c]pyrrole-2-carbonyl)cyclohexyl)-1H-pyrrole oxazol-4-yl)pyrazole[1,5-a]pyrimidine-3-carboxamide, and other required raw materials, reagents and preparation methods are the same as those in Example 2. LCMS (ESI) m/z: [M+1]=878.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.39(2s, 1H), 8.26(2s, 1H), 7.35(2s, 1H), 7.28-6.96(m, 2H), 6.90-6.43(m, 2H), 5.74-5.65(m, 1H) ), 5.18(2s, 1H), 4.84-4.69(m, 1H), 4.32-4.14(m, 1H), 3.85-3.71(m, 3H), 3.65-3.38(m, 4H), 3.28-3.20(m , 1H), 3.04-2.92(m, 2H), 2.91-2.79(m, 2H), 2.77-2.64(m, 3H), 2.60(s, 3H), 2.49-2.30(m, 7H), 2.23-2.13 (m, 1H), 2.08-1.90 (m, 4H), 1.89-1.72 (m, 6H), 1.62-1.41 (m, 2H).

Example eighty-four: N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3- (methyl)-3-methyl-1H-indazol-5-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl) Synthesis of -5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of 3-methyl-1H-indazole-5-carbaldehyde

At -78°C, a solution of 5-bromo-3-methyl-1H-indazole (1.2 g, 5.7 mmol) in 5 mL of THF was added to a solution of t-BuLi (11 mL, 14 mmol) in THF, stirred for 30 min, and DMF was added (1.3 g, 17 mmol). The reaction solution was gradually returned to room temperature and reacted for 2 hours. The reaction solution was quenched with NH4C1 solution and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, suction filtered, concentrated, and subjected to column chromatography (PE/EA=100/1 to 3/1) to obtain the product, 400 mg, yield 44%. LCMS (ESI) m/z: [M+1]=161.2.

Step 2. Synthesis of 1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-5-carbaldehyde

The product of step 1 (400 mg, 2.5 mmol) was dissolved in DMSO/THF (v/v, 10 mL/10 mL), at 0°C, under nitrogen protection, sodium hydrogen (500 mg, 12.5 mmol) was added, stirred for 30 minutes, and KI was added (332 mg, 2.0 mmol) in 5 mL of DMSO and 3-bromopiperidine-2,6-dione (1.2 g, 6.3 mmol) in 5 mL of THF. After the addition was complete, the reaction was allowed to react at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, suction filtered, concentrated, and subjected to column chromatography (PE/EA=3/1) to obtain the product , 280 mg, 41% yield. LCMS (ESI) m/z: [M+1]=272.1.

Steps three to seven, N-(3-(difluoromethyl)-1-((1r,4r)-4-(((1-((1-(2,6-dioxopyridin-3-yl )-3-Methyl-1H-indazol-5-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

Replace 1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazole-4-carbaldehyde with 1-(2,6-Dioxypiperidin-3-yl)- 3-methyl-1H-indazole-5-carboxaldehyde, other required raw materials, reagents and preparation methods are the same as in Example 80. LCMS (ESI) m/z: [M+1]=827.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz, 1H), 8.38(s, 1H), 8.29(s, 1H), 7.58(s, 1H), 7.49(2s, 1H), 7.36(2s, 1H), 7.09(t, J=54.0Hz, 1H ), 6.91(d, J=8.0Hz, 1H), 5.77-5.66(m, 1H), 4.25-4.12(m, 1H), 3.81-3.69(m, 8H), 3.62-3.50(m, 2H), 2.96-2.82(m, 3H), 2.76-2.68(m, 2H), 2.47(s, 3H), 2.31-2.15(m, 6H), 2.08-1.94(m, 4H), 1.91-1.81(m, 2H) ), 1.79-1.30 (m, 8H), 1.08-0.93 (m, 2H).

Example 85: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)methane yl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxylic acid was replaced by 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5 - base) pyrazole[1,5-a]pyrimidine-3-carboxylic acid, other required raw materials, reagents and preparation methods are the same as those in Example 80, to obtain the target product. LCMS (ESI) m/z: [M+1]=839.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.38(2s, 1H), 8.25(2s, 1H), 7.56(s, 1H), 7.48(2s, 1H), 7.38-7.32(m, 1H), 7.11(td, J=53.6, 3.6 Hz, 1H), 6.90-6.42(m, 1H), 5.77-5.66(m, 1H), 5.31-5.04(m, 1H), 4.82-4.72(m, 1H), 4.24-4.10(m, 1H), 3.85-3.70(m, 2H), 3.64-3.42(m, 4H), 2.93-2.80(m, 3H), 2.75-2.65(m, 2H), 2.47(s, 3H), 2.26-2.15(m, 6H) ), 2.06-1.82 (m, 9H), 1.78-1.69 (m, 2H), 1.65-1.56 (m, 2H), 1.50-1.37 (m, 3H), 1.05-0.92 (m, 2H).

Example 86: N-(3-(difluoromethyl)-1-((1r,4r)-4-((2-((E)-3-(1-(2,6-dioxo) piperidin-3-yl)-3-methyl-1H-indazol-4-yl)acryloyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl) Synthesis of -1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

Step 1. Synthesis of (E)-3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl) tert-butyl acrylate

Dissolve 3-(4-bromo-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (1 g, 3.1 mmol) in 30 mL of acetonitrile, add tert-butyl acrylate (2 g , 15.5 mmol), Pd(OAc)2 (45 mg, 0.2 mmol) and tris(o-methylphenyl)phosphorus (91 mg, 0.3 mmol). Under the protection of argon, the reaction was carried out at 100°C for 12 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, suction filtered, concentrated, and subjected to column chromatography (PE/EA=10/1-2/1) to obtain Product, 960 mg, 84% yield. LCMS (ESI) m/z: [M+1]=370.2.

Step 2. Synthesis of (E)-3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)acrylic acid

(E)-tert-butyl 3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)acrylate (900 mg, 2.4 mmol) was dissolved in In 10 mL of DCM, 1 mL of TFA was added. The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated to obtain (E)-3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)acrylic acid, without Purified for next step. LCMS (ESI) m/z: [M+1]=314.0. Step three, (E)-3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl)acryloyl)-2,7-di Synthesis of azaspiro[3.5]nonane-7-carboxylate tert-butyl ester

The product of step two (500 mg, 1.6 mmol) was dissolved in 5 mL of DMF, TCFH (364 mg, 1.3 mmol) and NMI (295 mg, 3.6 mmol) were added. After 1 hour of reaction, a solution of 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (270 mg, 1.2 mmol) in 2 mL of DMF was added, the addition was completed, and the mixture was stirred at room temperature for 16 hours. Acetonitrile was evaporated under reduced pressure, 50 mL of water was added, the white solid was removed, filtered with suction, and the solid was washed with water to obtain the product (300 mg, 48%); LCMS (ESI) m/z: [M+1]=522.2.

Step 4, (E)-3-(3-methyl-4-(3-oxo-3-(2,7-diazaspiro[3.5]nonan-2-yl)prop-1-ene-1 Synthesis of -yl)-1H-indazol-1-yl)piperidine-2,6-dione

The product of step three (300 mg, 0.58 mmol) was dissolved in 5 mL of dioxane, 4M HCl was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed, the crude product was concentrated to obtain the crude product, which was directly used in the next reaction without purification. LCMS (ESI) m/z: [M+1]=422.2.

Steps five to six, 3-(4-((E)-3-(7-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazole- 1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-oxaprop-1-en-1-yl)-3-methyl-1H -Synthesis of indazol-1-yl)piperidine-2,6-dione

Replace intermediate seven with (E)-3-(3-methyl-4-(3-oxo-3-(2,7-diazaspiro[3.5]nonan-2-yl)propan-1- Alken-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, other required raw materials, reagents and preparation methods are the same as the synthesis of intermediate eight. LCMS (ESI) m/z: [M+1]=749.2. Step seven, N-(3-(difluoromethyl)-1-((1r,4r)-4-((2-((E)-3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)acryloyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H- Synthesis of 1pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-5-(2-Methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxylic acid was replaced by 5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxylate acid, intermediate eight was replaced with 3-(4-((E)-3-(7-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyridine azol-1-yl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-3-oxaprop-1-en-1-yl)-3-methyl -1H-indazol-1-yl)piperidine-2,6-dione, the other required raw materials, reagents and preparation methods are the same as those in the synthesis of step 3 of embodiment 32. LCMS (ESI) m/z: [M+1]=879.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.40(2s, 1H), 8.29(2s, 1H), 8.12(d, J=15.6Hz, 1H), 7.61-7.53(m, 2H), 7.44-7.37(m, 1H), 7.26- 6.95(m, 1H), 6.91(d, J=8.0Hz, 1H), 6.79(d, J=15.6Hz, 1H), 5.82-5.71(m, 1H), 4.28-4.12(m, 1H), 4.02 (s, 2H), 3.82-3.70 (m, 8H), 3.66 (s, 2H), 2.88-2.70 (m, 3H), 2.63 (s, 3H), 2.32-2.17 (m, 4H), 2.11-1.97 (m, 4H), 1.90-1.68 (m, 8H), 1.63-1.45 (m, 2H), 1.23-0.85 (m, 2H).

Embodiment 87: N-(3-(difluoromethyl)-1-((1r,4r)-4-((2-(3-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)propionyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide was replaced by N-(3-(difluoromethyl)-1-((1r,4r)-4-((2 -((E)-3-(1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)acryloyl)-2,7-diazo Heterospiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide, the rest The required raw materials, reagents and preparation method are the same as those in the second embodiment. LCMS (ESI) m/z: [M+1]=881.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(2s, 1H), 8.29(2s, 1H), 7.38(2s, 1H), 7.30-7.24(m, 1H), 7.24-6.95(m, 1H), 6.93-6.87(m, 2H) ), 5.78-5.68(m, 1H), 4.29-4.10(m, 1H), 3.83-3.65(m, 9H), 3.55(s, 2H), 3.45(s, 2H), 3.22-3.15(m, 2H) ), 2.90-2.80(m, 1H), 2.75-2.67(m, 2H), 2.61(s, 3H), 2.45-2.38(m, 2H), 2.26-2.13(m, 4H), 2.06-1.94(m , 4H), 1.86-1.73 (m, 3H), 1.60-1.46 (m, 6H), 1.14-0.92 (m, 2H).

Example 88: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-((2-((E)-3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole- 4-yl)acryloyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazole[ Synthesis of 1,5-a]pyrimidine-3-carboxamide

Substitute (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane with morpholine, and other required raw materials, reagents and preparation methods are the same as those in Example 86. LCMS (ESI) m/z: [M+1]=891.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=8.0 Hz , 1H), 8.46-8.36(m, 1H), 8.26(2s, 1H), 8.12(d, J=15.2Hz, 1H), 7.63-7.53(m, 2H), 7.47-7.38(m, 1H), 7.26-6.97(m, 1H), 6.90-6.42(m, 2H), 5.83-5.73(m, 1H), 5.18(2s, 1H), 4.77(2s, 1H), 4.26-4.14(m, 1H), 4.02(s, 2H), 3.87-3.76(m, 2H), 3.66(s, 2H), 3.60-3.43(m, 2H), 2.91-2.67(m, 4H), 2.63(s, 3H), 2.33- 2.19 (m, 4H), 2.10-1.87 (m, 8H), 1.76-1.67 (m, 5H), 1.63-1.46 (m, 2H), 1.22-0.97 (m, 2H).

Example 89: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-((2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl) propionyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3 -Synthesis of formamide

Substitute (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane with morpholine, and other required raw materials, reagents and preparation methods are the same as those in Example 87. LCMS (ESI) m/z: [M+1]=893.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.38(2s, 1H), 8.25(2s, 1H), 7.49-7.35(m, 1H), 7.30-7.24(m, 1H), 7.23-6.95(m, 1H), 6.93-6.35(m , 2H), 5.82-5.64(m, 1H), 5.18(2s, 1H), 4.77(2s, 1H), 4.23-4.08(m, 1H), 3.83-3.73(m, 2H), 3.73-3.57(m , 2H), 3.55(s, 2H), 3.46(s, 2H), 3.24-3.12(m, 2H), 2.91-2.79(m, 1H), 2.74-2.59(m, 5H), 2.45-2.37(m , 2H), 2.28-2.15 (m, 3H), 2.07-1.91 (m, 7H), 1.89-1.66 (m, 5H), 1.62-1.44 (m, 5H), 1.13-0.92 (m, 2H).

Example ninety: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(3-((1-(2,6-dioxopyridin-3- yl)-3-methyl-1H-indazol-4-yl)oxy)propyl)piperazine-1-carbonyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazole[ Synthesis of 1,5-a]pyrimidine-3-carboxamide.

Intermediate twenty-three (116 mg, 0.24 mmol) was dissolved in 3 mL of acetonitrile, TCFH (90 mg, 0.32 mmol) and NMI (81 mg, 1 mmol) were added, and after stirring at room temperature for 1 hour, intermediate forty-eight (70 mg, 0.18 mmol) was added. ) in 2 mL of DMF solution, and the reaction was continued at room temperature for 16 hours. Concentrate under reduced pressure to remove acetonitrile, add 50 mL of water, remove a white solid, filter with suction, wash the solid with water, redissolve in 2 mL of DMF, and purify by preparative HPLC to obtain a white solid. LCMS (ESI) m/z: [M+1]=857.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.41 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.39(s, 1H), 8.29(s, 1H), 7.27-6.96(m, 3H), 6.91(d, J=8.0Hz, 1H), 6.52(d, J=7.6Hz, 1H) , 5.71-5.61(m, 1H), 4.32-4.21(m, 1H), 4.19-4.09(m, 2H), 3.83-3.71(m, 8H), 3.58-3.45(m, 4H), 2.87-2.78( m, 1H), 2.75-2.66 (m, 3H), 2.58-2.54 (m, 5H), 2.44-2.33 (m, 4H), 2.24-2.17 (m, 1H), 2.06-1.96 (m, 4H), 1.89-1.75 (m, 4H), 1.62-1.50 (m, 2H).

Example ninety-one: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(3-((1-(2,6-dioxopyrimidine- 3-yl)-3-methyl-1H-indazol-4-yl)oxy)propyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Synthesis of Morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide

The intermediate seven was replaced with the intermediate forty-eight, and the remaining required raw materials, reagents and preparation methods were the same as those in the third embodiment. LCMS (ESI) m/z: [M+1]=843.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.37(s, 1H), 8.29(s, 1H), 7.27-7.03(m, 3H), 6.91(d, J=8.0Hz, 1H), 6.51(d, J=8.0Hz, 1H) , 5.70-5.62(m, 1H), 4.20-4.09(m, 3H), 3.81-3.71(m, 8H), 2.88-2.78(m, 1H), 2.72-2.66(m, 2H), 2.55(s, 3H), 2.36-2.07 (m, 10H), 2.05-1.85 (m, 8H), 1.78-1.53 (m, 4H), 1.08-0.97 (m, 2H).

Example ninety-two: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-((4-(3-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl ) Oxy)propyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

The intermediate six is replaced by the intermediate four, the intermediate forty-eight is replaced by the intermediate seven, and the remaining required raw materials, reagents and preparation methods are the same as those in the third embodiment. LCMS (ESI) m/z: [M+1]=855.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.50 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.38(2s, 1H), 8.26(2s, 1H), 7.26-7.21(m, 1H), 7.13-6.96(m, 2H), 6.88-6.43(m, 2H), 5.69-5.62(m , 1H), 5.18(2s, 1H), 4.81-4.72(m, 1H), 4.19-4.09(m, 3H), 3.83-3.72(m, 2H), 3.64-3.45(m, 2H), 2.87-2.79 (m, 1H), 2.72-2.67 (m, 2H), 2.55 (s, 3H), 2.33-2.19 (m, 4H), 2.13-2.02 (m, 8H), 2.00-1.84 (m, 8H), 1.76 -1.52 (m, 4H), 1.09-0.97 (m, 2H).

Example ninety-three: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4R)-4-(4-(3-((1-(2,6-dioxopyridin-3-yl)-3-methyl-1H-indazol-4-yl) Synthesis of oxy)propyl)piperazine-1-carbonyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

The intermediate twenty-three is replaced by the intermediate twenty-four, and the remaining required raw materials, reagents and preparation methods are the same as those in embodiment ninety. LCMS (ESI) m/z: [M+1]=869.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.51 (2s, 1H), 8.79 (d, J=7.6 Hz , 1H), 8.39(2s, 1H), 8.26(2s, 1H), 7.27-6.96(m, 3H), 6.89-6.43(m, 2H), 5.70-5.61(m, 1H), 5.18(2s, 1H) ), 4.82-4.71(m, 1H), 4.32-4.20(m, 1H), 4.18-4.10(m, 2H), 3.86-3.71(m, 2H), 3.63-3.42(m, 6H), 2.90-2.78 (m, 1H), 2.77-2.65 (m, 3H), 2.58-2.52 (m, 5H), 2.44-2.33 (m, 4H), 2.24-2.17 (m, 1H), 2.08-1.95 (m, 6H) , 1.89-1.74 (m, 4H), 1.61-1.50 (m, 2H).

Example ninety-four: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- 1-((1r,4r)-4-((4-(3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4- Synthesis of pyrazol[1,5-a]pyrimidine-3-carboxamide

The intermediate four was replaced by the intermediate six, the intermediate seven was replaced by the intermediate sixteen, and the other required raw materials, reagents and preparation methods were the same as those in the third embodiment, and the yield was 31%. LCMS (ESI) m/z: [M+1]=882.3; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.05 (s, 1H), 9.50 (d, J=6.0 Hz, 1H), 8.79 (d, J=7.6Hz, 1H), 8.38 (d, J=4.0Hz, 1H), 8.26 (d, J=5.6Hz, 1H), 7.25-7.22 (m, 1H), 7.20-7.11 (m, 1H), 7.05(d, J=8.4Hz, 1H), 6.98-6.35(m, 2H), 5.68-5.63(m, 1H), 5.28-5.08(m, 1H), 4.79-4.74(m, 1H) , 4.50-4.46(m, 1H), 4.19-4.14(s, 1H), 3.90-3.83(m, 1H), 3.80(s, 1H), 3.75-3.62(m, 1H), 3.59(s, 1H) , 3.46-3.43(m, 1H), 2.97-2.92(m, 2H), 2.85-2.80(m, 1H), 2.74-2.66(m, 4H), 2.55(s, 3H), 2.33-2.32(m, 1H), 2.23-2.18(m, 1H), 2.09-2.08(m, 2H), 2.01-1.95(m, 6H), 1.92-1.86(m, 4H), 1.81-1.78(m, 2H), 1.75- 1.69 (m, 2H), 1.58-1.54 (m, 1H), 1.46-1.39 (m, 2H), 1.06-0.98 (m, 2H).

Example ninety-five: 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl-N-(3-(difluoromethyl)-1-((1r,4r) )-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yne Synthesis of -1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 8-oxo-3-azabicyclo[3.2.1]octane, and the rest of the required raw materials, reagents and preparation methods were the same as those in the synthesis of Example 32 to obtain target product. LCMS (ESI) m/z: [M+1]=863.8; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.41 (s, 1H), 8.81 (d, J=8.0 Hz , 1H), 8.37(s, 1H), 8.28(s, 1H), 7.60(d, J=8.4Hz, 1H), 7.39-7.35(m, 1H), 7.24-6.97(m, 2H), 6.82( d, J=8.0Hz, 1H), 5.81-5.75(m, 1H), 4.52(s, 2H), 4.49-4.45(m, 2H), 4.21-4.07(m, 2H), 3.60-3.58(m, 1H), 3.27-3.21(m, 2H), 2.86-2.65(m, 8H), 2.27-2.23(m, 1H), 2.11-2.02(m, 6H), 1.88-1.87(m, 6H), 1.78- 1.67 (m, 4H), 1.60-1.22 (m, 4H), 1.09-0.97 (m, 2H).

Example ninety-six: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(dioxopiperidin-3-yl) )-3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-((R)-2-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate eight is replaced by the intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods are the same as those in the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl)-1-((1r,4R) -4-((4-((4-(1-(dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl) Methyl)piperidin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methylmorpholine)pyrazo[1,5-a]pyrimidine -3-Carboxamide. LCMS (ESI) m/z: [M+1]=878.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.33 (s, 1H), 8.83(d, J=8.0Hz, 1H), 8.38(s, 1H), 8.29(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.8Hz, 1H ), 7.36(t, J=7.2Hz, 1H), 7.27-7.00(m, 1H), 6.95(dd, J=7.6Hz, 14.8Hz, 2H), 5.80-5.76(m, 1H), 4.44-4.37 (m, 2H), 4.21-4.15 (m, 1H), 4.07 (d, J=7.2Hz, 2H), 3.94-3.91 (m, 1H), 3.60-3.55 (m, 2H), 3.14-3.08 (m , 1H), 2.87-2.78(m, 4H), 2.75-2.67(m, 2H), 2.33(s, 3H), 2.26-2.20(m, 1H), 2.11-2.02(m, 4H), 1.89-1.78 (m, 5H), 1.75-1.69 (m, 2H), 1.62-1.57 (m, 1H), 1.52-1.48 (m, 2H), 1.30-1.24 (m, 2H), 1.19 (d, J=6.4Hz) , 3H), 1.07-0.98 (m, 2H).

Example ninety-seven: N-(3-(difluoromethyl)-1-((1r,4S)-4-((4-((4-(1-(dioxopiperidin-3-yl) )-3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced by (S)-2-methylmorpholine, intermediate eight is replaced by intermediate fourteen, and the other required raw materials, reagents and preparation methods are the same as those of embodiment thirty-two. Synthesized to give N-(3-(difluoromethyl)-1-((1r,4S)-4-((4-((4-(1-(dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-((S)-2-Methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.33 (s, 1H), 8.83 (d, J= 7.6Hz, 1H), 8.38(s, 1H), 8.29(s, 1H), 7.97(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.6Hz, 1H), 7.27-7.00 (m, 1H), 6.95 (dd, J=7.6Hz, 14.4Hz, 2H), 5.80-5.76 (m, 1H), 4.46-4.39 (m, 2H), 4.21-4.14(m, 1H), 4.07(d, J=7.2Hz, 2H), 3.94-3.91(m, 1H), 3.60-3.55(m, 2H), 3.14-3.07(m, 1H), 2.87- 2.78(m, 4H), 2.75-2.67(m, 2H), 2.33(s, 3H), 2.26-2.21(m, 1H), 2.11-1.98(m, 4H), 1.89-1.78(m, 5H), 1.75-1.69(m, 2H), 1.59-1.56(m, 1H), 1.51-1.48(m, 2H), 1.30-1.24(m, 2H), 1.19(d, J=6.4Hz, 3H), 1.07- 0.98 (m, 2H).

Example ninety-eight: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidin-3-yl) )-3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 4-oxa-7-azaspiro[2.5]octane, intermediate eight is replaced with intermediate fourteen, and the other required raw materials, reagents and preparation methods are implemented in the same manner Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.29 (s, 1H), 8.83 (d, J= 8.0Hz, 1H), 8.38(s, 1H), 8.29(s, 1H), 7.97(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.25-6.98 (m, 1H), 6.98 (d, J=7.2Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.07(d, J=6.4Hz, 2H), 3.87-3.82(m, 3H), 3.77(s, 4H), 2.88-2.78(m, 4H), 2.75-2.65(m, 3H), 2.29(s, 3H), 2.11-2.09(m, 2H), 2.04-2.02(m, 2H), 1.89-1.81(m, 5H), 1.78-1.72(m, 2H), 1.55-1.49(m, 2H), 1.31- 1.22 (m, 2H), 1.07-1.01 (m, 2H), 0.78-0.76 (m, 2H), 0.67-0.63 (m, 2H).

Example ninety-nine: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidin-3-yl) )-3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-(2,2-dimethylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 2,2-methylmorpholine, intermediate eight is replaced with intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two, to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidin-3-yl)-3-methyl) yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- (2,2-Dimethylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=893.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.29 (s, 1H), 8.81 (d, J= 8.4Hz, 1H), 8.39(s, 1H), 8.28(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.8Hz, 1H), 7.36(t, J=7.6Hz, 1H), 7.27-7.00 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.93 (d, J=8.0Hz, 1H), 5.80-5.75 (m, 1H), 4.20-4.14(m, 2H), 4.07(d, J=7.2Hz, 2H), 3.75-3.72(m, 4H), 3.67(s, 2H), 2.87-2.77(m, 3H), 2.76-2.65( m, 4H), 2.29(s, 3H), 2.17-2.09(m, 2H), 2.05-1.94(m, 4H), 1.93-1.81(m, 5H), 1.75-1.69(m, 2H), 1.54- 1.44 (m, 2H), 1.19 (s, 6H), 1.07-0.97 (m, 2H).

Example 100: 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl)-1-((1r,4r )-4-((4-((4-(1-(dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl )Methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-pyrazol[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with 8-oxo-3-azabicyclo[3.2.1]octane, replace intermediate eight with intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods With the synthesis of Example 32, 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl)-1- ((1r,4r)-4-((4-((4-(1-(dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyridine oxazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.41 (s, 1H), 8.82 (d, J= 8.0Hz, 1H), 8.37(s, 1H), 8.28(s, 1H), 7.97(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.6Hz, 1H), 7.24-6.98 (m, 1H), 6.97 (d, J=7.2Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 5.80-5.76 (m, 1H), 4.45(s, 2H), 4.21-4.11(m, 2H), 4.07(d, J=6.8Hz, 2H), 3.23-3.17(m, 2H), 2.88-2.79(m, 3H), 2.77-2.67( m, 2H), 2.29(s, 3H), 2.26-2.21(m, 1H), 2.11-2.09(m, 2H), 2.04-1.98(m, 2H), 1.86-1.79(m, 7H), 1.75- 1.72 (m, 4H), 1.59-1.54 (m, 1H), 1.51-1.48 (m, 3H), 1.30-1.22 (m, 2H), 1.07-0.98 (m, 2H).

Example 101: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-((4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(2-oxa-6-aza[3.3]heptan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with 2-oxa-6-aza-spiro[3,3]heptane, replace intermediate eight with intermediate fourteen, and the remaining required raw materials, reagents and preparations The method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-(2-oxa-6-aza[3.3]heptan-6-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 9.69 (s, 1H), 8.76 (d, J= 7.6Hz, 1H), 8.37(s, 1H), 8.25(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.0Hz, 1H), 7.36(t, J=6.8Hz, 1H), 7.29-7.02 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.38 (d, J=8.0Hz, 1H), 5.80-5.75 (m, 1H), 4.74(s, 4H), 4.39(s, 4H), 4.20-4.14(m, 1H), 4.08-4.06(m, 2H), 2.87-2.78(m, 3H), 2.75-2.67(m, 2H), 2.89(s, 3H), 2.25-2.19(m, 2H), 2.13-2.09(m, 2H), 2.05-1.99(m, 2H), 1.93-1.81(m, 6H), 1.75-1.63(m, 2H) ), 1.60-1.54 (m, 1H), 1.52-1.49 (m, 2H), 1.30-1.21 (m, 2H), 1.07-0.99 (m, 2H).

Embodiment 102: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-((4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate fourteen, and the other required raw materials, reagents and preparation methods are the same as in embodiment thirty-two synthesis of N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidin-3-yl)- 3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.31 (s, 1H), 8.78 (d, J= 7.6Hz, 1H), 8.38(s, 1H), 8.27(s, 1H), 7.97(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.23-6.98 (m, 1H), 6.97-6.96 (m, 1H), 6.83 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.20-4.14 (m, 1H), 4.07 (d, J=6.4Hz, 2H), 4.02-3.99 (m, 1H), 3.85-3.81 (m, 1H), 3.79-3.77 (m, 2H), 3.67 (t, J =5.2Hz, 2H), 2.87-2.82(m, 3H), 2.75-2.67(m, 2H), 2.29(s, 3H), 2.26-2.21(m, 1H), 2.11-2.09(m, 2H), 2.05-2.02(m, 2H), 1.90-1.81(m, 8H), 1.75-1.68(m, 2H), 1.58-1.48(m, 4H), 1.51-1.48(m, 2H), 1.30-1.22(m , 2H), 1.08-1.01 (m, 2H).

Embodiment 103: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-((4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with 2-oxa-6-aza-spiro[3,4]octane, replace intermediate eight with intermediate fourteen, and the remaining required raw materials, reagents and preparations The method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.63 (s, 1H), 8.77 (d, J= 7.6Hz, 1H), 8.39(s, 1H), 8.25(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=6.8Hz, 1H), 7.34-6.98 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.80-5.76 (m, 1H), 4.60-4.59(m, 2H), 4.56-4.55(m, 2H), 4.19-4.14(m, 1H), 4.07(d, J=7.2Hz, 2H), 3.89-3.86(m, 2H), 3.66- 3.57(m, 2H), 2.87-2.78(m, 3H), 2.75-2.66(m, 2H), 2.36-2.33(m, 2H), 2.29(s, 3H), 2.11-2.09(m, 2H), 2.05-1.99(m, 2H), 1.90-1.78(m, 6H), 1.76-1.70(m, 2H), 1.60-1.55(m, 1H), 1.51-1.49(m, 2H), 1.31-1.22(m , 2H), 1.07-0.98 (m, 2H).

Embodiment 104: N-(3-(difluoromethyl)-1-((1r, 4r)-4-((4-((4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 6-oxa-2-azaspiro[3.4]octane, intermediate eight is replaced with intermediate fourteen, and the other required raw materials, reagents and preparation methods are the same as the examples Synthesis of Thirty-two to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.08 (s, 1H), 9.68 (s, 1H), 8.77 (d, J= 7.6Hz, 1H), 8.36(s, 1H), 8.25(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.8Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.24-6.98 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.39 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.19(s, 5H), 4.07(d, J=6.8Hz, 2H), 3.84(s, 2H), 3.76(t, J=7.2Hz, 2H), 2.89-2.78(m, 3H), 2.75-2.67 (m, 2H), 2.29 (s, 3H), 2.25-2.21 (m, 3H), 2.11-2.09 (m, 2H), 2.04-1.99 (m, 2H), 1.89-1.81 (m, 6H), 1.78 -1.68 (m, 2H), 1.58-1.48 (m, 2H), 1.30-1.22 (m, 2H), 1.07-0.99 (m, 2H).

Example 105: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) Perid-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-(6-oxa-2-aza-spiro[3,4]octan-2-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide synthesis

(R)-2-methylmorpholine was replaced with 6-oxa-2-azaspiro[3.4]octane, and the rest of the required raw materials, reagents and preparation method were the same as those of Example 32, to obtain N-( 3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl yl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- (6-oxa-2-aza-spiro[3,4]octan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.4.

Example 106: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cycle Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate thirty-five, and the rest of the required raw materials, reagents and preparation methods are the same as those of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-(((5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.07 (s, 1H), 9.40 (s, 1H), 8.83 (d, J= 7.6Hz, 1H), 8.39(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.62(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.24-6.98 (m, 1H), 6.97 (d, J=6.4Hz, 1H), 6.91 (d, J=8.0Hz, 1H), 5.79-5.75 (m, 1H), 4.92-4.89(m, 1H), 4.23-4.18(m, 1H), 3.80(s, 4H), 3.72(s, 4H), 2.88-2.82(m, 1H), 2.77-2.67(m, 4H), 2.64-2.58(m, 2H), 2.45-2.40(m, 3H), 2.33-2.32(m, 1H), 2.28(s, 3H), 2.22-2.20(m, 3H), 2.07-2.04(m, 2H) ), 1.97-1.92 (m, 4H), 1.78-1.72 (m, 2H), 1.57-1.51 (m, 1H), 1.13-1.03 (m, 2H).

Example 107: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methan Synthesis of cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate thirty-nine, and the rest of the required raw materials, reagents and preparation methods are the same as those in the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-(((5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)-1H-pyrazol-1-yl)methyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4.

Example 108: N-(3-(difluoromethyl)-1-((1R, 4r)-4-(((3R)-3-(4-(1-(2,6-di oxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-pyrrolidin-1-yl)methyl)cyclohexyl)-1H Synthesis of -pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven is replaced by the intermediate fifty, and the other required raw materials, reagents and preparation methods are the same as those in the synthesis of Example 3 to obtain N-(3-(difluoromethyl)-1-((1R,4r)-4 -(((3R)-3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazole -1-yl)-pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=836.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.38(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.23-6.98 (m, 1H), 6.98 (d, J=6.8Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.99- 4.95(m, 1H), 4.22-4.19(m, 1H), 3.79(s, 4H), 3.72(s, 4H), 2.95-2.91(m, 1H), 2.89-2.81(m, 3H), 2.76- 2.71(m, 2H), 2.69-2.67(m, 1H), 2.34-2.32(m, 2H), 2.29(s, 3H), 2.25-2.15(m, 2H), 2.04-1.99(m, 3H), 1.97-1.91(m, 2H), 1.79-1.70(m, 2H), 1.58-1.53(m, 1H), 1.12-1.05(m, 2H).

Example 109: N-(3-(difluoromethyl)-1-((1S, 4r)-4-(((3S)-3-(4-(1-(2,6-di oxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-pyrrolidin-1-yl)methyl)cyclohexyl)-1H Synthesis of -pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

The intermediate seven is replaced by the intermediate fifty-one, and the rest of the required raw materials, reagents and preparation methods are the same as those in the synthesis of Example 3 to obtain N-(3-(difluoromethyl)-1-((1S,4r)- 4-(((3S)-3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyridine oxazol-1-yl)-pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide . LCMS (ESI) m/z: [M+1]=836.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.40 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.38(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.23-6.98 (m, 1H), 6.98 (d, J=6.8Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 5.80-5.75 (m, 1H), 4.99- 4.95(m, 1H), 4.22-4.16(m, 1H), 3.79(s, 4H), 3.72(s, 4H), 2.95-2.91(m, 1H), 2.86-2.81(m, 3H), 2.79- 2.73(m, 2H), 2.69-2.65(m, 1H), 2.34-2.32(m, 2H), 2.29(s, 3H), 2.26-2.11(m, 2H), 2.09-1.89(m, 5H), 1.84-1.71(m, 2H), 1.61-1.53(m, 1H), 1.14-1.03(m, 2H).

Example 110: N-(3-(difluoromethyl)-1-((1r,4r)-4-((2-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-6-azaspiro[3.4]octan-6-yl)methyl)cycle Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate seven with intermediate forty-nine, and the rest of the required raw materials, reagents and preparation methods are the same as those in the synthesis of Example 3 to obtain N-(3-(difluoromethyl)-1-((1r,4r)- 4-((2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1- yl)-6-azaspiro[3.4]octan-6-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazolo[1,5-a]pyrimidine- 3-Carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.41 (s, 1H), 8.84 (d, J=7.9 Hz , 1H), 8.39-8.38(m, 1H), 8.28(s, 1H), 8.09-8.07(m, 1H), 7.68(s, 25H), 7.50-7.48(m, 1H), 7.7.38-7.10 (m, 2H), 6.98-6.90 (m, 2H), 5.86-5.67 (m, 1H), 4.93-4.98 (m, 1H), 4.21-4.12 (m, 1H), 3.92-3.67 (m, 8H) , 2.91-2.46(m, 10H), 2.29(s, 3H), 2.27-2.21(m, 3H), 2.10-1.84(m, 6H), 1.83-1.67(m, 2H), 1.63-1.40(m, 2H), 1.40-0.98(m, 2H).

Example 111: N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate thirty-eight, and the rest of the required raw materials, reagents and preparation methods are the same as in the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=862.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.40 (s, 1H), 8.84 (d, J=7.6 Hz , 1H), 8.38(s, 1H), 8.29(s, 1H), 8.07(s, 1H), 7.68(s, 1H), 7.49(d, J=8.0Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.24-6.98 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.81 ( t, J=8.0Hz, 1H), 4.18-4.15(m, 1H), 3.80(s, 4H), 3.72(s, 4H), 3.28-3.26(m, 2H), 3.22-3.17(m, 2H) , 2.87-2.84(m, 1H), 2.76-2.67(m, 2H), 2.63(d, J=8.0Hz, 4H), 2.29(s, 3H), 2.26-2.22(m, 3H), 2.03-2.01 (m, 2H), 1.87-1.83 (m, 2H), 1.77-1.67 (m, 2H), 1.35-1.32 (m, 1H), 1.10-1.01 (m, 2H).

Example 112: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of 4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate thirty-six, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazole[ 1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=850.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.41 (s, 1H), 8.84 (d, J=2.8 Hz , 1H), 8.39(s, 1H), 8.29(s, 1H), 8.08(s, 1H), 7.65(s, 1H), 7.49(d, J=8.0Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.24-6.99 (m, 1H), 6.98 (d, J=6.4Hz, 1H), 6.92 (d, J=8.0Hz, 1H), 5.80-5.75 (m, 1H), 4.23- 4.16(m, 2H), 3.80(s, 4H), 3.72(s, 4H), 2.97-2.94(m, 2H), 2.89-2.84(m, 1H), 2.76-2.72(m, 1H), 2.70- 2.67(m, 1H), 2.33-2.32(m, 1H), 2.28(s, 3H), 2.21-2.15(m, 2H), 2.10-2.00(m, 8H), 1.95-1.89(m, 2H), 1.81-1.71(m, 2H), 1.65-1.58(m, 1H), 1.12-1.01(m, 2H).

Example 113: N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-((4-(1-(2,6-dioxo Piperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3 Synthesis of -yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate thirty-seven, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((6-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=862.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.39 (s, 1H), 8.83 (d, J=8.0 Hz , 1H), 8.37(s, 1H), 8.29(s, 1H), 8.03(s, 1H), 7.63(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.36(t, J= 7.6Hz, 1H), 7.09(s, 1H), 6.98(d, J=6.8Hz, 1H), 6.91(d, J=7.6Hz, 1H), 5.81-5.75(m, 1H), 4.41-4.01( m, 3H), 3.81-3.70 (m, 8H), 2.96-2.60 (m, 5H), 2.45-2.20 (m, 8H), 2.10-1.98 (m, 2H), 1.87-1.48 (m, 8H), 1.10-0.90(m, 2H).

Example 114: N-(3-(difluoromethyl)-1-((1r,4S)-4-((5-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-((S)-2-methylmorpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced by (S)-2-methylmorpholine, intermediate eight is replaced by intermediate thirty-five, and other required raw materials, reagents and preparation methods are the same as in embodiment thirty-two synthesis of N-(3-(difluoromethyl)-1-((1r,4S)-4-((5-(4-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)- 1H-pyrazol-4-yl)-5-((S)-2-methylmorpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+ 1] = 890.4.

Example 115: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

Replace (R)-2-methylmorpholine with 4-oxa-7-azaspiro[2.5]octane, replace intermediate eight with intermediate thirty-five, and the rest of the required raw materials, reagents and preparation methods are the same Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-(((5-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl )cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3 - Formamide. LCMS (ESI) m/z: [M+1]=902.4; ¹ H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.30 (s, 1H), 8.84 (d, J=7.9 Hz, 1H ), 8.40(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.63(s, 1H), 7.49-7.47(m, 1H), 7.37-6.99(m, 2H), 6.98- 6.19(m, 2H), 5.79-5.75(m, 1H), 4.95-4.87(m, 1H), 3.97-3.74(m, 6H), 2.90-2.65(m, 5H), 2.47-2.36(m, 5H) ), 2.31-2.08(m, 8H), 2.09-1.90(m, 6H), 1.68-1.48(m, 2H), 1.16-1.10(m, 2H), 0.870-0.73(m, 2), 0.68-0.61 (m, 2H).

Example 116: N-(3-(difluoromethyl)-1-((1r,4R)-4-((5-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methylmorpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate eight is replaced by the intermediate thirty-five, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl)-1-((1r,4R )-4-((5-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazole- 1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methylmorpholine Pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4; ¹ H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.34 (s, 1H), 8.83(d, J=7.9Hz, 1H), 8.40(s, 1H), 8.29(s, 1H), 8.05(s, 1H), 7.63(s, 1H), 7.49-7.47( m, 1H), 7.43-7.00 (m, 2H), 6.98-6.92 (m, 2H), 5.78-5.75 (m, 1H), 5.06-4.88 (m, 1H), 4.62-4.28 (m, 2H), 4.26-4.14(m 1H), 3.93-3.88(m 1H), 3.66-3.51(m, 2H), 3.19-3.03(m, 1H), 3.03-2.63(m, 6H), 2.45-2.35(m, 5H) ), 2.34-2.16(m, 8H), 2.09-1.90(m, 6H), 1.83-1.70(m, 2H), 1.60-1.42(m, 1H), 1.19(d, J=6.2Hz, 3H), 1.15-1.00(m, 2H).

Example 117: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Synthesis of cyclohexyl)-1H-pyrazol-4-yl)-5-(2,2-dimethylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 2,2-methylmorpholine, intermediate eight is replaced with intermediate thirty-five, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two , to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-(2,2-dimethylmorpholine)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=904.4.

Example 118: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

Replace (R)-2-methylmorpholine with 2-oxa-6-aza-spiro[3,4]octane, replace intermediate eight with intermediate thirty-five, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazol[1,5-a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=902.4.

Example 119: N-(3-(difluoromethyl)-1-(1-(((1r,4r)-4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperidin-4-yl)-1H-pyrazol-4 -yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

The intermediate eleven was replaced by the intermediate fifty-two, and the other required raw materials, reagents and preparation methods were the same as those in the synthesis of Example fifty-two, LCMS (ESI) m/z: [M+1]=850.4.

Example 120: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidine) Perid-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-(2,2-methylmorpholine)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with 2,2-methylmorpholine, and the rest of the required raw materials, reagents and preparation methods were the same as those in Example 32 to obtain N-(3-(difluoromethyl) yl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole -4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(2,2-methyl) morpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=866.0; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 9.29 (s, 1H), 8.81 (d, J= 7.9Hz, 1H), 8.38(s, 1H), 8.27(s, 1H), 7.60(d, J=8.5Hz, 1H), 7.39-7.35(m, 1H), 7.27-7.00(m, 2H), 6.93(d, J=7.9Hz, 1H), 5.80-5.76(m, 1H), 4.51(s, 2H), 4.20-4.14(m, 1H), 3.75-3.71(m, 4H), 3.67-3.62( m, 2H), 3.60-3.58 (m, 1H), 2.86-2.65 (m, 8H), 2.27-2.23 (m. 1H), 2.10-2.01 (m, 6H), 2.00-1.89 (m, 4H), 1.75-1.72 (m, 2H), 1.55-1.46 (m, 3H), 1.19, (s, 6H), 1.06-0.98 (m, 2H.

Example 121: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H - Synthesis of pyrazol-4-yl)-5-(4-methylpiperazin-1-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with N-methylpiperazine, and all the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl) -1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4 -yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-methylpiperazine- 1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=851.4; ¹ H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.41 (s, 1H), 8.96-8.55 (m, J=8.0 Hz , 1H), 8.39(s, 1H), 8.27(s, 1H), 7.78-7.50(m, 1H), 7.47-7.31(m, 1H), 7.31-6.94(m, J=77.6, 30.3Hz, 2H ), 6.94-6.81(m, J=22.8Hz, 1H), 5.95-5.56(m, J=11.9, 5.0Hz, 1H), 4.52(s, 1H), 4.33-4.00(m, 2H), 3.99- 3.69(m, 4H), 3.68-3.45(m, 1H), 2.96-2.59(m, 8H), 2.46(d, J=30.7Hz, 4H), 2.24(s, 3H), 2.28-1.96(m, 6H), 1.99-1.81 (m, 2H), 1.86-1.64 (m, J=23.4, 11.6Hz, 2H), 1.64-1.41 (m, J=9.5Hz, 4H), 1.18-0.91 (m, 2H) .

Example 122: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H - Synthesis of pyrazol-4-yl)-5-(3,3,4-trimethylpiperazin-1-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,2,2-trimethylpiperazine hydrochloride, and all the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two to obtain N-( 3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl yl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- (3,3,4-Trimethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=879.4; ¹ H NMR (400 MHz, DMSO) δ 11.22-10.84 (m, 2H), 9.32 (s, 1H), 8.87-8.55 (m, 1H) , 8.38(s, 1H), 8.26(s, 1H), 7.72-7.47(m, 1H), 7.49-7.30(m, 1H), 7.31-6.99(m, 2H), 6.99-6.93(m, 1H) , 5.85-5.69(m, 1H), 4.68-4.40(m, 2H), 4.30-4.04(m, 1H), 4.01-3.69(m, 2H), 3.65-3.48(m, 3H), 2.97-2.58( m, 8H), 2.59-2.52 (m, 2H), 2.31-2.20 (m, 1H), 2.17 (s, 3H), 2.15-2.00 (m, 6H), 1.97-1.81 (m, 4H), 1.82- 1.67(m, 2H), 1.64-1.37(m, 3H), 1.11-0.92(m, 8H).

Example 123: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H -pyrazol-4-yl)-5-(4-methyl-4,7-diaza[2.5]-1-yl)octan-7-yl)pyrazol[1,5-a]pyrimidine- Synthesis of 3-formamide

(R)-2-methylmorpholine was replaced with 4-methyl-4,7-diaza[2.5]octane, and the rest of the required raw materials, reagents and preparation methods were the same as those in the synthesis of Example 32 to obtain N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-(4-Methyl-4,7-diaza[2.5]-1-yl)octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=877.4; 1H NMR (400MHz, DMSO) δ 11.10 (s, 1H), 9.31 (s, 1H), 8.93-8.64 (m, 1H), 8.38 ( s, 1H), 8.26 (s, 1H), 7.82-7.57 (m, 1H), 7.54-7.32 (m, 1H), 7.32-6.95 (m, 2H), 6.95-6.74 (m, 1H), 5.89- 5.68(m, 1H), 4.52(s, 1H), 4.17(s, 1H), 3.85(s, 1H), 3.63(s, 1H), 3.01-2.60(m, 10H), 2.35(s, 3H) , 2.32-2.20(m, 1H), 2.19-1.96(m, 6H), 1.95-1.81(m, 4H), 1.82-1.64(m, 2H), 1.64-1.38(m, 3H), 1.15-0.97( m, 3H), 0.61 (M, 2H), 0.58-0.46 (m, 2H).

Example 124: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl )-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with homomorpholine hydrochloride, intermediate eight is replaced with intermediate fifty-four, and the other required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two, to obtain N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)- yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(1,4-oxazeptan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=879.4.

Embodiment 125: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)methyl ) cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with homomorpholine hydrochloride, intermediate eight is replaced with intermediate fifty-four, and the other required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two, to obtain N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)- yl)-1-methyl-1H-indazol-7-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=853.4.

Example 126: 5-(8-oxo-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl)-1-((1R , 4r)-4-(((3R)-3-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl) Prop-1-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis

(R)-2-methylmorpholine was replaced by 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride, intermediate eight was replaced by intermediate twenty-nine, and the remaining required raw materials, Reagents and preparation methods are the same as the synthesis of Example 32 to obtain 5-(8-oxo-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl) -1-((1R,4r)-4-(((3R)-3-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indole azol-4-yl)prop-1-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=850.3; 1H NMR (600MHz, DMSO-d6) δ 11.07(s, 1H), 9.41(s, 1H), 8.81(d, J=8.0Hz, 1H), 8.39 (d, J=29.6Hz, 1H), 8.28 (d, J=4.0Hz, 1H), 7.60 (dd, J=8.5, 3.0Hz, 1H), 7.39-7.33 (m, 1H), 7.24 (dd, J=7.1, 2.6Hz, 1H), 7.11 (td, J=53.6, 7.9Hz, 1H), 6.82 (d, J=8.0Hz, 1H), 5.77 (dd, J=12.1, 5.1Hz) , 1H), 4.45 (d, J=3.3Hz, 4H), 4.28 (q, J=11.0, 9.0Hz, 2H), 2.89-2.54 (m, 10H), 2.43-2.20 (m, 5H), 2.09- 1.44(m, 16H), 1.04(q, J=12.7Hz, 1H).

Example 127: 5-(8-oxo-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl)-1-((1S , 4r)-4-(((3S)-3-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl) Prop-1-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis

(R)-2-methylmorpholine was replaced with 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride, intermediate eight was replaced with intermediate fifty-four, and the remaining required raw materials, Reagents and preparation methods are the same as the synthesis of Example 32 to obtain 5-(8-oxo-3-azabicyclo[3.2.1]octan-3-yl)-N-(3-(difluoromethyl) -1-((1S,4r)-4-(((3S)-3-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indole azol-4-yl)prop-1-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=850.3; ¹ H NMR (600 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.34 (s, 1H), 8.74 (d, J=7.9 Hz , 1H), 8.35(s, 1H), 8.22(s, 1H), 7.54(d, J=8.5Hz, 1H), 7.30(t, J=8.1Hz, 1H), 7.17(d, J=7.0Hz) , 1H), 7.05 (t, J=53.6Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 5.71 (dd, J=12.0, 5.1Hz, 1H), 4.43-4.35 (m, 4H) , 4.25-4.15(m, 2H), 3.23-3.05(m, 2H), 2.83-2.73(m, 1H), 2.71-2.61(m, 3H), 2.59(s, 3H), 2.56-2.48(m, 2H) ), 2.36-2.25(m, 2H), 2.21-2.12(m, 2H), 2.03-1.36(m, 16H), 0.97(q, J=12.5Hz, 1H).

Example 128: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4- yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide Synthesis

(R)-2-methylmorpholine was replaced by (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate thirty-six, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5 -a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=862.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.80 (d , J=8.0Hz, 1H), 8.40(d, J=4.0Hz, 1H), 8.26(d, J=5.6Hz, 1H), 8.08(s, 1H), 7.65(s, 1H), 7.49(d , J=8.8Hz, 1H), 7.36 (t, J=7.2Hz, 1H), 7.26-6.99 (m, 1H), 6.98 (d, J=6.8Hz, 1H), 6.88-6.45 (m, 1H) , 5.80-5.76(m, 1H), 5.28-5.08(m, 1H), 4.79-4.75(m, 1H), 4.23-4.17(m, 2H), 3.83-3.73(m, 2H), 3.65-3.43( m, 2H), 2.98-2.96(m, 2H), 2.88-2.83(m, 1H), 2.75-2.67(m, 2H), 2.28(s, 3H), 2.19-2.18(m, 2H), 2.11- 2.06(m, 8H), 2.01-1.92(m, 4H), 1.80-1.72(m, 2H), 1.65-1.58(m, 1H), 1.23(s, 1H), 1.11-1.02(m, 2H).

Example 129: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate thirty-six, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6- Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.31-9.22 (s, 1H), 8.78 (d, J= 8.0Hz, 1H), 8.37(s, 1H), 8.27(s, 1H), 8.08(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.26-6.99 (m, 1H), 6.98 (d, J=6.8Hz, 1H), 6.88-6.82 (m, 1H), 5.80-5.76 (m, 1H), 4.47-4.42 (m, 1H), 4.22-4.20 (m, 2H), 4.17-4.07 (m, 1H), 3.94-3.89 (m, 1H), 3.79-3.55 (m, 2H), 3.31-3.28 (m, 1H) , 2.97-2.93(m, 2H), 2.88-2.82(m, 1H), 2.78-2.67(m, 2H), 2.33-2.32(m, 1H), 2.28(s, 3H), 2.26-2.22(m, 1H), 2.19-2.15(m, 2H), 2.10-2.00(m, 9H), 1.94-1.91(m, 4H), 1.81-1.72(m, 2H), 1.61-1.57(m, 1H), 1.16( d, J=5.2Hz, 3H), 1.12-1.02(m, 2H).

Example 130: N-(3-(difluoromethyl)-1-((1r,4S)-4-((4-(4-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-((S)-3-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced by 3-(S)-3-methylmorpholine, intermediate eight is replaced by intermediate thirty-six, and the other required raw materials, reagents and preparation methods are the same as those in embodiment three Synthesis of Twelve to give N-(3-(difluoromethyl)-1-((1r,4S)-4-((4-(4-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-((S)-3-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.36 (s, 1H), 8.84 (d, J=7.6 Hz , 1H), 8.39(s, 1H), 8.30(s, 1H), 8.08(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.24-6.99 (m, 1H), 6.98 (d, J=6.8Hz, 1H), 6.88 (d, J=7.6Hz, 1H), 5.80-5.76 (m, 1H), 4.64- 4.61(m, 1H), 4.23-4.16(m, 3H), 3.97-3.93(m, 1H), 3.76-3.73(m, 1H), 3.69-3.65(m, 1H), 3.55-3.49(m, 1H) ), 2.97-2.92(m, 2H), 2.88-2.78(m, 1H), 2.75-2.67(m, 2H), 2.28(s, 3H), 2.26-2.21(m, 1H), 2.19-2.17(m , 2H), 2.10-2.00(m, 9H), 1.95-1.91(m, 2H), 1.80-1.71(m, 2H), 1.64-1.57(m, 1H), 1.26(d, J=6.4Hz, 1H ), 1.12-1.01(m, 2H).

Embodiment 131: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 Synthesis of -yl)-5-((R)-3-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 3-(R)-3-methylmorpholine, intermediate eight is replaced with intermediate thirty-six, and the other required raw materials, reagents and preparation methods are the same as those in embodiment three Synthesis of Twelve to give N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-((R)-3-methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.36 (s, 1H), 8.84 (d, J=8.0 Hz , 1H), 8.39(s, 1H), 8.30(s, 1H), 8.08(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J= 7.2Hz, 1H), 7.24-6.99 (m, 1H), 6.98 (d, J=7.2Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 5.80-5.76 (m, 1H), 4.63- 4.60(m, 1H), 4.28-4.16(m, 3H), 3.96-3.93(m, 1H), 3.76-3.73(m, 1H), 3.68-3.65(m, 1H), 3.55-3.49(m, 1H) ), 2.97-2.94(m, 2H), 2.88-2.78(m, 1H), 2.75-2.67(m, 2H), 2.28(s, 3H), 2.26-2.23(m, 1H), 2.19-2.17(m , 2H), 2.10-2.01(m, 9H), 1.95-1.92(m, 2H), 1.80-1.72(m, 2H), 1.66-1.57(m, 1H), 1.26(d, J=6.8Hz, 1H ), 1.11-1.02(m, 2H).

Example 132: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate fourteen, and the remaining required raw materials, reagents and preparations The method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-di Oxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=892.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.30-9.20 (m, 1H), 8.78 (d, J= 8.0Hz, 1H), 8.36(s, 1H), 8.27(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.36(t, J=7.2Hz, 1H), 7.25-6.98 (m, 1H), 6.97 (d, J=6.8Hz, 1H), 6.88-6.80 (m, 1H), 5.81-5.77 (m, 1H), 4.48-4.36 (m, 1H), 4.21-4.14 (m, 1H), 4.07 (d, J=7.2Hz, 3H), 3.94-3.88 (m, 1H), 3.84-2.783.63 (m, 1H), 3.58-3.47 (m, 1H), 2.89-2.79 (m, 3H), 2.76-2.74 (m, 2H), 2.70-2.67 (m, 1H), 2.29 (s, 3H), 2.26-2.21 (m, 1H), 2.11 -2.09(m, 2H), 2.04-1.99(m, 3H), 1.89-1.83(m, 7H), 1.78-1.69(m, 2H), 1.59-1.55(m, 1H), 1.51-1.46(m, 2H), 1.30-1.21(m, 2H), 1.17-1.15(m, 3H), 1.07-0.98(m, 2H).

Example 133: N-(3-(difluoromethyl)-1-(4-((4-((3-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with (R)-2-methyl-1,4-oxazepane, and all the other required raw materials, reagents and preparation method are the same as the synthesis of embodiment thirty-two, to give N-(3-(difluoromethyl)-1-(4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H -Indazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R )-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=866.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.30-9.22 (m, 1H), 8.78 (d, J= 8.0Hz, 1H), 8.36(s, 1H), 8.27(s, 1H), 7.60(d, J=8.4Hz, 1H), 7.37(t, J=7.2Hz, 1H), 7.23(d, J= 7.2Hz, 1H), 7.21-6.97(m, 1H), 6.90-6.80(m, 1H), 5.81-5.77(m, 1H), 4.52(s, 2H), 4.20-4.12(m, 1H), 3.94 -3.89(m, 2H), 3.62-3.54(m, 1H), 2.85-2.67(m, 5H), 2.66(s, 3H), 2.33-2.31(m, 1H), 2.28-2.17(m, 2H) , 2.11-2.08(m, 3H), 2.04-2.02(m, 5H), 1.90-1.87(m, 7H), 1.78-1.69(m, 2H), 1.59-1.43(m, 4H), 1.16-1.12( m, 3H), 1.07-0.97 (m, 2H).

Example 134: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cycle Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate thirty-five, and the other required raw materials, reagents and preparation methods are the same as in embodiment thirty Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.31 (s, 1H), 8.79 (d, J=7.9 Hz , 1H), 8.40(s, 1H), 8.28(s, 1H), 8.05(s, 1H), 7.63(s, 1H), 7.49-7.47(m, 1H), 7.41-7.08(m, 2H), 7.04-6.93(m, 1H), 6.84-6.82(m, 1H), 5.79-5.75(m, 1H), 4.93-4.86(m, 1H), 4.24-4.15(m, 1H), 4.13-3.73(m , 6H), 3.72-3.60(m, 2H), 2.94-2.62(m, 5H), 2.50-2.36(m, 5H), 2.32-2.14(m, 8H), 2.13-1.86(m, 8H), 1.84 -1.68(m, 2H), 1.60-1.46(m, 1H), 1.15-1.10(m, 2H).

Example 135: N-(3-(difluoromethyl)-1-((1r,4R)-4-((5-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cycle Hexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate thirty-five, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((5-(4-(1-(2,6- Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=904.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.29 (s, 1H), 8.78 (d, J=8.0 Hz , 1H), 8.37(s, 1H), 8.27(s, 1H), 8.05(s, 1H), 7.62(s, 1H), 7.49-7.47(m, 1H), 7.43-7.06(m, 2H), 6.98-6.96(m, 1H), 6.89-6.79(m, 1H), 5.79-5.75(m, 1H), 4.93-4.86(m, 1H), 4.55-3.52(m, 4H), 2.92-2.63(m , 4H), 2.50-2.35(m, 7H), 2.31-2.15(m, 8H), 2.19-1.89(m, 8H), 1.89-1.62(m, 4H), 1.61-1.47(m, 1H), 1.19 -0.99(m, 5H).

Example 136: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate thirty-six, and the other required raw materials, reagents and preparation methods are the same as those in embodiment thirty Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine-3- (yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.31 (s, 1H), 8.78 (d, J=8.0 Hz, 1H), 8.39(s, 1H), 8.27(s, 1H), 8.06(s, 1H), 7.64(s, 1H), 7.48(d, J=8.4Hz, 1H), 7.36(dd, J =8.5, 7.1Hz, 1H), 7.24-6.95 (m, 2H), 6.83 (d, J=8.0Hz, 1H), 5.77 (dd, J=11.7, 5.0Hz, 1H), 4.26-4.14 (m, 2H), 4.13-3.74(m, 6H), 3.67(t, J=5.5Hz, 2H), 3.01-2.65(m, 5H), 2.31-2.17(m, 6H), 2.13-1.86(m, 12H) , 1.83-1.55(m, 3H), 1.15-1.00(m, 2H).

Example 137: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(4-oxo-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with 4-oxa-7-azaspiro[2.5]octane, replace intermediate eight with intermediate thirty-six, and the other required raw materials, reagents and preparation methods are the same Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiper) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)-5-(4-oxo-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.29 (s, 1H), 8.83 (d, J=8.0 Hz, 1H), 8.39(s, 1H), 8.29(s, 1H), 8.06(s, 1H), 7.64(s, 1H), 7.48(d, J=8.3Hz, 1H), 7.36(dd, J =8.5, 7.1Hz, 1H), 7.19 (t, J=53.8Hz, 1H), 6.98 (d, J=6.9Hz, 1H), 6.92 (d, J=8.1Hz, 1H), 5.77 (dd, J =11.7, 5.1Hz, 1H), 4.27-4.13(m, 2H), 3.94-3.82(m, 2H), 3.82-3.73(m, 4H), 3.01-2.63(m, 5H), 2.30-2.16(m , 6H), 2.12-1.85(m, 10H), 1.82-1.68(m, 2H), 1.66-1.59(m, 1H), 1.14-0.98(m, 2H), 0.79-0.73(m, 2H), 0.68 -0.62(m, 2H).

Example 138: N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)methyl)cycle Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate thirty-eight, and the other required raw materials, reagents and preparation methods are the same as those in embodiment thirty Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-(4-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4.

Example 139: N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-yl)methyl)cycle Hexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate thirty-eight, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-(4-(1-(2,6- Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4.

Example 140: N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-(4-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)cyclohexyl )-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide Synthesis

Replace (R)-2-methylmorpholine with 4-oxa-7-azaspiro[2.5]octane, replace intermediate eight with intermediate thirty-eight, and the rest of the required raw materials, reagents and preparation methods are the same Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-(4-(1-(2,6-dioxopiper) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazolo[1,5-a]pyrimidine-3- formamide. LCMS (ESI) m/z: [M+1]=888.4.

Example 141: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopipine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H- Synthesis of Pyrazol-4-yl)-5-(4-methoxypiperidin-1-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 4-methoxy piperidine, intermediate eight is replaced with intermediate fourteen, and the rest of the required raw materials, reagents and preparation methods are the same as those of embodiment thirty-two, to obtain N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-(4-Methoxypiperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=892.4.

Example 142: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopipine) pyridin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-six, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidine-3 -yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=864.4.

Example 143: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopipine) pyridin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-six, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6 -Dioxypiperidin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.4.

Example 144: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopipine) pyridin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate sixty-six, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazole- 4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=850.4; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.33 (s, 1H), 8.75 (d, J=7.9 Hz, 1H), 8.38(s, 1H), 8.35(s, 1H), 8.30(s, 1H), 8.22(s, 1H), 8.00(s, 1H), 7.44-7.26(m, 3H), 7.02(t , J=53.7Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 5.80 (dd, J=11.5, 5.0Hz, 1H), 4.14-3.98 (m, 3H), 3.79-3.60 (m, 8H), 2.89-2.61(m, 5H), 2.28-2.17(m, 1H), 2.04-1.90(m, 4H), 1.87-1.58(m, 8H), 1.54-1.36(m, 3H), 1.26- 1.12(m, 1H), 1.02-0.88(m, 2H).

Example 145: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-4-yl)-1H -Pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide synthesis

(R)-2-methylmorpholine was replaced by (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-six, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-1H- Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=862.4; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.43 (d, J=6.1 Hz, 1H), 8.71 (d, J=7.7Hz, 1H), 8.38(s, 1H), 8.35(s, 1H), 8.31(d, J=4.3Hz, 1H), 8.19(d, J=5.6Hz, 1H), 8.00(s, 1H), 7.44-7.26 (m, 3H), 7.19-6.88 (m, 1H), 6.59 (dd, J=164.4, 7.8Hz, 1H), 5.80 (dd, J=11.6, 5.0Hz, 1H), 5.23 -4.96(m, 1H), 4.70(d, J=17.1Hz, 1H), 4.17-3.96(m, 3H), 3.79-3.35(m, 4H), 2.89-2.57(m, 5H), 2.30-2.17 (m, 1H), 2.08-1.57 (m, 14H), 1.44 (d, J=11.3Hz, 3H), 1.28-1.13 (m, 1H), 0.95 (q, J=11.3Hz, 2H).

Example 146: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopipine) pyridin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- Synthesis of 5-((R)-2-methyl-1,4-oxazeptan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-six, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6 -Dioxypiperidin-3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-((R)-2-methyl-1,4-oxazeptan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=878.4.

Example 147: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5 Synthesis of -(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-seven, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine-3- yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(1 , 4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=850.4; 1H NMR (400MHz, DMSO-d6) δ 11.11(s, 1H), 9.31(s, 1H), 8.77(d, J=7.9Hz, 1H), 8.48(s, 1H), 8.44(s, 1H), 8.39(s, 1H), 8.27(s, 1H), 8.07(s, 1H), 7.47(d, J=8.1Hz, 1H), 7.43-7.32 (m, 2H), 7.10 (t, J=53.7Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 5.86 (dd, J=11.6, 5.1Hz, 1H), 4.29-4.13 (m, 2H), 4.10-3.81 (m, 4H), 3.82-3.73 (m, 2H), 3.67 (t, J=5.5Hz, 2H), 3.03-2.66 (m, 5H), 2.35-2.25 (m , 1H), 2.23-2.14 (m, 2H), 2.13-2.01 (m, 8H), 1.98-1.85 (m, 4H), 1.76 (q, J=12.4Hz, 2H), 1.67-1.53 (m, 1H) ), 1.07(q, J=12.5Hz, 2H).

Example 148: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5 -Synthesis of morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate sixty-seven, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazole-4 -yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinopyrazol[1,5-a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=836.3; 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.34 (s, 1H), 8.76 (d, J=7.9 Hz, 1H), 8.41(s, 1H), 8.38(s, 1H), 8.32(s, 1H), 8.23(s, 1H), 8.00(s, 1H), 7.41(d, J=8.0Hz, 1H), 7.36-7.27 (m, 2H), 7.03 (t, J=53.7Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 5.80 (dd, J=11.5, 4.9Hz, 1H), 4.15 (d , J=11.9Hz, 2H), 3.79-3.59(m, 8H), 2.96-2.59(m, 5H), 2.30-2.16(m, 1H), 2.12(d, J=7.1Hz, 2H), 2.00( d, J=5.2Hz, 8H), 1.87 (d, J=11.8Hz, 2H), 1.70 (d, J=11.6Hz, 2H), 1.55 (s, 1H), 1.01 (d, J=13.0Hz, 2H).

Example 149: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-1H-indazol-4-yl)-1H- Synthesis of pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-seven, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-1H-indole azol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine- 3-Carboxamide. LCMS (ESI) m/z: [M+1]=848.4; 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.44 (d, J=5.9 Hz, 1H), 8.71 (dd, J=7.7, 1.6Hz, 1H), 8.41(s, 1H), 8.38(s, 1H), 8.33(d, J=4.4Hz, 1H), 8.20(d, J=5.4Hz, 1H), 8.01( s, 1H), 7.43-7.38 (m, 1H), 7.36-7.27 (m, 2H), 7.20-6.89 (m, 1H), 6.59 (dd, J=165.6, 7.8Hz, 1H), 5.80 (dd, J=11.6, 5.0Hz, 1H), 5.24-4.97 (m, 1H), 4.70 (d, J=15.0Hz, 1H), 4.21-4.07 (m, 2H), 3.78-3.35 (m, 4H), 2.94 -2.59(m, 5H), 2.28-2.17(m, 1H), 2.15-2.07(m, 2H), 2.05-1.93(m, 9H), 1.93-1.80(m, 4H), 1.69(q, J= 12.2, 11.5Hz, 2H), 1.60-1.46(m, 1H), 1.06-0.93(m, 2H).

Example 150: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidine) -3-yl)-6-fluoro-1H-indazol-4-yl)-1H-1 bisazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-eight, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidine-3 -yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4 -yl)-5-(1,4-oxazeptan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=882.4.

Embodiment 151: N-(3-(difluoromethyl)-1-((1r, 4R)-4-((4-((4-(1-(2,6-dioxopipine) Perid-3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (R)-2-methyl-1,4-oxazepane, intermediate eight was replaced by intermediate sixty-eight, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6 -Dioxypiperidin-3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl) -1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3- formamide. LCMS (ESI) m/z: [M+1]=896.4.

Embodiment 152: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopipine) Perid-3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate sixty-eight, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two, to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H -Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyridine oxazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=867.4; 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.32 (s, 1H), 8.76 (d, J=7.9 Hz, 1H), 8.44(s, 1H), 8.41(s, 1H), 8.30(s, 1H), 8.22(s, 1H), 8.08(s, 1H), 7.31-7.25(m, 1H), 7.25-7.20 (m, 1H), 7.02 (t, J=53.7Hz, 1H), 6.84 (d, J=8.0Hz, 1H), 5.78-5.71 (m, 1H), 4.16-3.96 (m, 3H), 3.77- 3.59(m, 8H), 2.85-2.63(m, 5H), 2.28-2.17(m, 1H), 2.06-1.90(m, 4H), 1.86-1.58(m, 8H), 1.55-1.38(m, 3H) ), 1.26-1.13(m, 1H), 1.02-0.89(m, 2H).

Example 153: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-indazol-4-yl )-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-eight, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro -1H-Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1 , 5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=880.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.43 (d, J=6.1 Hz, 1H), 8.71 (d , J=7.7Hz, 1H), 8.44(s, 1H), 8.41(s, 1H), 8.30(d, J=4.2Hz, 1H), 8.18(d, J=5.6Hz, 1H), 8.08(s , 1H), 7.30-7.19 (m, 2H), 7.04 (t, J=53.5Hz, 1H), 6.81-6.35 (m, 1H), 5.74 (dd, J=11.7, 4.7Hz, 1H), 5.23- 4.98(m, 1H), 4.70(d, J=17.6Hz, 1H), 4.14-3.95(m, 3H), 3.78-3.50(m, 4H), 2.89-2.62(m, 5H), 2.29-2.19( m, 1H), 2.06-1.55 (m, 14H), 1.55-1.38 (m, 3H), 1.28-1.16 (m, 1H), 1.02-0.88 (m, 2H).

Example 154: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-indazol-4-yl )-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide synthesis

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-nine, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro -1H-Indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=886.3; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.44 (d, J=6.1 Hz, 1H), 8.72 (d , J=7.7Hz, 1H), 8.48(s, 1H), 8.45(s, 1H), 8.33(d, J=4.3Hz, 1H), 8.19(d, J=5.6Hz, 1H), 8.08(s , 1H), 7.32-7.20(m, 2H), 7.20-6.89(m, 1H), 6.82-6.36(m, 1H), 5.74(dd, J=11.4, 5.1Hz, 1H), 5.24-4.97(m , 1H), 4.75-4.66(m, 1H), 4.23-4.07(m, 2H), 3.79-3.36(m, 4H), 2.96-2.86(m, 2H), 2.82-2.63(m, 3H), 2.25 -2.19(m, 1H), 2.17-2.08(m, 2H), 2.05-1.95(m, 8H), 1.93-1.85(m, 3H), 1.76-1.63(m, 2H), 1.62-1.49(m, 1H), 1.08-0.94(m, 2H).

Example 155: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-nine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine-3- yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=868.3.

Example 156: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-nine, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6- Dioxypiperidin-3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=882.4.

Example 157: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-6-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate sixty-nine, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H- Indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=854.4; ¹ H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.34 (s, 1H), 8.76 (d, J=7.9 Hz , 1H), 8.49(s, 1H), 8.44(s, 1H), 8.33(s, 1H), 8.22(s, 1H), 8.13(s, 1H), 7.32-7.21(m, 2H), 7.17- 6.90 (m, 1H), 6.97 (d, J=53.7Hz, 1H), 6.84 (d, J=7.9Hz, 1H), 5.74 (m, 1H), 4.42-4.31 (m, 1H), 4.22-4.11 (m, 1H), 3.77-3.60 (m, 7H), 2.80-2.56 (m, 7H), 2.28-2.08 (m, 8H), 2.07-1.81 (m, 6H), 1.83-1.61 (m, 5H) , 1.15-1.02(m, 3H).

Example 158: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopipine) Perid-3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate seventy, and the other required raw materials, reagents and preparation methods are the same as in embodiment thirty-two synthesis of N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidine-3- yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=882.4.

Example 159: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6-dioxopipine) Perid-3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine Synthesis of oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate seventy, and other required raw materials, reagents and preparations The method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(1-(2,6- Dioxypiperidin-3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-methyl amide. LCMS (ESI) m/z: [M+1]=896.4.

Example 160: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidine) -3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole Synthesis of -4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate seventy, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3- (Difluoromethyl)-1-((1r,4r)-4-((4-((4-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H- Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazole [1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=867-4.

Example 161: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H-indazol-4-yl )-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Synthesis of formamide

Replace (R)-2-methylmorpholine with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, and replace intermediate eight with intermediate seventy, and the rest are required The raw materials, reagents and preparation methods are the same as those in the synthesis of Example 32, to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N- (3-(Difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro- 1H-Indazol-4-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=880.3.

Example 162: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate seventy-one, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine-3- yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=868.3.

Example 163: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate seventy-one, and the remaining raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-(4-(1-(2,6- Dioxypiperidin-3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyridine oxazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=882.4.

Example 164: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidine) -3-yl)-5-fluoro-1H-indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate seventy-one, and the rest of the required raw materials, reagents and preparation methods are the same as those of embodiment thirty-two, to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-(4-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-1H- Indazol-4-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=854.4.

Example 165: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3S)-3-((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate seventy-three, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3S)-3-(((1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 166: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3S)-3-((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate seventy-three, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of two to give N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-((1s,3S)-3-(((1-(2,6- Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl) -1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Example 167: N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3S)-3-((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate seventy-three, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3S)-3-(( 1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=912.4.

Example 168: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-((1s,3S)-3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1, Synthesis of 5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate seventy-three, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-((1s,3S)-3-((1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=896.4.

Example 169: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3R)-3-((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate seventy-four, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3R)-3-(((1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl )-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 170: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3R)-3-((1-(2, 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate seventy-four, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of two to give N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-((1s,3R)-3-(((1-(2,6- Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl) -1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Example 171: N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3R)-3-((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

(R)-2-methylmorpholine was replaced by (R)-2-methyl-1,4-oxazepane, intermediate eight was replaced by intermediate seventy-four, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3R)-3-(( 1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=912.4.

Example 172: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-((1s,3R)-3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl- 1H-Indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1, Synthesis of 5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate seventy-four, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-((1s,3R)-3-((1-(2,6-dioxopiperidine-3 -yl)-3-methyl-1H-indazol-4-yl)oxy)-1-methylcyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=896.4.

Example 173: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3S)-3-(((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate sixty-two, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3S)-3-((((1-(2,6-dioxopiperidin-3-yl) )-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 174: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-((1s,3S)-3-((((1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-two, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-((1s,3S)-3-(((1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4 -yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=896.4.

Embodiment 175: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3S)-3-(((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-two, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of two to give N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-((1s,3S)-3-(((1-(2,6 -Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Example 176: N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3S)-3-(((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)ring Hexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3 -Synthesis of formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-two, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3S)-3-(( (1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazol[1,5-a ] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=912.4.

Example 177: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3R)-3-(((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate sixty-three, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3R)-3-((((1-(2,6-dioxopiperidin-3-yl) )-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 178: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-((1s,3R)-3-((((1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-three, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-((1s,3R)-3-((((1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4 -yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=896.4.

Example 179: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-((1s, 3R)-3-(((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-three, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of two to give N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-((1s,3R)-3-(((1-(2,6 -Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Example 180: N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3R)-3-(((1-(2 , 6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl)methyl)cyclohexyl )-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3- Synthesis of formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-three, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((4-((1s, 3R)-3-(( (1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)methyl)cyclobutoxy)piperidin-1-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4oxazepan-4-yl)pyrazol[1,5-a ] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=912.4.

Example 181: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-(((1s, 3S)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate sixty-four, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-((4-(((1s,3S)-3-(((1-(2,6-dioxopiperidin-3-yl) )-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 182: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-(((1s,3S)-3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-four, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-(((1s,3S)-3-((1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4 -yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=896.4.

Example 183: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((((4-((1s, 3S)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-four, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of two to give N-(3-(difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3S)-3-(((1-(2,6) -Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Embodiment 184: N-(3-(difluoromethyl)-1-((1R, 4R)-4-((((4-((1s, 3S)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Hexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-four, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((((4-((1s, 3S)-3-( (1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Embodiment 185: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((4-(((1s, 3R)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate sixty-five, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1R,4r)-4-(((4-(((1s,3R)-3-(((1-(2,6-dioxopiperidin-3-yl) )-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) -5-Morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=884.4.

Example 186: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1R,4R)-4-((4-((((1s,3R)-3-((1-(2,6-dioxopiperidin-3-yl)-3-methyl -1H-Indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5 Synthesis of -a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate sixty-five, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1R,4R)-4-((4-(((1s,3R)-3-((1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4 -yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1] = 896.4.

Example 187: N-(3-(difluoromethyl)-1-((1R, 4r)-4-((((4-((1s, 3R)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Synthesis of Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate sixty-five, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1R,4r)-4-(((4-((1s,3R)-3-(((1-(2,6 -Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)cyclohexyl)- 1H-Pyrazol-4-yl)-5-(1,4oxazeptan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=898.4.

Example 188: N-(3-(difluoromethyl)-1-((1R, 4R)-4-(((4-((1s, 3R)-3-((1-( 2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl)methyl)ring Hexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 3-formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate sixty-five, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1R, 4R)-4-((((4-((1s, 3R)-3-( (1-(2,6-Dioxypiperidin-3-yl)-3-methyl-1H-indazol-4-yl)oxy)cyclobutyl)methoxy)piperidin-1-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5- a] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=912.4.

Embodiment 189: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl Synthesis of )-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate forty-one, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 -Methyl-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)- 5-Morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=839.4.

Example 190: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indole azol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a Synthesis of ]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate forty-one, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl) )-1-Methyl-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=851.3.

Example 191: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl )-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3 -Synthesis of formamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate seventy-one, and the remaining raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(3-(2,4 -Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl yl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5-a ] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=867.4.

Example 192: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H - Synthesis of Pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate seventy-two, and the other required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidine- 1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazole -4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1 ]=865.4.

Example 193: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H -Pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide Synthesis

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate seventy-two, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4 -Dioxytetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)ring Hexyl)-1H-pyrazol-4-yl)-5-(1,4oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m /z: [M+1]=879.4.

Example 194: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H Synthesis of -pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate seventy-two, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two, to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 -Methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5- Linopyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=851.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 9.33(s, 1H), 8.75(d, J=7.9Hz, 1H), 8.32(s, 1H), 8.22(s, 1H), 8.03(s, 1H), 7.60(s, 1H), 7.54 (dd, J=8.1, 1.0Hz, 1H), 7.19-6.88 (m, 3H), 6.84 (d, J=8.0Hz, 1H), 4.22-4.08 (m, 2H), 3.84 (t, J= 6.7Hz, 2H), 3.78-3.60(m, 11H), 2.97-2.84(m, 2H), 2.71(t, J=6.7Hz, 2H), 2.17-1.80(m, 12H), 1.76-1.62(m , 2H), 1.60-1.47(m, 1H), 1.07-0.92(m, 2H).

Example 195: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- Indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine Synthesis of -3-Carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate seventy-two, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl )-1-Methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyridine Azole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=863.4.

Example 196: N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(3-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-[pyrazol-1-yl)methyl)piperidin-1-yl)methan yl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1,5-a Synthesis of ]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate fifty-four, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((4-(3-(3-( 2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidine-1- yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-(1,4oxazepan-4-yl)pyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=893.4.

Example 197: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl ) Cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazol[1,5-a]pyrimidine-3-carboxamide synthesis

(R)-2-methylmorpholine is replaced with morpholine, intermediate eight is replaced with intermediate fifty-four, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((4-((4-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl) )-1-Methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- yl)-5-morpholinepyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=865.4; ¹ H NMR (400 MHz, DMSO-d6) δ 10 .50(s, 1H), 9.33(s, 1H), 8.76(d, J=7.9Hz, 1H), 8.31(s, 1H), 8.22(s, 1H), 7.94(s, 1H), 7.60( s, 1H), 7.54 (dd, J=8.1, 1.1Hz, 1H), 7.17-6.88 (m, 3H), 6.84 (d, J=8.0Hz, 1H), 4.16-4.05 (m, 1H), 4.01 (d, J=7.1Hz, 2H), 3.84 (t, J=6.7Hz, 2H), 3.76-3.61 (m, 11H), 2.80-2.74 (m, 2H), 2.71 (t, J=6.7Hz, 2H), 2.08-1.87(m, 5H), 1.86-1.72(m, 5H), 1.72-1.60(m, 2H), 1.56-1.35(m, 3H), 1.25-1.17(m, 1H), 1.02- 0.89(m, 2H).

Example 198: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) )-1-((1r,4R)-4-((4-((4-(3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl -1H-Indazol-7-yl)-1H-pyrazol-1-yl)methyl)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazol[1 , Synthesis of 5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate fifty-four, and the rest were The synthesis of raw materials, reagents and preparation method is the same as that of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-((4-(3 -(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)methyl) Piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/ z: [M+1]=876.4; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 9.43 (d, J=6.2 Hz, 1H), 8.71 (d, J=7.7 Hz) , 1H), 8.31 (d, J=4.4Hz, 1H), 8.19 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.54 (dd, J=8.1, 1.0Hz, 1H), 7.19-6.89(m, 3H), 6.81-6.36(m, 1H), 5.25-4.94(m, 1H), 4.70(d, J=17.0Hz, 1H), 4.15-4.05(m , 1H), 4.01(d, J=7.0Hz, 2H), 3.84(t, J=6.7Hz, 2H), 3.78-3.35(m, 7H), 2.80-2.74(m, 2H), 2.71(t, J=6.7Hz, 2H), 2.07-1.59 (m, 14H), 1.56-1.39 (m, 3H), 1.26-1.18 (m, 1H), 1.03-0.91 (m, 2H).

Example 199: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydro) Pyrimidine-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazol[1,5-a] Synthesis of Pyrimidine-3-Carboxamide

Replace (R)-2-methylmorpholine with 4-oxa-7-azaspiro[2.5]octane, replace intermediate eight with intermediate forty-four, and the rest of the required raw materials, reagents and preparation methods are the same Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetra Hydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl )methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazol[1,5-a ] Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=903.4.

Example two hundred: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidine-1) (2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Synthesis of Cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine is replaced with 1,4-oxazepine, intermediate eight is replaced with intermediate forty-four, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl) Cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=891.4.

Example 201: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methan yl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1,5- Synthesis of a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate forty-four, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4- Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H )-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazole [1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=905.4.

Example 202: N-(3-(difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidine) -1(2H)-yl)-1-methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methan Synthesis of cyclohexyl)-1H-pyrazol-4-yl)-5-morpholinepyrazo[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced with morpholine, intermediate eight was replaced with intermediate forty-four, and the rest of the required raw materials, reagents and preparation methods were the same as those of embodiment thirty-two, to obtain N-(3 -(Difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- Methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazole- 4-yl)-5-morpholinopyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=877.4.

Example 203: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazole -7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazole[ Synthesis of 1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate forty-four, and the rest were The synthesis of raw materials, reagents and preparation method is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4r)-4-((5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)) -1-Methyl-1H-indazol-7-yl)-1H-pyrazol-1-yl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclohexyl)-1H- Pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=889.4.

Example 204: N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-((4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- Synthesis of pyrazo[1,5-a]pyrimidine-3-carboxamide

Replace intermediate eight with intermediate thirty-seven, and the rest of the required raw materials, reagents and preparation methods are the same as the synthesis of embodiment thirty-two to obtain N-(3-(difluoromethyl)-1-((1r,4R )-4-((6-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazole -1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)- 2-Methylmorpholine)pyrazo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.32 (s, 1H), 8.82 (d, J=7.9 Hz, 1H), 8.37(s, 1H), 8.28(s, 1H), 8.02(s, 1H), 7.62(d, J=2.7Hz, 1H), 7.49(d, J=8.5Hz, 1H), 7.36(t, J=7.8Hz, 1H), 7.12(t, J=53.7Hz, 1H), 6.99(d, J=7.0Hz, 1H), 6.92(d, J=8.0Hz, 1H), 5.77( dd, J=11.9, 5.1Hz, 1H), 4.16 (t, J=12.1Hz, 1H), 4.03 (d, J=7.3Hz, 2H), 3.95-3.89 (m, 1H), 3.62-3.54 (m , 2H), 3.15-3.06(m, 1H), 2.97-2.67(m, 6H), 2.29(s, 3H), 2.26-2.18(m, 5H), 2.04-1.66(m, 7H), 1.63-1.40 (m, 5H), 1.19 (d, J=6.1Hz, 3H), 0.99 (q, J=12.7Hz, 2H).

Example 205: N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-((4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl)pyrazol[1, Synthesis of 5-a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with (R)-2-methyl-1,4-oxazepane, replace intermediate eight with intermediate thirty-seven, and the remaining required raw materials, reagents and The preparation method is the same as the synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-((4-(1-(2,6 -Dioxopiperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0] Hexan-3-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-((R)-2-methyl-1,4-oxazepan-4-yl) Pyrazole[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=890.4.

Example 206: 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) -1-((1r,4R)-4-((6-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-4 -yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl) Synthesis of Pyrazole[1,5-a]pyrimidine-3-carboxamide

(R)-2-methylmorpholine was replaced by (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane, intermediate eight was replaced by intermediate thirty-seven, and the rest were The synthesis of raw materials, reagents and preparation methods is the same as that of Example 32 to obtain 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N -(3-(Difluoromethyl)-1-((1r,4R)-4-((6-((4-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl)methyl)cyclohexyl) -1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=874.4; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.49 (d, J=9.0 Hz, 1H), 8.78 ( d, J=7.7Hz, 1H), 8.38 (d, J=21.2, 6.6Hz, 1H), 8.25 (dd, J=8.6, 3.2Hz, 1H), 8.02 (s, 1H), 7.62 (d, J = 2.4Hz, 1H), 7.48 (d, J=8.5Hz, 1H), 7.36 (dd, J=8.4, 7.1Hz, 1H), 7.21-7.00 (m, 1H), 6.98 (d, J=7.0Hz) , 1H), 6.65 (dd, J=246.8, 7.8Hz, 1H), 5.77 (dd, J=11.9, 5.1Hz, 1H), 5.17 (d, J=123.1Hz, 1H), 4.80-4.72 (m, 1H), 4.20(d, J=52.2Hz, 1H), 4.03(d, J=7.3Hz, 2H), 3.84-3.71(m, 2H), 3.66-3.41(m, 2H), 2.97-2.80(m , 3H), 2.78-2.67(m, 2H), 2.29(s, 3H), 2.26-2.17(m, 4H), 2.06-1.66(m, 9H), 1.62-1.41(m, 5H), 0.99(q , J=12.3Hz, 1H).

Example 207: N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-((4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazeptan-4-yl)pyrazolo[1,5-a]pyrimidine-3-methyl amide synthesis

(R)-2-methylmorpholine was replaced with 1,4-oxazepine, intermediate eight was replaced with intermediate thirty-seven, and the rest of the required raw materials, reagents and preparation methods were the same as those in Example 30 Synthesis of bis to give N-(3-(difluoromethyl)-1-((1r,4R)-4-((6-((4-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-yl) Methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(1,4-oxazepan-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=876.4; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.29 (s, 1H), 8.77 (d, J=7.8 Hz, 1H), 8.36(s, 1H), 8.26(s, 1H), 8.02(s, 1H), 7.62(d, J=2.6Hz, 1H), 7.48(d, J=8.4Hz, 1H), 7.36(t, J=8.4Hz, 1H), 7.09(t, J=53.7Hz, 1H), 6.99(d, J=7.0Hz, 1H), 6.83(d, J=8.3Hz, 1H), 5.79- 5.74(m, 1H), 4.28-4.10(m, 1H), 4.09-3.62(m, 10H), 2.96-2.68(m, 5H), 2.29(s, 3H), 2.26-2.16(m, 4H), 2.05-1.64 (m, 9H), 1.62-1.38 (m, 5H), 0.99 (q, J=12.7Hz, 1H).

Example 208: N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-((4-(1-(2,6-dioxopiperidine) pyridin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazol[1,5- Synthesis of a]pyrimidine-3-carboxamide

Replace (R)-2-methylmorpholine with 4-oxa-7-azaspiro[2.5]octane, replace intermediate eight with intermediate thirty-seven, and the rest of the required raw materials, reagents and preparation methods are the same Synthesis of Example 32 to obtain N-(3-(difluoromethyl)-1-((1r,4r)-4-((6-((4-(1-(2,6-dioxo piperidin-3-yl)-3-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)methyl)-3-azabicyclo[3.1.0]hexane- 3-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-5-(4-oxa-7-azaspiro[2.5]octan-7-yl)pyrazol[1, 5-a]Pyrimidine-3-carboxamide. LCMS (ESI) m/z: [M+1]=888.4; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 9.28 (s, 1H), 8.82 (d, J=8.0 Hz, 1H), 8.37(s, 1H), 8.28(s, 1H), 8.02(s, 1H), 7.62(s, 1H), 7.48(d, J=8.5Hz, 1H), 7.36(t, J =7.7Hz, 1H), 7.11 (t, J=53.9Hz, 1H), 6.98 (d, J=7.0Hz, 1H), 6.91 (d, J=8.0Hz, 1H), 5.77 (dd, J=12.0 , 5.1Hz, 1H), 4.27-4.11(m, 1H), 4.03(d, J=7.3Hz, 2H), 3.93-3.82(m, 2H), 3.82-3.74(m, 4H), 2.98-2.81( m, 3H), 2.78-2.68 (m, 2H), 2.35-2.14 (m, 7H), 2.04-1.39 (m, 12H), 0.99 (q, J=12.7Hz, 1H), 0.78-0.73 (m, 2H), 0.68-0.63(m, 2H).

The following test examples illustrate the beneficial effects of the compounds of the present invention.

The positive compound 1 used in the present invention comes from the patent of Kymera Therapeutics, Inc., patent number WO2020113233. The structure is as follows:

Test Example 1: Effect of Compound of the Invention Binding to CRBN

The compounds to be tested were diluted 3-fold in DMSO, 10 concentration gradients, the 11th concentration was the DMSO control, and 0.16 μL of the compounds were transferred to the 384 assay plate by ECHO. Add 8 μL of the indicated concentration of GST-CRBN to the 384 detection plate and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 15 minutes. Add 8 μL of Anti-GST Eu3+ antibody and Thalidomide-Red mixture to the assay plate. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 3 hours. The 665/615nm ratio was read on the Envision. Analyze raw data using equations.

The following are activity tests of CRBN ligand-linker compounds

"+" indicates that the _IC50 value is greater than 10 μM;

"++" indicates that the IC ₅₀ value is less than or equal to 10 μM and greater than or equal to 1 μM;

"+++" indicates an _IC50 value of less than 1 μM.

Table 1

Test Example 2: Inhibitory effect of the compounds of the present invention on the secretion level of TNFα in human THP-1 cells

(1) Experimental method:

The experiments were carried out in RPMI 1640 medium containing 10% FBS/1% penicillin/streptomycin, and compounds were assayed at a starting concentration of 1 uM.

Dissolve the compound in DMSO into a stock solution, dilute it with medium to 3X working concentration, add 100 μL per well to a 96-well plate; count THP1 cells in logarithmic growth phase, and dilute to a concentration of 2 x 10 ⁶ /mL, add the above-mentioned Compounds were placed in 100 μL per well of a 96-well plate, mixed well, and incubated at 37° C. in a 5% CO2 incubator for 1 hour. Then continue to add LPS to a final concentration of 1 ng/mL, and continue to incubate for 5 hours at 37°C, 5% CO2 incubator. Then centrifuge at 1000rpm for 1min, and take 16uL of the supernatant, respectively, to detect by TNFα ELISA detection kit, read the OD450 value, convert it into TNFα concentration according to the standard curve, and use GraphPad5.0 to fit the dose-effect curve to calculate the _EC50 value.

(2) Experimental results

The experimental results are shown in Table 1 below, where the EC ₅₀ values of each compound are classified according to the following instructions:

"++" indicates that the EC ₅₀ value is less than 1 μM and greater than 300 nM;

"+++" indicates that the EC ₅₀ value is less than 300nM and greater than 100nM;

"++++" indicates an _EC50 value of less than 100 nM.

Table 2 Inhibitory effect of compounds on the secretion level of TNFα in THP-1 cells

Test Example 3: Inhibitory effect of the compound of the present invention on the secretion level of IL-6 in human peripheral blood mononuclear cells (PBMC)

(1) Experimental method:

The experiments were carried out in RPMI 1640 medium containing 10% FBS/1% penicillin/streptomycin, and compounds were assayed at a starting concentration of 10 uM. Dissolve the compound in DMSO into a stock solution, dilute it with medium to a 4X working concentration, add 100 μL per well to a 96-well plate; count the PBMC cells in the logarithmic growth phase, and dilute to a concentration of 2 x 10 ⁶ /mL, add the above-mentioned Compounds were placed in 100 μL per well of a 96-well plate, mixed well, and incubated at 37° C. in a 5% CO2 incubator for 20 hours. Then continue to add LPS to a final concentration of 100ng/mL, and continue to incubate for 5 hours at 37°C, 5% CO2 incubator. Then centrifuge at 1000rpm for 1min, and take 16uL of the supernatant respectively, and detect it according to IL-6 ELISA detection kit, read the OD450 value, convert it into IL-6 concentration according to the standard curve, and use GraphPad 5.0 to fit the dose-effect curve to calculate the _EC50 value.

(2) Experimental results

The experimental results are shown in Table 2 below, where the EC ₅₀ values of each compound are classified according to the following description:

"+" indicates that the EC ₅₀ value is greater than 1 μM;

"++++" indicates an _EC50 value of less than 100 nM.

Table 3 Inhibitory effect of compounds on the secretion level of IL-6 in PBMC cells

Test Example 4: Study on the degradation level of IRAK4 in human peripheral blood mononuclear cells (PBMC) by the compounds of the present invention

(1) Experimental method:

Thaw frozen human PBMCs into culture medium. Cells were grown at a minimum of 2.5 x ¹⁰⁶ c/mL. PBMCs were incubated at 37°C/5% CO2 and allowed to stand overnight. After overnight recovery, cell counts/viability assessments were performed by trypan blue exclusion. Adjust the cell density to 2.5 x ¹⁰⁶ /mL. This was then added to a 96-well plate at 90uL per well.

Dissolve the compound in DMSO into a stock solution, dilute it with medium to a 3X working concentration, and add it to the above 96-well plate, 10 μL per well. Incubate for 20 hours at 37°C in a 5% CO2 incubator.

At the end of treatment, cells were harvested and centrifuged at 1800 rpm for 5 minutes. Washed with 1×PBS and centrifuged at 1800 rpm for 5 minutes. Cell pellets were frozen and stored at -80°C until further processing. Lysates are generated by resuspension in lysis buffer. Protein quantification was performed with the BCA kit.

20 μg of protein was loaded per lane and run on 26-well 4-12% Bis-Tris SDS-page gels. The PVDF membrane was transferred for 7 minutes using the BioRad Mixed MW turbo program. The membrane was blocked on a shaker for one hour at room temperature. Primary antibodies were incubated overnight at 4°C on a shaker. Membranes were washed 3x TBST, 5 min each. Secondary antibody was added and incubated on a shaker for one hour at room temperature. Membranes were washed 3 x TBST for 5 min each and rinsed extensively with deionized H2O. Membranes were scanned using the Rico Odyssey CLx and bands were quantified using Image Studio simplified version 5.2 software.

Test Example 5: Study on the degradation level of IRAK4 in OCI-LY10 by the compounds of the present invention.

(1) Experimental method:

The OCI-LY10 cell density was adjusted to 2.5×10 ⁶ /mL. This was then added to a 96-well plate at 90uL per well. Dissolve the compound in DMSO into a stock solution, dilute it with medium to a 3X working concentration, and add it to the above 96-well plate, 10 μL per well. Incubate for 20 hours at 37°C in a 5% CO2 incubator.

At the end of treatment, cells were harvested and centrifuged at 1000 rpm for 5 minutes. Cell pellets were washed once with 1×DPBS and resuspended in 60 μL of lysis buffer. Cells were lysed on ice for 10 minutes, then centrifuged at 14,000 rpm for 10 minutes at 4°C, and the supernatant collected for western blotting. Use RIPA buffer mixed with Halt protease and protein phosphatase inhibitors.

The protein concentration of cell lysates was quantified using PierceTM BCA Protein Assay Kit. Different concentrations of albumin standards were prepared involving 2,000 μg/mL, 1,500 μg/mL, 1,000 μg/mL, 750 μg/mL, 500 μg/mL, 250 μg/mL, 125 μg/mL, and 25 μg/mL. The BCA working reagent was prepared by mixing BCA Reagent A with Reagent B in a 50:1 ratio. Add 200 μL of BCA working reagent to 25 μL of BCA standard or cell lysate in the microplate and mix thoroughly for 30 seconds on a plate shaker. After 30 minutes incubation at 37°C, the absorbance of the samples at 562 nm was measured with an EnVision plate reader.

Protein lysates were prepared in NuPAGETM LDS sample buffer and NuPAGETM sample reducing agent and incubated at 95°C for 5 minutes. For Western blots, 20 to 25 μg of total protein were resolved in 4 to 12% Bis-Tris gels or 10% Bis-Tris Midi gels run with 1× MOPS SDS running buffer or 1× MES SDS running buffer. Proteins were transferred to low fluorescence PVDF membranes using the Trans-Blot Turbo Transfer System. Membranes were then blocked in Odyssey blocking buffer for 1 hour at room temperature, followed by a primary incubation overnight at 4°C. Primary antibodies were IRAK1 rabbit monoclonal antibody, IRAK3 rabbit polyclonal antibody, IRAK4 rabbit polyclonal antibody, MyD88 rabbit monoclonal antibody, β-actin mouse monoclonal antibody and Gapdh mouse monoclonal antibody, MAB374, 1:5,000 ). Membranes were washed three times with 1×TBST and then incubated with IR Dye 800 CW goat anti-rabbit and IR Dye700 CW goat anti-mouse secondary antibodies at a 1:10,000 dilution for 1 hour at room temperature. Western blot images were acquired using the Odyssey imaging system.

Test Example 6: Analysis and study of the compound of the present invention on the survival rate of OCI-LY10 cells.

(1) Experimental method:

OCI-LY10 cells were seeded into 384-well plates at a density of 10,000 cells/well. Compounds were then added to the assay plates at a final maximum concentration of 1 μM and a total of 5 doses in a 1:3 dilution series. The final DMSO concentration was normalized to 0.2%. The assay plates were incubated at 37°C for 4 days under 5% CO2. The assay plate was then equilibrated for 10 minutes at room temperature. 30 μL of CellTiter Glo reagent was added to each well and the assay plate was centrifuged at 1000 rpm for 30 seconds, incubated at room temperature for 10 minutes, and analyzed by detecting luminescence using a multi-mode plate reader. Data were then analyzed by Prism 7.0, and a three-parameter logistic equation was used to fit a dose-response curve to calculate EC50.

Test Example 7: The following is the efficacy test of the compound of the present invention on the Lewis rat model of arthritis induced by complete Freund's adjuvant (CFA).

experimental method:

(1) Establishment of animal model: Male Lewis rats (about 100-125 g) were divided into groups, and there were 8 rats in each group. Randomly divided into 6 groups, namely normal control group, model control group, test compound low, medium and high dose groups (10mg/kg, 30mg/kg, 100mg/kg) and positive drug control group (PF06650883, 30mg/kg) ). Except for the normal group, the AA model of each experimental group was established on the 0th day by injecting complete Freund's adjuvant containing inactivated Mycobacterium tuberculosis (H37RA, 10 mg/ml) into the left hind foot of the rat. 0.08ml creates a rat adjuvant arthritis model. Treatment with different doses of test substance was carried out by oral administration from day 10 of modeling. 10 consecutive days. On the 8th, 11th, 14th, 17th, 20th, 23rd and 26th days after modeling, the joint score and the diameter of the left and right hind paws were measured to observe the effect of drugs on adjuvant arthritis in rats.

Arthritis evaluation indicators are as follows:

A. Joint score

Limbs: On a 0-4 scale: no erythema or swelling (0); slight erythema or swelling, with erythema or swelling in one of the anterior/posterior toe joints (1); more than one toe with erythema or swelling ( 2); Swelling of the paw under the ankle or wrist joint (3); Swelling of the entire paw including the ankle joint (4). The four feet of the rat were scored separately, and the highest score was 16 points. Joint scoring was performed at 8, 11, 17, 14, 17, 20, 23 and 26 days after modeling and the results were recorded.

B, measure the diameter of the ankle

The diameter and thickness of the left and right ankles were measured with vernier calipers before modeling and at 8, 11, 17, 14, 17, 20, 23 and 26 days after modeling, and the results were recorded. The measurement data of the test results were expressed as the mathematical mean plus or minus the standard deviation (mean ± SD), and the SPSS11.0 software was used to conduct the test between each administration group and the control group.

Test Example 8: Experiment on the efficacy of the compounds of the present invention on the OCI-Ly10 cell DLBCL nude mouse xenograft model.

Count the flasks of OCI-Ly10 cells in the logarithmic growth phase, transfer them to a 15ml centrifuge tube, 1200rmp, 5min, discard the supernatant, resuspend the cells in serum-free medium IMDM, count the cells, and adjust the cell density to 2×10 ⁷ /ml. The skin of nude mice was sterilized, and cells of OCI-LY10 cell line (2×10 ⁷ cells/ml, 0.2 ml) were subcutaneously injected into the forelimbs of nude mice near the axilla. Observe whether there is tumor formation at the inoculation site and whether there is bleeding, redness, and ulceration at the injection site every other day, and record the body weight and tumor size changes of nude mice. When the tumor diameter reached 150-300mm3, it was considered that the lymphoma model was successfully established, and the nude mouse transplanted tumor model was randomly divided into the control group (physiological saline), the test compound low, medium and high dose groups (10mg/kg, 30mg/kg, 100mg/kg) and positive drug control group (PF06650883, 30mg/kg), 10 in each group. And by oral administration to carry out the treatment with different doses of test substances for 28 days, once a day, record the body weight of nude mice every other day after the administration, measure the tumor long diameter (a) and the vertical diameter of the tumor with a vernier caliper. Short axis (b), tumor volume [V=(a×b ² /2)/2] was calculated and tumor growth curve was drawn. The active diet, weight loss and death of nude mice were closely observed.

On the second day after drug withdrawal, the nude mice were anesthetized and decapitated the cervical vertebrae to kill the nude mice. The samples were collected and the general shape of the tumor was observed. Then, the samples were placed in 4% neutral formaldehyde solution, fixed for 8-18 hours, and then made into paraffin blocks for routine HE slice box immunization. Histochemical research.

Test Example 9: Degradation effect of compounds on IRAK4 protein in THP1 cells

THP-1 cells were seeded into 96-well cell culture plates at ⁵ x 104 cells per well in 100 μL of medium. Cell culture plates were incubated overnight in a 37°C, 5% _CO2 incubator. 100 nl of the prepared compound stock solution and compound-free DMSO stock solution were added to each well of cells. Cell culture plates were treated for 24 h in a 37 °C, 5% _CO2 incubator. To 20 mL of cell lysis buffer, add one tablet of protease inhibitor and one tablet of phosphatase inhibitor and mix gently until completely dissolved. Add a final concentration of 200mM DTT to 4x sample preparation buffer to make 4x sample preparation working solution. Dilute 20x running buffer to 1x with ultrapure water. Dilute 20x transfer buffer to 1x with ultrapure water and add 20% methanol. Dilute 10x running buffer to 1x with ultrapure water. IRAK4 protein primary antibody working solution: add 20 μl of IRAK4 antibody to 20 mL of blocking solution; β-Actin primary antibody working solution: add 2 μl of beta-actin(13E5) Rabbit mAb antibody to 20 mL of blocking solution. IRAK4 protein secondary antibody working solution: Donkey Anti-Goat IgG H&L (HRP) diluted 1/5000 in blocking solution; β-Actin secondary antibody working solution: Anti-rabbit IgG, HRP-linked antibody in blocking solution 1/ 10000 dilution. The cell culture plate was centrifuged at 3000 rpm for 3 min, and most of the medium was carefully aspirated. The cell plate was inverted, and centrifuged at 300 rpm for 30 s; 45 μL of lysis buffer was added to each well, 300 rpm, and shaken for 30 s. Add 6 μL of 4x sample preparation working solution to the supernatant for sample preparation, and heat at 70 °C for 10 min. The remaining protein samples were stored at -80°C. In the precast gel, load 8 μl of sample into each well, and conduct electrophoresis at constant voltage of 120V for about 60 minutes. Transfer membrane using PVDF membrane, constant current 300mA, 1 hour. After transfer, the cells were blocked with blocking solution for 1 hour at room temperature. The primary antibody working solution was incubated overnight at 4°C. Wash the membrane with 1×TBST buffer, 3×10min. Incubate with secondary antibody working solution for 1 hour at room temperature. Wash the membrane with 1 × TBST buffer for 3 × 10 min, and use the color developing solution to expose and develop the color. Using _ImagJ software, the gray value of each band was calculated, semi-quantitative analysis was performed and DC50 was calculated with GraphPad Prism 8.0.

"+" indicates that the DC ₅₀ value is greater than or equal to 1 μM;

"++" indicates that the DC ₅₀ value is less than 1 μM and greater than or equal to 100 nM;

"+++" indicates that the DC ₅₀ value is less than 100nM;

Table 4 The effect of compounds on IRAK4 protein degradation in THP1 cells

Test Example 9: Inhibitory effect of the compounds of the present invention on the secretion level of IL-6 in THP-1 cells

Transfer 100 nL of compound to a 96-well plate using an Echo. Seed 95uL of THP1 cells (1*10^5cells/well.) per well into a 96-well plate in step 1 and incubate at 37°C, 5% CO ₂ incubator for 24 hours. Add 5 uLR848 per well to the 96-well plate in step 2 at a final concentration of 10ug/ml and incubate for 20 hours in a 37°C, 5% _CO2 incubator. The cell plate was centrifuged, an appropriate amount of supernatant was transferred to a 96-well ELISA plate, and the IL6 ELISA experiment was performed according to the instructions (IL-6 elisa kit was purchased from RD, product number DY206-05). Read the OD450 value on the Envision.

"+" indicates that the DC ₅₀ value is greater than or equal to 1 μM;

"+++" indicates that the DC ₅₀ value is less than 100nM;

Table 5 Inhibitory effect of compounds on the secretion level of IL-6 in THP-1 cells

Test Example 10: Metabolic Stability Test

Pre-warm empty incubation plates T60 and NCF60 for 10 min; dilute liver microsomes to 0.56 mg/mL in 100 mM phosphate buffer, transfer 445 uL of microsomal working solution (0.56 mg/mL) to pre-warmed "incubator" Plate T60 and NCF60, then incubate plate T60 and NCF60 for 10 min at 37 °C with constant shaking. Transfer 54 μL of liver microsomes to a blank plate, then add 6 μL of NAPDH cofactor to the blank plate, then add 180 μL of quenching solution to the blank plate; add 5 μL of complex working solution (100 μM) to the incubation plate containing microparticles ( T60 and NCF60) and mix thoroughly 3 times; for NCF60 plates, add 50 uL of buffer and mix thoroughly 3 times. Start timing; plate will be incubated at 37°C for 60 minutes with shaking; in quench plate T0, add 180 μL of quenching solution and 6 μL of NAPDH cofactor. Make sure the plate has cooled to prevent evaporation, for T60 plates, mix thoroughly 3 times and immediately transfer 54 μL of the mixture to the quench plate at the 0 min time point. 44 μL of NAPDH cofactor was then added to the incubation plate (T60). Start the timer; the plate will be incubated at 37°C for 60 minutes with shaking. At 5, 15, 30, 45, and 60 min, 180 μL of the quenching solution was added to the quenching plate, mixed once, and then 60 μL of sample at each time point was serially transferred from the T60 plate to the quenching plate.

For NCF60, mix once and transfer 60 μL of sample from the NCF60 incubation to the quenching plate containing the quenching solution at the 60 minute time point. All sampling plates were shaken for 10 min, then centrifuged at 4000 rpm for 20 min at 4°C, 80 μL supernatant was transferred to 240 μL HPLC water and mixed by plate shaker for 10 min; prior to LC-MS/MS analysis , seal and shake each bioassay plate for 10 minutes.

Table 6 represents the stability of example compounds in human liver microparticles

Table 6 represents the stability of example compounds in mouse liver microparticles

Test Example 11: Therapeutic effect of the compound of the present invention on psoriasis model

Male BALB/c mice, 6-8 weeks old, were randomly divided into 9 groups after 1 week of adaptive feeding, namely blank group, imiquimod model group (ie IMQ group), and IRAK4 small molecule inhibitor PF-06650833 group (30mg/kg and 100mg/kg), IRAK4 protein degrader positive compound 1 (from patent WO2020113233) group (30mg/kg and 100mg/kg) and compound example seventy groups (15, 30, 100), each group of 6 to 7. On the 0th day, the mice were depilated with depilatory cream on the back, and the depilation area was 2 × 2 cm2. On the first day, IMQ cream was used for modeling, and corresponding drug treatment was given by gavage. The IRAK4 small molecule inhibitor PF-06650833 group (30mg/kg and 100mg/kg), and compound example seventy groups (15, 30, 100) were given the corresponding drugs twice a day in the morning and evening, with an interval of 8h between the two times. Two hours after the first gavage on the same day, IMQ cream was applied to the back depilation site and left ear of the mice, and the doses of IMQ cream were 80 mg and 10 mg, respectively, on the back depilation site and left ear. The positive compound 1 (from patent WO2020113233) group applied IMQ cream on the back hair loss site and left ear of the mice 4 hours after the first gavage on the same day. The blank group and the IMQ group were intragastrically administered with vehicle twice a day in the morning and evening, with an interval of 8 hours between the two intragastric administrations. After the first intragastric administration interval of 2 hours on the same day, Vaseline and IMQ cream were smeared on the back hair removal sites and ears of the mice, respectively, for continuous administration. 7 days.

Refer to the Psoriasis Area and Severity Index (PASI) scoring standard. From the first day of modeling, the psoriasis, erythema and thickness of the skin lesions on the back were scored on a 0-4 basis every morning. The scoring standards are shown in Table 1. The total score is obtained by adding the scores of the 3 items, which is the total score of PASI. On the 7th day of the experiment, the typical skin of the mice in each group was as shown in the pictures on the seventh day of the psoriasis modeling. Beginning on day 0, the ear thickness of the mouse's left ear was measured with a digital vernier caliper every morning, three times, and the average value was taken (see Figures 1 and 2).

Table 7 Psoriasis Area and Severity Index (PASI) scoring standard

In conclusion, the present invention discloses compounds represented by formula A, which can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways. Diseases mediated by IRAK4 include immune diseases (such as psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis and systemic lupus erythematosus, etc.), tumors (such as multiple myeloma, lymphocytic leukemia, etc.) and lymphoma, etc.), Alzheimer's disease and fibrotic diseases and other diseases, it has very good application prospects, and provides a new option for clinical screening and/or preparation of drugs for diseases related to IRAK4 activity.

Claims

A compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,

in,

Q is selected from CR 2a , N;

V is selected from C, N;

U is selected from CR 2 , NR 2 ;

W is selected from CR 3 , N;

X is selected from C, CR 4 , N;

Y is selected from C, CR 5 , N;

Z is selected from C, CR 6 , N;

R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted Saturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

A ring is independently selected from 0-4 R 7 substituted: 5-10-membered aromatic heterocycle, or 5-6-membered aromatic heterocycle-5-6 membered aromatic heterocycle; the heteroaryl group contains 1-4 selected from heteroatoms from oxygen, sulfur and nitrogen;

Re , R 2a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered Heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 Ring-membered hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered Cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched chain alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3 -10-membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3- C10 heterospirocyclyl, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 3-10-membered cycloalkyl, C1-C6 straight or branched chain alkyl-C(=O) -, 3-10 membered cycloalkyl-C(=O)-; Said heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 selected from oxygen, sulfur and nitrogen of heteroatoms;

L is selected from linking groups that are non-hydrogen.
The compound represented by formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that said formula I The compounds represented, their enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof satisfy one or more of the following conditions:

(1) The compound shown in formula I is shown in formula Ia or formula Ib,

For example, as shown in formula Ic or formula Id,

(2) R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl 3-10-membered cycloalkyl, wherein the substituents are independently selected from Deuterium, halogen, hydroxyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy; the number of the substitution is 1, 2 or 3; for example, R 1 is selected from hydrogen, Deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxymethyl base, ethoxymethyl, cyclopropoxymethyl;

(3)
for

(4)
In, V is selected from N, U is selected from CR 2 , W is selected from CR 3 , N;

(5) R e , R 2a , R 2 , R 3 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted C1-C6 Linear or branched alkoxy; for example H or methyl;

(6) X is selected from CR 4 , N; Y is selected from CR 5 , N; Z is selected from C, CR 6 , N; and at most one of X, Y and Z is N;

(7) R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy; for example H, F or methyl;

(8) Ring A is independently selected from the following rings substituted with 0, 1, 2, 3 or 4 R 7 :

E.g

(9) R 7 is selected from substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Or unsubstituted C1-C6 linear or branched alkylamino groups;

(10) R 7 is selected from substituted 4-10-membered heterocyclic group, substituted C5-C12 heterobridged cyclic group, substituted C3-C10 heterospirocyclic group, substituted C1-C6 straight chain or branched chain The substituents in the alkylamino group are independently selected from deuterium, halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, 4-10-membered heterocyclic group, 3-10-membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)-, 3-10-membered cycloalkyl-C(=O)-, such as selected from deuterium, halogen , C1-C6 linear or branched alkyl, 4-10-membered heterocyclic group, 3-10-membered cycloalkyl, C1-C6 linear or branched alkyl-C(=O)-, 3-10 membered cycloalkyl-C(=O)-; another example R 7 is selected from:

(11) L is
in,

L1 is selected from none,

a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, -N(R 8 )-, -C, respectively (=O)-R 9 -, -SO2R 10 -; R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring, substituted or unsubstituted Unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain or Branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group , substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 can be respectively combined with R L111 , R L112 , RL113 , RL114 , RL123 , RL124 , RL125 , RL126 , RL127 , RL128 , RL129 , RL130 form substituted or unsubstituted 3-10-membered through C, N, O, S ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight Chain or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -, - R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,

R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered Heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group , heterospirocyclyl, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L b' , L c' , L d' , L i' are independently selected from N, CR 38 ;

R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkane group, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted Substituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or Unsubstituted 3- to 10-membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, - R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,

The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 can be combined with R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1- C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 - , -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,
R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, - R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,
R L121 , R L122 , R L123 , R L124 , R L125 , R L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
R L127 , R L128 , R L129 , R L130 , R L131 , R L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L2a', L2e ' , L2f ' , L2g', L2h ' independently selected from In none, O, S, NR 39 , COR 40 , -SO2R 41 ;

L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ;

R 39 , R 40 , R 41 , R 44 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , R L243 , R L244 , R L245 , R L246 are independently selected from hydrogen, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted heterocyclyl C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, - R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1 -C6 straight or branched chain alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
R L211 , R L212 , R L213 , R L214 , R L215 , R L216 , R L217 , R L218 , R L219 , R L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, - R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
R L221 , R L222 , R L223 , R L224 , R L225 , R L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,
R L227 , R L228 , R L229 , R L230 , R L231 , R L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamine, 3-10-membered cycloalkylamine, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2NR 33 R 34 -,
Or R 44 and R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L231 , R L232 can pass C, N , O, S form a substituted or unsubstituted 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2- C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 Membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R2 6 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

For example, L1 is selected from None,

f, g, h, i, j, k, l, m, n, o, p are independently selected from 0, 1 or 2;

Ld and Le are independently selected from none, -C(=O)-R 9 - or -N(R 8 )-; R 8 is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkane base; R 9 is selected from unsubstituted, substituted or unsubstituted C1-C6 straight or branched chain alkyl;

L a' , L e' , L f' , L g' , L h' are independently selected from none;

L b' , L c' , L d' , L i' are independently selected from N, CR 38 ;

R38 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L25 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r are independently selected from 0, 1, 2 or 3;

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n are independently selected from none, -C(=O) -R40- , O, S or -N (R 39 )-; R 39 is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; R 40 is selected from unsubstituted, substituted or unsubstituted C1-C6 linear or branched alkane base;

L 2a' , L 2e' , L 2f' , L 2g' , L 2h' are independently selected from none; L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ;

R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , R L243 and R L244 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10-membered aromatic heterocycle;

The substituents are independently selected from deuterium, halogen, C1-C6 straight or branched chain alkyl; and at least one of L1, B ring, L2 and C ring is not absent.
The compound represented by formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that said formula I The compounds represented, their enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof satisfy one or more of the following conditions:

(1) each said halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine;

(2) The C1-C6 alkyl group in each of the substituted or unsubstituted C1-C6 straight or branched chain alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl; for example methyl, ethyl or propyl;

(3) The 3-10-membered cycloalkyl group in each of the substituted or unsubstituted 3-10-membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,

(4) The 4-10-membered heterocyclic group in each of the substituted or unsubstituted 4-10-membered heterocyclic groups may independently be

E.g

(5) The C3-C10 heterospirocyclyl group in each of the substituted or unsubstituted C3-C10 heterospirocyclyl groups may independently be 2-azaspiro[3.3]heptyl, 7- Azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 6-azaspiro[3.4]octane base, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[ 3.3] Heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example

(6) The C5-C12 heterobridged ring group in each of the substituted or unsubstituted C5-C12 heterobridged ring groups is independently octahydrocyclopentano[C]pyrrolyl, octahydropyrrole[ 3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3-nitrogen Heterobicyclo[3.2.1]octyl; for example

(7) The 5-10-membered aromatic heterocycle in each of the substituted or unsubstituted substituted 5-10-membered aromatic heterocycles can be independently

(8) At least one of L1, B ring, L2 and C ring is not null; for example, two, three or four of L1, B ring, L2 and C ring are not null;

(9) The structures of the compounds are shown in (Ie), (If) and (Ig):

(10)
Selected from:
The compound represented by formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that said formula I The compounds represented, their enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof satisfy one or more of the following conditions:

(1)
for

(2)
for
E.g

(3)
for

(4) Ring A is selected from:

(5) L is selected from:

its single cis-trans isomer or a mixture thereof;

E.g
The compound represented by formula I as claimed in claim 1, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that said formula I The compound represented is any of the following schemes:

plan 1,

A compound represented by formula I,

in,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3 -10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 linear or branched alkane Oxy group, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3- 10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from a 5-10 membered aromatic heterocycle substituted with 0-4 R 7 ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted Substituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched Saturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamine, C1 -C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10 A membered aromatic ring, a 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

Scenario 2,

Among the compounds described,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted Substituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched Saturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamine, C1 -C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10 A membered aromatic ring, a 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

Option 3,

Among the compounds described,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted Substituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched Saturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamine, C1 -C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged ring, C3-C10 heterospirocyclyl, 6-10 A membered aromatic ring, a 5-10 membered aromatic heterocycle; the heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

Option 4,

Among the compounds described,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10-membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10-membered cycloalkylamino, substituted or unsubstituted C1 -C6 straight-chain or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched chain alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkoxy Amine group, 3-10-membered cycloalkylamino group, C1-C6 straight or branched chain alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring base, C3-C10 heterospirocyclyl, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle; the heterocyclyl, heterobridged ring, heterospirocyclyl, and aromatic heterocycle contain 1 - 4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

L1 is selected from none,

a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 , COR 9 , -SO2R 10 ; R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , - R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2NR 33 R 34 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridge ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 can be respectively combined with R L111 , R L112 , R L113 , R L114 , R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 are independently selected from none, hydrogen, halogen, cyano, hydroxyl , amine group, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered ring Alkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkane Oxy group, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino , substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1 -C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 Linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 straight or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered heterocyclic, C5-C12 heterocyclic group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group Radical and aromatic heterocycles contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L b' , L c' , L d' , L i' are independently selected from N, CR 38 ;

R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, halogen, cyano, hydroxyl, amine, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, Substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted The 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 can be combined with R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight Chain or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or Branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2NR 33 R 34 ,
R L121 , R L122 , R L123 , R L124 , R L125 , R L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L127 , R L128 , R L129 , R L130 , R L131 , R L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2a', L2e ' , L2f ' , L2g', L2h ' independently selected from None, O, S, NR39 , COR40 , -SO2R41 ; L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ; R 39 , R 40 , R 41 , R 44 are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic Cyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5 -10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkane Oxy group, substituted or unsubstituted C1-C6 linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2NR 33R34 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic ring Heterocyclic ring; the heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 Linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear Or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L211 , R L212 , R L213 , R L214 , R L215 , R L216 , R L217 , R L218 , R L219 , R L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L221 , R L222 , R L223 , R L224 , R L225 , R L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L227 , R L228 , R L229 , R L230 , R L231 , R L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
Or R 44 and R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L231 , R L232 can pass C, N , O, S form a substituted or unsubstituted 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain alkyl, C2- C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 Membered cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Option 5,

The structures of the compounds are shown in (II) and (III):

V is selected from C, N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 Heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain Or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear Chain or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3-10 membered The cycloalkanoyl group; the substituents are independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 Linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched Chain alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5 -10-membered aromatic heterocycle; said heterocyclyl, heterobridged ring, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 42 and R 43 are selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted Substituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1 -C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3 -10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear Chain or branched alkanoyl group, 3-10-membered cycloalkanoyl group, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aryl group ring, 5-10-membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

Its fragments are selected from:

Option 6,

The structures of the compounds are shown in (IV), (V) or (VI):

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, and substituted or unsubstituted C5-C12 heterobridged ring base, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1- C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched Chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched chain alkanoyl, substituted or unsubstituted 3-10 membered cycloalkane Acyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon groups , C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 Linear or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged cyclyl, C3-C10 heterospirocyclyl, 6-10-membered Aromatic ring, 5-10-membered aromatic heterocycle; said heterocyclic group, heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 42 and R 43 are independently selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 straight or branched chain alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated Hydrocarbyl, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, C1- C6 straight-chain or branched alkanoyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclyl, C5-C12 heterobridged cyclyl, C3-C10 heterospirocyclyl, 6-10-membered The aromatic ring, 5-10-membered aromatic heterocycle; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from 0-4 R 7 substituted:

R 7 is selected from:

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

Its fragments are selected from:
A compound represented by formula I', its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,

in,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl Substituted C2-C6 straight-chain or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkane Oxy group, C1-C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, C1-C6 linear or branched chain alkanoyl group, C1-C6 cycloalkanoyl group, C3-C10 heterocyclic group cyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from a 5-10 membered aromatic heterocycle substituted with 0-4 R 7 ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine base, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents Independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy , C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkane Acyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from linking groups that are non-hydrogen.
The compound represented by formula I' as claimed in claim 6, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, characterized in that said The compound represented by formula I' is any of the following schemes:

plan 1,

Wherein, V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine base, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents Independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy , C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkane Acyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

Scenario 2,

Wherein, V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine base, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents Independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy , C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkane Acyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a linking group other than hydrogen;

Option 3,

in,

V is selected from C, N;

U is selected from CR 2 , N;

W is selected from CR 3 , N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamine base, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents Independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy , C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkane Acyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

L1 is selected from none,

a, b, d are independently selected from 1-6;

c, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 ; R 8 is selected from hydrogen, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aryl ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, Substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, Substituted or unsubstituted C1-C6 linear or branched alkylamino groups, substituted or unsubstituted C1-C6 cycloalkylamino groups, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; Heterocyclic group, hetero - bridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,

R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1-C6 straight or branched cycloalkyl, substituted or unsubstituted Substituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 cycloalkoxy Substituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted The C1-C6 cycloalkanoyl group; the substituents are independently selected from halogen, cyano, hydroxyl, amine group, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group , C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear Or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5- The aromatic heterocycle of 10; the heterocyclyl, heterobridged ring, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L b' , L c' , L d' , L i' are independently selected from N, CR 36 , respectively;

R36 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterocyclic group Heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted Substituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy , substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , - R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; Heterocyclyl, heterobridged, heterospiro, and aromatic heterocycles contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 36 can be combined with R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 forms a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkane base, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamine, Cycloalkylamino of C1-C6, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , - R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 any two groups of which can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L121 , R L122 , R L123 , R L124 , R L125 , R L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L127 , R L128 , R L129 , R L130 , R L131 , R L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, heterobridge Ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2a', L2e ' , L2f ' , L2g', L2h ' are independently selected from none, O, S, NR37; R37 is selected from hydrogen, Substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 Aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl , substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy , substituted or unsubstituted C1-C6 linear or branched alkylamino groups, substituted or unsubstituted C1-C6 cycloalkylamino groups, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
The substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched chain alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1- C6 cycloalkanoyl group, C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; Heterocyclic group, heterobridged ring group, heterospirocyclic group and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 37 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 forms a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituent is independently selected from halogen, cyano, hydroxyl, amino, C1-C6 straight or branched chain Alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino group , C1-C6 cycloalkylamino group, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L211 , R L212 , R L213 , R L214 , R L215 , R L216 , R L217 , R L218 , R L219 , R L220 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1- C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L221 , R L222 , R L223 , R L224 , R L225 , R L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
R L227 , R L228 , R L229 , R L230 , R L231 , R L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon, C1-C6 linear or branched alkoxy, C1 -C6 cycloalkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R 9 COR 10 , -R 11 OCOR 12 , -R 13 COOR 14 , -R 15 NR 16 COR 17 , -R 18 CONR 19 R 20 , -R 21 SO2R 22 , -R 23 OSO2R 24 , -R 25 SO2OR 26 , -R 27 NR 28 SO2R 29 , -R 30 SO2 NR 31 R 32 ,
C3-C10 heterocyclic group, C3-C10 heterobridged ring group, C3-C10 heterospirocyclic group, C5-10 aromatic ring, C5-10 aromatic heterocyclic ring; the heterocyclic group, heterobridge Ring group, heterospirocyclic group, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Option 4,

The structures of the compounds are as (II') and (III'):

Wherein, R 38 and R 39 are as defined as R 2 ;

V is selected from C, N;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

Ring A is independently selected from 0-4 R 7 substituted:

R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterocyclic group Bridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1- C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1-C6 cycloalkylamino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano group, hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 ring Alkoxy, C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 Heterocyclyl, C3-C10 heterobridged ring, C3-C10 heterospirocyclyl, C5-10 aromatic ring, C5-10 aromatic heterocycle; Spirocyclyl, aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

Its preferred fragment is:

Option 5,

Wherein, the structures of the compounds are as (IV') and (V'):

Wherein, R 38 and R 39 are as defined as R 2 ;

X is selected from CR 4 , N;

Y is selected from CR 5 , N;

Z is selected from CR 6 , N;

R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;

R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged cyclic group , substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain Or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1- C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted C1- C6 cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted C1-C6 cycloalkanoyl; the substituents are independently selected from halogen, cyano, hydroxyl , amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy , C1-C6 linear or branched alkylamino, C1-C6 cycloalkylamino, C1-C6 linear or branched alkanoyl, C1-C6 cycloalkanoyl, C3-C10 heterocyclic , C3-C10 heterobridged cyclyl, C3-C10 heterospirocyclyl, C5-10 aromatic ring, C5-10 aromatic heterocycle; the heterocyclyl, heterobridged, heterospirocyclyl , the aromatic heterocycle contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

Ring A is independently selected from 0-4 R 7 substituted:

R 7 is selected from:

L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:

Its preferred fragment is:
The compound represented by formula I or formula I' according to any one of claims 1 to 7, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof , it is characterised in that the compound represented by the formula I or formula I' is selected from the following structures:
An aromatic compound, enantiomer, diastereomer, racemate and mixture as shown in formula E, or a pharmaceutically acceptable salt thereof,

in,
Indicates a single bond or a double bond;

R a is halogen, H, OH, O= or C1-C6 linear or branched alkyl-O-;

L is selected from a linking bond or a non-hydrogen linking group;

Definitions of V, U, W, X, Y, Z, Q, Re V, U, W, X, Y, Z, Q, Re in the compound are defined in any scheme.
The aromatic compound, enantiomer, diastereomer, racemate and mixture or pharmaceutically acceptable salts thereof represented by formula E as claimed in claim 9, wherein the Aromatic compounds, enantiomers, diastereomers, racemates, and mixtures or pharmaceutically acceptable salts thereof represented by formula E satisfy one or more of the following conditions:

(1) The compound shown in formula I is shown in formula Ea or formula Eb,

For example, as shown in formula Ec, formula Ed or Ee,

(2) when R a is halogen, it is bromine or chlorine;

(3) When R a is C1-C6 linear or branched alkyl-O-, the C1-C6 linear or branched alkyl can be methyl, ethyl, n-propyl, isopropyl butyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(4) R 2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, wherein said substituents are independently selected from deuterium, halogen, hydroxyl, amino, C1-C6 straight or branched alkoxy, 3-10-membered cycloalkoxy, 3-10-membered ring Alkyl, 4-10-membered heterocyclic group; the number of the substitution is 1, 2 or 3;

For example R 2 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl base, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetane base, 2-azetidinyl, 3-azetidinyl;

(5)
wherein U is selected from CR 2a , N; X is selected from C, CR 4 , N; Y is selected from C, CR 5 , N; Z is selected from C, CR 6 , N; is N; one or both of U, V and W are N;

(6) R e , R 2a , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, Substituted or unsubstituted C1-C6 linear or branched alkoxy; for example H, F or methyl;

(7) When L is a non-hydrogen linking group, it is
in,

L1 is selected from none,

a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;

La, Lb, Lc, Ld, Le, Lf, Lg, L a' , Le ' , L f' , L g' , L h' are independently selected from None, O, S, NR 8 (-N( R 8 )-), COR 9 (-C(=O)-R 9 -), -SO2R 10 ; R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino group, substituted or unsubstituted 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 8 can be respectively combined with R L111 , R L112 , RL113 , RL114 , RL123 , RL124 , RL125 , RL126 , RL127 , RL128 , RL129 , RL130 form substituted or unsubstituted 3-10-membered through C, N, O, S ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon, C1-C6 straight Chain or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 straight or branched chain alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkane Amino, substituted or unsubstituted C1-C6 straight or branched alkanoyl, substituted or unsubstituted 3-10 membered cycloalkanoyl; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, C1-C6 linear or branched alkanoyl, 3-10 membered cycloalkanoyl, 4-10 membered Heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group, heterobridged ring group , heterospirocyclyl, aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L b' , L c' , L d' , L i' are independently selected from N, CR 38 ;

R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L25 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 , R L133 , R L134 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, Substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight Chain or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2-C6 straight or branched chain Saturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or branched Alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38 can be combined with R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L125 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1- C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 where any two groups can be substituted or unsubstituted through C, N, O, S 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L121 , R L122 , R L123 , R L124 , R L125 , R L126 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L127 , R L128 , R L129 , R L130 , R L131 , R L132 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,

Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from oxo, deuterium, halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , Heterobridged cyclyl, heterospirocyclyl, and aromatic heterocycle contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;

L2 is selected from none,

2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;

L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L2a', L2e ' , L2f ' , L2g', L2h ' independently selected from Yu, O, S, NR 39 , COR 40 , -SO2R 41 ; L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ; R 39 , R 40 , R 41 , R 44 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , R L243 , R L244 , R L245 , R L246 are independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridge Cyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1 -C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon, substituted or unsubstituted C2-C6 linear or branched Chain unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1-C6 linear or Branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2NR 33 R 34 ,
The substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered The aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 39 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1 -C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L211 , R L212 , R L213 , R L214 , R L215 , R L216 , R L217 , R L218 , R L219 , R L220 where any two groups can be formed by C, N, O, S to form a substituted or unsubstituted 3-12-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10-membered cycloalkylamino, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L221 , R L222 , R L223 , R L224 , R L225 , R L226 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R L227 , R L228 , R L229 , R L230 , R L231 , R L232 wherein any two groups can form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected From deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy , 3-10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycloalkylamine, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
R 44 and R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L231 , R L232 can pass C, N, O, S form a substituted or unsubstituted 3-10-membered ring; the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 straight or branched chain alkyl, C2-C6 Linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered Cycloalkylamino, -R 11 COR 12 -, -R 13 OCOR 14 -, -R 15 COOR 16 -, -R 17 NR 18 COR 19 -, -R 20 CONR 21 R 22 -, -R 23 SO2R 24 -, -R 25 OSO2R 26 -, -R 27 SO2OR 28 -, -R 29 NR 30 SO2R 31 -, -R 32 SO2 NR 33 R 34 -,

Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxy group, C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 ,
4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered aromatic heterocyclic ring; the heterocyclic group , heterobridged ring group, heterospirocyclic group, and aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; and at least one of L1, B ring, L2 and C ring is not absent.
The aromatic compound, enantiomer, diastereomer, racemate and mixture or pharmaceutically acceptable salts thereof represented by formula E as claimed in claim 9, wherein the Aromatic compounds, enantiomers, diastereomers, racemates, and mixtures or pharmaceutically acceptable salts thereof represented by formula E satisfy one or more of the following conditions:

(1)
for

(2)
for

(3)
Selected from:

(4) L is selected from the following fragments:

Its single cis-trans isomers or mixtures thereof; for example

(5) R a is bromine, H, OH,
The aromatic compound, enantiomer, diastereomer, racemate and mixture or pharmaceutically acceptable salts thereof represented by formula E as claimed in claim 9, wherein the The aromatic compound represented by formula E or a pharmaceutically acceptable salt thereof is selected from the following structures:
A ligand of ubiquitin ligase, which contains the structure shown in formula E3,

Wherein, the definitions of Q, U, V, W, X, Y, Z and Re are as described in any one of claims 9-12. The aromatic compound represented by formula E, its enantiomer, non-pair As defined by Q, U, V, W, X, Y, Z and Re in enantiomers, racemates and mixtures or pharmaceutically acceptable salts thereof; which may be attached to a linker and further to the target Linked to degrading protein ligands.
A linker-ubiquitin ligase ligand comprising the structure shown in formula E2,

Wherein, L, Q, U, V, W, X, Y, Z and Re are as defined in any one of claims 9-12. The aromatic compound represented by formula E, its enantiomer, L, Q, U, V, W, X, Y, Z and R e in diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof are as defined; Degradation protein ligands are linked.
A kind of aromatic compound shown as formula E as described in any one of claim 9-12, its enantiomer, diastereomer, racemate and mixture or its pharmaceutically acceptable The use of a salt, a ligand for a ubiquitin ligase as claimed in claim 13, or a linker-ubiquitin ligase ligand as claimed in claim 14 for preparing an antibody-drug conjugate; wherein, The E3 fragment shown below can act as a (recruiting) ligand for E3 ubiquitin ligase,

The ligand of the E3 ubiquitin ligase can bind to the Cereblon ligase.
An aromatic compound represented by formula X, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,

Wherein, T is the ligand group targeting degradation protein;

Definitions of L, Q, U, V, W, X, Y, Z and Re The aromatic compound represented by formula E, its enantiomer, non- L, Q, U, V, W, X, Y, Z and Re are as defined in enantiomers, racemates and mixtures or pharmaceutically acceptable salts thereof.
The aromatic compound represented by formula X, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof as claimed in claim 16, characterized in that said The aromatic compound represented by formula X, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, satisfy one or both of the following conditions:

(1) The compound represented by formula X is represented by formula Xa or formula Xb,

For example, as shown in formula Xc, formula Xd or formula Xe,

(2) the ligand group T of targeting degradation protein The T is selected from the following:

in,
Definitions of compounds of formula I, enantiomers, diastereomers, racemates and mixtures thereof as described in any one of claims 1-5 or 8 or pharmaceutically acceptable forms thereof Salts or compounds represented by formula I' as described in any one of claims 6-8, enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof shown in

.
The aromatic compound, enantiomer, diastereomer, racemate and mixture or pharmaceutically acceptable salts thereof represented by formula X as claimed in claim 16, wherein said Aromatic compounds, enantiomers, diastereomers, racemates, and mixtures or pharmaceutically acceptable salts thereof represented by formula X satisfy one or more of the following conditions:

(1) The aromatic compound represented by the formula X is the compound represented by the formula I according to any one of claims 1-5 or 8, its enantiomer, diastereomer, external Racemates and mixtures or pharmaceutically acceptable salts thereof or compounds represented by formula I' as claimed in any one of claims 6-8, enantiomers, diastereomers, racemates thereof Convolved forms and mixtures or pharmaceutically acceptable salts thereof;

(2) The ligand group T of the targeted degradation protein is
, it is the IRAK4 targeting ligand group.
A pharmaceutical composition containing a therapeutically effective amount of substance B, and one or more pharmaceutically acceptable carriers; the substance B is the formula I according to any one of claims 1-5 or 8 The compound shown, its enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, are represented by formula I' according to any one of claims 6-8. Shown compounds, their enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, as shown in formula E as described in any one of claims 9-12 The aromatic compounds, enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, or as described in any one of claims 16-18 as represented by formula X The aromatic compounds, enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts.
The purposes of a kind of substance B in preparing medicine, described substance B is the compound shown in formula I as described in any one of claim 1-5 or 8, its enantiomer, diastereomer isomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, or the compound represented by the formula I' according to any one of claims 6-8, its enantiomers, diastereomers isomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, aromatic compounds, enantiomers, diastereomers represented by formula E as described in any one of claims 9-12 isomers, racemates and mixtures or pharmaceutically acceptable salts thereof, or aromatic compounds, enantiomers, diastereomers of formula X as described in any one of claims 16-18 body, racemate and mixture or pharmaceutically acceptable salts thereof; the medicament can be used for the treatment and prevention of interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL -6) Drugs for diseases related or mediated by one or more of receptors and tumor necrosis factor alpha (TNFα), or the drugs may be for the treatment and/or prevention of autoimmune diseases and/or cancer or drugs for proliferative diseases.
The use of claim 20, wherein the diseases include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, and metabolic disorders , Organ transplantation-related diseases, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, cardiovascular diseases;

The cancer or proliferative disease can be selected from brain cancer, kidney cancer, liver cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, esophageal cancer, lung cancer, prostate cancer, pancreatic cancer, vaginal cancer, cervical cancer, Testicular cancer, genitourinary tract cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, head and neck cancer, epidermoid cancer, large cell cancer, non- Small cell lung cancer, lymphoma, Hodgkin or non-Hodgkin lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma, ABC DLBCL, chronic lymphocytic leukemia, chronic lymphocytic lymphoma , primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell lymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma , plasmacytoma or intravascular large B-cell lymphoma; epidermal hyperproliferative disease, psoriasis, benign prostatic hyperplasia, IL-1 driven disease, MyD88 driven disease;

The MyD88-driven disease can be selected from the group consisting of ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia;

The neurodegenerative disease can be selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, traumatic neurodegenerative disease, and graft-versus-host disease;

The inflammatory disease can be selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, phlebitis conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic platelets Hypoglycemia, cutaneous acne; or another inflammatory disease in which an autoimmune reaction occurs, selected from systemic lupus erythema, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis , chronic active hepatitis, myasthenia gravis, Stephen Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, Periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary liver disease Sclerosis, uveitis, Sjögren's syndrome, uveitis, keratoconjunctivitis, interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, micronephritis Glomerulonephritis, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, chronic obstructive pulmonary disease, pulmonary Diseases, cystic fibrosis, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, conjunctivitis, cystitis , dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, fasciitis, fibritis, gastritis, gastroenteritis, allergic purpura, hepatitis, hidradenitis suppurativa , IgA nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps, pericarditis inflammation, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, enteritis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, vaginitis, Vasculitis, vulvitis, alopecia areata, dermatitis herpetiformis, subcutaneous dermatitis, vitiligo, hypersensitivity vasculitis, urticaria, pemphigus bullosa, pemphigus vulgaris, pemphigus phyllox, epidermolysis bullosa , Acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis.