A protac compound, pharmaceutical compositions thereof, and uses thereof

Abstract

The present application belongs to the technical field of drugs, and relates to a PROTAC compound, a pharmaceutical composition thereof and a use thereof. Specifically, the present application relates to a PROTAC BTK compound and a pharmaceutical composition containing the PROTAC BTK compound, which can be used as a Bruton's tyrosine kinase (BTK) degradation agent. The present application further relates to a method for preparing the compound and the pharmaceutical composition, and a use of the compound and the pharmaceutical composition in preventing or treating a disease related to BTK.

Description

Invention Field This invention belongs to the field of pharmaceutical technology and relates to a PROTAC compound, pharmaceutical compositions thereof, and their uses. The PROTAC compound described in this invention can act as a Bruton's tyrosine kinase (BTK) degrader. This invention also relates to pharmaceutical compositions of this type of compound, methods for preparing such compounds and pharmaceutical compositions, and their uses for the prevention or treatment of BTK-related diseases. Background Technology

[0001] Bruton's tyrosine kinase (BTK) is one of the five members of the Tec family of non-receptor tyrosine protein kinases. It consists of 659 amino acids and contains multiple domains, such as the Pleckstrin homology (PH) domain, Tec homology (TH) domain, Src homology 3 (SH3) domain, SH2 domain, and SH1 domain (Future Med Chem, 2014, 6(6): 675-695). BTK is a signaling enzyme expressed in all hematopoietic cells except natural killer cells and T lymphocytes. Studies have shown that BTK, as an important component of the B cell receptor (BCR) signaling pathway, plays a crucial role in many physiological processes such as B cell development, maturation, differentiation, and proliferation (Nature, 1993, 361(6409): 226-233).

[0002] Precise regulation of BTK is crucial for maintaining normal physiological function of B cells (Anticancer Agents MedChem, 2007, 7(6): 624-632). Excessive activation of BTK can induce B cells to resist apoptosis and make them more susceptible to autoimmune reactions, thereby inducing the occurrence and development of diseases such as B-cell lymphoma and inflammation (Int Rev Immunol, 2012, 31(2): 119-132).

[0003] BTK plays a crucial role in the occurrence and development of tumors and is essential for the survival of various B-cell malignant tumor cells. Small molecule BTK inhibitors have shown unexpectedly excellent anti-tumor activity in clinical trials (Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chroniclymphocytic leukemia [J]. N Engl J Med, 2013, 369(1): 32-42; Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chroniclymphocytic leukemia [J]. N Engl J Med, 2016, 374(4): 323-332), attracting great attention.

[0004] Currently, BTK inhibitors are not only used to treat B-cell malignancies, but are also being studied in clinical trials for the treatment of solid tumors and other hematologic and immune system malignancies.

[0005] Protein degradation-targeting chimeras (PROTACs) are bifunctional compounds that can simultaneously bind to a target protein and an E3 ubiquitin ligase. They consist of three parts: a target protein ligand that specifically binds to the target protein, an E3 ligase ligand that binds to the E3 ubiquitin ligase, and a linker connecting the two ligands. PROTACs bind to both the target protein and the E3 ligase, forming a ternary complex. The E3 ligase ubiquitinates the target protein, which is then recognized and degraded by the proteasome, effectively reducing the concentration of the target protein in the cell.

[0006] PROTAC molecules possess unique advantages: 1) Targeting undrugable targets: They can degrade non-enzymatic and scaffold proteins that are difficult for traditional inhibitors to act on; 2) High selectivity: They degrade specific proteins, reducing off-target effects; 3) Durable effect: Due to their catalytic cycling properties, a single PROTAC molecule can degrade multiple target proteins; 4) Overcoming drug resistance: They directly clear proteins, rather than inhibiting activity, reducing mutation escape. Currently, PROTAC technology has shown breakthrough potential in fields such as cancer, neurodegenerative diseases, immune diseases, and anti-infectives, bringing new hope for the treatment of various diseases.

[0007] BTK plays a crucial role in various B-cell malignancies and autoimmune diseases, but existing BTK inhibitors suffer from problems such as drug resistance. PROTAC BTK can target and degrade wild-type and mutant BTK, overcoming drug resistance, and requires only lower drug doses to produce good therapeutic activity while reducing drug toxicity. Currently, several PROTAC BTK projects are under development globally, some of which have entered clinical trials, such as BGB-16673, NX-2127, and NX-5948. With in-depth research and continuous technological advancements, PROTAC BTK is expected to bring new breakthroughs in the treatment of related diseases, possessing enormous market potential and clinical application value.

[0008] Although several PROTAC BTK drugs have entered clinical trials, there is still a need to develop PROTAC BTK molecules with good molecular permeability, in vivo stability, and selectivity. Summary of the Invention

[0009] The following is a summary description of some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0010] This invention relates to a novel class of substituted pyrimidine compounds. Experimental results show that the compounds of this invention exhibit significant degradation activity against BTK, demonstrating unexpectedly excellent activity. Therefore, the compounds of this invention can be used as BTK degrading agents for the prevention or treatment of BTK-related diseases, including but not limited to tumors, thromboembolism, inflammatory diseases, and autoimmune diseases, particularly tumors.

[0011] The compounds of this invention are stable, have good safety, few toxic side effects, and possess pharmacodynamic and pharmacokinetic advantages, such as a good brain-plasma ratio, good bioavailability, or good metabolic stability, thus showing good prospects for clinical application.

[0012] The present invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

[0013] On one hand, the present invention provides a compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of the compound represented by formula (IA). (IA) in, M1 is a key or , where X4 Connected to Y; M2 is or , where X 1 Connected to Cy1; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -、-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 )y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 is independently 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL Rn R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) when Y is M2 is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) when T is 0 Y is or M2 is When m1 is 1 and m2 is 1, n2 is not 0.

[0014] In some embodiments, the present invention provides a compound that is a compound of formula (I-1) or formula (I-2), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (I-1) or (I-2) in, M1 is a key or , where X 4 Connected to Y; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 )y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -、-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 alkyl; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 can be independently represented as 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In the compound of formula (I-1), when Y is X 3 For CH and X 4 When N is present, m3 and m4 are not simultaneously 0; (2) In compound (I-1), when T is present... Y is or When m1 is 1 and m2 is 1, n2 is not 0.

[0015] In some embodiments, the present invention provides a compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I), formula (Ia), formula (Ib), or formula (Ic). (I) (Ia) (Ib) or (Ic), in, T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -、-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Ya Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 alkyl; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 can be independently represented as 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R dIndependently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In compound (I), when Y is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) In compound (I), when T is 0 Y is or When m1 is 1 and m2 is 1, n2 is not 0.

[0016] In some implementation schemes, Y is , , , , , , or ; Among them, Z 7 For CH or N; X 6 -(CR) c7 R c8 ) y6 -、-C(O)-、-C(S)- or -NR n5 -;R n5 It is H, D, C1-C6 alkyl or C1-C6 haloalkyl; each R c7 and R c8 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; y6 is 1, 2, or 3; Each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R cC3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; f is 0, 1, 2, 3 or 4; R 9 R 10 Together with the attached atoms, it forms a C5-C6 carbon ring, a heterocycle of 5-6 atoms, a benzene ring, or a heteroaromatic ring of 5-6 atoms, wherein each of the C5-C6 carbon ring, the heterocycle of 5-6 atoms, the benzene ring, and the heteroaromatic ring of 5-6 atoms is independently unsubstituted or is independently substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, a heterocyclic group of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-10 atoms.

[0017] In some implementation schemes, Y is , , , , , , , , , , , , or ; Among them, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0018] In some implementation schemes, Y is , , , , , , , , , , , , , , , , , , , , , or ; Among them, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0019] In some embodiments, Cy1, Cy2, and Cy3 are each independently a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C3-C6 cycloalkyl group, the heterocyclic group consisting of 3-6 atoms, the C6-C6 aryl group, and the heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and SH; Each R c3 R c4 R c5 and R c6Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R n2 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0020] In some embodiments, Cy1 and Cy2 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclopropyl, oxacyclobutyl, oxacyclopropyl, cyclobutyl ... Heterocyclic butyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazine are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

[0021] In some embodiments, the compound of the present invention is a compound of formula (II), (IIa), (IIb) or (IIc), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. (II) (IIa) (IIb) or (IIc), Among them, Z a Z b Z c Z d Z e Z f Z g and Z h Each is N or CR z Each R z Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 A aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

[0022] In some embodiments, Cy3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl... Pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroloyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

[0023] In some implementation schemes, each R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R fCyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, or cyclopropyl Cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; Each R n2 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0024] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

[0025] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c It is substituted by substituents such as C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, phenyl, and heteroaryl groups consisting of 5-6 atoms.

[0026] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1-、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -, -O(C6H4)-, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl The following groups are present: propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -COOR a -CONR b R c It is substituted by substituents such as C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, phenyl, and heteroaryl groups consisting of 5-6 atoms.

[0027] In some implementation schemes, each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R ce R c1 and R c2Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0028] In some implementation schemes, each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, or -COOR. d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; Each R ce R c1 and R c2 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, or cyclopropyl Cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; Each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0029] In some implementation schemes, R 9 R 10Together with the attached atoms, it forms a C5 carbon ring, a C6 carbon ring, a 5-atom heterocycle, a 6-atom heterocycle, a benzene ring, a 5-atom heteroaromatic ring, or a 6-atom heteroaromatic ring, wherein each of the C5 carbon ring, C6 carbon ring, 5-atom heterocycle, 6-atom heterocycle, benzene ring, 5-atom heteroaromatic ring, and 6-atom heteroaromatic ring is independently unsubstituted or substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 3-6 atom heterocyclic group, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

[0030] In some implementation schemes, each R a and R d Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R b R c R e and R f Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0031] In some implementation schemes, each R a and R d Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl; Each R b R c R e and R fIndependently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxadiazolyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroleyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0032] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein and a pharmaceutically acceptable carrier, excipient or excipient.

[0033] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to prevent or treat diseases related to BTK.

[0034] In some embodiments, the BTK-related diseases described in this invention are tumors, thromboembolic events, inflammatory conditions, and / or autoimmune diseases.

[0035] In some embodiments, the BTK-related disease described in this invention is a tumor.

[0036] In some embodiments, the tumors described in this invention are B-cell lymphomas, solid tumors, and / or hematologic and immune system tumors.

[0037] In some embodiments, the B-cell lymphoma described in this invention is diffuse large B-cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and / or chronic lymphocytic leukemia.

[0038] In other embodiments, the solid tumors described in this invention are gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, urogenital tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0039] In some other embodiments, the hematologic and immune system tumors described in this invention are acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, and / or chronic myeloid leukemia.

[0040] In some embodiments, the inflammatory conditions or autoimmune diseases described in this invention are asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

[0041] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0042] Detailed specifications Definitions and general terms Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to encompass all alternatives, modifications, and equivalents, all of which are included within its scope. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict the invention (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), the invention shall prevail.

[0043] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0044] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0045] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the periodic table (CAS edition) and the *Handbook of Chemistry and Physics*, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry* by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0046] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles concerning one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0047] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0048] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0049] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0050] "Chirality" refers to molecules that have the property that they cannot be superimposed on their mirror image; while "chirality" refers to molecules that can be superimposed on their mirror image.

[0051] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0052] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0053] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0054] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, for example ( R )-、(S )- or( R , S The configuration exists. In some implementations, the asymmetric atoms are in ( R )-or( S - In terms of configuration, it has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

[0055] Depending on the choice of starting materials and method, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active ( R )-or( S The )-isomer can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be... E or Z Configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans configuration.

[0056] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0057] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is pyridine-4-ol and pyridine-4(1... H Tautomerism of keto tautomers. Unless otherwise indicated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0058] The term "optional" or "optionally" means that an event or situation described below may, but is not guaranteed to, occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "optional key" means that the key may or may not be present, and the description includes single, double, or triple keys.

[0059] The term "substituted" indicates that one or more hydrogen atoms in the given structure are replaced by a specific substituent. As described in this invention, the compounds of this invention may optionally be substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted," meaning that the structure is unsubstituted or substituted by one or more substituents as described in this invention.

[0060] Unless otherwise indicated, an optional substituent group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at each position in the same or different manner.

[0061] The term "unsubstituted" means that the specified group does not have substituents.

[0062] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0063] In various parts of this specification, the substituents of the disclosed compounds are disclosed according to the type or range of groups. In particular, the invention includes every independent secondary combination of the members of these types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0064] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0065] The term "alkyl" as used in this invention refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing a carbon atom. For example, the terms "C1-C6 alkyl" or "C..." 1-6 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 6 carbon atoms. Unless otherwise specified, the alkyl group described in this invention contains 1-12 carbon atoms; in some embodiments, the alkyl group contains 1-10, 1-8, or 1-6 carbon atoms; in some embodiments, the alkyl group contains 1-4 carbon atoms; and in other embodiments, the alkyl group contains 1-3 carbon atoms. "C1-C4 alkyl" includes C1 alkyl (i.e., methyl), C2 alkyl (i.e., ethyl), C3 alkyl (including n-propyl, isopropyl), and C4 alkyl (including n-butyl, isobutyl, sec-butyl, tert-butyl). Examples of the alkyl group include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (... n -Pr, -CH2CH2CH3), isopropyl ( i -Pr, -CH(CH3)2), n-butyl ( n -Bu、-CH2CH2CH2CH3), isobutyl ( i -Bu、-CH2CH(CH3)2), sec-butyl( s -Bu、-CH(CH3)CH2CH3), tert-butyl( t-Bu、-C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), n-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3- Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), etc.

[0066] The term "alkenyl" indicates the presence of at least one unsaturated site (i.e., a carbon-carbon sp). 2 A straight-chain or branched monovalent hydrocarbon group (with a double bond). Unless otherwise stated, the alkenyl group contains 2-12 carbon atoms; in some embodiments, the alkenyl group contains 2-10, 2-8, or 2-6 carbon atoms; in some embodiments, the alkenyl group contains 2-4 carbon atoms. For example, the term "C2-C6 alkenyl" or "C 2-6 "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 Double bonds, which include " cis "and" tans The positioning of "or" E "and" Z The alkenyl group is positioned as follows. Examples of the alkenyl group include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0067] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing at least one unsaturated site (i.e., a carbon-carbon sp triple bond). Unless otherwise stated, the alkynyl group contains 2-12 carbon atoms; in some embodiments, the alkynyl group contains 2-10, 2-8, or 2-6 carbon atoms; in some embodiments, the alkynyl group contains 2-4 carbon atoms. For example, the terms "C2-C6 alkynyl" or "C 2-6 "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-6 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0068] The term "C1-C6 alkoxy" indicates that an alkyl group is attached to the remainder of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group described in this invention contains 1-6 carbon atoms; in some embodiments, the alkoxy group contains 1-4 carbon atoms; in other embodiments, the alkoxy group contains 1-3 carbon atoms. Examples of the alkoxy group include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy ( n -PrO、 n -propoxy, -OCH2CH2CH3), 2-propoxy ( i -PrO、 i -propoxy, -OCH(CH3)2), 1-butoxy n -BuO、 n -Butoxy, -OCH2CH2CH2CH3), 2-Methyl-1-propoxy ( i -BuO、 i -butoxy, -OCH2CH(CH3)2), 2-butoxy ( s -BuO、 s -Butoxy, -OCH(CH3)CH2CH3), 2-Methyl-2-propoxy t -BuO、 t -Butyloxy, -OC(CH3)3), 1-pentyloxy ( n-Pentoxy, -OCH2CH2CH2CH2CH3), 2-Pentoxy (-OCH(CH3)CH2CH2CH3), 3-Pentoxy (-OCH(CH2CH3)2), 2-Methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-Methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-Methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-Methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0069] The term “haloalkyl” or “haloalkoxy” means that an alkyl or alkoxy group is replaced by one or more halogen atoms. Examples of such replacements include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, etc.

[0070] The term "composed of x atoms" or "x-ary," where x is an integer, typically describes the number of atoms forming a ring in a molecule. For example, piperidinyl is a 6-atom heterocyclic alkyl group, while 1,2,3,4-tetrahydronaphthalene is a 10-atom cycloalkyl group. The "3-7 atom heterocycle" described in this invention includes heterocycles composed of 3-6 atoms, specifically 3-atom, 4-atom, 5-atom, or 6-atom heterocyclic groups.

[0071] Term "C" x1 -C x2 "Carbocyclic group" or "C" x1 -C x2 "Carbocyclic" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic system containing x1-x2 (x1 and x2 are integers, where x2 > x1) carbon atoms. Carbocyclic groups include spirobicyclic, fused, and bridged carbocyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloynyl groups. Further examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, and 1-cyclopentyl-2-enyl groups. Cyclohexyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Unless otherwise stated, the "C3-C7 carbon ring" or "C3-C6 carbon ring" described in this invention refers to a non-aromatic saturated or partially unsaturated monocyclic ring composed of 3-7 or 3-6 carbon atoms. For example, the "C3-C7 carbon ring" or "C3-C6 carbon ring" can be... , , ,or wait.

[0072] The term "C3-C6 cycloalkyl" refers to a monovalent or polyvalent non-aromatic saturated monocyclic system containing 3-6 carbon atoms. Unless otherwise stated, the cycloalkyl groups described in this invention comprise 3-6 carbon atoms. Examples of cycloalkyl groups described in this invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0073] The terms “heterocyclic,” “heterocyclic group,” or “heterocyclic” are used interchangeably herein unless otherwise stated. A heterocyclic group refers to a monocyclic, bicyclic, or tricyclic system comprising 3 to 14 ring atoms, in which one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described herein. The ring may be fully saturated or contain one or more unsaturations, but no aromatic rings are permitted. Unless otherwise stated, the “heterocyclic,” “heterocyclic group,” or “heterocyclic” group as used herein is composed of the aforementioned atoms. For example, a heterocyclic group consisting of 3 to 6 atoms refers to a monocyclic ring of 3 to 6 members (2 to 5 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by one or more oxygen atoms to obtain groups like SO, SO2, PO, PO2). The heterocyclic group described in this invention can be a carbonyl or heteroatom-based group; wherein, the -CH2- group of the ring can optionally be replaced by -C(=O)-, the sulfur atom of the ring can optionally be oxidized to an S-oxide, and the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of the heterocyclic group described in this invention include, but are not limited to, ethylene oxide, azirrobutyl, oxacyclobutyl, thiohexacyclobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2 H -pyranyl,4 H -pyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazineyl, dioxalyl, dithiaranyl, thiaxalyl, etc. Examples of heterocyclic groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridine, pyrimidinedionyl, etc. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, etc.

[0074] Unless otherwise stated, the term "aryl" in this invention refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more attachment sites connected to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene.

[0075] Unless otherwise stated, the term "heteroaryl" or "heteroary ring" as used in this invention refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing 5-10 or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. Heteroaryl groups are typically, but not necessarily, linked to a parent molecule via the aromatic ring of the heteroaryl group. The term "heteroaryl" may be used interchangeably with the terms "heteroary ring" or "heteroary aromatic compound." In some embodiments, a heteroaryl group consisting of 5-10 ring atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, a heteroaryl group consisting of 5-6 ring atoms is a monocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Examples of heteroaryl groups described in this invention include, but are not limited to, 2-furanyl, 3-furanyl, N -Imidazolyl, 2-Imidazolyl, 4-Imidazolyl, 5-Imidazolyl, 3-Isoxazolyl, 4-Isoxazolyl, 5-Isoxazolyl, 2-Oxazolyl, 4-Oxazolyl, 5-Oxazolyl, Oxadiazolyl N -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- b[1,2,4]triazolo[4,3-]pyridazinyl,[1,2,4]triazolo[4,3-] b [1,2,4]triazolo[1,5-]pyridazinyl, [1,2,4]triazolo[1,5-] a [Pyrimidinyl, [1,2,4]triazolo[1,5-] a ]Pyridyl, etc.

[0076] The term "unsaturated" as used in this invention means that the group contains one or more degrees of unsaturation.

[0077] The term “heteroatom” refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom in the heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrroleyl), or NR (like NR in N-substituted pyrroleyl).

[0078] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0079] The term "fused ring" refers to a polycyclic structure formed by two or more ring structures connected together by sharing two adjacent atoms (i.e., sharing a side). "Fused tricyclic ring" refers to a polycyclic system formed by three ring structures connected by sharing a side, including fused tricyclic carbocyclic rings and fused tricyclic heterocyclic rings. Fused tricyclic carbocyclic rings refer to rings composed entirely of carbon atoms, such as the fused tricyclic ring structures of certain polycyclic alkanes, and fused tricyclic ring structures composed of two benzene rings and an unsaturated cyclic hydrocarbon ring. Fused tricyclic heterocyclic rings refer to fused tricyclic ring structures containing heteroatoms such as nitrogen, oxygen, and sulfur in addition to carbon atoms, such as partially nitrogen-containing fused tricyclic heterocyclic rings; the heteroatoms can be N, O, or S. Unless otherwise specified, the rings forming the fused tricyclic structure (such as fused tricyclic carbocyclic rings or fused tricyclic heterocyclic rings) can be aromatic rings, heteroaromatic rings, carbocyclic rings (including cycloalkanes, cycloalkenyl groups, etc.), or saturated or partially unsaturated heterocyclic rings.

[0080] Unless otherwise stated, the amide linking group -C(O)-NR described in this invention n0 - It connects to the rest of the molecule from left to right, that is, it connects to some groups on the left through the C atom in C(O) and to some groups on the right through the N principle.

[0081] As described in this invention, a substituent R formed by a single bond connecting to a central double ring (as shown in formula c) means that the substituent R can be substituted at any substituted or reasonable position on any ring in the connected ring system (such as ring B or ring A in formula c). For example, formula c represents that any substituted position on ring B or ring A can be substituted by R, as in formula c. 1-7 As shown.

[0082]

[0083] As described in this invention, substituent (R) f A ring system formed by a single bond connecting to a central ring represents f substituents R that can be substituted at any substituted or reasonable position on the ring. For example, formula d represents that ring G can be substituted by f Rs, where when f is greater than 1, each R can be independently selected from the same or different substituents.

[0084]

[0085] As described in this invention, the attachment point can be connected to the rest of the molecule at any connectable location on the ring. For example, formula e represents any possible connectable location on ring A or ring B as the attachment point.

[0086]

[0087] The term "pharmaceuticalally acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar undesirable reactions, such as gastrointestinal upset, dizziness, etc. Preferably, as used herein, the term "pharmaceuticalally acceptable" means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0088] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0089] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound containing a hydroxyl group can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent compound. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al. , Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery ,2008, 7, 255-270, and SJ Hecker et al. , Prodrugs ofPhosphates and Phosphonates, Journal of Medicinal Chemistry ,2008, 51, 2328-2345.

[0090] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0091] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0092] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0093] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0094] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0095] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0096] The term “prevention” or “protection” refers to the reduction of the risk of acquiring a disease or disorder (i.e., stopping the development of at least one clinical symptom of the disease in a subject who may be facing or predisposed to facing the disease, but has not yet experienced or exhibited symptoms of the disease).

[0097] The term "therapeutic effective dose" refers to the amount of a compound that is sufficient to treat a disease when administered to a subject. The "therapeutic effective dose" can vary depending on the compound, the disease and its severity, and the condition, age, weight, and sex of the subject being treated.

[0098] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by using suitable isotope-labeled reagents instead of the previously used unlabeled reagents, as described in the examples and preparation processes of the present invention.

[0099] Unless otherwise stated, all tautomeristic forms of the compounds of this invention are included within the scope of this invention. Furthermore, unless otherwise stated, the structural formulas of the compounds described in this invention comprise enriched isotopes of one or more different atoms.

[0100] Description of the compounds of the present invention This invention relates to a novel class of substituted pyrimidine compounds. Experimental results show that the compounds of this invention exhibit significant degradation activity against BTK, demonstrating unexpectedly excellent activity. Therefore, the compounds of this invention can be used as BTK degrading agents for the prevention or treatment of BTK-related diseases, including but not limited to tumors, thromboembolism, inflammatory diseases, and autoimmune diseases, particularly tumors.

[0101] The compounds of this invention are stable, have good safety, few toxic side effects, and possess pharmacodynamic and pharmacokinetic advantages, such as a good brain-plasma ratio, good bioavailability, or good metabolic stability, thus showing good prospects for clinical application.

[0102] The present invention also provides methods for preparing such compounds and pharmaceutical compositions containing such compounds.

[0103] On one hand, the present invention provides a compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of the compound represented by formula (IA). (IA) in, M1 is a key or , where X 4 Connected to Y; M2 is or , where X 1 Connected to Cy1; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 )y5 -、-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CRce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 is independently 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) when Y is M2 is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) when T is 0 Y is or M2 is When m1 is 1 and m2 is 1, n2 is not 0.

[0104] On one hand, the present invention provides a compound, a compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, of the compound shown in formula (I-1) or (I-2). (I-1) or (I-2) in, M1 is a key or , where X 4 Connected to Y; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -、-(CR c5 Rc6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 can be independently represented as 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In the compound of formula (I-1), when Y is X 3 For CH and X 4 When N is present, m3 and m4 are not simultaneously 0; (2) In compound (I-1), when T is present... Y is or When m1 is 1 and m2 is 1, n2 is not 0.

[0105] On the other hand, the present invention provides a compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I), formula (Ia), formula (Ib), or formula (Ic). (I) (Ia) (Ib) or (Ic), in, T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2-W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR) c3 R c4 ) y3 -、-(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -、-NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -、-(CR c5 Rc6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 can be independently represented as 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In compound (I), when Y is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) In compound (I), when T is 0 Y is or When m1 is 1 and m2 is 1, n2 is not 0.

[0106] In some embodiments, the fused tricyclic carbocyclic ring and the fused tricyclic heterocyclic ring containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S are each independently coated with Y. aSubstitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of a heteroaryl group consisting of 5-6 atoms, wherein Y a R a R b and R c Each has its own independent meaning as described in this invention.

[0107] In some embodiments, the fused tricyclic carbocyclic ring and the fused tricyclic heterocyclic ring containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S are each independently coated with Y. a The substituted and replaced by 0, 1, 2, 3, 4, 5, 6, 7, or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR a -CONR b R c The substituents of cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophene, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, and pyrimidinyl are substituted, wherein Y a R a R b and R c Each has its own independent meaning as described in this invention.

[0108] In some implementations, each L4 is independently a key, -O-, -S-, -NR n4 -、-C(O)-、-NR n4 -C(O)- or -C 1-3 alkyl-.

[0109] In some implementation schemes, Y is , , , , , , or ; Among them, Z 7 For CH or N; X 6 -(CR) c7 R c8 ) y6 -、-C(O)-、-C(S)- or -NR n5 -;R n5 It is H, D, C1-C6 alkyl, or C1-C6 haloalkyl; each R c7 and R c8 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; y6 is 1, 2, or 3; Each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; f is 0, 1, 2, 3 or 4; R 9 R 10 Together with the attached atoms, it forms a C5-C6 carbon ring, a heterocycle of 5-6 atoms, a benzene ring, or a heteroaromatic ring of 5-6 atoms, wherein each of the C5-C6 carbon ring, the heterocycle of 5-6 atoms, the benzene ring, and the heteroaromatic ring of 5-6 atoms is independently unsubstituted or is independently substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, a heterocyclic group of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Z 4 Z 5 Z 6 X 5 L3, L4, R 6 R 7 R 8 R 5 n5 and m5 each have the meaning described in this invention independently.

[0110] In some implementation schemes, Y is , , , , , , , , , , , , or Among them, Z 4 Z 5 Z 6 X 5 L3, L4, R 6 R 7 R 8 R 9 R 10 R 5 R y f, n5, and m5 each have their own independent meaning as described in this invention.

[0111] In some implementation schemes, Y is , , , , , , , , , , , , , , , , , , , , , or , where R y R 9 R 10 R 5 f and n5 each have their own independent meaning as described in this invention.

[0112] In some implementation schemes, R n5 It is H, D, C1-C4 alkyl, or C1-C4 haloalkyl.

[0113] In some implementation schemes, R n5It can be H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, or difluoromethyl.

[0114] In some implementation schemes, each R c7 and R c8 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy.

[0115] In some implementation schemes, each R c7 and R c8 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, or difluoromethoxy.

[0116] In some implementation schemes, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0117] In some implementation schemes, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0118] In some implementation schemes, each R yIndependently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR a -CONR b R c Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0119] In some embodiments, Cy1, Cy2, and Cy3 are each independently a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C3-C6 cycloalkyl group, the heterocyclic group consisting of 3-6 atoms, the C6-C6 aryl group, and the heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0120] In some implementation schemes, each R c3 R c4 R c5 and R c6Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0121] In some implementation schemes, each R n2 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0122] In some embodiments, Cy1 and Cy2 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclopropyl, oxacyclobutyl, oxacyclopropyl, cyclobutyl ... Heterocyclic butyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazine are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0123] In some embodiments, the compound of the present invention is a compound of formula (II), (IIa), (IIb) or (IIc), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof. (II) (IIa) (IIb) or (IIc), Among them, Z a Z b Z c Z d Z e Z f Z g and Z h Each is N or CR z Each R z Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 A aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Among them, Cy3, T, Y, X 1 X 2X 3 X 4 L1, L2, R 2 R 3 n1, n2, n3, m1, m2, m3 and m4 each have the meaning described in this invention independently.

[0124] In some embodiments, Cy3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl... Pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroloyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0125] In some implementation schemes, each R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR eR f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, cyclopropyl, cyclobutyl The following groups are substituted independently and optionally, including cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl groups, each of which is independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0126] In some implementation schemes, each R n2 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0127] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent consisting of 5-6 atoms of a heteroaryl group, wherein R a R b R c R n1 R c1 R c2 y1 and y2 each have the meaning described in this invention independently.

[0128] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c Substituents include C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, phenyl groups, and heteroaryl groups consisting of 5-6 atoms, wherein R a Rb R c R n1 R c1 R c2 y1 and y2 each have the meaning described in this invention independently.

[0129] In some implementation schemes, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -, -O(C6H4)-, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl The following groups are present: propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -COOR a -CONR b R c Substituents include C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, phenyl groups, and heteroaryl groups consisting of 5-6 atoms, wherein R a R b R c R n1 R c1 R c2 y1 and y2 each have the meaning described in this invention independently.

[0130] In some embodiments, unless otherwise stated, -O(C6H4)- in this invention refers to -O-phenyl-.

[0131] In some implementation schemes, each R1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0132] In some implementation schemes, each R ce R c1 and R c2 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0133] In some implementation schemes, each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7aR 7b and R 8 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0134] In some implementation schemes, each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, or -COOR. d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0135] In some implementation schemes, each R ce R c1 and R c2 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R fCyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, cyclopropyl, cyclo Butyl, cyclopentyl, cyclobutyl, aziridinepropyl, oxacyclopropyl, aziridinepropyl, oxacyclobutyl, pyrrolylyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; wherein, R d R e and R f Each has its own independent meaning as described in this invention.

[0136] In some implementation schemes, each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0137] In some implementation schemes, R 9 R 10Together with the attached atoms, it forms a C5 carbon ring, a C6 carbon ring, a 5-atom heterocycle, a 6-atom heterocycle, a benzene ring, a 5-atom heteroaromatic ring, or a 6-atom heteroaromatic ring, wherein each of the C5 carbon ring, C6 carbon ring, 5-atom heterocycle, 6-atom heterocycle, benzene ring, 5-atom heteroaromatic ring, and 6-atom heteroaromatic ring is independently unsubstituted or substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 3-6 atom heterocyclic group, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

[0138] In some implementation schemes, R 9 R 10 Together with the attached atoms, they form a benzene ring, wherein the benzene ring is unsubstituted or is formed by 1, 2, 3 or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

[0139] In some implementation schemes, R 9 R 10 Together with the attached atoms, a benzene ring is formed, wherein the benzene ring is either unsubstituted or substituted by 1, 2, 3, or 4 independent substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxaziridine, oxaziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazine, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazole, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, and pyrimidinyl.

[0140] In some implementation schemes, R 9 R 10 Together with the atoms they are attached to form The Unsubstituted or composed of 1, 2, 3 or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

[0141] In some implementation schemes, R 9 R 10 Together with the atoms they are attached to form The It is either unsubstituted or substituted by 1, 2, 3 or 4 independent substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxaziridine, oxaziridine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl and pyrimidinyl.

[0142] In some implementations, Y is , where R y Each of them has the meaning described in this invention.

[0143] In some implementations, Y is Where f is 0, 1, 2, 3, or 4; each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0144] In some implementations, Y is Where f is 0, 1, 2, 3, or 4; each R yIndependently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0145] In some implementations, Y is Where f is 0, 1, 2, 3, or 4; each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR a -CONR b R c Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; wherein, R a R b and R c Each has its own independent meaning as described in this invention.

[0146] In some implementations, Y is .

[0147] In some implementations, Y is , , , , , , or .

[0148] In some implementation schemes, each R a and R d Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R b R c R e and R f Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

[0149] In some implementation schemes, each R a and R d Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl; Each R b R c R e and R f Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxadiazolyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroleyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0150] In some embodiments, the compound of the present invention is one of the following compounds or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof: , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0151] In some embodiments, the compound of the present invention is one of the following compounds or its stereoisomers, geometric isomers, tautomers, nitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof: , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0152] On the other hand, the present invention provides a pharmaceutical composition comprising the compound described herein and a pharmaceutically acceptable carrier, excipient or excipient.

[0153] On one hand, the present invention relates to the use of the compounds or pharmaceutical compositions described herein in the preparation of a medicament, wherein the medicament is used to prevent or treat diseases related to BTK.

[0154] On the other hand, the compounds or pharmaceutical compositions provided by the present invention can be used to prevent or treat diseases related to BTK.

[0155] On one hand, the present invention relates to a method for preventing or treating BTK-related diseases using the compounds or pharmaceutical compositions described herein.

[0156] In some embodiments, the BTK-related diseases described in this invention are tumors, thromboembolic events, inflammatory conditions, and / or autoimmune diseases.

[0157] In some embodiments, the BTK-related disease described in this invention is a tumor.

[0158] In some embodiments, the tumors described in this invention are B-cell lymphomas, solid tumors, and / or hematologic and immune system tumors.

[0159] In some embodiments, the B-cell lymphoma described in this invention is diffuse large B-cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and / or chronic lymphocytic leukemia.

[0160] In other embodiments, the solid tumors described in this invention are gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, urogenital tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0161] In some other embodiments, the hematologic and immune system tumors described in this invention are acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, and / or chronic myeloid leukemia.

[0162] In some embodiments, the inflammatory conditions or autoimmune diseases described in this invention are asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

[0163] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention According to another aspect, the pharmaceutical compositions of the present invention are characterized by comprising compounds represented by any of the general formulas of the present invention, compounds listed in the present invention, or compounds of the examples, and pharmaceutically acceptable carriers, excipients, or excipients. The amounts of compounds in the compositions of the present invention are effective in treating or alleviating BTK-related diseases in patients.

[0164] The compounds of the present invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly as needed by a patient, compounds described in other aspects of the present invention, their metabolites, or their residues.

[0165] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the content of this literature demonstrates that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of a pharmaceutically acceptable composition that occur in a harmful manner, their use is also within the scope of this invention.

[0166] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. Sodium thiosulfate, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and spices, preservatives and antioxidants.

[0167] Preferably, the compound is mixed with a suitable drug diluent, excipient, or carrier (in this case, a drug carrier) selected according to the form of administration and conventional pharmaceutical practice, and the administration method may be oral tablets, capsules, elixirs, syrups, etc.

[0168] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be conjugated with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical ingredient can be conjugated with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerin, water, etc. Furthermore, suitable binders, lubricants, dissolving agents, and colorants can be added to the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, astragalus gum, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Decomposing agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0169] The compounds of this invention can be administered in oral dosage forms, such as tablets, capsules (each comprising a sustained-release or timed-release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsifiers. They can also be administered intravenously (in pills or infusions), intraperitoneally, subcutaneously, or intramuscularly, all dosage forms used being well known to those skilled in the art of pharmacy. They can be administered alone, but generally a pharmaceutical carrier will be selected for co-administration based on the chosen route of administration and standard pharmaceutical practice.

[0170] The compounds of the present invention can be administered intranasally via a suitable intranasal carrier or transdermally via a transdermal patch. When administered via a transdermal delivery system, the dose is continuous rather than intermittent throughout the course of treatment.

[0171] The compounds of this invention can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0172] The compounds of this invention are also coupled with soluble polymers that serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate-phenol, polyhydroxyethyl asparagine, or polyvinyl oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be coupled with a class of biodegradable polymers for controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.

[0173] When the compounds of the present invention are administered together with other therapeutic agents, the amount of each component in a typical daily dose and typical dosage form may generally be reduced relative to the usual dose when administered alone, taking into account the additional or synergistic effects of the therapeutic agents when administered in combination.

[0174] The compounds and pharmaceutical compositions provided by this invention exhibit excellent BTK degradation activity and low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, and carcinogenicity). Furthermore, the compounds or pharmaceutical compositions are excellent in terms of oral absorption, duration of action, stability, and pharmacokinetics. The compounds or pharmaceutical compositions thereof involved in this invention can be effectively used to prevent, treat, or alleviate BTK-related diseases in patients.

[0175] In some embodiments, the diseases associated with BTK overactivation described in this invention are tumors, thromboembolism, inflammatory conditions, and / or autoimmune diseases.

[0176] In some embodiments, the disease caused by BTK overactivation described in this invention is tumor.

[0177] In some embodiments, the tumors described in this invention are B-cell lymphomas, solid tumors, and / or hematologic and immune system tumors.

[0178] In some embodiments, the B-cell lymphoma described in this invention is diffuse large B-cell lymphoma, small lymphocytic tumor, mantle cell lymphoma, multiple myeloma, and / or chronic lymphocytic leukemia.

[0179] In other embodiments, the solid tumors described in this invention are gastric cancer, intestinal cancer, liver cancer, kidney cancer, lung cancer, brain cancer, laryngeal cancer, esophageal cancer, head and neck cancer, squamous cell carcinoma, lymphatic system cancer, thyroid cancer, bladder cancer, cervical cancer, prostate cancer, urogenital tract cancer, breast cancer, small cell lung cancer, lung adenocarcinoma, pancreatic cancer, colon cancer, glioblastoma, and / or monocytic leukemia.

[0180] In some other embodiments, the hematologic and immune system tumors described in this invention are acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, and / or chronic myeloid leukemia.

[0181] In some embodiments, the inflammatory conditions or autoimmune diseases described in this invention are asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

[0182] The compounds and pharmaceutical compositions of the present invention, in addition to their therapeutic benefits for humans, can also be used in veterinary treatment of mammals, including pets, introduced breeds of animals, and farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0183] General Synthesis Process Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0184] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as described herein. The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0185] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0186] The examples described below are in Celsius unless otherwise specified. Reagents were purchased from a commercial supplier.

[0187] 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1 ¹H NMR spectra with CDCl₃ and DMSO- d 6. CD3OD or acetone - d 6 represents the solvent (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constant. J It is represented by Hertz (Hz).

[0188] Mass spectrometry (MS) determination conditions: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm), electrospray ionization (ESI) at 210 nm / 254 nm, with UV detection.

[0189] The following abbreviations are used throughout this invention:

[0190] The following reaction scheme describes the steps for preparing the compounds disclosed in this invention.

[0191] Synthesis scheme Synthesis Scheme 1

[0192] R is or Where L0 is a bond or an optional substituted C 1-4 Alkyl, X 3 X 4 R 3 n3, m3, m4 and Y each have the meaning obtained in this invention.

[0193] Mode( 8 The compound shown in formula () can be prepared by the following process: 1 The compound shown is similar to the compound of formula ( 2 The compound shown in the figure is coupled to obtain formula (3 The compound shown in formula () 3 The compound shown is related to ( 4 The compound shown in the figure is coupled to obtain formula ( 5 The compound shown is represented by formula (). 5 The compound shown was deprotected by the Boc protecting group to obtain the compound of formula ( 6 The compound shown in the formula () 6 The compound shown in the figure and the compound of formula ( 7 The compound shown was reduced and aminationd to obtain the compound of formula ( 8 The compound shown in the figure.

[0194] Synthesis Scheme 2

[0195] R 0 For CH or N; R is or Where L0 is a bond or an optional substituted C 1-4 Alkyl, X 3 X 4 R 3 n3, m3, m4 and Y each have the meaning obtained in this invention.

[0196] Mode( 13 The compound shown in formula () can be prepared by the following process: 9 The compound shown is similar to the compound of formula ( 10 The compound shown in the figure is coupled to obtain formula ( 11 The compound shown in formula () 11 The compound shown was deprotected by the Boc protecting group to obtain the compound of formula ( 12 The compound shown in the formula () 12 The compound shown in the figure and the compound of formula ( 7 The compound shown was reduced and aminationd to obtain the compound of formula ( 13 The compound shown in the figure.

[0197] Example Example 1 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-{2-[4-(1-{2,6-dioxopiperidin-3-yl}-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-1-yl]ethyl}piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0198] Step 1) 4-[5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl Ester Synthesis 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 7.16 mmol), 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 7.16 mmol), sodium carbonate (0.83 g, 7.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.26 g, 0.36 mmol), dioxane (80 mL), and water (12 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 85 °C and stirred for 12 hours, after which the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 30:1) to give the title compound as a pale yellow solid (2.56 g, yield: 86.2%).

[0199] MS (ESI, pos. ion) m / z:415.0[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm)12.90 (s, 1H), 8.77 (d, J = 2.2 Hz,1H), 8.53 (s, 1H), 8.15 (dd, J = 9.0, 2.3 Hz, 1H), 7.02 – 6.92 (m, 2H), 3.65 –3.54 (m, 4H), 3.43 (s, 4H), 1.43 (s, 9H). Step 2) tert-butyl(R)-4-[5-(4-{4-[1-(3-tert-butyl-1,2,4-oxadiazole-5-carboxamido)ethyl Synthesis of [3-methylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl]piperazine-1-carboxylic acid ester 4-[5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (2.50 g, 6.03 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (2.49 g, 6.03 mmol), sodium carbonate (1.92 g, 18.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.22 g, 0.30 mmol), dioxane (150 mL), and water (25 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 12 hours, after which the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 30:1) to give the title compound as a pale yellow solid (3.05 g, yield: 76.0%).

[0200] MS (ESI, pos. ion) m / z:666.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 9.95 (d, J = 7.8 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.76 (s, 1H), 8.20 (dd, J = 9.0, 2.3 Hz, 1H), 8.08(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 5.41-5.31 (m, 1H), 3.59 (d, J = 5.5 Hz, 4H), 3.44(s, 4H), 2.53 (s, 3H), 1.60 – 1.48 (m, 3H), 1.43 (s, 9H), 1.36 (s, 9H). Step 3)(R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrole] Synthesis of [2,3-d]pyrimidin-4-yl]phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide 0.60 g (0.90 mmol) of tert-butyl(R)-4-[5-(4-{4-[1-(3-tert-butyl-1,2,4-oxadiazol-5-carboxamido)ethyl]-3-methylphenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl]piperazine-1-carboxylic acid ester, 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid were added sequentially to the reaction flask. The mixture was stirred at room temperature for 4 hours, and then the reaction was stopped. The solution was concentrated, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The solution was filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol (v:v) = 30:1 to 10:1) to give the title compound as a yellow solid (0.46 g, yield: 90.2%).

[0201] MS (ESI, pos. ion) m / z:566.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 9.96 (d, J = 7.7 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.18 (dd, J = 9.0, 2.3 Hz, 1H), 8.09(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 6.93(d, J = 9.0 Hz, 1H), 5.41-5.34 (m, 1H), 3.60 – 3.51 (m, 4H), 2.92 – 2.75 (m,4H), 2.53 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). Step 4) 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-{2-[4-(1-{2,6-dioxopiperidine-3- [2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-1-yl]ethyl]piperazin-1-yl]pyridin-3-yl]-7H- Synthesis of pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide 2-[4-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-1-yl]acetaldehyde (0.10 g, 0.25 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.14 g, 0.25 mmol), dichloromethane (60 mL), ethanol (20 mL), and acetic acid (0.015 g, 0.25 mmol) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (0.079 g, 1.25 mmol) was added. The mixture was stirred at room temperature for 12 hours (mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 30:1 to 10:1) to give the title compound as a yellow solid (0.05 g, yield: 21.2%).

[0202] MS (ESI, pos. ion) m / z: 955.5[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.61 (s, 1H), 11.14 (s, 1H), 9.97(d, J = 7.7 Hz, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.20(d, J = 7.3 Hz, 1H), 8.11 (t, J = 8.6 Hz, 2H), 8.04 (s, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.31 (s, 1H), 7.12 (d, J =7.7 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.46 (dd, J= 12.6, 5.1 Hz, 1H), 5.40 –5.34 (m, 1H), 3.62 (s, 4H), 3.51 (s, 4H), 3.17 (s, 1H), 2.95 (dd, J = 21.0, 9.1Hz, 2H), 2.82 – 2.71 (m, 2H), 2.66 (d, J = 16.2 Hz, 3H), 2.59 (s, 4H), 2.54 (s,3H), 2.13 – 2.06 (m, 1H), 1.93 (s, 1H), 1.91 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). Example 2 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-{[1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0203] The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, 1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-carboxaldehyde (0.052 g, 0.13 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.050 g, 0.088 mmol), dichloromethane (30 mL), ethanol (10 mL), and acetic acid (0.011 g, 0.18 mmol) were added sequentially to a reaction flask, stirred at room temperature for 1 hour, and then sodium cyanoborohydride (0.028 g, 0.028 g) was added. The mixture was stirred at room temperature for 12 hours (0.44 mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 30:1 to 10:1) to give the title compound as an orange solid (0.055 g, yield: 66.1%).

[0204] MS (ESI, pos. ion) m / z:941.5 [M+H]+ ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 11.12 (s, 1H), 9.96(d, J = 7.7 Hz, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.18(d, J = 8.8 Hz, 1H), 8.08 (t, J = 6.9 Hz, 2H), 8.04 (s, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.94 (t, J =9.9 Hz, 2H), 5.47 – 5.31 (m, 2H), 3.60 (s, 4H), 3.42 (d, J = 10.3 Hz, 2H), 2.94(dd, J = 20.5, 9.1 Hz, 1H), 2.78 – 2.60 (m, 4H), 2.53 (s, 3H), 2.49 – 2.45 (m,4H), 2.29 (d, J = 5.0 Hz, 2H), 2.13 – 2.04 (m, 1H), 1.90 (d, J = 7.7 Hz, 2H),1.75 (s, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.46 (t, J = 15.9 Hz, 2H), 1.36 (s, 9H). Example 3 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-{2-[1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-4-yl]ethyl}piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0205] The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, 2-[1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-4-yl]acetaldehyde (0.17 g, 0.42 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.20 g, 0.35 mmol), dichloromethane (30 mL), ethanol (10 mL), and acetic acid (0.04 mL, 0.70 mmol) were added sequentially to a reaction flask, stirred at room temperature for 1 hour, and then sodium cyanoborohydride (0.11 g, The mixture was stirred at room temperature for 12 hours (1.75 mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 30:1 to 10:1) to give the title compound as an orange-yellow solid (0.075 g, yield: 22.2%).

[0206] MS (ESI, pos. ion) m / z 955.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.62 (s, 1H), 11.12 (s, 1H), 9.97(d, J = 7.6 Hz, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.22 (t, J = 9.1 Hz, 2H), 8.13 –8.07 (m, 2H), 8.04 (s, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H),7.31 (s, 1H), 6.98 (dd, J = 31.8, 7.7 Hz, 3H), 5.51 – 5.31 (m, 2H), 3.56 (d, J =36.6 Hz, 4H), 3.42 (d, J= 11.1 Hz, 3H), 3.30 (brs, 4H), 2.94 (dd, J = 24.4, 12.6Hz, 1H), 2.70 (dd, J = 36.8, 13.0 Hz, 5H), 2.54 (s, 3H), 2.09 (d, J = 6.4 Hz,1H), 1.87 (s, 2H), 1.55 (d, J = 6.9 Hz, 8H), 1.37 (s, 9H). Example 4 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-{[1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl]piperazin-1-yl}pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0207] The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl]piperidin-4-carboxaldehyde (0.078 g, 0.21 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.12 g, 0.21 mmol), methane (30 mL), ethanol (10 mL), and acetic acid (0.060 mL, 1.05 mmol) were added sequentially to a reaction flask, stirred at room temperature for 1 hour, and then sodium cyanoborohydride (0.026 g, 0.42 mmol) was added. The mixture was stirred at room temperature for 12 hours (mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (ethyl acetate) to give the title compound as a yellow solid (0.10 g, yield: 51.3%).

[0208] MS (ESI, pos. ion) m / z 919.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ (ppm) 12.59 (s, 1H), 11.08 (s, 1H), 9.95(d, J = 7.7 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.09(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.67-7.64 (m, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 5.43 – 5.31 (m, 1H), 5.07(dd, J = 12.8, 5.3 Hz, 1H), 4.09 – 3.95 (m, 3H), 3.59 (s, 4H), 2.97 (t, J = 12.0Hz, 2H), 2.91 – 2.80 (m, 1H), 2.53 (s, 4H), 2.46 (s, 3H), 2.18 (s, 2H), 2.05– 1.96 (m, 2H), 1.84-1.81 (m, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.36 (s, 9H), 1.22(s, 2H). Example 5 Synthesis of 3-(tert-butyl)-N-[(R)-1-(4-{6-[6-(4-{[1-(6-{[(S)-2,6-dioxopiperidin-3-yl]carbamoyl}pyridin-3-yl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0209] The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, by sequentially adding (S)-5-(4-formylpiperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-2-carboxamide (0.14 g, 0.41 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.15 g, 0.27 mmol), dichloromethane (30 mL), ethanol (10 mL), and acetic acid (0.03 mL, 0.54 mmol) to a reaction flask, stirring at room temperature for 1 hour, and then adding sodium cyanoborohydride (0.085 g, 1.35 mmol). The mixture was stirred at room temperature for 12 hours (mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 20:1) to give the title compound as a pale yellow solid (0.065 g, yield: 27.4%).

[0210] MS (ESI, pos. ion) m / z 894.5 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 12.58 (s, 1H), 10.85 (s, 1H), 9.95(d, J = 7.8 Hz, 1H), 8.81 (d, J = 1.9 Hz, 1H), 8.76 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.8, 1.8 Hz, 1H), 8.09 (d, J = 8.3 Hz,1H), 8.04 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.8, 2.2 Hz, 1H), 7.29 (s, 1H), 6.98 – 6.91 (m, 1H), 5.38 (p, J= 7.0 Hz,1H), 4.77 – 4.71 (m, 1H), 3.93 (d, J = 12.0 Hz, 2H), 3.58 (s, 4H), 3.36 (s,2H), 2.86 (t, J = 11.9 Hz, 2H), 2.83 – 2.75 (m, 1H), 2.53 (s, 4H), 2.45 (s,4H), 2.23 – 2.14 (m, 3H), 2.01 (dd, J = 11.7, 6.4 Hz, 1H), 1.82 (d, J = 10.2 Hz, 3H), 1.54 (d, J = 6.9 Hz, 3H), 1.40 – 1.34 (m, 9H). Example 6 Synthesis of (S)-3-(tert-butyl)-N-[(R)-1-[4-[6-[[5-[1-[[1-[6-[[(S)-2,6-dioxopiperidin-3-yl]carbamoyl]pyridin-3-yl]piperidin-4-yl]methyl]piperidin-4-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0211] Step 1) tert-butyl(R)-4-[6-({6-[4-(1-{3-(tert-butyl)-1,2,4-oxadiazole-5-formamido} Synthesis of ethyl(3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl]piperidine-1-carboxylate The title compound in this step was prepared according to the method described in step 2 of Example 1, namely, by sequentially adding tert-butyl-4-[6-({6-chloropyrimidin-4-yl}amino)pyridin-3-yl]piperidin-1-carboxylate (2.50 g, 6.41 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (3.18 g, 7.69 mmol), sodium carbonate (2.04 g, 19.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.23 g, 0.32 mmol), and dioxane (20 mL) to the reaction flask. Add water (5 mL), under nitrogen protection, heat to 100 °C and stir for 12 hours, then stop the reaction. Concentrate, and purify the crude product by column chromatography (dichloromethane:methanol (v:v) = 200:1 to 80:1) to give the title compound as a pale yellow solid (3.32 g, yield: 80.8%).

[0212] MS (ESI, pos. ion) m / z:641.3 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 10.17 (s, 1H), 9.88 (d, J = 7.8 Hz, 1H), 8.75 (d, J = 0.6 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J =7.6 Hz, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.66 (dd, J = 8.6, 2.3 Hz, 1H), 7.61 (d, J =8.1 Hz, 1H), 5.36-5.31 (m, 1H), 4.12 – 4.04 (m, 2H), 2.80 (s, 2H), 2.67 (ddd, J = 12.1, 8.9, 3.2 Hz, 1H), 2.47 (s, 3H), 1.75 (d, J = 12.5 Hz, 2H), 1.55 – 1.46(m, 5H), 1.41 (s, 9H), 1.36 (s, 9H). Step 2)(R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[(5-(piperidin-4-yl)pyridin-2-yl)amino]pyrimidine Synthesis of pyridin-4-yl[phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride The following solutions were added sequentially to a reaction flask: tert-butyl(R)-4-[6-({6-[4-(1-{3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido}ethyl)-3-methylphenyl]pyrimidin-4-yl}amino)pyridin-3-yl]piperidine-1-carboxylate (0.50 g, 0.78 mmol), dichloromethane (5 mL), and an ethyl acetate solution of hydrogen chloride (1.95 mL, 7.80 mmol). The mixture was stirred at room temperature for 3 hours, after which the reaction was stopped. The solution was concentrated to give the title compound as a pale yellow solid (0.45 g, yield: 99.9%).

[0213] MS (ESI, pos. ion) m / z:541.3 [M+H] + ; Step 3)(S)-3-(tert-butyl)-N-[(R)-1-[4-[6-[[5-[1-[[1-[6-[[(S)-2,6-dioxanone) [Pyridine-3-yl]carbamoyl]pyridin-3-yl]piperidin-4-yl]methyl]piperidin-4-yl]pyridin-2-yl]amino]pyrimidine-4- Synthesis of 1,2,4-oxadiazole-5-carboxamide The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[(5-(piperidin-4-yl)pyridin-2-yl)amino]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.45 g, 0.78 mmol), (S)-N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridinecarboxamide (0.27 g, 0.78 mmol), dichloromethane (60 mL), ethanol (20 mL), triethylamine (0.079 g, 0.78 mmol), and acetic acid (0.094 g, 1.56 mmol) were added to the reaction flask, and the mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (0.25 g, 3.90 mmol) was added. The mixture was stirred at room temperature for 12 hours (mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 10:1) to give the title compound as an off-white solid (0.33 g, yield: 48.7%).

[0214] MS (ESI, pos. ion) m / z:869.4 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 10.85 (s, 1H), 10.18 (s, 1H), 9.89(d, J = 7.8 Hz, 1H), 8.75 (s, 1H), 8.70 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.5 Hz,1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.85 (dd, J = 8.4, 2.8 Hz, 3H), 7.74 (s, 1H), 7.67 (dd, J = 8.6, 1.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.40 (dd, J = 8.9, 2.6Hz, 1H), 5.34 (p, J = 7.0 Hz, 1H), 4.77 – 4.69 (m, 1H), 3.95 (t, J= 15.7 Hz,2H), 3.43 – 3.26 (m, 6H), 2.86 (t, J = 11.8 Hz, 2H), 2.78 (ddd, J = 30.2, 17.1,12.4 Hz, 1H), 2.55 – 2.52 (m, 1H), 2.47 (s, 3H), 2.36 – 2.13 (m, 3H), 2.00(ddd, J = 17.0, 11.0, 4.0 Hz, 2H), 1.86 – 1.66 (m, 7H), 1.51 (d, J = 7.0 Hz, 3H), 1.35 (d, J = 13.6 Hz, 9H). Example 7 Synthesis of 3-tert-butyl-N-[(R)-1-(4-{6-[(4-{1-[(1-{6-[((S)-2,6-dioxopiperidin-3-yl)carbamoyl]pyridin-3-yl}piperidin-4-yl)methyl]piperidin-4-yl}phenyl)amino]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0215] Step 1) tert-butyl(R)-4-[4-({6-[4-(1-{[3-tert-butyl-1,2,4-oxadiazole-5-formyl]amino} Synthesis of ethyl(3-methylphenyl)pyrimidin-4-yl)amino)phenyl]piperidine-1-carboxylate The title compound in this step was prepared according to the method described in step 2 of Example 1, namely, by sequentially adding tert-butyl 4-[4-((6-chloropyrimidin-4-yl)amino)phenyl]piperidine-1-carboxylate (1.00 g, 2.57 mmol), (R)-3-tert-butyl-N-[1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (1.17 g, 2.83 mmol), sodium carbonate (0.82 g, 7.71 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.094 g, 0.13 mmol), dioxane (36 mL), and water (9 mL) to a reaction flask under nitrogen protection, heating to 100°C and stirring for 12 hours, then stopping the reaction. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 200:1 to 100:1) to give the title compound as a pale yellow solid (0.98 g, yield: 59.6%).

[0216] MS (ESI, pos. ion) m / z:640.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 9.87 (d, J = 7.8 Hz, 1H), 9.59 (s,1H), 8.66 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 8.0, 4.0 Hz, 3H), 7.26– 7.09 (m, 3H), 5.33 (p, J = 6.9 Hz, 1H), 4.05 (dd, J = 17.5, 10.3 Hz, 2H), 2.79(s, 2H), 2.63 (t, J = 12.0 Hz, 1H), 2.46 (s, 3H), 1.74 (d, J = 12.4 Hz, 2H), 1.51(d, J = 6.9 Hz, 3H), 1.49 – 1.43 (m, 2H), 1.41 (s, 9H), 1.36 (s, 9H). Step 2)(R)-3-tert-butyl-N-[1-(2-methyl-4-(6-((4-(piperidin-4-yl)phenyl)amino)pyrimidine-4- Synthesis of [[(phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride] The following solutions were added sequentially to a reaction flask: tert-butyl(R)-4-[4-({6-[4-(1-{[3-tert-butyl-1,2,4-oxadiazol-5-carboxyl]amino}ethyl)-3-methylphenyl]pyrimidin-4-yl}amino)phenyl]piperidine-1-carboxylate (0.20 g, 0.31 mmol), dichloromethane (2 mL), and an ethyl acetate solution of hydrogen chloride (1 mL, 3.10 mmol). The mixture was stirred at room temperature for 3 hours, after which the reaction was stopped. The solution was concentrated to give the title compound as a yellow solid (0.19 g, yield: 99.2%).

[0217] MS (ESI, pos. ion) m / z:540.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 9.95 (d, J= 7.6 Hz, 1H), 9.03 (s,1H), 8.84 (s, 1H), 7.79 (d, J = 9.2 Hz, 2H), 7.67 (d, J = 8.0 Hz, 3H), 7.38 (s,1H), 7.28 (d, J = 8.4 Hz, 2H), 5.34 (dd, J = 14.3, 7.1 Hz, 1H), 3.35 (d, J = 12.0Hz, 2H), 3.03 – 2.93 (m, 2H), 2.85 (t, J = 11.2 Hz, 1H), 2.48 (s, 3H), 1.95 (s,2H), 1.89 – 1.77 (m, 2H), 1.51 (d, J = 6.9 Hz, 3H), 1.36 (s, 9H). Step 3) 3-tert-butyl-N-[(R)-1-(4-{6-[(4-{1-[(1-{6-[((S)-2,6-dioxopiperidine-3- [[carbamoyl]pyridin-3-yl}piperidin-4-yl]methyl]piperidin-4-yl}phenyl]amino]pyrimidin-4-yl}-2-methyl Synthesis of [phenyl(ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound in this step was prepared according to the method described in step 4 of Example 1, namely, by sequentially adding (R)-3-tert-butyl-N-[1-(2-methyl-4-(6-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl]-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.19 g, 0.31 mmol), (S)-N-(2,6-dioxopiperidin-3-yl)-5-(4-formylpiperidin-1-yl)pyridinecarboxamide (0.12 g, 0.34 mmol), dichloromethane (60 mL), ethanol (20 mL), triethylamine (0.063 g, 0.62 mmol), and acetic acid (0.037 g, 0.62 mmol) to a reaction flask, stirring at room temperature for 1 hour, and then adding sodium cyanoborohydride (0.097 g, 1.55 mL). The mixture was stirred at room temperature for 12 hours (mmol), and then the reaction was stopped. The crude product was concentrated and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 10:1) to give the title compound as a pale yellow solid (0.16 g, yield: 59.4%).

[0218] MS (ESI, pos. ion) m / z:868.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ (ppm) 10.85 (s, 1H), 9.88 (d, J = 7.8 Hz,1H), 9.62 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.89 –7.72 (m, 3H), 7.61 (t, J = 6.9 Hz, 3H), 7.40 (d, J = 6.7 Hz, 1H), 7.21 (d, J = 8.7Hz, 3H), 5.35-5.31 (m, 1H), 4.81 – 4.65 (m, 1H), 3.94 (d, J = 11.9 Hz, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.88 (dd, J = 30.1, 18.2 Hz, 4H), 2.77 (dd, J = 17.7, 5.0Hz, 1H), 2.54 (s, 2H), 2.46 (s, 3H), 2.18 (dt, J = 12.8, 8.8 Hz, 3H), 1.88(ddd, J = 63.8, 31.5, 16.5 Hz, 11H), 1.50 (d, J = 6.9 Hz, 3H), 1.35 (s, 9H). Example 8 Synthesis of 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0219] Step 1) Synthesis of 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione 6-Bromobenzo[CD]indol-2(1H)-one (1.00 g, 4.03 mmol) and tetrahydrofuran (20 mL) were added sequentially to a reaction flask. The mixture was placed at 0 °C, and sodium hydride (0.81 g, 20.15 mmol, 60% purity) was slowly added. After stirring at room temperature for 1 hour, 3-bromopiperidin-2,6-dione (1.55 g, 8.06 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The reaction was stopped, and the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL). The mixture was extracted with water (20 mL) and ethyl acetate (60 mL × 3). The organic phase was evaporated to dryness and purified by column chromatography (DCM:MeOH (v:v) = 500:1 to 200:1) to give the title compound as a yellow solid (0.65 g, yield: 44%).

[0220] MS (ESI, pos. ion) m / z:359.00 [M+H] + . Step 2): (E)-3-(6-(2-ethoxyvinyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2, Synthesis of 6-dione 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (0.57 g, 1.59 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (0.47 g, 2.39 mmol), cesium fluoride (0.48 g, 3.18 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.12 g, 0.16 mmol), 1,4-dioxane (15 mL), and water (3 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90 °C under a nitrogen atmosphere and stirred for 7 hours. The reaction was stopped, cooled to room temperature, and the solvent was evaporated. The crude product was purified by column chromatography (DCM:MeOH (v:v) = 200:1~100:1) to give the title compound as an orange-yellow solid (0.32 g, yield: 57%).

[0221] MS (ESI, pos. ion) m / z:351.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.13 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.52 (d,J = 7.5 Hz, 1H), 7.24 (d, J = 12.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 12.7 Hz, 1H), 5.45 (dd, J = 12.8, 5.2 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.02 – 2.88 (m, 1H), 2.84 – 2.60 (m, 2H), 2.19 – 2.03 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H). Step 3): 2-[(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-] Synthesis of acetaldehyde (E)-3-(6-(2-ethoxyvinyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (0.30 g, 0.86 mmol) and acetonitrile (36 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred until dissolved. After cooling to room temperature, macroporous resin (0.30 g) was added, and the mixture was stirred at room temperature for 7 hours. The reaction was stopped, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (DCM:MeOH (v:v) = 100:1~50:1) to give the title compound as a pale yellow solid (0.036 g, yield: 13%).

[0222] MS (ESI, pos. ion) m / z:321.1[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.15 (s, 1H), 9.80 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 7.0 Hz, 1H), 7.90 – 7.81 (m, 1H), 7.40 (d, J = 7.3Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 5.47 (dd, J= 12.9, 5.4 Hz, 1H), 4.26 (s, 2H), 3.02 – 2.90 (m, 1H), 2.84 – 2.75 (m, 1H), 2.66 (d, J = 17.3 Hz, 1H), 2.16 –2.07 (m, 1H).

[0223] Step 4): 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 2-Oxo-1,2-dihydrobenzo[cd]indol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine Synthesis of pyridin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.06 g, 0.11 mmol), 2-[(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)]acetaldehyde (0.035 g, 0.11 mmol), chloroform (4 mL), and triethylamine (0.046 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.12 g, 0.55 mmol) was added, and the reaction was stirred at room temperature for 8 hours. The reaction was stopped, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phase was collected, concentrated, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 30:1~20:1) to give the title compound as a yellow solid (0.06 g, yield: 64%).

[0224] MS (ESI, pos. ion) m / z:872.40 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 11.14 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.19 (dd, J = 8.9, 1.9 Hz, 1H), 8.10 (t, J = 6.2 Hz, 2H), 8.05 (s, 1H), 7.87(t, J= 7.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.30 (s,1H), 7.10 (d, J = 7.3 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 5.51 – 5.33 (m, 2H), 3.62 (s, 4H), 3.24 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 12.6 Hz, 1H), 2.83 – 2.60(m, 8H), 2.54 (s, 3H), 2.16 – 2.04 (m, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H).

[0225] Example 9 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-(6-(6-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0226] Step 1) (E)-3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium) Synthesis of (azol-1-yl)piperidine-2,6-dione 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (0.700 g, 2.07 mmol), (E)-1-ethoxyvinyl-2-boronate pinacol ester (0.533 g, 2.69 mmol), cesium fluoride (0.943 g, 6.21 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.151 g, 0.210 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90°C under a nitrogen atmosphere. oThe reaction was stirred at C for 17 hours. The reaction was stopped and cooled to room temperature. The solvent was evaporated, and the crude product was purified by column chromatography (PE:EA (v:v) = 1:2) to give the title compound as a pale yellow solid (0.530 g, yield: 78%).

[0227] MS (ESI, pos. ion) m / z:330.15 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.10 (s, 1H), 7.03 – 6.92 (m, 4H), 6.39 (d, J = 12.6 Hz, 1H), 5.44 – 5.30 (m, 1H), 3.95 (d, J = 6.4 Hz, 2H), 3.56(s, 3H), 2.88 (dd, J = 20.8, 9.2 Hz, 1H), 2.72 (dd, J = 14.7, 11.2 Hz, 1H), 2.63(d, J = 17.9 Hz, 1H), 2.01 (d, J = 6.0 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H).

[0228] Step 2) 2-[(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]] Synthesis of imidazole-4-yl)[acetaldehyde (E)-3-(4-(2-ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.450 g, 1.37 mmol), AMBERLYST 15 (0.2 g), and acetonitrile (20 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 12 hours. The reaction was then stopped. The filtrate was collected by filtration, concentrated, and the crude product was purified by column chromatography (PE:EA (v:v) = 1:2~EA) to give the title compound as a pale yellow solid (0.091 g, yield: 22%).

[0229] MS (ESI, pos. ion) m / z:302.20 [M+H] + .

[0230] Step 3): 3-(tert-butyl)-N-[(1R)-1-(4-(6-(6-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrole Synthesis of [2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide 2-[(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)]acetaldehyde (0.090 g, 0.30 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.203 g, 0.30 mmol), chloroform (15 mL), and triethylamine (0.21 mL) were added sequentially to the reaction flask. The mixture was stirred at 60 °C for 1 h, then transferred to room temperature. Sodium triacetoxyborohydride (0.318 g, 1.50 mmol) was added, and the reaction was continued to be stirred at room temperature for 17 h. The reaction was stopped, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 50:1~20:1) to give the title compound as a yellow-green solid (154 mg, yield: 60.6%).

[0231] MS (ESI, pos. ion) m / z: 851.40 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 11.11 (s, 1H), 9.96(d, J = 7.7 Hz, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.10(d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.04 –6.91 (m, 4H), 5.44 – 5.33 (m, 2H), 3.62 (s, 7H), 3.14 (s, 1H), 3.08 (dd, J =14.6, 7.3 Hz, 2H), 2.89 (dd, J = 20.7, 9.5 Hz, 1H), 2.73 (dd, J = 15.1, 10.8 Hz,1H), 2.62 (s, 6H), 2.54 (s, 3H), 2.04 – 1.96 (m, 1H), 1.55 (d,J = 6.9 Hz, 3H), 1.38 (s, 9H); 13 C NMR (150 MHz, DMSO- d 6) δ (ppm) 177.64 (s), 172.76 (s), 172.03 (s), 169.92 (s), 168.71 (s), 158.49 (s), 153.98 (s), 153.73 (s), 153.49 (s), 152.60 (s), 150.50 (s), 145.53 (s), 143.48 (s), 138.12 (s), 136.68 (s), 135.34 (s), 135.00 (s), 130.05 (s), 129.66 (s), 127.38 (s), 126.52 (s),126.03 (s), 123.88 (s), 122.20 (s), 120.91 (s), 115.93 (s), 106.83 (s), 94.99 (s), 60.32 (s), 52.44 (s), 51.68 (s), 45.64 (d, J = 4.9 Hz), 44.54 (s), 32.31(s), 31.30 (s), 31.10 (s), 29.40 (s), 28.21 (s), 28.09 (s), 21.91 (s), 21.07(s), 20.63 (s), 18.92 (s); Example 10 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-(6-(6-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0232] Step 1): 3-(3-methyl-2-oxo-5-vinyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- Synthesis of 2,6-dione 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (0.70 g, 2.07 mmol), pinacol vinylborate (0.38 g, 2.48 mmol), cesium fluoride (0.94 g, 6.21 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.15 g, 0.21 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90°C under a nitrogen atmosphere. o The reaction was stirred at C for 7 hours. The reaction was stopped and cooled to room temperature. The crude product was concentrated under reduced pressure and purified by column chromatography (PE:EA (v:v) = 1:1~1:2) to give the title compound as a white solid (0.40 g, yield: 68%).

[0233] MS (ESI, pos. ion) m / z: 286.10[M+H] + .

[0234] Step 2): 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Synthesis of 5-formaldehyde 3-(3-methyl-2-oxo-5-vinyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (0.40 g, 1.40 mmol), potassium osmium tetroxide dihydrate (0.052 g, 0.14 mmol), tetrahydrofuran (16 mL), and water (4 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 30 min, and sodium periodate (0.90 g, 4.20 mmol) was added under an ice-water bath. The mixture was stirred at room temperature for 3 h. The reaction was stopped, and the reaction solution was diluted with water (100 mL). After extraction with EA (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA (v:v) = 1:2~EA) to give the title compound as a white solid (310 mg, yield: 77%).

[0235] MS (ESI, pos. ion) m / z: 288.05 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.18 (s, 1H), 9.95 (s, 1H), 7.71(t, J = 3.4 Hz, 2H), 7.43 – 7.33 (m, 1H), 5.49 (dd,J = 12.8, 5.3 Hz, 1H), 3.43(s, 3H), 2.98 – 2.85 (m, 1H), 2.81 – 2.71 (m, 1H), 2.67 (t, J = 12.5 Hz, 1H),2.12 – 2.04 (m, 1H). Step 3): 3-(tert-butyl)-N-[(1R)-1-(4-(6-(6-(4-((1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrole Synthesis of [2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde (0.150 g, 0.52 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.294 g, 0.52 mmol), N,N-dimethylacetamide (10 mL), and acetic acid (63 mg) were added sequentially to the reaction flask. The mixture was stirred at 60 °C for 1 h, then transferred to room temperature. Sodium triacetoxyborohydride (0.330 g, 1.56 mmol) was added, and the reaction was continued to be stirred at room temperature for 17 h. The reaction was stopped, water (100 mL) was added to dilute the product, the filter cake was filtered, washed with water and dried, and the crude product was purified by column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the title compound as a yellow solid (70 mg, yield: 16%).

[0236] MS (ESI, pos. ion) m / z: 837.20 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 11.11 (s, 1H), 9.96 (d, J = 7.7 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J= 8.1 Hz, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 7.06 (dd, J = 22.8, 8.0 Hz, 2H), 6.95 (d, J = 9.1 Hz, 1H), 5.44 – 5.34 (m, 2H), 3.61 (s, 4H), 3.56 (s, 2H), 3.36 (s, 3H), 2.91 (dd, J = 20.8, 8.8 Hz, 2H), 2.80 – 2.69 (m, 2H), 2.64 (d, J = 18.1 Hz, 2H), 2.53 (s, 3H), 2.02 (dd, J = 13.0, 6.3 Hz, 2H), 1.55 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H); 13 C NMR (150 MHz, DMSO- d 6) δ (ppm) 177.64 (s), 172.78 (s), 170.00 (s), 168.71 (s), 158.50 (s), 153.97 (s), 153.72 (s), 153.41 (s), 152.60 (s), 150.49 (s), 145.52 (s), 143.48 (s), 138.12 (s), 136.68 (s), 135.34 (s), 134.98 (s), 131.16 (s), 130.05 (s), 129.87 (s), 129.66 (s), 126.51 (s), 126.03 (s), 121.81 (s), 115.93 (s), 108.62 (s), 108.17 (s), 106.77 (s), 94.97 (s), 62.28 (s), 52.33 (s), 51.67 (s), 45.65 (s), 44.52 (s), 32.31 (s), 31.30 (s), 31.15 (s), 28.18 (d, J = 27.2 Hz), 26.98 (s), 22.08 (d, J = 7.4 Hz), 20.63 (s), 18.91 (s). Example 11 Synthesis of (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0237] Step 1): 1-[6-[4-(dimethoxymethyl)piperidin-1-yl]-5-fluoro-1-methyl-1H-indazol-3-yl]di Synthesis of hydropyrimidine-2,4(1H,3H)-dione 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.29 mmol), 4-(dimethoxymethyl)piperidine (0.069 g, 0.43 mmol), sodium tert-butoxide (0.070 g, 0.72 mmol), tris(dibenzylideneacetone)dipalladium (0.027 g, 0.029 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.028 g, 0.058 mmol), and dioxane (5 mL) were added sequentially to the reaction flask. The mixture was purged with nitrogen three times, and the mixture was heated to 100 °C under nitrogen protection and stirred for 11 hours before the reaction was stopped. The crude product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 100:1 to 50:1 (v:v)) to give the title compound as an off-white solid (0.030 g, yield: 24.40%).

[0238] MS (ESI, pos. ion) m / z: 420.90 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.52 (s, 1H), 7.33 (d, J = 12.8 Hz, 1H), 7.08 (d, J = 7.1 Hz, 1H), 4.14 (d, J = 6.3 Hz, 1H), 3.93 (s, 3H), 3.89 (t, J =6.7 Hz, 2H), 3.45 (d, J = 11.8 Hz, 2H), 3.29 (s, 6H), 2.73 (t, J = 6.7 Hz, 2H), 2.65 (t,J = 11.4 Hz, 2H), 1.76 (d, J = 10.9 Hz, 3H), 1.44 (dd, J = 24.2, 14.0 Hz, 2H). Step 2): 1-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl] Synthesis of piperidine-4-carboxaldehyde 1-[6-[4-(dimethoxymethyl)piperidin-1-yl]-5-fluoro-1-methyl-1H-indazol-3-yl]dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.48 mmol), tetrahydrofuran (10 mL), and hydrochloric acid solution (4N) (5 mL) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 2 hours, and then stopped. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation to give the title compound as a grayish-white solid (0.175 g, yield: 98.30%). MS (ESI, pos. ion) m / z: 374.85 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.52 (s, 1H), 9.67 (s, 1H), 7.34(dd, J = 12.7, 7.7 Hz, 1H), 7.10 (dd, J = 15.2, 7.1 Hz, 1H), 3.94 (d, J = 2.7 Hz, 3H), 3.89 (t, J = 6.6 Hz, 2H), 3.44 (d, J = 4.6 Hz, 1H), 3.37 (s, 1H), 2.83 (t, J =10.1 Hz, 1H), 2.73 (t, J = 6.6 Hz, 2H), 2.62 (t, J = 11.1 Hz, 1H), 2.06 – 1.95(m, 1H), 1.82 (d, J = 12.4 Hz, 1H), 1.77 – 1.65 (m, 1H), 1.47 (dd, J = 14.1, 8.0Hz, 2H). Step 3): (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1)) (2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrole Synthesis of [2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-[1-(2-methyl-4-[6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.280 g, 0.46 mmol), 1-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl]piperidine-4-carboxaldehyde (0.17 g, 0.46 mmol), N,N-dimethylacetamide (10 mL), and triethylamine (0.28 g, 2.76 mmol) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.49 g, 2.30 mmol) was added. The reaction was continued at room temperature for 11 hours (mmol), then stopped. Water (100 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, the filter cake was washed with water (20 mL), and purified by column chromatography (dichloromethane:methanol = 60:1 to 30:1 (v:v)) to give the title compound as a yellow solid (0.24 g, yield: 55.92%).

[0239] MS (ESI, pos. ion) m / z:923.45[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 10.53 (s, 1H), 9.96(d, J = 7.7 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.18 (d, J = 7.4 Hz, 1H), 8.09(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.38 – 7.27 (m, 2H), 7.09 (d, J = 7.0 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 5.41 – 5.35 (m, 1H), 3.94 (s,3H), 3.89 (t, J = 6.6 Hz, 2H), 3.60 (s, 4H), 3.45 (d, J= 11.1 Hz, 2H), 2.75 (d, J = 6.6 Hz, 2H), 2.70 (d, J = 16.2 Hz, 2H), 2.53 (s, 3H), 2.26 (d, J = 6.5 Hz, 2H), 2.00 (d, J = 7.4 Hz, 1H), 1.87 (d, J = 11.6 Hz, 2H), 1.75 (s, 1H), 1.55 (d, J = 6.9Hz, 3H), 1.39 (s, 1H), 1.37 (s, 9H), 1.34 (d, J = 5.7 Hz, 4H). Example 12 Synthesis of (R)-3-tert-butyl-N-(1-(4-(6-(6-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0240] Step 1): Synthesis of 3-[4-(2-hydroxyethyl)phenylamino]propionic acid 2-(4-aminophenyl)ethanol (1.75 g, 12.76 mmol), acrylic acid (0.87 g, 12.12 mmol), and toluene (20 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90°C under a nitrogen atmosphere. o The reaction was stirred at C for 4 hours. The reaction was stopped and cooled to room temperature. The product was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 30:1 to 10:1 (v:v)) to give the title compound as a pale yellow oil (2.00 g, yield: 75%).

[0241] MS (ESI, pos. ion) m / z:210.0 [M+H] + .

[0242] Step 2): Synthesis of 4-[2,4-dioxotetrahydropyrimidin-1(2H)-yl]phenylacetate 3-[4-(2-hydroxyethyl)phenylamino]propionic acid (2.00 g, 9.56 mmol), urea (1.15 g, 19.12 mmol), and acetic acid (20 mL) were added sequentially to the reaction flask, and the mixture was heated to 110 °C. oThe reaction was stirred at C for 12 hours. The reaction was stopped, cooled to room temperature, and water (100 mL) was added. The pH was adjusted to 8 by adding saturated sodium bicarbonate aqueous solution. Ethyl acetate (30 mL × 3) was added for extraction. The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1~1:2) to give the title compound as a white solid (1.13 g, yield: 43%).

[0243] MS (ESI, pos. ion) m / z:276.95 [M+H] + .

[0244] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.34 (s, 1H), 7.26 (s, 4H), 4.21(t, J = 6.8 Hz, 2H), 3.77 (t, J = 6.6 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.70 (t, J =6.6 Hz, 2H), 1.99 (s, 3H).

[0245] Step 3): Synthesis of 1-[4-(2-hydroxyethyl)phenyl]dihydropyrimidine-2,4(1H,3H)-dione 4-[2,4-dioxotetrahydropyrimidin-1(2H)-yl]phenylacetate (1.10 g, 3.98 mmol) and an aqueous solution of hydrogen chloride (20 mL, 40 mmol, 2.0 mol / L) were added sequentially to the reaction flask. After the addition was complete, the mixture was heated to 80 °C and stirred for 5 hours. The reaction was then stopped, and the solution was concentrated under reduced pressure to give the title compound as a white solid (0.91 g, yield: 97%).

[0246] MS (ESI, pos. ion) m / z:235.00 [M+H] + .

[0247] Step 4): Synthesis of 2-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]acetaldehyde 1-[4-(2-hydroxyethyl)phenyl]dihydropyrimidine-2,4(1H,3H)-dione (0.90 g, 3.84 mmol) and dichloromethane (50 mL) were added sequentially to the reaction flask. Dys-Martin oxidant (5.70 g, 13.44 mmol) was added under ice-water bath conditions. The mixture was stirred at room temperature for 4 hours, after which the reaction was stopped. The solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1 ~ ethyl acetate) to give the title compound as a pale yellow viscous substance (0.510 g, yield: 57%).

[0248] MS (ESI, pos. ion) m / z:233.00 [M+H] + .

[0249] Step 5): (R)-3-tert-butyl-N-(1-(4-(6-(6-(4-(4-(2,4-dioxotetrahydropyrimidine-1(2H)- (Phenyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1, Synthesis of 2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-[1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.25 g, 0.42 mmol), 2-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]acetaldehyde (0.098 g, 0.42 mmol), sodium acetate (0.17 g, 2.1 mmol), dichloromethane (50 mL), and ethanol (15 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 0.5 hours, then sodium cyanoborohydride (0.13 g, 2.1 mmol) was added, and the reaction was continued to be stirred at room temperature for 12 hours. The reaction was then stopped. The crude product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (v:v) = 30:1 to 15:1) to give the title compound as a yellow solid (0.19 g, yield: 58.53%).

[0250] MS (ESI, pos. ion) m / z:782.3[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 10.34 (s, 1H), 9.95 (d, J = 7.7 Hz, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09(d, J= 8.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.33 – 7.21 (m, 5H), 6.98 (d, J = 8.8 Hz, 1H), 5.45 – 5.27 (m, 1H), 4.09 (s, 2H), 3.76 (t, J = 6.6 Hz,2H), 3.61 (s, 2H), 3.17 (s, 4H), 2.82 (s, 2H), 2.70 (t, J = 6.7 Hz, 2H), 2.63(s, 2H), 2.53 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). Example 13 Synthesis of (R)-3-tert-butyl-N-(1-(4-(6-(6-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenylethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0251] Step 1: Synthesis of (S)-4-bromo-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide 4-Bromo-2-fluorobenzoic acid (1.63 g, 7.44 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (1.35 g, 8.18 mmol), dichloromethane (80 mL), triethylamine (2.26 g, 22.32 mmol), 1-hydroxybenzotriazole (1.51 g, 11.16 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.14 g, 11.16 mmol) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 12 hours. The reaction was then stopped, and the mixture was washed with 100 mL of water. The organic layer was distilled under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 200:1–100:1) to give the title compound as a white solid (2.21 g, yield: 90%).

[0252] MS (ESI, pos. ion) m / z:329.0 [M+H] + ; 1H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.89 (s, 1H), 8.67 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 10.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 4.83 – 4.70 (m, 1H), 2.87 – 2.73 (m, 1H), 2.56 (d, J = 3.4 Hz, 1H), 2.17 – 1.95(m, 2H).

[0253] Step 2: (S,E)-N-(2,6-dioxopiperidin-3-yl)-4-(2-ethoxyvinyl)-2-fluorobenzamide Synthesis (S)-4-bromo-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (2.21 g, 6.71 mmol), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (1.99 g, 10.06 mmol), cesium fluoride (2.04 g, 13.42 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.49 g, 0.67 mmol), 1,4-dioxane (60 mL), and water (12 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90 °C under a nitrogen atmosphere and stirred for 7 hours. The reaction was stopped, water (100 mL) and dichloromethane (80 mL) were added, the mixture was separated, the organic phase was collected, the organic phase was washed with water (100 mL × 2), the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 150:1) to give the title compound as an off-white solid (1.76 g, yield: 81%).

[0254] MS (ESI, pos. ion) m / z:320.9 [M+H] + .

[0255] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.87 (s, 1H), 8.36 (dd, J = 8.0, 4.3Hz, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.47 (d, J= 12.9 Hz, 1H), 7.27 (d, J = 13.0 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.88 (d, J = 12.9 Hz, 1H), 4.88 – 4.61 (m, 1H), 4.00 – 3.87 (m, 2H), 2.87 – 2.70 (m, 1H), 2.22 – 1.92 (m, 2H), 1.27 (t, J = 7.0Hz, 3H).

[0256] Step 3: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2-oxoethyl)benzamide (S,E)-N-(2,6-dioxopiperidin-3-yl)-4-(2-ethoxyvinyl)-2-fluorobenzamide (0.50 g, 1.56 mmol) and anhydrous acetonitrile (50 mL) were added sequentially to the reaction flask. Macroporous resin (0.50 g) was added with stirring, and the reaction was carried out at room temperature for 5 hours. The reaction was stopped, filtered, and the filtrate was distilled under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 60:1~40:1) to give the title compound as a pale yellow solid (0.22 g, yield: 48%).

[0257] 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.87 (s, 1H), 8.48 (dd, J = 8.1, 3.1Hz, 1H), 7.70 – 7.49 (m, 1H), 7.28 – 7.07 (m, 2H), 6.19 (d, J = 7.7 Hz, 1H), 4.83 – 4.68 (m, 1H), 3.22 (s, 2H), 2.96 – 2.71 (m, 2H), 2.22 – 1.93 (m, 2H).

[0258] Step 4: (R)-3-tert-butyl-N-(1-(4-(6-(6-(4-(4-(((S)-2,6-dioxopiperidin-3-yl)amino) (-3-fluorophenylethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzene Synthesis of (ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.10 g, 0.17 mmol), (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2-oxoethyl)benzamide (0.050 g, 0.17 mmol), sodium acetate (0.070 g, 0.85 mmol), dichloromethane (20 mL), and ethanol (6 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 0.5 hours, then sodium cyanoborohydride (0.053 g, 0.85 mmol) was added, and the reaction was continued to be stirred at room temperature for 12 hours. The reaction was then stopped. The crude product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 20:1) to give the title compound as a yellow solid (0.10 g, yield: 71.52%).

[0259] MS (ESI, pos. ion) m / z:842.40[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.58 (s, 1H), 10.86 (s, 1H), 9.95(d, J = 7.7 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.76 (s, 1H), 8.47 (dd, J = 8.1, 3.3Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.66(d, J = 8.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 12.3 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.96 (d, J= 9.1 Hz, 1H), 5.42 – 5.33 (m, 1H), 4.82 – 4.69 (m, 1H), 3.58 (s, 4H), 2.86 (t, J = 7.2 Hz, 2H), 2.82 – 2.73 (m,1H), 2.61 (t, J = 6.9 Hz, 2H), 2.55 (s, 4H), 2.53 (s, 3H), 2.18 – 2.08 (m, 1H), 2.07 – 1.88 (m, 2H), 1.56 (s, 3H), 1.37 (s, 9H). Example 14 Synthesis of (3R)-3-tert-butyl-N-((1R)-1-(4-(6-(6-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0260] Step 1: 6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol- Synthesis of 2-keto 6-Bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.50 g, 2.20 mmol), 4-(dimethoxymethyl)piperidine (0.53 g, 3.30 mmol), sodium tert-butoxide (0.53 g, 5.5 mmol), tris(dibenzylideneacetone)dipalladium (0.10 g, 0.11 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.10 g, 0.22 mmol), and toluene (15 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C under nitrogen protection and stirred for 14 hours, after which the reaction was stopped. The crude product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol (v:v) = 100:1 to 30:1) to give the title compound as a pale red solid (0.24 g, yield: 35.69%).

[0261] MS (ESI, pos. ion) m / z: 306.20 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ (ppm) 10.47 (s, 1H), 6.80 (d, J = 8.4 Hz,1H), 6.71 (s, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 6.7 Hz, 1H), 3.55 (d, J =11.9 Hz, 2H), 3.27 (s, 6H), 3.23 (s, 3H), 2.56 (d, J = 11.7 Hz, 2H), 1.72 (d, J =12.7 Hz, 2H), 1.68 – 1.58 (m, 1H), 1.43 – 1.33 (m, 2H). Step 2: (3S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro- Synthesis of 1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.80 g, 5.89 mmol) and tetrahydrofuran (70 mL) were added sequentially to the reaction flask under nitrogen protection. Bistrimethylsilylaminolithium (17.67 mL, 17.67 mmol, 1 N) was slowly added at 0 °C. After the addition was complete, the mixture was transferred to room temperature and stirred for 1 hour. Subsequently, a solution of 3-bromopiperidin-2,6-dione (2.26 g, 11.78 mmol) dissolved in tetrahydrofuran (18 mL) was added. After the addition was complete, the mixture was heated to 60 °C and stirred for 7 hours. The reaction was stopped, cooled to room temperature, transferred to 0°C, and quenched by adding 20 mL of saturated ammonium chloride aqueous solution. Most of the solvent was removed by vacuum distillation, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 200:1 to 100:1) to obtain the title compound as a pale yellow solid (0.80 g, yield: 32.59%).

[0262] MS (ESI, pos. ion) m / z: 417.00 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.07 (s, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.82 (d, J= 1.7 Hz, 1H), 6.63 (dd, J = 8.5, 1.8 Hz, 1H), 5.29 (dd, J = 12.9, 5.3 Hz, 1H), 4.10 (d, J = 5.8 Hz, 1H), 3.60 (d, J = 11.7 Hz, 2H), 3.31 (s, 3H), 3.28 (s, 6H), 2.96 – 2.83 (m, 1H), 2.74 – 2.65 (m, 1H), 2.58 (t, J = 11.4 Hz,3H), 2.05 – 1.94 (m, 1H), 1.73 (d, J = 12.4 Hz, 2H), 1.67 (dd, J = 7.4, 3.8 Hz, 1H), 1.38 (d, J = 12.1 Hz, 2H). Step 3: (1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]) Synthesis of imidazole-5-yl)piperidine-4-carbaldehyde (3S)-3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (0.80 g, 1.92 mmol), tetrahydrofuran (8 mL), and hydrochloric acid (4 M, 4 mL) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 3 hours, and then stopped. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a grayish-white solid (0.70 g, yield: 98.38%). MS (ESI, pos. ion) m / z: 371.00 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.06 (s, 1H), 9.65 (s, 1H), 6.95 –6.87 (m, 1H), 6.83 (dd, J = 12.8, 2.0 Hz, 1H), 6.63 (td, J = 8.6, 2.0 Hz, 1H), 5.28 (dd, J= 7.5, 5.1 Hz, 1H), 3.59 (s, 1H), 3.54 – 3.47 (m, 1H), 3.30 (d, J =1.7 Hz, 3H), 2.89 (dd, J = 17.4, 12.4 Hz, 1H), 2.83 – 2.74 (m, 1H), 2.72 – 2.53(m, 3H), 2.48 – 2.42 (m, 1H), 1.97 (dd, J = 12.2, 8.8 Hz, 2H), 1.78 (d, J = 12.1Hz, 1H), 1.63 (td, J = 14.2, 3.7 Hz, 1H), 1.45 (dd, J = 11.8, 8.8 Hz, 1H). Step 4: (3R)-3-tert-butyl-N-((1R)-1-(4-(6-(6-(4-((1-(1-(2,6-dioxopiperidine-3- )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridine- Synthesis of 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.30 g, 0.50 mmol), (1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-carboxaldehyde (0.19 g, 0.50 mmol), N,N-dimethylacetamide (10 mL), and triethylamine (0.30 g, 3 mmol) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (0.53 g, 2.5 mmol). The reaction was continued at room temperature for 14 hours (mmol), and then stopped. Water (50 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, and the filter cake was washed with water (10 mL). The mixture was purified by column chromatography (dichloromethane:methanol (v:v) = 50:1 to 15:1) to give the title compound as a yellow solid (0.26 g, yield: 56.72%).

[0263] MS (ESI, pos. ion) m / z:920.45[M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ (ppm) 12.60 (s, 1H), 11.07 (s, 1H), 9.96(d, J = 7.7 Hz, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.09(d, J = 8.2 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 6.96(dd, J = 14.4, 8.8 Hz, 2H), 6.84 (s, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.44 – 5.34(m, 1H), 5.30 (dd, J = 13.1, 5.2 Hz, 1H), 3.60 (d, J = 11.1 Hz, 5H), 3.31 (s,3H), 2.90 (t, J = 14.7 Hz, 1H), 2.64 (t, J = 15.6 Hz, 5H), 2.54 (s, 3H), 2.34 (s,2H), 2.00 (d, J = 7.6 Hz, 2H), 1.85 (d, J = 11.7 Hz, 2H), 1.73 (s, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 2.9 Hz, 1H), 1.38 (d, J = 6.8 Hz, 9H), 1.32 (dd, J =20.4, 8.7 Hz, 4H). Example 15 Synthesis of (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0264] Step 1: (E)-1-[7-(2-ethoxyvinyl)-1-methyl-1H-indazol-3-yl]dihydropyrimidine-2,4(1H, Synthesis of 3H)-dione 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 3.09 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (0.80 g, 4.02 mmol), cesium fluoride (1.41 g, 9.27 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.23 g, 0.31 mmol), dioxane (30 mL), and water (6 mL) were added sequentially to the reaction flask. After purging with nitrogen three times, the temperature was raised to 90 °C and the reaction was stirred for 6 hours before the reaction was stopped. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 1:1 to 1:2) to give the title compound as a pale yellow solid (0.520 g, yield: 53.46%).

[0265] MS (ESI, pos. ion) m / z:315.05[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.54 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.09 – 6.93 (m, 2H), 6.50 (d, J = 12.6 Hz, 1H), 4.18 (s, 3H), 3.98 (q, J = 6.9 Hz, 2H), 3.87 (t, J = 6.6 Hz, 2H), 2.76 (t, J = 6.7Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). Step 2: 2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl]acetaldehyde synthesis (E)-1-[7-(2-ethoxyvinyl)-1-methyl-1H-indazol-3-yl]dihydropyrimidine-2,4(1H,3H)-dione (0.50 g, 1.59 mmol) and acetonitrile (50 mL) were added sequentially to a reaction flask, and the mixture was stirred until dissolved. Macroporous resin (0.500 g) was then added, and the reaction was carried out at room temperature for 6 hours. The filtrate was filtered, concentrated, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 100:1 to 40:1) to give the title compound as a yellow solid (0.28 g, yield: 61.49%).

[0266] MS (ESI, pos. ion) m / z: 287.05 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.53 (s, 1H), 9.86 (s, 1H), 7.47(d, J = 8.0 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.06 – 6.99 (m, 1H), 4.21 (s, 3H), 4.04 (s, 2H), 3.87 (t, J = 6.6 Hz, 2H), 2.77 (d, J = 6.5 Hz, 2H). Step 3: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-(2-(3-(2,4-dioxotetrahydropyrimidine-1) (2H)-yl)-1-methyl-1H-indazol-7-yl)ethyl)piperazine-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-tert-butyl-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.20 g, 0.33 mmol), 2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl]acetaldehyde (0.094 g, 0.33 mmol), chloroform (20 mL), and triethylamine (0.20 g, 1.98 mmol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.35 g, 1.65 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction was then stopped. The solvent was removed by vacuum distillation of the reaction solution, and saturated sodium bicarbonate solution (50 mL) was added. The mixture was filtered, and the filter cake was purified by column chromatography (dichloromethane:methanol (v:v) = 40:1 to 20:1) to give the title compound as a yellow solid (0.15 g, yield: 54.03%).

[0267] MS (ESI, pos. ion) m / z: 836.5 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 12.61 (s, 1H), 10.55 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.2Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.31(s, 1H), 7.24 (d, J = 6.9 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.03 – 6.94 (m, 1H), 5.41 – 5.34 (m, 1H), 4.25 (s, 3H), 3.89 (t, J = 6.7 Hz, 2H), 3.64 (s, 4H), 3.25(s, 2H), 3.18 (s, 1H), 2.77 (t, J= 6.7 Hz, 2H), 2.65 (s, 5H), 2.54 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.38 (s, 9H). Example 16 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[(2S)-4-[2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl]ethyl]-2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0268] 3-(tert-butyl)-N-[(R)-1-(2-methyl-4-{6-[(5-[(S)-2-methylpiperazin-1-yl]pyridin-2-yl)amino]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.21 g, 0.35 mmol), 2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl]acetaldehyde (0.10 g, 0.35 mmol), chloroform (20 mL), and triethylamine (0.21 g, 2.10 mmol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.37 g, 1.75 mmol) was added, and the reaction was continued at room temperature for 6 hours. The reaction was stopped, the solvent was removed by vacuum distillation of the reaction solution, saturated sodium bicarbonate solution (50 mL) was added, and the mixture was filtered. The filter cake was purified by column chromatography (dichloromethane:methanol (v:v) = 40:1 to 20:1) to give the title compound as a yellow solid (0.160 g, yield: 54.62%).

[0269] MS (ESI, pos. ion) m / z: 826.6 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 10.55 (s, 1H), 9.99 (s, 1H), 9.88(d, J = 7.8 Hz, 1H), 8.70 (s, 1H), 8.02 (t, J = 9.1 Hz, 2H), 7.84 (d, J= 6.2 Hz, 2H), 7.70 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 9.1, 2.5 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H), 7.08 – 7.00 (m, 1H), 5.39 – 5.28(m, 1H), 4.24 (s, 3H), 3.88 (t, J = 6.7 Hz, 2H), 3.31 – 3.19 (m, 4H), 3.17 (d, J = 4.1 Hz, 1H), 3.02 (t, J = 9.3 Hz, 1H), 2.92 (d, J = 9.4 Hz, 1H), 2.77 (t, J = 6.7Hz, 2H), 2.66 (s, 2H), 2.54 (s, 1H), 2.47 (s, 3H), 2.37 (d, J = 10.0 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.36 (s, 9H), 1.00 (d, J = 6.3 Hz, 3H). Example 17 Synthesis of (R)-3-(tert-butyl)-N-[(1-(4-(6-(6-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0270] Step 1: (E)-1-[6-(2-ethoxyvinyl)-5-fluoro-1-methyl-1H-indazol-3-yl]dihydropyrimidine-2, Synthesis of 4(1H,3H)-dione The following substances were added sequentially to the reaction flask: 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.500 g, 1.47 mmol), (E)-1-ethoxyvinyl-2-boronate pinacol ester (0.378 g, 1.91 mmol), cesium fluoride (0.670 g, 4.41 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.108 g, 0.150 mmol), 1,4-dioxane (20 mL), and water (4 mL). The reaction system was purged with nitrogen three times, and the temperature was raised to 90°C under a nitrogen atmosphere. o The reaction was stirred at C for 17 hours. The reaction was stopped and cooled to room temperature. The crude product was concentrated under reduced pressure and purified by column chromatography (PE:EA (v:v) = 3:1~1:2) to give the title compound as a pale yellow solid (0.391 g, yield: 80%).

[0271] MS (ESI, pos. ion) m / z: 333.90 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.56 (s, 1H), 7.70 (d, J = 6.2 Hz, 1H), 7.40 (dd, J = 27.2, 12.1 Hz, 2H), 5.95 (d, J = 12.9 Hz, 1H), 4.02 – 3.94 (m,5H), 3.91 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H).

[0272] Step 2: 2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl]ethyl Aldehyde synthesis (E)-1-[6-(2-ethoxyvinyl)-5-fluoro-1-methyl-1H-indazol-3-yl]dihydropyrimidine-2,4(1H,3H)-dione (0.250 g, 0.75 mmol), macroporous resin (0.250 g), and acetonitrile (30 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 12 hours, after which the reaction was stopped. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA (v:v) = 1:2~EA) to give the title compound as a pale yellow solid (0.080 g, yield: 35%).

[0273] MS (ESI, pos. ion) m / z: 304.90 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.56 (d, J = 13.3 Hz, 1H), 9.77 (s,1H), 7.60 (d, J = 5.8 Hz, 1H), 7.44 (d, J = 10.1 Hz, 1H), 4.07 – 3.88 (m, 7H), 2.77 (t, J = 6.6 Hz, 2H).

[0274] Step 3: (R)-3-(tert-butyl)-N-[(1-(4-(6-(6-(4-(2-(3-(2,4-dioxotetrahydropyrimidine-1 (2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d] Synthesis of pyrimidin-4-yl)-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide 2-[3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl]acetaldehyde (0.080 g, 0.26 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.164 g, 0.27 mmol), chloroform (15 mL), and triethylamine (0.18 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After being transferred to room temperature, sodium triacetoxyborohydride (0.276 g, 1.30 mmol) was added, and the reaction was continued to be stirred at room temperature for 17 hours. The reaction was then stopped. The crude product was concentrated by vacuum distillation and purified by column chromatography (DCM:MeOH (v:v) = 40:1~25:1) to give the title compound as a bluish-yellow solid (158 mg, yield: 70.37%).

[0275] MS (ESI, pos. ion) m / z: 854.40 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 10.57 (s, 1H), 9.97(d, J = 7.8 Hz, 1H), 8.82 (d, J= 2.0 Hz, 1H), 8.77 (s, 1H), 8.23 ​​– 8.16 (m, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 6.0Hz, 1H), 7.39 (d, J = 10.4 Hz, 1H), 7.30 (s, 1H), 6.97 (d, J = 9.1 Hz, 1H), 5.44– 5.33 (m, 1H), 3.98 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.61 (s, 4H), 2.95 (d, J = 6.9 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.70 – 2.63 (m, 2H), 2.59 (s, 4H), 2.54 (s, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.39 (d, J = 9.6 Hz, 9H).

[0276] Example 18 Synthesis of 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0277] Step 1: Synthesis of 3-iodo-1-methyl-6-nitro-1H-indazole 3-Iodo-6-nitro-1H-indazole (3 g, 10.38 mmol), N,N-dimethylformamide (20 mL), potassium carbonate (7.17 g, 51.90 mmol), and iodomethane (2.21 g, 15.57 mmol) were added sequentially to the reaction flask. The mixture was heated to 60 °C and reacted for 5 hours, after which the reaction was stopped. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA (v:v) = 20:1~10:1) to give the title compound as a yellow solid (2.20 g, yield: 69.94%).

[0278] MS (ESI, pos. ion) m / z: 303.75 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 8.77 (d, J = 1.4 Hz, 1H), 8.00 (dd, J =8.9, 1.8 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 4.22 (s, 3H).

[0279] Step 2: Synthesis of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-6-nitro-1H-indazole 3-Iodo-1-methyl-6-nitro-1H-indazole (2.2 g, 7.26 mmol), 2,6-di(benzyloxy)-3-(tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (3.94 g, 9.44 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.53 g, 0.73 mmol), sodium carbonate (2.31 g, 21.78 mmol), 1,4-dioxane (50 mL), and water (10 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 4 hours. The reaction was stopped, cooled to room temperature, and concentrated by vacuum distillation. The crude product was purified by column chromatography (PE:EA (v:v) = 20:1~15:1) to give the title compound as a yellow solid (2.33 g, yield: 69%).

[0280] MS (ESI, pos. ion) m / z:467.30 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6) δ (ppm) 8.69 (d, J = 1.7 Hz, 1H), 7.99 – 7.88(m, 2H), 7.80 (dd, J = 9.0, 1.9 Hz, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.43 – 7.34(m, 5H), 7.34 – 7.27 (m, 3H), 6.63 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 5.45 (s,2H), 4.21 (d, J = 7.4 Hz, 3H).

[0281] Step 3: Synthesis of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazole-6-amine 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-6-nitro-1H-indazole (2.3 g, 4.93 mmol), iron powder (2.75 g, 49.3 mmol), ammonium chloride (1.32 g, 24.65 mmol), ethanol (50 mL), and water (5 mL) were added sequentially to the reaction flask. The mixture was heated to 90 °C and stirred for 12 hours. The reaction was stopped, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 200:1 to 100:1) to give the title compound as a pale red solid (1.76 g, yield: 82%).

[0282] MS (ESI, pos. ion) m / z:437.05 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 7.87 (t, J = 6.5 Hz, 1H), 7.47 (d, J =7.1 Hz, 2H), 7.43 – 7.35 (m, 5H), 7.31 (dt, J = 9.3, 5.6 Hz, 4H), 6.55 (d, J =8.1 Hz, 1H), 6.44 – 6.37 (m, 2H), 5.44 (s, 2H), 5.42 (s, 2H), 5.34 (d, J = 9.2Hz, 2H), 3.85 (s, 3H).

[0283] Step 4: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazole-6-amine (1.76 g, 4.03 mmol), 10% palladium on carbon (0.51 g, 0.48 mmol), 10% palladium hydroxide (1.03 g, 0.73 mmol), acetic acid (0.24 g, 4.03 mmol), tetrahydrofuran (15 mL), and ethanol (15 mL) were added sequentially to the reaction flask. The mixture was purged with hydrogen three times, heated to 50 °C, and stirred for 12 hours. The reaction was stopped, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 100:1 to 50:1) to give the title compound as a white solid (795 mg, yield: 76%).

[0284] MS (ESI, pos. ion) m / z:259.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.83 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.49 (dd, J = 8.6, 1.4 Hz, 1H), 6.42 (s, 1H), 5.36 (s, 2H), 4.18 (dd, J =8.7, 5.1 Hz, 1H), 3.77 (s, 3H), 2.61 (t, J = 6.1 Hz, 2H), 2.35 – 2.21 (m, 1H), 2.15 (td, J = 11.4, 5.7 Hz, 1H).

[0285] Step 5: Synthesis of 3-(6-iodo-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (500 mg, 1.94 mmol), acetic acid (5 mL), and sulfuric acid (665.96 mg, 6.79 mmol) were added sequentially to the reaction flask. Sodium nitrite (334.65 mg, 4.85 mmol) and potassium iodide (1610.20 mg, 9.7 mmol) were added in an ice-water bath. The mixture was stirred in an ice-water bath for 1 hour, then stirred at room temperature for 12 hours. The reaction was stopped, water (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA (v:v) = 2:1~1:1) to give the title compound as a yellow, fluffy solid (419 mg, yield: 58%).

[0286] MS (ESI, pos. ion) m / z:370.85 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.91 (s, 1H), 8.12 (s, 1H), 7.55(d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 4.37 (dt, J = 21.3, 10.6 Hz, 1H),4.02 – 3.94 (m, 3H), 2.76 – 2.57 (m, 2H), 2.43 – 2.29 (m, 1H), 2.17 (dq, J =10.4, 5.1 Hz, 1H).

[0287] Step 6: (E)-3-[6-(2-ethoxyvinyl)-1-methyl-1H-indazol-3-yl]piperidine-2,6-dione synthesis 3-(6-iodo-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (410 mg, 1.11 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (81.22 mg, 0.11 mmol), cesium fluoride (505.83 mg, 3.33 mmol), 1,4-dioxane (20 mL), water (4 mL), and (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (263.83 mg, 1.33 mmol) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 90 °C and stirred for 4 hours. The reaction was stopped, and the mixture was concentrated by vacuum distillation. The crude product was purified by column chromatography (PE:EA (v:v) = 3:1~1:1) to give the title compound as a white solid (247 mg, yield: 71%).

[0288] MS (ESI, pos. ion) m / z:314.10 [M+H] + .

[0289] Step 7: Synthesis of 2-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]acetaldehyde (E)-3-[6-(2-ethoxyvinyl)-1-methyl-1H-indazol-3-yl]piperidine-2,6-dione (220 mg, 0.70 mmol), macroporous resin (300 mg), and anhydrous acetonitrile (15 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 9 hours. The reaction was stopped, the mixture was filtered, and the filtrate was concentrated by vacuum distillation. The crude product was purified by column chromatography (PE:EA (v:v) = 1:1~1:4) to give the title compound as a pale yellow solid (61 mg, yield: 30%).

[0290] MS (ESI, pos. ion) m / z:286.10 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 10.89 (d, J = 11.1 Hz, 1H), 9.75 (t, J =1.8 Hz, 1H), 7.70 (t, J = 8.9 Hz, 1H), 7.49 (s, 1H), 7.01 (dd, J = 13.2, 4.9 Hz, 1H), 4.37 (dt, J= 12.8, 6.4 Hz, 1H), 4.03 – 3.96 (s, 3H), 3.92 (s, 2H), 2.72 –2.66 (m, 1H), 2.61 (dt, J = 17.3, 5.2 Hz, 1H), 2.37 (ddd, J = 20.0, 10.0, 5.0 Hz,1H), 2.21 – 2.15 (m, 1H).

[0291] Step 8: 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)- 1-Methyl-1H-indazol-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl Synthesis of (phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 2-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]acetaldehyde (60 mg, 0.21 mmol), 3-tert-butyl-N-[(1R)-1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (147.53 mg, 0.23 mmol), chloroform (15 mL), and triethylamine (106.25 mg, 1.05 mmol) were added sequentially to the reaction flask, and the mixture was heated to 60 °C and stirred for 1 hour. The mixture was then transferred to room temperature, and sodium triacetoxyborohydride (222.54 mg, 1.05 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was stopped, water (30 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, concentrated by vacuum distillation, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 40:1~20:1) to give the title compound as a yellow solid (62 mg, yield: 35.31%).

[0292] MS (ESI, pos. ion) m / z:835.45 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 10.95 – 10.86 (m,1H), 9.96 (d, J = 7.8 Hz, 1H), 8.83 (t, J = 7.8 Hz, 1H), 8.77 (s, 1H), 8.24 –8.16 (m, 1H), 8.10 (d, J= 8.2 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.47 (s, 1H), 7.32 (d, J = 21.7 Hz, 1H), 7.04 (d, J = 8.4Hz, 1H), 6.96 (t, J = 11.3 Hz, 1H), 5.39 (p, J = 7.0 Hz, 1H), 4.38 – 4.29 (m,1H), 3.99 (d, J = 16.7 Hz, 3H), 3.64 (d, J = 33.9 Hz, 4H), 3.01 – 2.87 (m, 2H), 2.73 – 2.62 (m, 4H), 2.60 (d, J = 17.2 Hz, 4H), 2.54 (s, 3H), 2.41 – 2.31 (m,1H), 2.18 (td, J = 10.7, 5.2 Hz, 1H), 1.56 (d, J = 6.9 Hz, 3H), 1.42 – 1.33 (m,9H).

[0293] Example 19 Synthesis of 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0294] Step 1: Synthesis of 8-bromo-4-hydroxy-2H-benzopyran-2-one 1-(3-bromo-2-hydroxyphenyl)ethyl-1-one (4.0 g, 18.60 mmol) and toluene (80 mL) were added sequentially to a reaction flask. Sodium hydride (5.95 g, 148.8 mmol) was added under an ice-water bath. After stirring for 0.5 hours under an ice-water bath, diethyl carbonate (21.97 g, 186 mmol) was added dropwise. Stirring was continued under an ice-water bath for 15 minutes, followed by stirring at 100°C for 12 hours. The reaction was stopped, and the reaction was quenched with ice water in an ice-water bath. The mixture was washed with ethyl acetate (30 mL × 2), and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 2-3 with hydrochloric acid (1N), and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a white solid (3.8 g, yield: 85%).

[0295] MS (ESI, pos. ion) m / z: 242.80 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.78 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.36 – 7.23 (m, 1H), 5.64 (s, 1H).

[0296] Step 2: Synthesis of 2-(7-bromobenzo[d]isoxazol-3-yl)acetic acid 8-Bromo-4-hydroxy-2H-benzopyran-2-one (3.8 g, 15.77 mmol), hydroxylamine hydrochloride (2.19 g, 31.54 mmol), sodium ethoxide (2.15 g, 31.54 mmol), and ethanol (50 mL) were added sequentially to a reaction flask. The mixture was heated to 85 °C under nitrogen protection and stirred. After the reaction was complete, the mixture was concentrated by vacuum distillation. Water (20 mL) and saturated sodium carbonate solution (50 mL) were added to the residue. The mixture was washed with dichloromethane (50 mL × 2). The aqueous layer was adjusted to pH < 3 with dilute hydrochloric acid (3 M) and extracted with dichloromethane (50 mL × 2). The organic phases were combined and concentrated by vacuum distillation to give the title compound as a yellowish-white solid (2.90 g, yield: 72%).

[0297] MS (ESI, pos. ion) m / z: 257.80 [M+H] + ; 1 H NMR (400 MHz, DMSO - d6) δ (ppm) 12.99 (s, 1H), 7.90 (dt, J = 21.4, 10.6 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 4.15 (s, 2H).

[0298] Step 3: Synthesis of ethyl 2-(7-bromobenzo[d]isoxazol-3-yl)acetate 2-(7-bromobenzo[d]isoxazol-3-yl)acetic acid (2.9 g, 11.33 mmol), ethanol (30 mL), and sulfuric acid (5.56 g, 56.65 mmol) were added sequentially to the reaction flask, and the mixture was heated to 85 °C and stirred for 2 hours. The reaction was stopped, cooled to room temperature, and water (10 mL) was added. The pH was adjusted to 9-10 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was collected, concentrated by vacuum distillation, and the crude product was purified by column chromatography (PE:EA (v:v) = 5:1) to give the title compound as a pale yellow oil (2.90 g, yield: 90%).

[0299] MS (ESI, pos. ion) m / z: 285.80 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 7.90 (dd, J = 16.5, 7.7 Hz, 2H), 7.43– 7.30 (m, 1H), 4.27 (d, J = 17.4 Hz, 2H), 4.14 (p, J = 7.1 Hz, 2H), 1.19 (t, J =7.1 Hz, 3H).

[0300] Step 4: Synthesis of 3-(7-bromobenzo[d]isoxazol-3-yl)piperidine-2,6-dione 2-(7-bromobenzo[d]isoxazol-3-yl)ethyl acetate (2.8 g, 9.86 mmol) and tetrahydrofuran (50 mL) were added sequentially to the reaction flask. Acrylamide (1.05 g, 14.79 mmol) and potassium tert-butoxide (1.66 g, 14.79 mmol) were added under ice-water bath conditions, and the reaction was stirred at 0 °C for 4 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL) at 0 °C, and the mixture was brought to room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 40:1) to give the title compound as a white solid (0.956 g, yield: 31%).

[0301] MS (ESI, pos. ion) m / z: 309.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.14 (s, 1H), 7.93 (dd, J = 11.2, 7.8Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 4.66 (dd, J = 12.2, 4.9 Hz, 1H), 2.78 (ddd, J =18.4, 11.8, 6.0 Hz, 1H), 2.70 – 2.53 (m, 2H), 2.28 – 2.18 (m, 1H).

[0302] Step 5: Synthesis of (E)-3-[7-(2-ethoxyvinyl)benzo[d]isoxazol-3-yl]piperidine-2,6-dione 3-(7-bromobenzo[d]isoxazol-3-yl)piperidine-2,6-dione (920 mg, 2.98 mmol), (E)-1-ethoxyvinyl-2-boronate pinacol ester (0.767 g, 3.87 mmol), cesium fluoride (1.358 g, 8.94 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.218 g, 0.30 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90°C under a nitrogen atmosphere. o The reaction was stirred at C for 17 hours. The reaction was stopped and cooled to room temperature. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1~1:2) to give the title compound as a yellow viscous substance (0.631 g, yield: 71%).

[0303] MS (ESI, pos. ion) m / z: 301.20 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.13 (d, J = 13.0 Hz, 1H), 7.63 (d, J =13.0 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.6Hz, 1H), 6.09 (d, J = 13.0 Hz, 1H), 4.70 – 4.55 (m, 1H), 4.04 (dd, J = 13.9, 7.0Hz, 2H), 2.79 (ddd, J = 17.2, 12.0, 5.2 Hz, 1H), 2.71 – 2.58 (m, 1H), 2.20 (dt, J = 23.3, 9.6 Hz, 1H), 1.31 (t, J = 7.0 Hz, 3H).

[0304] Step 6: Synthesis of 2-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazo-7-yl]acetaldehyde (E)-3-[7-(2-ethoxyvinyl)benzo[d]isoxazol-3-yl]piperidine-2,6-dione (0.460 g, 1.53 mmol), macroporous resin (0.460 g), and acetonitrile (15 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 12 hours. The reaction was stopped, the mixture was filtered, the filtrate was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1~1:1) to give the title compound as a pale yellow solid (0.062 g, yield: 15%).

[0305] MS (ESI, pos. ion) m / z: 273.15 [M+H] + .

[0306] Step 7: 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-(2-(3-(2,6-dioxopiperidin-3-yl)benzene) [d]isoxazo-7-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl Synthesis of phenyl(ethyl)-1,2,4-oxadiazole-5-carboxamide 2-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl]acetaldehyde (0.057 g, 0.21 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.142 g, 0.21 mmol), chloroform (10 mL), and triethylamine (0.15 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After being transferred to room temperature, sodium triacetoxyborohydride (0.223 g, 1.05 mmol) was added, and the reaction was continued to be stirred at room temperature for 17 hours. The reaction was stopped, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 40:1~25:1) to give the title compound as a greenish-yellow solid (75 mg, yield: 43.45%).

[0307] MS (ESI, pos. ion) m / z: 822.95 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 12.59 (s, 1H), 11.11 (s, 1H), 9.96 (d, J = 7.8 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.77 (s, 1H), 8.19 (dd, J = 8.9, 2.2Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.69 (dd, J = 14.8, 8.0 Hz, 2H), 7.55 (d, J = 7.1 Hz, 1H), 7.36 – 7.28 (m, 2H), 6.97 (d, J = 9.0 Hz, 1H), 5.39 (p, J = 7.0 Hz, 1H), 4.61 (dd, J= 12.0, 5.0 Hz, 1H), 3.60 (s, 4H), 3.19 – 3.08 (m,2H), 2.83 – 2.77 (m, 1H), 2.77 – 2.75 (m, 1H), 2.75 – 2.69 (m, 2H), 2.64 (d, J = 4.2 Hz, 1H), 2.61 (d, J = 2.7 Hz, 4H), 2.57 – 2.53 (m, 3H), 2.21 (qd, J = 9.1, 4.6 Hz, 1H), 1.56 (d, J = 7.0 Hz, 3H), 1.43 – 1.32 (m, 9H).

[0308] Example 20 Synthesis of 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-((2S)-4-(2-(3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl)ethyl)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0309] 2-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl]acetaldehyde (0.088 g, 0.32 mmol), 3-(tert-butyl)-N-((R)-1-(2-methyl-4-(6-((5-(((S)-2-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.208 g, 0.35 mmol), chloroform (15 mL), and triethylamine (0.22 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After being transferred to room temperature, sodium triacetoxyborohydride (0.340 g, 1.60 mmol) was added, and the reaction was continued to be stirred at room temperature for 17 hours. The reaction was stopped, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (v:v) = 40:1~25:1) to give the title compound as a greenish-yellow solid (128 mg, yield: 48.77%).

[0310] MS (ESI, pos. ion) m / z: 812.60 [M+H] + ; 1H NMR (600 MHz, DMSO- d 6) δ (ppm) 11.10 (s, 1H), 9.99 (s, 1H), 9.89(d, J = 7.8 Hz, 1H), 8.71 (s, 1H), 8.04 (s, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.84(d, J = 6.3 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.56 (d, J =7.1 Hz, 1H), 7.43 (dd, J = 9.0, 2.5 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.39 –5.29 (m, 1H), 4.60 (td, J = 12.2, 5.3 Hz, 1H), 3.86 (s, 1H), 3.22 (d, J = 10.7Hz, 1H), 3.12 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 9.7 Hz, 1H), 2.89 (d, J = 7.7 Hz,1H), 2.82 – 2.71 (m, 3H), 2.68 (dd, J = 10.9, 6.0 Hz, 1H), 2.65 – 2.58 (m, 1H),2.48 (s, 3H), 2.34 (t, J = 9.0 Hz, 1H), 2.24 – 2.17 (m, 1H), 1.52 (d, J = 7.0 Hz,3H), 1.43 – 1.30 (m, 9H), 0.93 (d, J = 6.3 Hz, 3H).

[0311] Example 21 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[(2S)-4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]ethyl]-2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0312] 3-(tert-butyl)-N-[(R)-1-(2-methyl-4-{6-[(5-[(S)-2-methylpiperazin-1-yl]pyridin-2-yl)amino]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazol-5-carboxamide (0.17 g, 0.29 mmol), 2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]acetaldehyde (0.087 g, 0.29 mmol), chloroform (10 mL), and triethylamine (0.12 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.31 g, 1.45 mmol) was added, and the reaction was continued to be stirred at room temperature for 20 hours. The reaction was stopped, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 30:1~20:1) to give the title compound as a yellow solid (0.14 g, yield: 58%).

[0313] MS (ESI, pos. ion) m / z: 841.3[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.10 (s, 1H), 9.99 (s, 1H), 9.89(d, J = 7.7 Hz, 1H), 8.71 (s, 1H), 8.14 – 7.94 (m, 2H), 7.85 (d, J = 5.6 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.45 (dd, J= 9.1, 2.4 Hz, 1H),7.06 – 6.87 (m, 3H), 5.44 – 5.26 (m, 2H), 3.86 (s, 1H), 3.62 (s, 3H), 3.27 –2.84 (m, 11H), 2.67 (dd, J = 33.7, 13.7 Hz, 5H), 2.48 (s, 3H), 2.38 (d, J = 9.2Hz, 1H), 2.04 – 1.97 (m, 1H), 1.52 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H), 1.00 (d, J = 6.3 Hz, 3H).

[0314] Example 22 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzi[d]imidazol-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0315] Step 1: 3-(3-methyl-2-oxo-4-vinyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2, Synthesis of 6-dione 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol), vinyl borate (0.68 g, 4.44 mmol), cesium fluoride (0.90 g, 5.92 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.22 g, 0.30 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 90 °C under a nitrogen atmosphere and stirred for 6 hours. The reaction was stopped, cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 100:1) to give the title compound as a yellowish-brown solid (0.80 g, yield: 94%).

[0316] MS (ESI, pos. ion) m / z: 286.10 [M+H] + .

[0317] Step 2: 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Synthesis of 4-formaldehyde 3-(3-methyl-2-oxo-4-vinyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (0.10 g, 0.35 mmol), tetrahydrofuran (10 mL), water (2.5 mL), and potassium osmium tetroxide dihydrate (0.13 g, 0.035 mmol) were added sequentially to the reaction flask. After stirring at room temperature for 1 hour, sodium periodate (0.22 g, 1.05 mmol) was added, and the reaction was continued to be stirred at room temperature for 6 hours. The reaction was stopped, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate) to give the title compound as an off-white solid (0.042 g, yield: 43%).

[0318] MS (ESI, pos. ion) m / z: 288.00 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 11.16 (s, 1H), 10.41 (s, 1H), 7.61(d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 5.48 (dd, J = 12.7, 5.3 Hz, 1H), 3.66 (d, J = 14.5 Hz, 3H), 2.99 – 2.83 (m, 1H), 2.83 –2.58 (m, 2H), 2.17 – 2.01 (m, 1H).

[0319] Step 3: 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide 3-tert-butyl-N-[(1R)-1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.42 g, 0.70 mmol), 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium-4-carboxaldehyde (0.20 g, 0.70 mmol), chloroform (24 mL), and triethylamine (0.29 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.74 g, 3.50 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was stopped, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 40:1~20:1) to give the title compound as a yellow solid (0.28 g, yield: 48%).

[0320] MS (ESI, pos. ion) m / z: 837.3[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.60 (s, 1H), 11.13 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.09(d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.11(d, J = 7.7 Hz, 1H), 7.05 – 6.84 (m, 3H), 5.39 (dd, J = 13.3, 6.4 Hz, 2H), 3.73(s, 5H), 3.59 (s, 4H), 3.18 (d, J = 2.8 Hz, 1H), 2.98 – 2.83 (m, 1H), 2.80 –2.55 (m, 3H), 2.53 (d, J= 5.2 Hz, 5H), 2.09 – 1.94 (m, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H).

[0321] Example 23 Synthesis of 3-(tert-butyl)-N-[(R)-1-[4-[6-[[5-[(S)-4-[4-[[(S)-2,6-dioxopiperidin-3-yl]carbamoyl]-3-fluorophenylethyl]-2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0322] (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2-oxoethyl)benzamide (0.13 g, 0.44 mmol), 3-(tert-butyl)-N-[(R)-1-(2-methyl-4-{6-[(5-[(S)-2-methylpiperazin-1-yl]pyridin-2-yl)amino]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide (0.26 g, 0.44 mmol), chloroform (16 mL), and triethylamine (0.24 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.47 g, 2.20 mmol) was added, and the reaction was stirred at room temperature for 17 hours. The reaction was stopped, water (15 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 2). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (v:v) = 60:1~30:1) to give the title compound as a yellow solid (0.24 g, yield: 64%).

[0323] MS (ESI, pos. ion) m / z:832.7 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 10.89 (s, 1H), 10.00 (s, 1H), 9.89(d, J = 7.4 Hz, 1H), 8.72 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.05 (s, 1H), 8.00(s, 1H), 7.85 (s, 2H), 7.71 (s, 1H), 7.63 (dd,J = 12.8, 7.6 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 15.8, 10.2 Hz, 2H), 5.43 – 5.26 (m, 1H), 4.79 (s,1H), 3.84 (s, 1H), 3.17 (s, 1H), 2.96 (s, 1H), 2.78 (d, J = 38.1 Hz, 4H), 2.68(d, J = 8.4 Hz, 1H), 2.54 (d, J = 25.0 Hz, 5H), 2.42 (d, J = 8.9 Hz, 1H), 2.28 (s,1H), 2.19 – 2.10 (m, 1H), 2.04 (t, J = 21.2 Hz, 2H), 1.52 (d, J = 6.3 Hz, 3H), 1.36 (s, 9H), 0.95 (d, J = 5.4 Hz, 3H). Example 24 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]azacyclobutane-3-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0324] Step 1: Synthesis of 3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane 3-Hydroxymethylazine hydrochloride (2.5 g, 20.22 mmol), dichloromethane (50 mL), triethylamine (6.14 g, 60.66 mmol), and tert-butyldimethylchlorosilane (3.35 g, 22.24 mmol) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 12 hours. Water (20 mL) was added, and the mixture was separated. The aqueous phase was further extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a white solid product (3.95 g, yield: 96.99%).

[0325] MS (ESI, pos. ion) m / z:202.2 [M+H] + .

[0326] Step 2: 6-[3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane-1-yl]-1,2-dihydrobenzo[] Synthesis of [cd]indol-2-one 3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane (1.89 g, 7.63 mmol), 3-{[(tert-butyldimethylsilyl)oxymethyl}azacyclobutane (2.00 g, 9.92 mmol), 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (0.73 g, 1.52 mmol), tris(dibenzylacetone)dipalladium (0.70 g, 0.76 mmol), sodium tert-butoxide (2.20 g, 22.86 mmol), and toluene (50 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction was stopped, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA (V:V) = 4:1) to give the title compound as a red viscous solid product (0.9 g, yield: 32.05%).

[0327] MS (ESI, pos. ion) m / z:369.0 [M+H] + .

[0328] Step 3: 3-[6-(3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane-1-yl)-2-oxo-1, Synthesis of 2-dihydrobenzo[cd]indol-1-yl]piperidine-2,6-dione 6-[3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane-1-yl]-1,2-dihydrobenzo[cd]indol-2-one (770 mg, 2.09 mmol) and tetrahydrofuran (20 mL) were added sequentially to the reaction flask. Sodium hydride (250.8 mg, 10.45 mmol) was added at 0 °C. After reacting for 30 min, 3-bromopiperidin-2,6-dione (802.60 mg, 4.18 mmol) was added, and the mixture was then transferred to room temperature and stirred for 12 h. The reaction was stopped, and 15 mL of saturated ammonium chloride solution was added to quench the reaction. Tetrahydrofuran was removed under reduced pressure, and 20 mL of water was added. The mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was purified by column chromatography (DCM:MeOH (V:V) = 150:1~50:1) to give the title compound as a yellow solid (438 mg, yield: 43.71%).

[0329] MS (ESI, pos. ion) m / z:480.0 [M+H] + .

[0330] Step 4: 3-[6-(3-(hydroxymethyl)azacyclobutane-1-yl)-2-oxo-1,2-dihydrobenzo[cd]indole- Synthesis of 1-yl]piperidine-2,6-dione 3-[6-(3-[(tert-butyldimethylsilyl)oxymethyl]azacyclobutane-1-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-1-yl]piperidin-2,6-dione (430 mg, 0.90 mmol) and tetrahydrofuran (15 mL) were added sequentially to the reaction flask. Tetrabutylammonium fluoride (352.97 mg, 1.35 mmol) was added under ice-water bath, and the mixture was then transferred to room temperature and stirred for 2 hours. The reaction was stopped, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH (V:V) = 70:1~50:1) to give the title compound as a red solid (266 mg, yield: 81.21%).

[0331] MS (ESI, pos. ion) m / z:366.30 [M+H] + .

[0332] Step 5: 1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]nitrogen Synthesis of heterocyclic butane-3-carboxaldehyde 3-[6-(3-(hydroxymethyl)azacyclobutane-1-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-1-yl]piperidin-2,6-dione (260 mg, 0.71 mmol), triethylamine (718.45 mg, 7.1 mmol), and dimethyl sulfoxide (10 mL) were added sequentially to the reaction flask. Pyridine trioxide (904.03 mg, 5.68 mmol) was added with stirring, and the reaction was carried out at room temperature for 12 hours. The reaction was stopped, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 6). The organic phases were combined, washed with water (50 mL × 3), concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (V:V) = 100:1 ~ 30:1) to give the title compound as a red viscous substance (110 mg, yield: 42.54%).

[0333] 1 H NMR (600 MHz, DMSO- d6) δ(ppm) 11.09 (s, 1H), 9.91 (d, J = 1.9 Hz,1H), 8.26 (dd, J = 8.2, 3.3 Hz, 1H), 8.08 (dd, J = 11.3, 7.0 Hz, 1H), 7.74 –7.68 (m, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.26 (dd, J = 13.3, 7.5 Hz, 1H), 5.46– 5.36 (m, 1H), 4.36 – 4.29 (m, 1H), 4.25 – 4.16 (m, 2H), 3.96 (dt, J = 13.1,5.6 Hz, 2H), 3.00 – 2.87 (m, 2H), 2.74 (ddd, J = 26.2, 13.1, 4.2 Hz, 1H), 2.11 – 2.03 (m, 1H). Step 6: 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[1-(2,6-dioxopiridine-3-yl)- 2-Oxo-1,2-Dihydrobenzo[cd]indol-6-yl]azacyclobutane-3-yl]methyl]piperazin-1-yl]pyridin-3-yl]- Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide 1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]azacyclobutane-3-carboxaldehyde (0.03 g, 0.083 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.05 g, 0.083 mmol), chloroform (4 mL), and triethylamine (0.07 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.09 g, 0.42 mmol) was added, and the reaction was stirred at room temperature for 5 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH (V / V) = 40 / 1~20 / 1) to obtain the title compound as a reddish-brown solid (0.046 g, yield: 60%).

[0334] MS (ESI, pos. ion) m / z:913.6 [M+H] + ; 1 H NMR (600 MHz, DMSO- d6) δ(ppm) 12.60 (s, 1H), 11.10 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.83 (s, 1H), 8.77 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H),8.20 (d, J = 6.8 Hz, 1H), 8.09 (t, J = 7.0 Hz, 2H), 8.05 (s, 1H), 7.74 (t, J= 7.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.00 (t, J = 8.1 Hz,2H), 6.29 (d, J = 7.7 Hz, 1H), 5.44 – 5.36 (m, 2H), 4.35 (s, 2H), 3.85 (s,2H), 3.62 (s, 4H), 3.10 (dd, J = 14.3, 7.1 Hz, 3H), 2.98 – 2.91 (m, 1H), 2.79– 2.61 (m, 4H), 2.54 (s, 4H), 2.10 – 2.04 (m, 1H), 1.92 (s, 2H), 1.56 (d, J =7.0 Hz, 3H), 1.38 (s, 9H). Example 25 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0335] Step 1: 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methyl Synthesis of 1H-indazole 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-iodo-1-methyl-1H-indazole (0.13 g, 0.24 mmol), 4-(dimethoxymethyl)-piperidine (0.057 g, 0.36 mmol), sodium tert-butoxide (0.058 g, 0.60 mmol), tris(dibenzylideneacetone)dipalladium (0.022 g, 0.024 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.023 g, 0.048 mmol) and dioxane (8 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 12 hours. The reaction was stopped, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate (V:V) = 10:1~2:1) to give the title compound as a pale yellow viscous substance (0.060 g, yield: 43.66%).

[0336] MS (ESI, pos. ion) m / z:579.85[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 7.89 (d,J= 8.1 Hz, 1H), 7.51 – 7.27(m, 12H), 6.80 (s, 1H), 6.57 (d,J= 8.1 Hz, 1H), 5.43 (d,J= 13.6 Hz, 4H), 4.11(d,J= 6.5 Hz, 1H), 3.96 (s, 3H), 3.79 (d,J= 12.4 Hz, 2H), 3.29 (s, 6H), 2.69(t,J= 11.9 Hz, 2H), 1.99 – 1.93 (m, 1H), 1.74 (d,J= 10.6 Hz, 2H), 1.37 (d,J=12.3 Hz, 2H). Step 2: 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6- Diketone Synthesis 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-[4-(dimethoxymethyl)piperidin-1-yl]-1-methyl-1H-indazole (0.050 g, 0.086 mmol), ethanol (2 mL), tetrahydrofuran (2 mL), 10% palladium on carbon (0.010 g, 0.094 mmol), and palladium hydroxide (0.010 g, 0.071 mmol) were added sequentially to the reaction flask. The mixture was purged three times with a hydrogen balloon, and the mixture was heated to 50 °C under hydrogen atmosphere and stirred for 14 hours. The reaction was stopped, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol (V:V) = 100:1~50:1) to give the title compound as a grayish-white solid (0.029 g, yield: 83.81%).

[0337] MS (ESI, pos. ion) m / z:401.3[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 10.84 (s, 1H), 7.47 (d,J= 9.0 Hz,1H), 6.89 (d,J= 9.0 Hz, 1H), 6.82 (s, 1H), 4.24 (dd,J= 9.1, 5.0 Hz, 1H), 4.10(d,J= 6.5 Hz, 1H), 3.88 (s, 3H), 3.80 (d,J= 12.5 Hz, 2H), 3.28 (s, 6H), 2.74– 2.55 (m, 4H), 2.39 – 2.23 (m, 1H), 2.15 (dd,J= 13.5, 5.8 Hz, 1H), 2.07 –1.94 (m, 1H), 1.73 (d,J= 10.7 Hz, 2H), 1.40 – 1.33 (m, 2H); Step 3: Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-carboxaldehyde 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (0.160 g, 0.40 mmol), tetrahydrofuran (4 mL), and hydrochloric acid (4N) (2 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 4 hours. The reaction was stopped, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a grayish-white solid (0.13 g, yield: 91.81%). MS (ESI, pos. ion) m / z:355.20[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 10.85 (s, 1H), 9.65 (s, 1H), 7.49 (d,J= 8.9 Hz, 1H), 6.91 (d,J= 9.0 Hz, 1H), 6.86 (s, 1H), 4.25 (dd,J= 9.1, 5.0Hz, 1H), 3.89 (s, 3H), 3.69 (d,J= 12.5 Hz, 2H), 2.89 (dd,J= 16.8, 6.4 Hz,2H), 2.65 – 2.51 (m, 3H), 2.38 – 2.22 (m, 1H), 2.21 – 2.09 (m, 1H), 2.00 –1.89 (m, 2H), 1.63 (td,J= 14.2, 3.7 Hz, 2H). Step 4: 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[3-(2,6-dioxopiperidin-3-yl)- [1-Methyl-1H-indazol-6-yl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.220 g, 0.37 mmol), 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-carboxaldehyde (0.13 g, 0.37 mmol), N,N-dimethylacetamide (10 mL) and triethylamine (0.22 g, 2.22 mmol) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.39 g, 1.85 mmol) was added. The reaction was continued at room temperature for another 6 hours. The reaction was stopped, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with water (50 mL × 3), concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol (V:V) = 30:1~20:1) to give the title compound as a yellow solid (0.230 g, yield: 69.63%). MS (ESI, pos. ion) m / z:904.00[M+H] + ; 1H NMR (400 MHz, DMSO- d 6) δ(ppm) 12.59 (s, 1H), 10.86 (s, 1H), 9.96(d,J= 7.7 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.18 (d,J= 7.9 Hz, 1H), 8.09(d,J= 8.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d,J= 8.1 Hz, 1H), 7.48 (d,J= 8.9 Hz,1H), 7.29 (s, 1H), 6.92 (dd,J= 17.1, 9.1 Hz, 2H), 6.83 (s, 1H), 5.38 (t,J=7.2 Hz, 1H), 4.25 (dd,J= 8.9, 5.1 Hz, 1H), 3.89 (s, 3H), 3.78 (d,J= 11.6 Hz,2H), 3.59 (s, 4H), 2.74 (t,J= 11.5 Hz, 2H), 2.62 (dd,J= 11.5, 6.4 Hz, 2H),2.53 (s, 3H), 2.46 (s, 4H), 2.30 (dd,J= 14.0, 5.4 Hz, 1H), 2.22 (d,J= 6.1 Hz,2H), 2.16 (dd,J= 13.1, 5.7 Hz, 1H), 1.83 (d,J= 11.5 Hz, 2H), 1.75 (s, 1H), 1.55 (d,J= 6.9 Hz, 3H), 1.36 (s, 9H), 1.27 (d,J= 16.0 Hz, 2H). Example 26 Synthesis of 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-((1-{3-[(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl]piperidin-4-yl}methyl)piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methylphenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide

[0338] Step 1: Synthesis of 7-bromo-4-hydroxy-2H-chromen-2-one 4-Bromo-2-hydroxyacetophenone (3.0 g, 13.95 mmol), diethyl carbonate (8.50 mL, 69.75 mmol), and toluene (30 mL) were added sequentially to the reaction flask. The mixture was transferred to 0°C, and 60% sodium hydride (1.67 g, 41.85 mmol) was added. After the addition was complete, the mixture was heated to 120°C and reacted for 3 hours. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was stirred at room temperature for 30 min, separated, and the aqueous phase was collected. The pH was adjusted to acidic with 3M hydrochloric acid, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was purified by column chromatography (dichloromethane / methanol (v / v) = 30 / 1-20 / 1) to give the title compound as a white solid (2.88 g, 85.6%).

[0339] MS (ESI, pos. ion) m / z: 240.80 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 7.72 (d, J = 8.4 Hz, 1H), 7.67 (s,1H), 7.52 (d, J = 8.3 Hz, 1H), 5.60 (s, 1H). Step 2: Synthesis of 2-(6-bromobenzo[D]isoxazol-3-yl)acetic acid 7-Bromo-4-hydroxy-2H-chromene-2-one (2.0 g, 8.30 mmol), hydroxylamine hydrochloride (2.02 g, 29.05 mmol), sodium ethoxide (2.38 g, 29.05 mmol), and ethanol (20 mL) were added sequentially to the reaction flask. The mixture was heated to 80 °C and reacted for 11 hours. After cooling to room temperature, the pH was adjusted to acidic with 3M hydrochloric acid. The mixture was concentrated under reduced pressure, and ethyl acetate (30 mL) was added. The mixture was stirred at room temperature for 30 min, filtered, and the filtrate was concentrated to give the title compound as a white solid (2.0 g, 94.1%).

[0340] MS (ESI, pos. ion) m / z: 257.80 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 8.11 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 4.11 (s, 2H). Step 3: Synthesis of 2-(6-bromobenzo[d]isoxazol-3-yl)ethyl acetate 2-(6-bromobenzo[D]isoxazol-3-yl)acetic acid (2.0 g, 7.81 mmol), ethanol (20 mL), and sulfuric acid (4.60 g, 46.86 mmol) were added sequentially to the reaction flask. The mixture was heated to 80 °C and reacted for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / petroleum ether (v / v) = 3 / 1) to obtain the title compound as a colorless oil (1.50 g, 67.6%).

[0341] MS (ESI, pos. ion) m / z: 284.70 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ(ppm) 7.77 (d, J = 0.6 Hz, 1H), 7.58 (d, J =8.4 Hz, 1H), 7.45 (dd, J = 8.4, 1.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.18(s, 2H), 1.25 (t, J = 7.1 Hz, 3H). Step 4: Ethyl 2-(6-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl)ethyl acetate synthesis 2-(6-bromobenzo[d]isoxazol-3-yl)ethyl acetate (4.0 g, 14.08 mmol), 4-(dimethoxymethyl)-piperidine (3.36 g, 21.12 mmol), cesium carbonate (9.18 g, 28.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.20 g, 2.82 mmol), tris(dibenzylideneacetone)dipalladium (1.29 g, 1.41 mmol), and toluene (50 mL) were added sequentially to the reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and reacted for 12 hours. The reaction was then stopped, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give the title compound as a yellow oil (0.97 g, 19.01%).

[0342] MS (ESI, pos. ion) m / z: 362.90 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 7.54 (d, J = 8.9 Hz, 1H), 7.08 (d, J= 9.0 Hz, 1H), 7.03 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.08 (d, J = 6.8 Hz,1H), 4.05 (s, 2H), 3.90 (d, J = 12.6 Hz, 2H), 3.27 (s, 6H), 2.80 (t, J = 11.9Hz, 2H), 1.84-1.78 (m, 1H), 1.73-1.70 (m, 2H), 1.38 – 1.29 (m, 2H), 1.20 (t,J = 7.1 Hz, 3H). Step 5: 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl)piperidin-2,6- Diketone Synthesis 2-(6-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl)ethyl acetate (0.1 g, 0.28 mmol) and anhydrous tetrahydrofuran (10 mL) were added sequentially to the reaction flask. The mixture was transferred to -10 °C, and acrylamide (0.024 g, 0.34 mmol) and potassium tert-butoxide (0.047 g, 0.42 mmol) were added. The reaction was continued for 2.5 hours, and then stopped. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), followed by the addition of ethyl acetate (30 mL). The mixture was stirred for 20 min, separated, and the organic phase was collected. The organic phase was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1-1 / 3) to obtain the title compound as a white solid (0.052 g, 48.64%).

[0343] MS (ESI, pos. ion) m / z: 387.90 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 11.05 (s, 1H), 7.55 (d, J = 8.8 Hz,1H), 7.07-7.04 (m, 2H), 4.46-4.23 (m, 1H), 3.92-3.89 (m, 2H), 3.27 (s, 1.36 – 1.08 (m, 3H). Step 6: Synthesis of 1-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl]piperidine-4-carboxaldehyde 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl)piperidin-2,6-dione (0.045 g, 0.12 mmol) and tetrahydrofuran (4 mL) were added sequentially to the reaction flask, followed by 4 N hydrochloric acid (1 mL). The reaction was carried out at room temperature for 2 hours. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL), separated, and the ethyl acetate layer was collected and concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1-1 / 3) to obtain the title compound as a white solid (0.036 g, 90.80%).

[0344] MS (ESI, pos. ion) m / z: 342.2[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.05 (s, 1H), 9.63 (s, 1H), 7.57 (d,J = 9.4 Hz, 1H), 7.09-7.08 (m, 2H), 4.45 (dd, J = 11.4, 4.9 Hz, 1H), 3.81-3.78 (m, 2H), 3.05-2.99 (m, 2H), 2.81 – 2.68 (m, 1H), 2.63 – 2.54 (m, 2H), 2.46-2.39 (m, 1H), 2.19 – 2.15 (m, 1H), 1.97 – 1.88 (m, 2H), 1.64-1.58 (m,2H). Step 7: 3-(tert-butyl)-N-[(1R)-1-(4-{6-[6-(4-((1-{3-[(2,6-dioxopiperidin-3-yl) Benz[d]isoxazol-6-yl]piperidin-4-yl}methyl)piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (R)-3-(tert-butyl)-N-[(1R)-1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.11 g, 0.18 mmol), triethylamine (0.15 mL, 1.08 mmol), N,N-dimethylacetamide (4 mL), and 1-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-6-yl]piperidin-4-carboxaldehyde (0.074 g, 0.22 mmol) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.19 g, 0.90 mmol) was added, and the reaction was continued at room temperature for 6 hours. Finally, water (20 mL) was added. Add ethyl acetate (40 mL), stir at room temperature for 20 min, separate the liquid and collect the organic phase, concentrate under reduced pressure, and separate the crude product by column chromatography (dichloromethane / methanol (v / v) = 50 / 1-30 / 1) to obtain the title compound as a yellow solid (0.081 g, 49.8%).

[0345] MS (ESI, pos. ion) m / z: 890.7[M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 12.60 (s, 1H), 11.06 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.19 (d, J = 7.2Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 7.09-7.05 (m, 2H), 6.96 (d, J = 9.0Hz, 1H), 5.40-5.37 (m, 1H), 4.45 (dd, J = 11.4, 5.0 Hz, 1H), 3.90 (d, J =12.0 Hz, 2H), 3.60 (s, 4H), 2.85 (t, J = 11.7 Hz, 2H), 2.80 – 2.68 (m, 1H),2.62-2.57 (m, 2H), 2.54 (s, 3H), 2.49 – 2.31 (m, 5H), 2.25 – 2.12 (m, 3H),2.02-1.97 (m, 1H), 1.84-1.81 (m, 3H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). Example 27 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0346] Step 1: Synthesis of 6-[4-(dimethoxymethyl)piperidin-1-yl]-1,3-benzoxazol-2(3H)-one 6-Bromo-benzoxazolone (0.50 g, 2.34 mmol), 4-(dimethoxymethyl)-piperidine (0.56 g, 3.51 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.11 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0.21 g, 0.23 mmol), sodium tert-butoxide (0.67 g, 7.02 mmol), and toluene (20 mL) were added sequentially to the reaction flask. The reaction system was purged with nitrogen three times, and the temperature was raised to 100 °C under a nitrogen atmosphere and stirred for 5 hours. The reaction was stopped, and ethyl acetate (30 mL), water (30 mL), and saturated ammonium chloride (10 mL) were added. The mixture was separated, the organic layer was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (V:V) = 100:1) to give the title compound as a dark brown solid (0.4 g, yield: 58%).

[0347] MS (ESI, pos. ion) m / z:293.0[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.27 (s, 1H), 6.93 (dd, J = 14.0,5.2 Hz, 2H), 6.71 (dd, J = 8.6, 2.1 Hz, 1H), 4.09 (d, J = 6.4 Hz, 1H), 3.56(d, J = 12.0 Hz, 2H), 3.34 (s, 6H), 2.57 (d, J = 11.1 Hz, 2H), 1.70 (d, J =11.3 Hz, 2H), 1.41 – 1.29 (m, 2H).

[0348] Step 2: 3-[6-[4-(dimethoxymethyl)piperidin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl]piperidin Synthesis of pyridine-2,6-dione 6-[4-(dimethoxymethyl)piperidin-1-yl]-1,3-benzoxazol-2(3H)-one (0.62 g, 2.12 mmol), cesium carbonate (1.32 g, 4.24 mmol), and N,N-dimethylformamide (12 mL) were added sequentially to the reaction flask. After stirring at room temperature for 0.5 hours, 3-bromopiperidin-2,6-dione (0.81 g, 4.24 mmol) was added, and the mixture was stirred at 50 °C for 17 hours. The reaction was stopped, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA (V:V) = 1:1~EA) to give the title compound as an off-white solid (0.26 g, yield: 30%).

[0349] MS (ESI, pos. ion) m / z:404.2[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.21 (s, 1H), 7.40 (s, 1H), 7.24 (d,J = 12.9 Hz, 1H), 7.11 (dd, J = 19.5, 8.2 Hz, 2H), 5.86 (d, J = 12.9 Hz, 1H), 5.34 (dd, J = 12.9, 5.2 Hz, 1H), 3.88 (q, J = 7.0 Hz, 2H), 2.96 – 2.82 (m,1H), 2.69 (dt, J = 22.6, 9.7 Hz, 2H), 2.16 (dd, J = 10.1, 4.8 Hz, 1H), 1.26(t, J = 7.0 Hz, 3H).

[0350] Step 3: 1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl]piperidin Synthesis of pyridine-4-carboxaldehyde 3-[6-[4-(dimethoxymethyl)piperidin-1-yl]-2-oxobenzo[d]oxazol-3(2H)-yl]piperidin-2,6-dione (0.12 g, 0.30 mmol), tetrahydrofuran (8 mL), and dilute hydrochloric acid (4N aqueous solution, 4 mL) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 2 hours. The reaction was then stopped, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 2), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow solid (0.10 g, yield: 94%).

[0351] 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.19 (s, 1H), 9.64 (s, 1H), 7.09(dd, J = 5.3, 3.2 Hz, 2H), 6.80 (dd, J = 8.7, 2.0 Hz, 1H), 5.30 (dd, J =13.0, 5.2 Hz, 1H), 3.52 (d, J = 12.3 Hz, 2H), 2.94 – 2.73 (m, 3H), 2.69 –2.59 (m, 2H), 2.47 (d, J = 11.0 Hz, 1H), 2.12 (dd, J = 10.3, 5.2 Hz, 1H), 1.94 (d, J = 13.3 Hz, 2H), 1.67 – 1.53 (m, 2H).

[0352] Step 4: 3-(tert-butyl)-N-[(1R)-1-[4-[6-[6-[4-[[1-[3-(2,6-dioxopiperidin-3-yl)- 2-Oxo-2,3-Dihydrobenzo[d]oxazol-6-yl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo Synthesis of [2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide 1-[3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl]piperidin-4-carboxaldehyde (0.10 g, 0.28 mmol), (R)-3-(tert-butyl)-N-[(1R)-1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.20 g, 0.34 mmol), chloroform (15 mL), and triethylamine (0.16 mL) were added sequentially to the reaction flask. The mixture was heated to 60 °C and stirred for 1 hour. After cooling to room temperature, sodium triacetoxyborohydride (0.30 g, 1.40 mmol) was added, and the reaction was stirred at room temperature for 15 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (50 mL) was added, the mixture was stirred at room temperature for 0.5 hours, filtered, and the filter cake was purified by column chromatography (DCM:MeOH (V:V) = 50:1~25:1) to obtain the title compound as a yellow-green solid (0.18 g, yield: 70%).

[0353] MS (ESI, pos. ion) m / z:907.7 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 12.59 (s, 1H), 11.20 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.18 (dd, J =8.8, 1.8 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.29 (s, 1H), 7.06 (dd, J = 9.4, 5.1 Hz, 2H), 6.94 (d, J = 9.0 Hz,1H), 6.78 (d, J = 8.7 Hz, 1H), 5.38 (p, J = 7.0 Hz, 1H), 5.30 (dd, J = 13.0,5.3 Hz, 1H), 3.59 (s, 6H), 2.98 – 2.81 (m, 1H), 2.67 (dt, J = 24.4, 7.5 Hz,4H), 2.54 (s, 3H), 2.45 (s, 4H), 2.26 – 2.07 (m, 3H), 1.80 (d, J = 11.6 Hz, 2H), 1.68 (s, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). Example 28 Synthesis of R-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0354] Step 1: Synthesis of 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propionic acid 7-Bromo-1-methyl-1H-indazole-3-amine (1.00 g, 4.42 mmol), acrylic acid (0.48 g, 6.63 mmol), and toluene (15 mL) were added sequentially to the reaction flask. The mixture was heated to 110 °C and reacted for 21 hours. After cooling to room temperature, the crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 1-ethyl acetate) to obtain the title compound as a gray solid (1.00 g, 75.8%).

[0355] MS (ESI, pos. ion) m / z: 298.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 12.18 (s, 1H), 7.72 (d, J = 7.9 Hz,1H), 7.50 (d, J = 7.4 Hz, 1H), 6.82 (t, J = 7.7 Hz, 1H), 6.29 (s, 1H), 4.04(s, 3H), 3.46-3.45 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H). Step 2: Synthesis of 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propionic acid (1.0 g, 3.35 mmol), sodium cyanate (0.28 g, 4.36 mmol), and acetic acid (10 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and reacted for 16 hours. After cooling to room temperature, the pH was adjusted to alkaline with ammonia. A solid precipitated out. The solid was filtered and separated by column chromatography (dichloromethane / methanol (v / v) = 100 / 1-30 / 1) to obtain the title compound as a white solid (0.3 g, 27.7%).

[0356] MS (ESI, pos. ion) m / z: 323.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 10.62 (s, 1H), 7.67 (t, J = 7.4 Hz,2H), 7.04 (t, J = 7.8 Hz, 1H), 4.30 (s, 3H), 3.91 (t, J = 6.6 Hz, 2H), 2.78(t, J = 6.6 Hz, 2H). Step 3: 1-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine Synthesis of pyridine-2,4-dione 1-(7-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.3 g, 0.93 mmol), 4-(dimethoxymethyl)-piperidine (0.22 g, 1.40 mmol), sodium tert-butoxide (0.22 g, 2.33 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.089 g, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (0.085 g, 0.093 mmol), and dioxane (10 mL) were added sequentially to the reaction flask. The mixture was heated to 100 °C and reacted for 16 hours under nitrogen protection. The product was cooled to room temperature, concentrated, and the crude product was separated by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2-ethyl acetate) to give the title compound as a gray solid (0.087 g, 23.34%).

[0357] MS (ESI, pos. ion) m / z: 402.1 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ(ppm) 10.54 (s, 1H), 7.34 – 7.22 (m, 1H),7.07 – 6.95 (m, 2H), 4.23 (s, 3H), 4.17-4.16 (m, 1H), 3.88 (t, J = 6.7 Hz,2H), 3.31 (s, 6H), 3.26 (t, J = 10.2 Hz, 2H), 2.76 (t, J = 6.7 Hz, 2H), 2.68-2.64 (m, 2H), 2.04 – 1.94 (m, 2H), 1.80-1.75 (d, J = 12.9 Hz, 2H), 1.75 (s,1H). Step 4: 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)piperidine- Synthesis of 4-formaldehyde 1-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4-dione (0.08 g, 0.20 mmol) and tetrahydrofuran (3 mL) were added sequentially to the reaction flask, followed by 4 N hydrochloric acid (1 mL). The reaction was carried out at room temperature for 1.5 hours. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL), and the ethyl acetate layer was collected, concentrated, and the crude product was separated by column chromatography (dichloromethane / methanol (v / v) = 50 / 1-30 / 1) to obtain the title compound as a yellow solid (0.052 g, 73.4%).

[0358] MS (ESI, pos. ion) m / z: 356.3[M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ(ppm) 10.55 (s, 1H), 9.70 (s, 1H), 7.31 (d,J = 7.4 Hz, 1H), 7.10 – 6.89 (m, 2H), 4.23 (s, 3H), 3.89 (t, J = 6.7 Hz, 2H),3.25 (s, 2H), 2.77-2.75 (m, 4H), 2.39 (s, 1H), 2.10 – 2.01 (m, 2H), 1.69 (d,J = 10.9 Hz, 2H). Step 5: R-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(3-(2,4-dioxotetrahydropyrimidine-1) (2H)-yl)-1-methyl-1H-indazol-7-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2, Synthesis of 3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (R)-3-(tert-butyl)-N-[(1R)-1-(2-methyl-4-{6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)ethyl]-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.06 g, 0.10 mmol), triethylamine (0.08 mL, 0.60 mmol), N,N-dimethylacetamide (4 mL), and 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carboxaldehyde (0.043 g, 0.12 mmol) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.11 g, 0.50 mmol) was added, and the reaction was allowed to proceed at room temperature for 12 hours. After 20 hours, water (20 mL) and ethyl acetate (40 mL) were added, and the mixture was stirred at room temperature for 20 min. The mixture was separated, and the ethyl acetate layer was collected and washed with water (10 mL x 2). The organic phase was concentrated under reduced pressure, and the crude product was separated by column chromatography (dichloromethane / methanol (v / v) = 30 / 1-20 / 1) to obtain the title compound as a yellow solid (0.045 g, 49.9%).

[0359] MS (ESI, pos. ion) m / z: 905.7[M+H] + ; 1 H NMR (600 MHz, DMSO- d6) δ(ppm) 12.59 (s, 1H), 10.51 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.77 (s, 1H), 8.19 (dd, J =8.9, 2.0 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H), 6.96 (d, J = 9.0Hz, 1H), 6.91 (dd, J = 9.2, 1.2 Hz, 1H), 6.82 (s, 1H), 5.42 – 5.33 (m, 1H), 3.93 – 3.86 (m, 5H), 3.81 (d, J = 12.1 Hz, 2H), 3.60 (s, 3H), 2.78-2.73 (m,4H), 2.54 (s, 3H), 2.47 (s, 3H), 2.23 (d, J = 6.5 Hz, 2H), 1.84 (d, J = 11.7Hz, 2H), 1.77 (s, 1H), 1.55 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H), 1.32 – 1.21(m, 4H). Example 29 Synthesis of 3-tert-butyl-N-((1R)-1-(4-(6-(6-(4-((1-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0360] Step 1: Ethyl 2-[7-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazo-3-yl]ethyl acetate synthesis The following substances were added sequentially to the reaction flask: ethyl 2-(7-bromobenzo[D]isoxazol-3-yl)acetate (5.30 g, 18.65 mmol), 4-(dimethoxymethyl)piperidine (4.45 g, 27.97 mmol), tris(dibenzylacetone)dipalladium (1.71 g, 1.86 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (1.58 g, 3.73 mmol), cesium carbonate (15.19 g, 46.63 mmol), and toluene (100 mL). The reaction system was purged with nitrogen three times, and the mixture was heated to 80 °C and stirred for 12 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature. The crude product was concentrated and purified by column chromatography (PE:EA (V:V) = 8:1) to give the title compound as a pale yellow oil (0.905 g, yield: 13.39%).

[0361] MS (ESI, pos. ion) m / z:363.10 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ (ppm) 7.19 (dd, J = 9.0, 7.1 Hz, 2H), 6.91 (d, J = 6.9 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.02 (s, 2H), 3.99 (d, J = 12.2 Hz, 2H), 3.42 (d, J = 8.3 Hz, 6H), 2.79 (td, J = 12.1, 1.8 Hz, 2H), 2.06 (s, 1H), 1.92 (d, J = 13.7 Hz, 2H), 1.83 (ddd, J = 14.9, 7.3, 3.6 Hz, 1H), 1.60 (ddd, J = 15.8,12.5, 3.9 Hz, 2H), 1.26 (t, J = 3.5 Hz, 3H). Step 2: 3-[7-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl]piperidin-2,6-di Ketone synthesis Ethyl 2-[7-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl]ethyl acetate (900 mg, 2.48 mmol) and tetrahydrofuran (45 mL) (ultra-dry solvent) were added to a two-necked reaction flask. The reaction system was protected with nitrogen and cooled to -10 °C. Acrylamide (212 mg, 2.98 mmol) and potassium tert-butoxide (334 mg, 2.98 mmol) were then added sequentially. After the addition was complete, the reaction was stirred at -10 °C for 6 hours. The reaction was stopped, and quenched by adding saturated ammonium chloride solution (20 mL) at -10 °C. The mixture was transferred to room temperature, allowed to stand, and separated. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA (V:V) = 3:1:~1:1) to give the title compound as a white solid (253 mg, yield: 26.30%).

[0362] MS (ESI, pos. ion) m / z:388.05 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ(ppm) 8.32 (s, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 4.33 (dd, J = 8.5, 5.2 Hz, 1H), 4.17 – 4.10 (m, 1H), 4.02 – 3.92 (m, 2H), 3.41 (s, 6H), 2.99 (ddd, J = 17.7,6.8, 5.0 Hz, 1H), 2.87 – 2.70 (m, 3H), 2.66 – 2.53 (m, 1H), 2.43 (td, J = 12.3, 5.2 Hz, 1H), 1.92 (d, J = 13.7 Hz, 2H), 1.88 – 1.79 (m, 1H), 1.59 (dd, J = 22.3, 10.3 Hz, 2H). Step 3: Synthesis of 1-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl]piperidine-4-carboxaldehyde 3-[7-(4-(dimethoxymethyl)piperidin-1-yl)benzo[d]isoxazol-3-yl]piperidin-2,6-dione (0.25 g, 0.65 mmol), tetrahydrofuran (5 mL), and 4M hydrochloric acid solution (5 mL) were added sequentially to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 4 hours. The solution was adjusted to alkalinity with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was concentrated to give a white solid (0.20 g, yield: 90.80%).

[0363] MS (ESI, pos. ion) m / z:342.20 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 11.10 (s, 1H), 9.67 (s, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 8.6 Hz, 1H), 4.58 (dd, J =11.8, 4.9 Hz, 1H), 3.73 (d, J = 12.3 Hz, 2H), 2.99 (t, J = 10.5 Hz, 2H), 2.77(ddd, J = 17.1, 11.9, 5.3 Hz, 1H), 2.58 (ddd, J = 15.8, 12.3, 4.4 Hz, 2H), 2.45(dd, J = 12.1, 4.3 Hz, 1H), 2.24 – 2.14 (m, 1H), 2.01 (dd, J = 10.0, 7.4 Hz, 2H), 1.71 (td, J = 13.8, 3.4 Hz, 2H).

[0364] Step 4: 3-tert-butyl-N-((1R)-1-(4-(6-(6-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)- Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide 3-tert-butyl-N-[(1R)-1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (130 mg, 0.22 mmol), 1-[3-(2,6-dioxopiperidin-3-yl)benzo[d]isoxazol-7-yl]piperidin-4-carboxaldehyde (76 mg, 0.22 mmol), N,N-dimethylacetamide (20 mL), and triethylamine (0.18 mL, 1.32 mmol) were added sequentially to the reaction flask. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (234 mg, 1.10 mmol) was added. After the addition was complete, the reaction was stirred at room temperature for another 12 hours. After the reaction was completed, 10 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined and washed successively with water (15 mL × 2) and saturated brine (15 mL). The organic phases were collected, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (V:V) = 50:1~20:1) to give the title compound as a pale yellow solid (118 mg, yield: 61.34%).

[0365] MS (ESI, pos. ion) m / z:891.00 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ(ppm) 12.59 (s, 1H), 11.10 (s, 1H), 9.96(d, J = 7.8 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.19 (dd, J = 8.9, 2.1Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.30(d, J = 1.2 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.01 (d, J =7.3 Hz, 1H), 6.96 (d, J= 9.0 Hz, 1H), 5.39 (p, J = 7.0 Hz, 1H), 4.57 (dd, J =11.8, 5.0 Hz, 1H), 3.85 (d, J = 11.7 Hz, 2H), 3.61 (s, 4H), 2.82 (t, J = 11.2 Hz,2H), 2.79 – 2.73 (m, 1H), 2.64 – 2.58 (m, 1H), 2.53 (d, J = 11.9 Hz, 3H), 2.51(d, J = 1.6 Hz, 3H), 2.49 (d, J = 4.7 Hz, 4H), 2.25 (t, J = 11.2 Hz, 2H), 2.22 –2.18 (m, 1H), 1.90 (d, J = 11.6 Hz, 2H), 1.79 (s, 1H), 1.56 (d, J = 7.0 Hz, 3H), 1.38 (s, 9H). Example 30 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[2-methyl-4-[6-[[5-[(2S)-4-[[1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzis[d]imidazol-4-yl]azacyclobutane-3-yl]methyl]-2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0366] Step 1: 3-[4-[3-(hydroxymethyl)azacyclobutane-1-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzene Synthesis of [d]imidazol-1-yl]piperidine-2,6-dione 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione (0.5 g, 1.48 mmol), 3-hydroxymethylazacyclobutane hydrochloride (0.27 g, 2.22 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (0.12 g, 0.15 mmol), cesium carbonate (1.45 g, 4.44 mmol), and 1,4-dioxane (20 mL) were added sequentially to the reaction flask, and the reaction was stirred at 100 °C for 1 hour under nitrogen protection. The reaction was stopped, water (100 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 7). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale yellow solid product (0.48 g, yield: 94.27%).

[0367] MS (ESI, pos. ion) m / z: 345.00 [M+H] + .

[0368] Step 2: 1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolium] Synthesis of [azol-4-yl]azacyclobutane-3-carboxaldehyde 3-[4-[3-(hydroxymethyl)azacyclobutan-1-yl]-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione (0.480 g, 1.39 mmol), dimethyl sulfoxide (15 mL), triethylamine (1406.54 mg, 13.90 mmol), and pyridine sulfur trioxide (1769.86 mg, 11.12 mmol) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 4 hours. The reaction was stopped, water (100 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 10). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH (V:V) = 60:1~30:1) to give the title compound as a yellow solid (119 mg, yield: 24.94%).

[0369] MS (ESI, pos. ion) m / z: 343.10 [M+H] + .

[0370] Step 3: 3-(tert-butyl)-N-[(1R)-1-[2-methyl-4-[6-[[5-[(2S)-4-[[1-[1-(2,6-dioxane)] Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]azacyclobutane-3-yl]methyl [2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide Synthesis 3-(tert-butyl)-N-[(1R)-1-[2-methyl-4-[6-[[5-[(2S)-2-methylpiperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.060 g, 0.10 mmol), 1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]azacyclobutane-3-carboxaldehyde (0.034 g, 0.10 mmol), chloroform (10 mL), and triethylamine (0.061 g, 0.60 mmol) were added sequentially to the reaction flask, and the mixture was heated to 60 °C and reacted for 1 hour. Cool to room temperature, add sodium triacetoxyborohydride (0.11 g, 0.50 mmol), and react at room temperature for 22 hours, then stop the reaction. Concentrate under reduced pressure, adjust pH to 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane (30 mL × 2), combine the organic phases, concentrate, and purify the crude product by column chromatography (DCM / MeOH (V / V) = 50 / 1-30 / 1) to give the title compound as a yellow solid (0.070 g, yield: 78.33%).

[0371] MS (ESI, pos. ion) m / z:883.95[M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 11.07 (s, 1H), 9.99 (s, 1H), 9.89 (d,J = 7.7 Hz, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.83 (s, 2H), 7.70(d, J = 7.1 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 6.9 Hz, 1H), 6.95(t, J = 8.0 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.32(dd, J = 13.2, 6.0 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 1H), 3.58 (s, 3H), 3.54(s, 2H), 3.18 (t, J = 9.0 Hz, 1H), 2.98 (t, J = 9.0 Hz, 1H), 2.90 (d, J =13.2 Hz, 2H), 2.81 – 2.54 (m, 7H), 2.47 (s, 3H), 2.29 (t, J = 8.8 Hz, 1H), 1.99 (d, J = 5.6 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.36 (s, 9H), 0.98 (d, J= 6.1 Hz, 3H).

[0372] Example 31 Synthesis of (R)-3-(tert-butyl)-N-[1-[4-[6-[6-[4-[[1-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trideuterated methyl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0373] (R)-3-(tert-butyl)-N-[1-[2-(trideuteratedmethyl)-4-[6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.60 g, 0.99 mmol), N,N-dimethylformamide (12 mL), and triethylamine (0.30 g, 2.97 mmol) were added sequentially to the reaction flask. The mixture was stirred for 10 min, then acetic acid (0.48 g, 7.92 mmol) and 1-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]piperidine-4-carboxaldehyde (0.36 g, 1.19 mmol) were added. The mixture was reacted at room temperature for 1 hour, and then sodium cyanoborohydride (0.31 g, The mixture was stirred at room temperature for 4 hours (4.95 mmol), and the reaction was stopped. Water (60 mL) was added, and the mixture was stirred at room temperature for 20 min. The mixture was filtered to obtain the crude product, which was purified by column chromatography (DCM:MeOH (v:v) = 50:1-20:1) to give the title compound as a yellow solid (0.61 g, yield: 72.04%).

[0374] MS (ESI, pos. ion) m / z:854.40[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ (ppm) 12.58 (s, 1H), 10.25 (s, 1H), 9.94(d, J = 7.8 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.17 (dd, J = 8.9, 2.2Hz, 1H), 8.08 (d, J = 9.5 Hz, 1H), 8.04 (s, 1H), 7.69 – 7.63 (m, 1H), 7.28 (s,1H), 7.13 (d, J = 8.8 Hz, 2H), 6.95-6.91 (m, 3H), 5.37 (t, J = 7.3 Hz, 1H), 3.70-3.67 (m, 4H), 3.59 (s, 4H), 2.69-2.66 (m, 4H), 2.46 (s, 4H), 2.21 (d, J = 6.9Hz, 2H), 1.81 (d,J = 11.9 Hz, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.36 (s, 9H), 1.22(s, 3H). Example 32 Synthesis of (R)-3-(tert-butyl)-N-[1-[4-[6-[6-[4-[[1-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-2,2,2-trideuteratedethyl]-1,2,4-oxadiazole-5-carboxamide

[0375] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-2,2,2-trideuterated ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.054 g, 0.089 mmol), N,N-dimethylacetamide (3 mL), and triethylamine (0.027 g, 0.27 mmol) were added sequentially to the reaction flask. Then, 1-[4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl]piperidine-4-carboxaldehyde (0.027 g, 0.089 mmol) and sodium triacetoxyborohydride (0.094 g, 0.44 mmol) were added. The mixture was stirred at room temperature for 19 hours, after which the reaction was stopped. Add dichloromethane (20 mL) and water (10 mL), separate the layers, collect the dichloromethane layer, wash the organic phase with water (10 mL × 3), collect the organic phase, concentrate under reduced pressure, and purify the crude product by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain the title compound as a yellow solid (0.04 g, yield: 52.49%).

[0376] MS (ESI, pos. ion) m / z:854.40[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 12.57 (s, 1H), 10.24 (s, 1H), 9.93(d, J = 7.9 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.75 (s, 1H), 8.17 (dd,J = 8.9, 2.2Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.28(s, 1H), 7.13-7.11 (m, 2H), 6.95-3.91 (m, 3H), 5.35 (d, J = 7.8 Hz, 1H), 3.70-3.67 (m, 4H), 3.59 (s, 4H), 2.69 – 2.63 (m, 5H), 2.52 (s, 3H), 2.47-2.46 (m,4H), 2.21 (d, J = 6.7 Hz, 2H), 2.02-1.96 (m, 1H), 1.83-1.71 (m, 3H), 1.36 (s,9H). Example 33 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[4-[2-[1-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)piperidin-4-yl]ethyl]piperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0377] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[[5-(piperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (0.2 g, 0.37 mmol), 2-[1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-yl]acetaldehyde (0.15 g, 0.37 mmol), triethylamine (0.22 g, 2.22 mmol), and N,N-dimethylacetamide (20 mL) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.39 g, 1.85 mmol) was added. After the addition was complete, the mixture was stirred at room temperature for another 15 hours, and then the reaction was stopped. Water (200 mL) was added to the reaction solution, stirred at room temperature for 10 min, filtered, and the filter cake was collected and purified by column chromatography (DCM:MEOH (v:v) = 50:1-20:1) to obtain the title compound as a yellow solid (227 mg, yield: 66.03%).

[0378] MS (ESI, pos. ion) m / z:931.40[M+H] + ; 1 H NMR (600 MHz, DMSO d 6) δ(ppm) 11.12 (s, 1H), 10.00 (s, 1H), 9.89 (d, J = 7.8 Hz, 1H), 8.71 (s, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 16.9, 4.7Hz, 3H), 7.88 – 7.79 (m, 3H), 7.70 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 9.1, 2.6 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 5.47 –5.28 (m, 2H), 3.40 (d, J = 9.4 Hz, 4H), 3.20 – 3.08 (m, 4H), 2.71 (ddd, J = 45.0,27.0, 10.5 Hz, 4H), 2.54 (s, 4H), 2.48 (s, 3H), 2.42 (s, 2H), 2.18 – 2.04 (m,1H), 1.85 (d, J = 8.5 Hz, 2H), 1.52 (d, J = 6.9 Hz, 7H), 1.42 – 1.34 (m, 9H). Example 34 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[4-[2-[4-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-1-yl]ethyl]piperazin-1-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0379] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[[5-(piperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (230 mg, 0.42 mmol), N,N-dimethylacetamide (5 mL), 2-[4-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-1-yl]acetaldehyde (171 mg, 0.42 mmol) and triethylamine (0.35 mL, 2.53 mmol) were added sequentially to the reaction flask, and the mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (446 mg, 2.10 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was stopped, water (50 mL) was added, the mixture was stirred at room temperature for 0.5 hours, filtered, the filter cake was collected, and purified by column chromatography (DCM:MeOH (v:v) = 50:1~10:1) to obtain the title compound as a yellow-green solid (65 mg, yield: 16.44%).

[0380] MS (ESI, pos. ion) m / z:931.40 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ(ppm) 11.13 (s, 1H), 10.00 (s, 1H), 9.89(d, J = 7.7 Hz, 1H), 8.70 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 6.9 Hz, 1H), 8.05 (t, J = 8.5 Hz, 2H), 7.90 – 7.85 (m, 1H), 7.83 (d, J = 7.0 Hz, 2H),7.70 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 9.0, 2.5 Hz, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 5.46 (dd, J = 12.7, 4.9 Hz, 1H), 5.33(p, J= 7.0 Hz, 1H), 3.43 (d, J = 27.7 Hz, 6H), 3.17 (s, 5H), 3.02 – 2.91 (m,2H), 2.80 – 2.60 (m, 9H), 2.47 (s, 3H), 2.12 – 2.06 (m, 1H), 1.92 (d, J = 20.6Hz, 2H), 1.51 (d, J = 6.9 Hz, 3H), 1.36 (s, 9H). Example 35 Synthesis of 3-(tert-butyl)-N-[(R)-1-[4-[6-[6-[4-[2-[1-[6-[[(S)-2,6-dioxopiperidin-3-yl]carbamoyl]pyridin-3-yl]piperidin-4-yl]ethyl]piperazin-1-yl]pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0381] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[6-(piperazin-1-yl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (0.1 g, 0.18 mmol), N,N-dimethylacetamide (3 mL), and triethylamine (0.055 g, 0.54 mmol) were added sequentially to the reaction flask. Then, (S)-N-(2,6-dioxopiperidin-3-yl)-5-[4-(oxoethyl)piperidin-1-yl]pyridinecarboxamide (0.065 g, 0.18 mmol) and sodium triacetoxyborohydride (0.19 g, 0.90 mmol) were added. The mixture was stirred at room temperature for 19 hours, and then the reaction was stopped. Add dichloromethane (20 mL) and water (10 mL), separate the layers, collect the dichloromethane layer, wash with water (10 mL × 3), collect the organic phase, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain the title compound as a yellow solid (0.094 g, yield: 58.56%).

[0382] MS (ESI, pos. ion) m / z:908.35[M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ(ppm) 12.58 (s, 1H), 10.84 (s, 1H), 9.95(d, J = 7.8 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.76 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H),8.03 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.40 (dd, J =9.0, 2.5 Hz, 1H), 7.29 (s, 1H), 6.95 (d, J = 9.2 Hz, 1H), 5.42 – 5.33 (m, 1H), 4.81 – 4.65 (m, 1H), 3.93 (d, J = 12.4 Hz, 2H), 3.58 (s, 4H), 2.89 – 2.72 (m,3H), 2.53 (s, 3H), 2.39-2.33 (m, 2H), 2.21 – 2.10 (m, 1H), 2.05 – 1.93 (m,2H), 1.79(d, J = 11.7 Hz, 2H), 1.55 (d, J = 6.9 Hz, 3H), 1.46 (s, 2H), 1.37 (s,9H), 1.31 – 1.25 (m, 2H), 1.23 (s, 5H). Example 36 Synthesis of 3-(tert-butyl)-N-[(R)-1-[4-[6-[[5-[1-[2-[1-[6-[[(S)-2,6-dioxopiperidin-3-yl]carbamoyl]pyridin-3-yl]piperidin-4-yl]ethyl]piperidin-4-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0383] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[[5-(piperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.10 g, 0.18 mmol), N,N-dimethylacetamide (3 mL), and triethylamine (0.055 g, 0.54 mmol) were added sequentially to the reaction flask. Then, (S)-N-(2,6-dioxopiperidin-3-yl)-5-[4-(oxoethyl)piperidin-1-yl]pyridinecarboxamide (0.065 g, 0.18 mmol) and sodium triacetoxyborohydride (0.19 g, 0.90 mmol) were added. The mixture was stirred at room temperature for 13 hours, and then the reaction was stopped. Add dichloromethane (20 mL) and water (10 mL), separate the layers, collect the dichloromethane layer, wash with water (10 mL × 3), collect the organic phase, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain the title compound as a white solid (0.09 g, yield: 58.82%).

[0384] MS (ESI, pos. ion) m / z:883.40[M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ(ppm) 10.84 (s, 1H), 10.18 (s, 1H), 9.89(d, J = 7.7 Hz, 1H), 8.75 (s, 1H), 8.69 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 8.25(s, 1H), 8.16 (s, 1H), 7.85-7.84 (m, 3H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 (d, J =8.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.43 – 7.38 (m, 1H), 5.40 – 5.23 (m,1H), 4.77-4.70 (m, 1H), 3.94 (d, J = 12.6 Hz, 2H), 2.88-2.76 (m, 4H), 2.64 (d, J= 23.2 Hz, 3H), 2.47 (s, 4H), 2.21 – 2.06 (m, 2H), 2.02-1.97 (m, 4H), 1.80-1.77 (m, 5H), 1.51 (d, J = 6.8 Hz, 4H), 1.36 (s, 9H), 1.29-1.27 (s, 4H). Example 37 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[1-[[1-[1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-yl]methyl]piperidin-4-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0385] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[[5-(piperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide hydrochloride (270 mg, 0.47 mmol), N,N-dimethylacetamide (10 mL), and triethylamine (0.46 mL, 3.29 mmol) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 10 minutes, followed by the addition of 1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-carboxaldehyde (185 mg, 0.47 mmol). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (498 mg, 2.35 mmol) was then added, and the reaction was continued with stirring at room temperature for 17 hours. The reaction was then stopped. Water (50 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was collected. The filter cake was purified by column chromatography (DCM:MeOH (v:v) = 50:1~10:1) to give the title compound as an orange-red solid (260 mg, yield: 60.67%).

[0386] MS (ESI, pos. ion) m / z:916.40 [M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 11.11 (s, 1H), 10.17 (s, 1H), 9.89(d, J= 7.7 Hz, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.23 ​​(d, J = 8.2 Hz, 1H), 8.17(s, 1H), 8.07 (d, J = 6.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.81 (t, J = 7.6 Hz,1H), 7.73 (s, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.01 (d, J =7.6 Hz, 1H), 6.92 (t, J = 9.5 Hz, 1H), 5.42 (dd, J = 12.7, 4.8 Hz, 1H), 5.37 –5.29 (m, 1H), 3.42 (d, J = 8.9 Hz, 2H), 3.04 – 2.90 (m, 3H), 2.74 (dd, J = 12.3,4.4 Hz, 3H), 2.68 – 2.61 (m, 1H), 2.47 (s, 3H), 2.27 (s, 2H), 2.11 – 2.04 (m,1H), 1.99 (s, 3H), 1.90 (d, J = 12.4 Hz, 2H), 1.71 (dd, J = 27.9, 16.9 Hz, 5H), 1.51 (d, J = 6.9 Hz, 3H), 1.49 – 1.43 (m, 2H), 1.35 (s, 9H).

[0387] Example 38 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[1-[2-[1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-yl]ethyl]piperidin-4-yl]pyridin-2-yl]amino]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide

[0388] (R)-3-(tert-butyl)-N-[1-[2-methyl-4-[6-[[[5-(piperidin-4-yl)pyridin-2-yl]amino]pyrimidin-4-yl]phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (0.1 g, 0.18 mmol), N,N-dimethylacetamide (2 mL), and triethylamine (0.055 g, 0.54 mmol) were added sequentially to the reaction flask. Then, 2-[1-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl]piperidin-4-yl]acetaldehyde (0.073 g, 0.18 mmol) was added, and the mixture was stirred for 5 min. Finally, sodium triacetoxyborohydride (0.19 g, 0.90 mmol) was added, and the reaction was stopped after 13 hours at room temperature. Add water (20 mL), stir for 0.5 hours, filter, collect the filter cake, and purify by column chromatography (DCM:MeOH (v:v) = 15:1) to obtain the title compound as a red solid (0.12 g, yield: 69.75%).

[0389] MS (ESI, pos. ion) m / z: 930.40[M+H] + ; 1 H NMR (600 MHz, DMSO- d 6) δ (ppm) 11.13 (s, 1H), 10.18 (s, 1H), 9.89(d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.18(s, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.86-7.85 (m, 2H), 7.81 (t, J = 7.6 Hz, 1H),7.74 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.4Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.42 (d, J = 7.9 Hz, 1H), 5.40 – 5.26 (m, 1H), 3.07 (s, 2H), 2.95 (t, J= 12.7 Hz, 1H), 2.78 – 2.62 (m, 4H), 2.47 (s, 3H), 2.20 – 1.97 (m, 3H), 1.82 (d, J = 8.7 Hz, 2H), 1.77 (s, 2H), 1.71 (d, J = 9.5 Hz, 2H), 1.52-1.50 (m, 9H), 1.35 (s, 9H), 1.33 (s, 1H), 1.24 – 1.14 (m, 3H). Example 39 Synthesis of 3-(tert-butyl)-N-[(1R)-1-[4-[6-[[5-[1-[2...

Claims

1. A compound that is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, of formula (IA). (I-A) in, M1 is a key or , where X 4 Connected to Y; M2 is or , where X 1 Connected to Cy1; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR c3 R c4 ) y3 -, -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -, -NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -, -(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 is independently 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) when Y is M2 is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) when T is 0 Y is or M2 is When m1 is 1 and m2 is 1, n2 is not 0.

2. The compound according to claim 1, wherein it is a compound of formula (I-1) or formula (I-2), or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. (I-1) or (I-2) in, M1 is a key or , where X 4 Connected to Y; T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)-、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR c3 R c4 ) y3 -, -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -, -NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -, -(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 is independently 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In the compound of formula (I-1), when Y is X 3 For CH and X 4 When N is present, m3 and m4 are not simultaneously 0; (2) In compound (I-1), when T is present... Y is or When m1 is 1 and m2 is 1, n2 is not 0.

3. The compound according to claim 1 or 2, wherein it is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I), formula (Ia), formula (Ib), or formula (Ic). (I), (Ia), (Ib) or (Ic), in, T is or ; Z, Z 1 Z 2 and Z 3 Each can be independently CH or N; Each X 1 X 2 X 3 and X 4 Independently CH or N; Cy1, Cy2, and Cy3 are each independently C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-10 atoms, wherein the C3-C 10 Cycloalkyl groups, heterocyclic groups consisting of 3-10 atoms, C6-C 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-10 atoms of a heteroaryl group, wherein the substituent is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; L1 is -W 1 -W 2 -W 3 -W 4 -W 5 -; W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)–、-C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 Cycloalkyl or heterocyclic group consisting of 3-10 atoms, wherein the -C 1-12 Alkyl-, -C 2-12 alkenyl-, -C 2-12 alkynyl-, C3-C 10 The cycloalkyl group and the heterocyclic group consisting of 3-10 atoms are each independently unsubstituted or independently selected by 1, 2, 3 or 4 atoms from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; L2 is -(CR c3 R c4 ) y3 -, -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -NR n2 -, -NR n2 -(CR c3 R c4 ) y4 -C(O)-(CR c5 R c6 ) y5 -, -(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -C(O)- or -C(O)-(CR c5 R c6 ) y5 -NR n2 -(CR c3 R c4 ) y4 -; Y is a fused tricyclic carbon ring, a fused tricyclic heterocycle containing 1, 2, 3, or 4 heterocyclic atoms independently selected from N, O, and S. , , , , , or ; wherein, the fused tricyclic carbon ring and the fused tricyclic heterocycle containing 1, 2, 3 or 4 heterocyclic atoms independently selected from N, O and S are each independently controlled by Y a Substitution and being replaced by 0, 1, 2, 3, 4, 5, 6, 7 or 8 elements selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Substituted by aryl groups and heteroaryl groups consisting of 5-10 atoms; Each Y a Independently Among them, each X 5 Independently CH or N, each L4 is independently a bond, -O-, -S-, or -NR. n4 -、-C(O)-、-C(O)-NR n4 -、-NR n4 -C(O)- or -C 1-3 alkyl-; Z 4 Z 5 and Z 6 Each can be N or CH independently; E 1 and E 3 Each independently as NR ne O or S; E 2 For N or CR ce ;L5 is C(=O), C(=S), S(=O), S(=O)2, NR nL , O, S or C 1-4 Alkylene; L3 is -C(O)-NR n3 -or-NR n3 -C(O)-; Each of m1, m2, m3, m4, m5, m6, m7, n1, and n2 is independently 0, 1, 2, or 3; Each n3 and n4 is independently 0, 1, 2, 3, 5, 6, 7 or 8; Each of n5, n6, and n7 is independently 0, 1, 2, 3, or 4; Each of y1, y2, and y3 is independently 1, 2, 3, 4, 5, or 6; Each y4 and y5 is independently 0, 1, 2, 3, 4, 5, or 6; Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R ce R c1 R c2 R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n2 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R a and R d Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; Each R b R c R e and R f Independently H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; The condition is: (1) In compound (I), when Y is X 3 For CH and X 4 When N is 0, m3 and m4 are not simultaneously 0; (2) In compound (I), when T is 0 Y is or When m1 is 1 and m2 is 1, n2 is not 0.

4. The compound according to any one of claims 1-3, wherein, Y is , , , , , , or ; Among them, Z 7 For CH or N; X 6 -(CR) c7 R c8 ) y6 -、-C(O)-、-C(S)- or -NR n5 -;R n5 It is H, D, C1-C6 alkyl or C1-C6 haloalkyl; each R c7 and R c8 Independently, it is H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; y6 is 1, 2, or 3; Each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-10 atoms; f is 0, 1, 2, 3 or 4; R 9 R 10 Together with the attached atoms, it forms a C5-C6 carbon ring, a heterocycle of 5-6 atoms, a benzene ring, or a heteroaromatic ring of 5-6 atoms, wherein each of the C5-C6 carbon ring, the heterocycle of 5-6 atoms, the benzene ring, and the heteroaromatic ring of 5-6 atoms is independently unsubstituted or is independently substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, a heterocyclic group of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-10 atoms.

5. The compound according to claim 4, wherein, Y is , , , , , , , , , , , , or ; Among them, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

6. The compound according to claim 4 or 5, wherein, Y is , , , , , , , , , , , , , , , , , , , , , or ; Among them, each R y Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

7. The compound according to any one of claims 1-6, wherein, Cy1, Cy2, and Cy3 are each independently a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C... 10 The aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C3-C6 cycloalkyl group, the heterocyclic group consisting of 3-6 atoms, the C6-C6 aryl group, and the heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 atoms selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R n2 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

8. The compound according to any one of claims 1-7, wherein, Cy1 and Cy2 are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, cyclobutyl, aziridine... Pyrroloyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroloyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

9. The compound according to any one of claims 1-7, wherein it is a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (II), (IIa), (IIb), or (IIc). (II), (IIa), (IIb) (IIc), in, Z a Z b Z c Z d Z e Z f Z g and Z h Each is N or CR z Each R z Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 A aryl group or a heteroaryl group consisting of 5-10 atoms, wherein the C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 alkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-10 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

10. The compound according to any one of claims 1-7 and 9, wherein, Cy3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, or pyrrolyl group is... Tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 groups selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and -COOR. a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 The aryl group is replaced by a substituent of 5-6 atoms of a heteroaryl group, wherein the substituent is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C3-C6 cycloalkyl group, a heterocyclic group consisting of 3-6 atoms, or a C6-C6 cycloalkyl group. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH.

11. The compound according to any one of claims 1-10, wherein, Each R c3 R c4 R c5 and R c6 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, or cyclopropyl Cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; Each R n2 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

12. The compound according to any one of claims 1-11, wherein, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)–、-C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-6 Alkyl-, -C 2-6 alkenyl-, -C 2-6 The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -COOR a -CONR b R c C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

13. The compound according to any one of claims 1-12, wherein, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -、-O(C6H4)–、-C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 Alkyne-, C3-C6 cycloalkyl, or a heterocyclic group consisting of 3-6 atoms, wherein the -C 1-4 Alkyl-, -C 2-4 alkenyl-, -C 2-4 The alkynyl group, C3-C6 cycloalkyl group, and heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -COOR a -CONR b R c It is substituted by substituents such as C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, phenyl, and heteroaryl groups consisting of 5-6 atoms.

14. The compound according to any one of claims 1-13, wherein, W 1 W 2 W 3 W 4 and W 5 Each can be a separate key, -O-, -S-, or -NR. n1 -、-C(O)-、-C(O)-NR n1 -、-NR n1 -C(O)-、-(O-(CR c1 R c2 ) y1 ) y2 -, -O(C6H4)-, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl The following groups are present: propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl, each independently unsubstituted or substituted by 1, 2, 3, or 4 independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -COOR a -CONR b R c It is substituted by substituents such as C3-C6 cycloalkyl, heterocyclic groups consisting of 3-6 atoms, phenyl, and heteroaryl groups consisting of 5-6 atoms.

15. The compound according to any one of claims 1-14, wherein, Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR. d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R ce R c1 and R c2 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, or -COOR d -CONR e R f C3-C6 cycloalkyl groups, heterocyclic groups consisting of 3-6 atoms, C6-C 10 An aryl group or a heteroaryl group consisting of 5-6 atoms, wherein the C1-C4 alkyl group, C1-C4 haloalkyl group, C1-C4 alkoxy group, C1-C4 haloalkoxy group, C3-C6 cycloalkyl group, heterocyclic group consisting of 3-6 atoms, or C6-C6 cycloalkyl group is used. 10 The aryl group and the heteroaryl group consisting of 5-6 atoms are each independently and optionally replaced by 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH and -SH; Each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

16. The compound according to any one of claims 1-15, wherein, Each R 1 R 2 R 3 R 4 R 5 R 5a and R 5b Independently, it can be D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, or -COOR. d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl; Each R ce R c1 and R c2 Independently, it can be H, D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, -COOR d -CONR e R f Cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, azircyclopropyl, oxacyclopropyl, azircyclobutyl, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, or cyclopropyl Cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, and pyrazinyl are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, and -SH; Each R ne R nL R n R n1 R n3 R n4 R 6 R 7 R 7a R 7b and R 8 Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxazolidine, aziridine, oxazolidine, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

17. The compound according to any one of claims 4-16, wherein, R 9 R 10 Together with the attached atoms, it forms a C5 carbon ring, a C6 carbon ring, a 5-atom heterocycle, a 6-atom heterocycle, a benzene ring, a 5-atom heteroaromatic ring, or a 6-atom heteroaromatic ring, wherein each of the C5 carbon ring, C6 carbon ring, 5-atom heterocycle, 6-atom heterocycle, benzene ring, 5-atom heteroaromatic ring, and 6-atom heteroaromatic ring is independently unsubstituted or substituted by 1, 2, 3, or 4 atoms independently selected from D, F, Cl, Br, I, -NO2, -CN, -NH2, -OH, -SH, oxo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C3-C6 cycloalkyl, 3-6 atom heterocyclic group, C6-C 10 It is replaced by substituents of aryl and heteroaryl groups consisting of 5-6 atoms.

18. The compound according to any one of claims 1-17, wherein, Each R a and R d Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups composed of 5-6 atoms; Each R b R c R e and R f Independently H, D, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6-C 10 Aryl or heteroaryl groups consisting of 5-6 atoms.

19. The compound according to any one of claims 1-18, wherein, Each R a and R d Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxacyclopropyl, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl; Each R b R c R e and R f Independently, it is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, aziridine, oxadiazolyl, pyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrroleyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, furanyl, pyridinyl, pyrazinyl, or pyrimidinyl.

20. A compound that is one of the following: a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

21. A compound that is one of the following: a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

22. A pharmaceutical composition comprising the compound of any one of claims 1-21 and a pharmaceutically acceptable carrier.

23. Use of the compound according to any one of claims 1-21 or the pharmaceutical composition according to claim 22 in the preparation of a medicament, wherein, The drug is used to prevent or treat diseases associated with BTK.

24. The use according to claim 23, wherein, The diseases associated with BTK are tumors, thromboembolism, inflammatory conditions and / or autoimmune diseases; Optionally, the tumor is a B-cell lymphoma, a solid tumor, and / or a hematologic and immune system tumor; Optionally, the inflammatory condition or autoimmune disease is asthma, psoriasis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, xenoimmune diseases, idiopathic thrombocytopenic purpura, immune complex-mediated vasculitis, and / or autoimmune-mediated hemolytic anemia.

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